Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of pro-inflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower pro-inflammatory cytokine levels in vivo, and to restore function after a moderate TBI.

(1) Background: There is a need to assess the availability of essential antimicrobials as the availability of an antimicrobial is a critical element of its rational use. We aimed to assess the availability of antimicrobials listed in National List of Essential Medicines 2015, India (primary list) and a selected (secondary) list comprising of agents indicated for commonly encountered infectious illnesses in various healthcare settings and to identify the reasons for their non-availability. (2) Methods: A cross-sectional survey of 25 public, private, and other sector pharmacies was carried out in Rohtak, a district of North Indian state of Haryana, from April to June 2022. (3) Results: Most of the antimicrobials surveyed were optimally available in various sector pharmacies with the exception of benzathine benzyl penicillin, benzyl penicillin, cloxacillin, cefazolin, cefuroxime, cefadroxil, amphotericin B and antimalarials. Most frequent reasons for limited availability were low demand, no prescriptions and non-listing of drugs in state essential medicine list. (4) Conclusions: Enough evidence needs to be generated with respect to status of availability of essential antimicrobials from different regions of India as well as other lower-middle income countries to devise measures for ascertaining better availability of these agents especially antibiotics at regional, national and global scales.

Background: Poisoning is a growing public problem that has shown increased prevalence in many countries worldwide, contributing to increased costs and mortalities. A lack of or insufficient information regarding the circumstances, chemicals, drugs and people at risk due to imperfect reporting system is regarded as a barrier to successful poisoning prevention and intervention efforts. In Saudi Arabia, poisoning cases are monitored at the central level in the Ministry of Health, with meticulous follow-up of cases across country areas through public health departments. The current study's objective was to describe the poisoning notification and reporting system in Makkah.Subjects and methods: All reports of chemical and drug overdose poisoning delivered to the environmental health and occupational safety department in Makkah Almukarramah over two years (2018-2019) were reviewed, together with verification of all systems, rules and guidelines organizing the performance of the department.Results: The total number of cases reported in 2018 was 209 cases, while it reached 42 cases in 2019. The overwhelming majority of the cases were Saudi (91.6%), with a slight predominance of males (57.4%) over females (42.6%). Generally, almost two-thirds of the cases occurred in children below 13 years (61.4%), most of the poisoning cases resulted from drug overdose (63.3%), while 34.7% were chemical poisoning. The most common drug poisoning was attributed to analgesics followed by antiepileptics, antihypertensive drugs, antipsychotics and antimicrobials, while cleaning and detergent agents were the most commonly poisoned chemicals. The majority of these agents were taken by the oral route. Children's chemical poisoning was significantly higher than that in older age groups (p<0.05). All intentional poisoning occurred in adults; the great majority of them (88.9%) used drug overdosing rather than chemical substances.Conclusion and recommendations: The current study results are consistent with most of the previous studies carried out in different regions in Saudi Arabia. Reviewing the performance and adherence of the “Environmental Health and Occupational Safety Department” to the guidelines and instruction regulating monitoring, notification and reporting of poison cases are satisfactory and the poisoning surveillance system is effective. Further in-depth studies are needed to elaborate other socioeconomic and demographic factors associated with chemical and drug overdose poisoning. Public health plans, policies and legislations should be implemented to reduce these factors, including prohibition over-the-counter pharmaceutical sales, selling the possibly harmful substances in kid-proof bottles and additional stringent rules governing chemical sale and storage. Intensive supervision of children is needed. Suicidal poisoning patients should seek psychiatric help to limit the possibility of attempting suicide again in the future. Furthermore, efforts are needed to plan and implement health education programs and campaigns about the factors proven in the current study to be significantly related to chemical and drug overdose poisoning to raise public knowledge about exposure to chemicals and its consequences. Popular communication media, commercial malls, road ads, learning institutions and workplaces can be used to deliver health education campaigns and programs. Advice on how to store chemicals safely and how to keep kids safe should be focused on during such programs.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 – 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

SARS-CoV2 RNA depended RNA polymerase is an essential enzyme for the survival of the virus in hosts as it helps in the replication of viral RNA. There are no human polymerases that share either sequence or structural homology with viral RNA depended RNA polymerase. These make it a good target for inhibitor discovery, as a specific inhibitor cannot cross-react with the human polymerases. We have used virtual screening, docking, binding energy calculation and simulation to show that valproic acid Co-A, a metabolite from prodrug valproic acid, forms stable interaction with nsP12 of CoV. Our results suggest valproic acid Co-A could be a potential inhibitor of nsP12 of SARS-CoV2.

Age-related macular degeneration (AMD) causes visual impairment in individuals >50 years of age. However, no study has investigated AMD using ultra-wide-field swept-source optical co-herence tomography (UWF SS-OCT). We aimed to evaluate central and peripheral choroidal thickness using UWF SS-OCT and compare AMD subtypes. We included 75 eyes of patients with typical AMD (tAMD), 56 with polypoidal choroidal vasculopathy (PCV), 29 with pachychoroid neovasculopathy (PNV), and 12 with retinal angiomatous proliferation (RAP). To compare cho-roidal thicknesses in the central and peripheral choroids, we established subfields of <3 mm, <9 mm, and 9–18 mm from the fovea. PNV patients were significantly younger than those with tAMD (P=0.01). The choroidal thicknesses of PNV were significantly greater than that of tAMD in all subfields (P<0.01) and choroidal thickness significantly correlated with age and axial length in all subfields (P<0.05). Even after adjusting for age and axial length, the choroidal thickness in PNV was significantly greater than that in tAMD (P<0.05). In addition, the ratio of the posterior < 9 mm to peripheral 9–18 mm choroidal thickness in PNV was significantly greater than that in tAMD (P<0.01). A thickened choroid in PNV was more pronounced in the posterior choroid than in the periphery.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year clinical trial data in Duchenne muscular dystrophy patients suggests a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50> 5000mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic studies of the best scoring ligands against each target. The chosen molecular targets were Spike receptor binding domain, Nucleocapsid protein RNA binding domain, and key non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.

Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted population analysis and selected two variations in POR for further investigation. The human POR wild type, along with the R268W and L577P variants, were expressed in bacteria and subjected to enzyme kinetic assays using model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency.

Neuronal lesion or injury is a traditional approach to investigate neural circuit. Is any new neural pathway or new neurodegeneration related central nerve system injury? Spinal disc herniation can cause the spinal cord injury. However, the histological examination is still lack. It happened that a case of spinal disc herniation of a 10-year old dog was examined with NADPH diaphorase (N-d) histology. We did not find the N-d neurodegenerative aberrant in the tissue of the mid-rostral lumber segment besides the metamorphoses by the compression of the disc herniation. However, the severe neuropathological changes majorly occurred in the lumbosacral spinal cord. We found more diverse neurodegenerative alterations: the aging-related N-d body (ANB), megaloneurite and N-d homogeneous formazan globule in the lumbosacral spinal cord. We also found that a new circuit pathway (intermedial collateral pathway) showed by a megaloneurite between the lateral collateral pathway and the medial collateral pathway. The enormous notch caused by spinal disc herniation located at the mid-rostral lumber segments. The aging-related neurodegeneration occurred the specific lumbosacral segments. The homogeneous formazan globule was round or oval homogeneous N-d positivity which distributed in the gray matter and dorsal column. In the medulla oblongata, ANBs were revealed in the gracile nucleus, nucleus reticularis lateralis (ventrolateral spinal trigeminal nucleus) and middle of the spinal trigeminal nucleus.

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

The COVID-19-medical emergency has ended worldwide, yet there is still a need to evaluate the psychological impact of these years of unprecedented changes on students’ life. Methods: This study aims to assess and compare COVID-19-related stressors (Relationships-and-Academic-Life; Isolation; Fear-of-Contagion) and psychophysical symptoms reported by university students in April-2020, April 2021, and April 2022. The predictive role of COVID-19-related stressors on psychophysical symptoms within each time was also tested. Data were collected among 637 university students in April-2020 (n = 197), April-2021 (n = 200), April-2022 (n = 240). Results: In April-2022, perceived Isolation and Fear-of-Contagion decreased from the peak registered in April-2021, but stress related to Relationships-and-Academic-Life remained noteworthy high. A sharp and ongoing increase in psychophysical symptoms was found, with more than 50% of students reporting clinical levels of Sleep-Disorders, Depression, Psychoticism, and Interpersonal-Sensitivity. In April-2022, students still perceiving stress related to Relationships-and-Academic-Life and Isolation were at risk for Anxiety, Somatization, and Sleep-Disorders, while those still perceiving stress related to Fear-of-Contagion were also at risk for Depression, Obsessive-Compulsive, and Psychoticism. Conclusion: Findings emphasized the long-lasting detrimental effects of the COVID-19-related stress. Interventions must pinpoint the complex post-pandemic adjustment process and their effects on university students' psychophysical health.

Antibiotic resistance has emerged as one of the major concerns to public human health due to issues in treatment and control of major infectious diseases. From discovery of penicillin in 1940, the antibiotic resistance originated and now developed the microorganisms as resistive strains to the major available antibiotics. Furthermore, studies on this captivating activity of the microbes provide insight into the complexities of microbial physiology and may offer some guidance in preventing the onset and consequent development of antibiotic resistance. Despite of initiatives taken in last few decades to overcome the issues, the trends of antibiotic resistance gained much peak. Antibiotic resistance appears to have emerged as a result of various factors including antibiotics being misused and overused in both the medical field and the agricultural sector. Important factors in the development of antibiotic resistance also include bacterial mutation, unplanned evolution, and horizontal gene transfers. In addition, antibiotics resistance imposed the financial consequences to public health and drug development research. Future advancements related to innovative antibiotics and molecular drug designing become challenge for researchers due to intensive multiple antibiotics resistance among human population. Many researches have been conducted on origin, evolutionary aspect of antibiotic resistance and mechanisms of antibiotics resistance, but its effect on future drug development is little understood. Therefore, the recent review will highlight the role of antibiotic resistance in drug designing and impacts of antibiotic resistance on drug development in future.

New hybrid composites based on the inclusion of a vegetal extract, i.e., Boswellia Serrata extract (BSE), rich in boswellic acids, well known as a potent anti-inflammatory natural drug, in a lamellar solid layered double hydroxide (LDH), i.e. a Magnesium Aluminum Carbonate, were developed and characterized in the present work. The adopted LDH exhibits a layered crystal structure, comprised of positively charged hydroxide layers and interlayers composed of carbonate anions and water molecules, thus it was expected to embed negatively charged boswellic acids. In the present case, a calcination process was also adopted on LDH to increase organic acids loading, based on the replacement of original inorganic anions. An accurate investigation was carried out by TGA, PXRD, FT-IR/ATR, XPS and LC-MS to ascertain the nature, interaction, and quantifica-tion of the active molecules of the vegetal extract loaded in the developed hybrid materials. As a result, a significant disruption of the original layered structure was observed in LDH subjected to calcination (LDHc), and this material was able to include a higher amount of organic acids when its composite with BSE was prepared. However, in vitro tests on composites bioactivity, expressed in terms of antimicrobial and anti-inflammatory activity, evidenced LDH-BSE as a better material compared to BSE and to LDHc-BSE, thus suggesting that, though the embedded organic acids amount was lower, they could be more available since not firmly bound to the clay. The composite was able to significantly decrease the number of viable pathogens such as Escherichia Coli and Staphylococcus aureus, as well as the internalization of toxic active species into human cells imposed to oxidative stress in comparison to the BSE.

Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.

Drug-target affinity (DTA) prediction is crucial for understanding molecular interactions and aiding drug discovery and development. While various computational methods have been proposed for DTA prediction, their predictive accuracy remains limited, failing to delve into the structural nuances of interactions. With increasingly accurate and accessible structure prediction of targets, we developed a novel deep learning model, named S2DTA, to accurately predict DTA by fusing sequence and structural knowledge of drugs, targets, and pockets using heterogeneous models based on graph and semantic networks. Experimental findings underscored that complex feature representations imparted negligible enhancements to the model’s performance. However, the integration of heterogeneous models demonstrably bolstered predictive accuracy. In comparison to three state-of-the-art methodologies, the supremacy of S2DTA became strikingly apparent. It showcased a noteworthy 25.2% reduction in Mean Absolute Error (MAE) and an impressive 20.1% decrease in Root Mean Square Error (RMSE). Furthermore, S2DTA exhibited substantial advancements in other pivotal metrics, including Pearson Correlation Coefficient (PCC), Spearman, Concordance Index (CI), and R2. These metrics experienced remarkable increments of at least 19.6%, 17.5%, 8.1%, and a remarkable 49.4%, respectively. Finally, we conducted interpretability analysis on the effectiveness of S2DTA by bidirectional self-attention mechanism, fully proving that S2DTA is a valuable and accurate tool for predicting DTA. For further exploration, the source data and code repository can be accessed at https://github.com/dldxzx/S2DTA.

The COVID-19 pandemic has led to a substantial revolution in the incorporation of digital solutions in healthcare. This systematic review investigates the enduring physical and psychological consequences individuals experience up to two years post-recovery. Additionally, it focuses on examining the influence of mHealth interventions on these effects. Significantly, 41.7% of survivors experience lingering symptoms that have not been addressed, while 14.1% encounter difficulties in returning to work. The presence of anxiety, compromised respiratory functioning, and persistent symptoms highlight the immediate requirement for specific therapies. Telehealth, particularly telerehabilitation, presents itself as a possible way to address these difficulties. The study thoroughly examines 10 studies encompassing 749 COVID-19 patients, investigating the efficacy of telerehabilitation therapies in addressing various health markers. Telerehabilitation-based breathing exercises yield substantial enhancements in functional performance, dyspnea, and overall well-being. The results emphasize the potential of telerehabilitation to have a favorable effect on patient outcomes, however more research is needed to strengthen the existing evidence basis as one of the most important limitation is the limited number of trials and the evaluation of varied therapies. The analysis highlights the significance of digital solutions in post-COVID care and calls for ongoing research to improve comprehension and implementation of telehealth interventions in a swiftly changing healthcare environment.

Background and Objectives: Chemokines have various biological functions and potential roles in the development or progression of neuroinflammatory diseases. However, the specific pathogenic roles of chemokines in age-related macular degeneration (AMD), the leading cause of blindness in older individuals, remain elusive. Chemokines interact with their receptors expressed in the endothelium and on leukocytes. The sulfation of tyrosine residues in chemokine receptors increases the strength of ligand–receptor interaction and modulates signaling. Therefore, in the present study, we aimed to construct a human recombinant sulfated CXCR3 peptide trap (hCXCR3-S2) and mouse recombinant sulfated CXCR3 peptide trap (mCXCR3-S2) to demonstrate in vivo effects in preventing choroidal neovascularization and chemotaxis. Materials and Methods: First, the effect of hCXCR3-S was validated in vitro. Interestingly, hCXCR3-S2 inhibited the migration and invasion of two human cancer cell lines. Subsequently, the in vivo efficacy of mCXCR3-S2 was investigated using a mouse model of neovascular AMD. Results: Intravitreal injection of mCXCR3-S2 attenuated choroidal neovascularization and macrophage recruitment in neovascular lesions. These in vitro and in vivo effects were significantly stronger with CXCR3-S2 than with wild-type CXCR3 peptides. Conclusion: These findings demonstrate that the sulfated form of the CXCR3 peptide trap is a valuable tool that could be supplemented with antivascular endothelial growth factors in AMD treatment.

Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, activates the trigeminovascular system. In the present study, we investigated CGRP mRNA expression in TG neurons in a CSD-based mouse migraine model. Our in situ hybridization analysis showed that CGRP mRNA expression was observed in smaller neuronal populations. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral TG. However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger in the 48 h and 72 h post-CSD groups than in the control group. The proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters less than 14 μm became significantly less at several time points after CSD. In contrast, we found significantly greater proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters of 14–18 μm at 24 h, 48, and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift in CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy.

Disrupted biological function, manifesting through the hallmarks of aging, poses as one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease of nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds to restore youthful NAD+ levels. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NMN supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.

The persistence of diseases that affect construction workforce as a result of activities on construction sites poses a danger to the sustainable development of the industry. This resulted to a huge loss of skilled labour and economic development of the industry and the entire country. The arrival of the fourth industrial revolution (4IR) technologies urges an urgent need to assess the effect of the technology’s biological driver on the construction occupation related diseases. Therefore, this study is aimed at assessing the effect of 4IR on the construction occupation related diseases in Gauteng, South Africa. The study is quantitative in design and questionnaire survey were administered to project and Health and Safety (H&S) managers in Gauteng, South African construction sector using a proportionate simple random sampling technique. For data analysis, the Warp PLS-SEM 8.0 software algorithm was used for the analysis of the collated data. The study found that the effects of the 4IR’s biological driver variables ranges between moderate to high effects for genome sequencing (GENSE) and Neurotechnology (NEURO) respectively. The combined predictive relevance of the two (2) variables predicts 64% of the construction occupation related diseases. This implies that the adoption of the driver would help reduce the causes of construction-related diseases. Hence, implies that continuous deployment of 4IR technologies would ensure that construction occupation related diseases are easily identified and put on alert.

The main aim of the present study was to explore health professionals’ reported experiences and approaches to managing children who receive a designation of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive inconclusive diagnosis following a positive NBS result for cystic fibrosis. An online questionnaire was distributed via Qualtrics Survey Software and circulated to a purposive, international sample of health professionals involved in managing children with this designation. In total, 101 clinicians completed the online survey; 39 from the US, six from Canada and 56 from Europe (including the UK). Results indicated that while respondents reported minor deviations in practice, they were cognizant of recommendations in the updated guidance and for the most part, attempted to implement these into practice consistently internationally. Where variation was reported, the purpose of this appeared to be to enable clinicians to respond to either clinical assessments or parental anxiety in order to improve outcomes for the child and family. Further research is needed to determine if these findings are reflective of both a wider audience of clinicians and actual (rather than reported) practice.

The retina is a complex and fragile photosensitive part of the central nervous system which is prone to degenerative diseases leading to permanent vision loss. No proven treatment strategies exist to treat or reverse the degenerative conditions. Recent investigations demonstrate that cell transplantation therapies to replace the dysfunctional retinal pigment epithelial (RPE) cells and or the degenerating photoreceptors (PRs) are viable options to restore vision. Pluripotent stem cells, retinal progenitor cells and somatic stem cells are the main cell sources used for cell transplantation therapies. The success of retinal transplantation based on cell suspension injection is hindered by limited cell survival and lack of cellular integration. Recent advances in material science helped to develop strategies to grow cells as intact monolayers or as sheets on biomaterial scaffolds for transplantation into the eyes. Such implants are found to be more promising than the bolus injection approach. Tissue engineering techniques are specifically designed to construct biodegradable or non-degradable polymer scaffolds to grow cells as a monolayer and construct implantable grafts. The engineered cell construct along with the extracellular matrix formed, can hold the cells in place to enable easy survival, better integration and improved visual function. This article reviews the advances in the use of scaffolds for transplantation studies in animal models and its application in current clinical trials.

Cellular oxidation is responsive to external and internal stimulation and is generated via signal molecules in defense mechanisms through networks of cell proliferation, differentiation, intracellular detoxification, bacterial infection, and immune reactions. Oxidative stress is not necessarily harmful per se; it depends on the balance between oxidation and antioxidation cascades, which are induced according to stimuli and can maintain oxygen homeostasis. The reactive oxygen species (ROS) that are generated during influenza virus (IV) infection have critical effects on both the virus and host cells. In this review, we outline the link between viral infection and ROS production, using IV as an example. We introduce the current state of knowledge on the molecular relationship between cellular oxidation mediated by ROS production and various effects of IV infection. We also summarize the potential anti-IV agents that act by targeting oxidative stress.

Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in the endocytic/phagosome and autophagy pathways leads to the accumulation of lipofuscin and N-retinylidene-N-retinylethanolamine aggregates and chemically-modified compounds such as malondialdehyde and 4-hydroxynonenal within RPE. These contribute to increased proteolytic and oxidative stress, resulting in irreversible damage to post-mitotic RPE cells and development of blinding conditions such as Age-related Macular Degeneration, Stargardt disease and Choroideremia. Here, we review how impaired cargo handling in the RPE results in their dysfunction, discuss new findings from our laboratory and consider how newly discovered roles for lysosomes and the autophagy pathway could provide insights into retinopathies. Studies of these dynamic, molecular events have also been spurred on by recent advances in optics and imaging technology. Mechanisms underpinning lysosomal impairment in other degenerative conditions including storage disorders, a-synuclein pathologies and Alzheimer’s disease are also discussed. Collectively, these findings help transcend conventional understanding of these intracellular compartments as simple waste disposal bags to bring about a paradigm shift in the way lysosomes are perceived.

Background: Currently, limited number of therapeutic options are available to treat Diabetes mellitus, and to find a potential candidate, laboratory work takes time and also needs animal studies. So, the aim of this study was to determine the efficacy of some natural phytocompounds with the aid of molecular docking, bioinformatics and in silico drug design approaches. Method: Two proteins (Human CYP3A4 linked to metformin and Human dipeptidyl peptidase-IV) were selected and molecular docking studies were conducted using Pymol, AutoDock Vina, PyRx, and Discovery Studio. Different important pharmacokinetic parameters like ADME and toxicity data were obtained from online databases SwissADME and pkCSM program. Results: It was found that human dipeptidyl peptidase-IV (PDB ID: 4A5S) has exhibited a maximal affinity of -9.7 Kcal/mol for bryonolic acid and hesperidin, but only -6.7 kcal/mol for metformin hydrochloride. Similarly, the highest affinity of hesperidin for human CYP3A4 bound to metformin (PDB ID: 5G5J) is -10.7 Kcal/mol compared to metformin hydrochlor (-6.3 Kcal/mol). Besides, all the compounds have been documented outstanding ADMET profile, and accepted by drug-likeness or Lipinski rule. Conclusions: The present study suggested that these compounds can be further investigated in vitro and in vivo to establish them as lead compounds against Diabetes mellitus..

Complex-structured polymeric microparticles hold significant promise as advance in next-generation medicine mostly due to demand from developing targeted drug delivery. However, the conventional methods for producing these microparticles of defined size, shape and sophisticated composition often face challenges in scalability, reliance on specialized components such as micro-patterned templates, or have limited control over particle size distribution and cargo release kinetics. In this study, we introduce a novel and reliably scalable approach for manufacturing microparticles of defined structures and sizes with variable parameters. The concept behind this method involves the deposition of a specific number of polymer layers on a substrate with low surface energy. Each layer can serve as either the carrier for cargo or a programmable shell-former with predefined permeability. Subsequently, this layered structure is precisely cut into desired-sized blanks using a laser. The manufacturing process is completed by applying of heat to the substrate what results on sealing the edges of the blanks. The combination of the high surface tension of the molten polymer and the low surface energy of the substrate enables the formation of discrete particles, each possessing semi-spherical or other designed geometries determined by their internal composition. Such anisotropic microparticles are envisaged versatile applications.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease. A group of potent BACE1 inhibitors with known x-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values were compared with experimental values, the structures were discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp 32, Asp228 and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

Zn is an essential element for children related to optimal growth, development and nutritional metabolism. We measured Zn bioaccesibility (Zn-BA) levels of foods by Inductively coupled plasma mass spectrometry (ICP-MS) after in vitro digestion-fermentation method from children with gluten related disorders (GRD-CH), obesity (OB-CH) and allergy/intolerance to cow’s milk proteins (AICM-CH). Zn-BA levels in sick children (34.7 ± 28.8, 29.6 ± 30.1 and 26.7 ± 30.4%, respectively) were significantly lower (p &lt; 0.05) than in healthy norm-weight children (HE-CH). For AICM-CH, Zn-BA in animal foods was significantly lower than in plant foods, and in both plant and animal foods from sick and healthy children (p &lt; 0.05). In foods of animal origin in sick and healthy children, Zn-BA in foods heated in liquid media (frying and boiling) was significantly higher than in foods heated by hot air (roasting and grilling). In conclusion, in children the studied diseases diminished the Zn-BA, probably by the alteration of the gut microbiota which could negatively affect their appropriate long-term development. In AICM-CH, the allergy to cow's milk proteins could induce intestinal dysbiosis and inflammatory processes, leading to allergies to other animal food proteins, and to a more pronounced decrease of Zn-BA.

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.

Mathematical modeling is crucial in investigating the pandemic of the ongoing coronavirus disease (COVID-19). The primary target area of the SARS-CoV-2 virus is epithelial cells in the human lower repertory track. During this viral infection, infected cells can initiate innate and adaptive immune responses to viral infection. Immune response in COVID -19 infection can lead to longer recovery time and more severe secondary complications. We formulate a target cell limited mathematical model by incorporating a saturation term for SARS-CoV-2 infected epithelial cell loss reliant on infected cell levels. Forward and backward bifurcation between disease-free and endemic equilibrium points has been analyzed. Global stability of both disease-free and endemic equilibrium is provided. We have seen that the disease-free equilibrium is globally stable for $R_0<1$, and endemic equilibrium exists and is globally stable for $R_0>1$. Impulsive application of drug dosing has been applied for the treatment of covid-19 patients. Also, the dynamics of the impulsive system are discussed when a patient takes drug holidays. The numerical simulations are performed in support of our analytical findings and for the qualitative analysis of the system's dynamics with and without impulse drug dosing.

Neuroscience is a vast discipline that deals with the anatomy, biochemistry, molecular biology, physiology and pathophysiology of central and peripheral nerves. Advances made through basic, translational, and clinical research in the field of neuroscience have great potential for long-lasting and beneficial impacts on human health. The emerging field of biological therapy is intersecting with the disciplines of neuroscience and rheumatology, creating new horizons for interdisciplinary and applied research. Biological drugs, growth factors, neuropeptides and monoclonal antibodies are being developed and tested for the treatment of painful arthritic and rheumatic diseases. This concise communication focuses on the solutions provided by the fields of neuroscience and neuroimmunology for real-world clinical problems in the field of rheumatology, focusing on synovial joint pain and the emerging biological treatments that specifically target pathways implicated in osteoarthritis pain in peripheral nerves.

In an era of unparalleled technical advancement, the pharmaceutical industry is struggling to transform data into increased research and development efficiency, and as a corollary, new drugs for patients. Here, we briefly review some of the commonly discussed issues around this counterintuitive innovation crisis. Looking at both industry and science related factors, we posit that traditional preclinical research is front-loading the development pipeline with data and drug candidates that are unlikely to succeed in patients. Applying a first principles analysis, we highlight the critical culprits and provide suggestions as to how these issues can be rectified through pursuit of a Human Data-driven Discovery (HD3) paradigm. Consistent with other examples of disruptive innovation, we propose that new levels of success are not dependent on new inventions, but rather the strategic integration of existing data and technology assets. In support of these suggestions, we highlight the power of HD3, through recently published proof-of-concept applications in the areas of drug safety analysis and prediction, drug repositioning, rational design of combination therapies and the global response to the Covid19 pandemic. We conclude that innovators must play a key role in expediting the path to a largely human focused, systems-based approach to drug discovery and research.

Monkeypox virus infection is a recognized public health emergency. Little research has been done on treatment options for this disease. Until recently, there was not a single published work describing the usage of specific drugs in human patients with monkeypox virus infection. This paper gives the first bibliometric analysis of monkeypox treatment options based on data available on PubMed and Scopus. It also reviews the specific drugs used in the treatment of monkeypox. That includes data on Tecovirimat, Cidofovir, Brincidofovir, and Vaccinia Immune Globulin. Tecovirimat is a promising option in progressive disease in terms of efficacy and safety. However, Brincidofovir has been associated with discontinuation of treatment. Cidofovir is also not the preferred drug among physicians. Currently, Tecovirimat can be further used for the management of aggravating cases. More studies should be conducted on Tecovirimat to treat this condition, mainly through controlled trials.

Intratumoral heterogeneity can exist along multiple axes: Cancer Stem Cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states and a spectrum of epithelial-hybrid-mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple “attractors”. These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.

Healthcare workers' stress, burnout, and job dissatisfaction were exacerbated by the Covid-19 pandemic, whose mid-term negative effects are still present. The aim of this study was to investigate in healthcare workers the effect of the dimensions of burnout (Psychophysical exhaustion, Relational deterioration, and Professional inefficacy) on Career satisfaction. These relationships were evaluated by considering the direct and mediated effects of Disillusion. For these purposes, the Link Burnout Questionnaire (LBQ) and the Career Satisfaction Scale (Occupational Stress Indicator - OSI) were administered to 295 healthcare professionals working at three Italian public hospitals in Cagliari, Italy. The analyses were conducted using the Partial Least Square Structural Equation Model (PLS-SEM) method. Findings highlight that healthcare workers were in a condition of work distress, high risk of burnout, and career dissatisfaction. Also recognized was the direct negative effect of burnout dimensions on career satisfaction. Finally, the mediated negative effect of Disillusion in the relationship between burnout and career satisfaction was identified. This study emphasizes the relevance of the dimension of Disillusion, and its “bright side” Fulfilment, in healthcare workers, specifically referring to the disregarded relationship between burnout and career satisfaction.

Objective: Diabetes is associated with increased cardiovascular and cerebrovascular disease-related mortality. We investigated the association between carotid intima-media thickness (CIMT) with clusterin (CLU), amylin, secreted frizzled-related protein-4 (SFRP-4), total and active glucagon-like peptide-1 (GLP-1) levels, and dipeptidyl peptidase-4 (DPP-4) in type 2 diabetes mellitus (T2DM) individuals with or without coronary artery disease (CAD). Methods: This study consisted of four groups in Medicine Hospital between April- October, 2017: Control group (mean ages: 50.3 ± 10.7 years, 20 females and 15 males), diabetic group (DM) (mean ages: 53.9 ± 11.1, 14 females and 23 males), CAD group (mean ages: 62.6 ± 11.8, 17 females and 17 males) and CAD+ DM group: (mean ages: 62.6 ± 11.8 years, 18 females and 18 males). Results: Both CAD and CAD+DM groups have higher CIMT levels than controls. CAD+DM group have also significantly higher CIMT levels than DM group. Left external carotid artery (ECA) was only found different in DM group from controls. When compared with controls, DM, CAD groups have low DPP-4 and GLP-1_total concentration. Control group have significantly lower SFRP-4 levels than DM, CAD and CAD+DM (p<0.001) groups. Serum GLP-1_total levels were found to be significantly low in CAD+DM group when compared to control group. Conclusion: DPP-4 and SFRP-4 levels are predictive marker for atherosclerosis in diabetes, correlates well with HOMA-IR particularly in diabetes. CIMT has the potential to be a clinically useful predictor of vascular risk in diabetic patients with CAD. Large cohorts and at-risk populations are needed to confirm the predictive value of these findings.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus, and in SH-SY5Y cells, after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with most pronounced effects in latently infected-HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

This review critically evaluates the role of Antibody-drug conjugates (ADCs) in the treatment of urothelial cancer, exploring their therapeutic potential and addressing the scientific and clinical challenges encountered in the development of these agents. It also discusses the recent approvals and clinical trials that are shaping the future of ADC therapy in this field. Through a detailed examination of the mechanism of action of ADCs, including the bystander effect, this paper aims to highlight both the successes and the limitations of these drugs in clinical settings. The main objective of this work is to provide a thorough overview of the current state of ADCs in urothelial cancer treatment, elucidating how these drugs can offer improved outcomes for patients. By discussing the broader implications of ADC technology and its integration into existing treatment paradigms, this review outlines the next steps in research and application necessary to overcome the existing challenges and harness the full potential of ADCs in cancer therapy.

Curcumin is a nutraceutical known to have numerous medicinal effects including anticancer activity. However, due to its poor water solubility and bioavailability, the therapeutic impact of curcumin against cancer, especially breast cancer, has been constrained. Encapsulating curcumin into chitosan nanoparticles (CHNPs) is an effective method to increase its bioavailability as well as antitumorigenic activity. In the present study, the effect of curcumin encapsulated CHNPs (Cur-CHNPs) on cell migration, targeted homing and tumour growth was examined using in vitro and in vivo breast cancer models. Cur-CHNPs possessed monodispersed nature with long term colloidal stability, and demonstrated significant inhibition of cell viability in vitro, which was potentiated by 5-fluorouracil (5-FU). Outcomes of the in vivo imaging studies confirmed effective tumour targeting and retention ability of Cur-CHNPs, thereby suppressing breast tumour growth in mice models. Overall, the results demonstrated that Cur-CHNPs, could be an effective candidate drug formulation for management of breast cancer.

Neurologic symptoms associated with Long COVID result from the persistent infection of SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation in the central nervous sys-tem (CNS). As of today, there is no evidence that vaccines or medications can clear the persistent viral infection in the olfactory mucosa. Recently published clinical data demonstrate that only 5% of Long COVID anosmia patients have fully recovered during the past 2 years and 10.4% of COVID patients are still symptomatic 18 months post infection. Our group demonstrated that ep-igallocatechin-3-gallate-monopalmitate (EC16m) nanoformulations possess strong antiviral activ-ity against human coronavirus, suggesting this green tea-derived compound in nanoparticle for-mulations could be developed as an intranasally delivered new drug targeting the persistent SARS-CoV-2 infection, as well as inflammation and oxidative stress in the CNS, leading to resto-ration of neurologic functions. The objective of the current study is to evaluate the mucociliary safety of the EC16m nasal nanoformulations and the efficacy against human coronavirus. Meth-ods: nanoparticle size and Zeta potential were measured using the ZetaView Nanoparticle Tracking Analysis system; mucociliary safety was determined using MucilAir Human Nasal Epi-thelium Model; contact antiviral activity and post-infection inhibition against OC43 viral strain were assessed by TCID50 assay for cytopathic effect on MRC-5 cells. Results: the saline-based EC16 mucoadhesive nanoformulations containing 0.005 to 0.02% w/v EC16m have no significant difference in comparison to saline (0.9% NaCl) on tissue integrity, cytotoxicity, and cilia beat fre-quency. A 5-minute contact inactivated 99.9% of the β-coronavirus OC43. OC43 viral replication was inhibited by >99% after infected MAR-5 cells were treated with one of the formulations. Con-clusion: the saline-based novel EC16m mucoadhesive nasal nanoformulations rapidly inactivated human coronavirus with mucociliary safety measurements comparable to saline, a solution widely used for nasal applications.

Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous report using the Drug Adverse Event Database revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence on its treatment or prevention. This study examined molecular initiating events (MIEs), which are the starting point of adverse events, to investigate the drug-induced pathways of hiccups. We extracted drugs suspected to cause hiccups using FDA Adverse Event Reporting System, a large database on adverse drug reactions. Information on drugs suspected to be associated with hiccups were extracted from the overall population and sex-specific subgroups divided. In each data table, the predicted activity values of nuclear receptors (NRs) and stress response pathways (SPs) for each drug were calculated using the toxicity predictor, a machine-learning model. Univariate analysis extracted NRs and SPs associated with hiccups, and a multivariate analysis was performed to evaluate independent factors. Transforming growth factor-beta and antioxidant response element were considered an independent factor for hiccups in the male and female subgroups, respectively. This report first examined one of the mechanisms of drug-induced hiccups and identified MIEs associated with drug-induced hiccups.

The active form of fingolimod (FTY720; FT) is a sphingosine-1-phosphate receptor agonist with potential ocular applications. The goal of the present study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. FT-NE formulations were prepared with homogenization followed by probe sonication method. The lead FT-NE formulation (0.15% and 0.3% w/v loading), comprising soybean oil as lipid and Tween® 80 and Poloxamer 188 as surfactants, was further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature post-filtration through polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release, compared with the control FT solution (FT-S), over 24 h. The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.

Polyelectrolyte multilayers (PEMs) deposited on porous composite polylactic acid/poly(ε-caprolactone) substrates were studied. The substrates were previously charged in a corona discharge. Time dependences of the normalized surface potential for positively and negatively charged electrets were investigated. The morphology of the obtained porous substrates was examined by means of scanning electron microscopy (SEM). The chitosan and the casein polyelectrolytes were deposited on the substrates using the layer-by-layer (LbL) technique. A drug loading efficiency and the release kinetics were determined spectrophotometrically.

Zika Virus (ZIKV) is a pathogenic member of the flavivirus family, with several unique charac-teristics. Unlike any other arbovirus, ZIKV can be transmitted sexually and maternally, and thus produce congenital syndromes (CZS) due to its neurotropism. This challenges the search for safe active molecules that can protect pregnant women and their fetuses. In this context, and in the ab-sence of any existing treatment, it seemed worthwhile to test whether the known cytoprotective properties of adiponectin and its pharmacological analog, AdipoRon, could influence the outcome of ZIKV infection. We showed that both AdipoRon and adiponectin could significantly reduce in vitro infection of A549 epithelial cells, a well-known cell model for flaviviruses infection studies. This effect was particularly observed when a pre-treatment was carried out. Conversely, ZIKV revealed an ability to down-regulate adiponectin receptor expression and thereby limit adi-ponectin signaling.

The integration of bioinformatics in drug discovery has revolutionized the field of pharmaceutical research. The use of computational tools and techniques has enabled researchers to analyze vast amounts of data, identify potential drug targets, and design new drugs with greater precision and efficiency. The integration of bioinformatics has also facilitated the development of personalized medicine, where drugs can be tailored to individual patients based on their genetic makeup. However, there are still challenges that need to be addressed, such as the need for more accurate predictive models and the ethical considerations surrounding the use of patient data. Overall, the integration of bioinformatics in drug discovery holds great promise for improving human health and advancing our understanding of disease mechanisms. In this mini-review, we discuss how Bioinformatics plays a crucial role in each step of drug discovery by providing tools and techniques to analyze large amounts of data generated from various sources, as well as the challenges and the opportunities offered by bioinformatics.

The number of people affected by eye conditions is growing every year, due to the popularity of electronic devices and an aging population. In the world of medicine, accomplishing eye medication administration has always been a difficult task. Despite the fact that there are many eye drops on the market, most of them have important limitations due to quick clearance mechanisms and ocular barriers. One solution with tremendous potential is the contact lens used as medication delivery vehicle to bypass this constraint. Therapeutic contact lenses for ocular medication delivery have attracted a lot of attention because they have the potential to improve ocular bioavailability, patient compliance, and reduce side effects. However, it is essential not to compromise essential features such as water content, optical transparency, and modulus in order to target successful in vitro and in vivo sustained drug delivery profile from impregnated contact lenses. Aside from difficulties like drug stability and burst release, the changing of lens physical and chemical properties caused by therapeutic or non-therapeutic components can limit the commercialization potential of pharmaceutical-loaded lenses. Research has progressed towards bioinspired techniques and smart materials to improve the efficacy of drug-eluting contact lenses. The bioinspired method uses bioinspired polymeric materials to improve biocompatibility, a specialized molecule recognition technique called molecular imprinting, or a stimuli-responsive system to improve biocompatibility and support drug delivery efficacy of drug-eluting contact lenses. This review encompasses strategies of material design, lens manufacturing and drug impregnation under the current auspices in ophthalmic therapies and projects an outlook onto future opportunities in the field of eye conditions management by means of active principles-eluting contact lens.

Hydrogels prepared from natural polymer have attracted extensive attentions in biomedical fields such as drug delivery, wound healing, and regenerative medicine due to their good biocompatibility, degradability and flexibility. This review outlines the commonly used natural polymer in hydrogel preparation, including cellulose, chitosan, collagen/gelatin, alginate, hyaluronic acid and starch. The polymeric structure and process/synthesis of natural polymers are illustrated, and natural polymer-based hydrogels including the hydrogel formation and properties are elaborated. Subsequently, the biomedical application of hydrogels based on natural polymer in drug delivery, tissue regeneration, wound healing and other biomedical field is summarized. Finally, the future perspectives of natural polymers and hydrogels based on them are discussed. For natural polymer, novel technologies such as enzymatic and biological methods are developed to improve the structural properties and the development of new natural based polymers or natural polymer derivatives with high performance is still very important and challenging. For natural polymer-based hydrogels, novel hydrogel materials, like double-network hydrogel, multifunctional composite hydrogels and hydrogel microrobots are designed to meet the advanced requirements in biomedical application, and new strategies such as dual-crosslinking, microfluidic chip, micropatterning and 3D/4D bioprinting, have been explored to fabricate advanced hydrogel materials with designed properties for biomedical application. Overall, natural polymeric hydrogels have attracted increasing interests in biomedical application, and the development of novel natural polymer-based materials and new strategies/methods for hydrogel fabrication is badly desirable and still challenging.

Primary central nervous system and brain tumors are one of the global burdens that are continuously increasing in cases and requiring more treatment options. Surgery has been the leading treatment option for tumors, however, the localization of the tumor and its infiltrating nature make this option challenging. DNA microarray expression profiles of different CNS tumors provide insight into potential biomarkers for identifying different tumor types and subtypes. Here, we utilized the differentially expressed genes common in four expression profiles, GSE66354, GSE68848, GSE74195, and GSE43290 to reconstruct the gene co-expression network. In this study, we were able to identify preserved cluster genes, hub genes, co-regulating transcription factors, miRNA families, and candidate repurposed drugs. Fourteen identified hub genes, which were, CACNA1A, DNM1, GABRA1, GRIA2, MAPT, SLC17A7, SNAP25, SNAP91, STXBP1, SYT1, COL1A1, COL6A2, FBN2, and FN1 appeared to play a role in tumor progression and may serve as drug targets. We also reported the DEGs in each tumor type, which were ATRT, EPN, PA, MED, PNET, MEN, ACM, ODG, and GBM. Five identified miRNA families, which were, let-7 family, mir-124 family, mir-1 family, mir-103 family, and mir-27 family described in the literature to have tumor-suppressing characteristics. Drug-gene and drug-transcription factor network revealed 32 candidate repurposed drugs and 13 were validated through connectivity map analysis. Here, two main repurposed drugs fit the regulatory requirement for gene interaction, these were, quercetin and vorinostat. Future validation in experimental studies may utilize the future use of the candidate repurposed drugs. Our study provides insights into drug repurposing prospects and understanding tumor expressions.

Non-systemic oral drugs, which do not get absorbed through the gastrointestinal membrane, are an important group of compounds for targeting diseases residing within the gastrointestinal lumen. However, they require a set of design principles not sufficiently covered by traditional druglikeness metrics, such as Lipinski’s Rule of 5. These druglikeness metrics fail to accurately identify true negative outcomes; such is the requirement for novel cheminformatic based approaches for the discovery of non-systemic small molecules. One such example of these newer metrics is the fraction of SP3-hybridised carbon atoms (fSP3) which has shown promising application as an identifier of poor oral-bioavailability. Herein, we discuss the application of fSP3 in the drug discovery process in a number of case studies, including our own work discovering non-systemic fructose scavengers for the treatment of fructose malabsorption.

In this work, alkylammonium-functionalized hollow mesoporous silica as nonocarrier of drugs was synthesized to realize enhanced cancer therapy by pH stimuli for sustained drug release. First, functionalized hollow mesoporous silica nanoparticles (Hollow MSNs) were synthesized using dodecyl dimethyl(3-sulfopropyl)ammonium hydroxide (DDAPS), sodium dodecyl sulfate (SDS), and triethanolamine as structure-directing agents, and tetraethyl orthosilicate (TEOS) and N-trimethoxysilypropyl-N,N,N-trimethylammonium chloride (TMAPS) as silica sources under basic condition via the sol-gel process. The structure and morphology of the alkylammonium-functionalized hollow mesoporous silica nanoparticles (Hollow MSN-N+CH3) were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption analysis, and Fourier-transform infrared (FT-IR) spectroscopy. The functionalized hollow MSNs had a particle size of about 450 nm and a shell thickness of about 60 nm with uniform size. The nanoparticle had a surface area of 408 m2g-1, pore volume of 0.8 cm3g-1 and a uniform pore diameter of 45.9 Å. In the cancer cell viability test with MCF-7 cell, fludarabine-incorporated and alkylammonium-functionalized hollow mesoporous silica nanoparticles (Flu/Hollow MSN-N+CH3) showed excellent cancer cell death comparable with pure fludarabine drug with the controlled drug release by pH stimuli. It is considered that our current materials have the potential applicability as pH-responsive nanocarriers in the field of cancer therapy.

Microfluidic technology has become a powerful tool for several applications in chemistry, physics, biology, and engineering. Benefiting from the advantages of flowing fluids in the laminar regime, droplet-based microfluidics enable the development of various delivery systems based on food-grade emulsions, such as multiple emulsions, microgels, microcapsules, solid lipid micro-particles, and giant liposomes. Besides, by manipulating fluids on a micrometer scale with low-energy demand, it is possible to control the size, shape, and dispersity of droplets generated, which makes microfluidic emulsification an excellent strategy to modulate delivery system properties depending on the entrapped compound type. Thus, this review points out the most current advances in droplet-based microfluidic processes, in which food-grade materials were successfully utilized to develop simple and complex delivery systems. In that context, we sum-marized the principles of droplet-based microfluidics, introducing the most common microde-vices geometries, manufacturing materials, and forces involved in the different droplet generation processes within the microchannels. Subsequently, the encapsulated compound type, classified as lipophilic or hydrophilic functional compounds, was used as a starting point to present current advances in delivery systems based on food-grade emulsions and assembly using microfluidic technologies. Finally, we discuss the limitations and perspectives of scale-up in droplet-based microfluidic approaches, including the challenges that have limited the transition of microfluidic processes from lab-scale to industrial-scale.

Polymeric microparticles of polyethyleneglycol-polylactic acid-co-glycolic acid (PEG-PLGA) are widely used as drug carriers for a variety of applications due to their unique characteristics. Herein, we developed a novel method for the synthesis of uniformly sized microparticles via coaxial flow-phase separation. The study evaluated the effect of various process parameters on microparticle size and polydispersity including polymer concentration, stirring rate, surfactant concentration, and the organic/aqueous phase flow rate and volume ratio. The results demonstrated that stirring rate and polymer concentration had the most significant impact on the mean particle size and distribution whereas surfactant concentration had the most substantial impact on the morphology of particles. Several microparticle formulations yielding particle sizes in the range of (5-50 µm), morphology, and concentration were synthesized as a demonstration of the tunability and scalability of this method. Notably, by controlling the process parameters microparticles of less than ~ 7 μm could be made using polymer concentrations varying by an order of magnitude. Finally, we demonstrated the tunability and scalability of this method by showing a 10-fold increase in encapsulation efficiency, a 3-fold increase in drug loading of a model hydrophilic drug, and modified release kinetics in microparticle formulations of comparable sizes but different polymer concentrations.

Polymeric hydrogels are promising polymeric functional materials that have been widely used in the biomedical field as an emerging carrier of various therapeutic agents. Polymeric hydrogels as a carrier of therapeutics can leverage therapeutically beneficial outcomes of drug delivery than systemic chemotherapy and can provide spatial and temporal control over the release of various therapeutic agents. Polymeric hydrogels are cross-linked three-dimensional networks constructed by hydrophilic polymers and they are capable of absorbing and re-taining a large amount of water. Polymeric hydrogels share many physiochemical features with natural tissues due to their water abundance, biomimetic microstructure, and intrinsic flexibility. Polymeric hydrogels have excellent biocompatibility, biodegradability, and lower toxicity. Polymeric hydrogels enhance the convenience and efficiency of drug delivery by assisting in situ gelation and controlling drug release by changing their volume and other properties when it encounters some stimuli (e.g., heat, pH, light, and ultrasound). This review aims to outline the overview of polymeric hydrogels, properties, types, advantage, disadvantages, characteri-zation, and their application with present status and future perspective used for the delivery of therapeutics in pharmaceutical and biomedical sciences.

The supramolecular based macrocyclic amphiphiles have attracted great attention in the field of drug delivery due to their unique self-assembling nature. Therefore, these macrocycles are used as nanocarriers for the delivery of poor water soluble drugs, and also for those which have lower permeability, and cannot cross the barrier to reach the desired site. Herein, we design and synthesized a new supramolecular amphiphilic macrocycle to overcome these problems. The macrocycle was synthesized in two steps. In first step 4-hydroxybenzaldehyde was treated with 1-bromotetradecane to obtain a derivatized product which was then treated with resorcinol to cyclize and get calix(4)resorcinarene based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized by Mass spectrometry, IR and 1H-NMR spectroscopic techniques. The amphiphile was screened for biocompatibility studies, vesicles formation, and then Amphotericin-B was loaded in the supramolecular amphiphile based vesicles and was characterized for shape, size, homogeneity, surface charge, drug entrapment, in-vitro release profile and stability through atomic force microscopy (AFM), Zetasizer, HPLC and FT-IR. Amp-B loaded macrocycle based vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle was nontoxic in cancer cells, hemo-compatible and safe in mice. The drug-loaded macrocycle based vesicles appeared spherical, nano-ranged, and homogeneous in size with negative surface charge and were able to load an increased amount of drug. The vesicles are stable upon storage and when incubated with gastric simulated fluid. Amp-B increased oral bioavailability was achieved when delivered in synthesized macrocycle based vesicles. These results point out that the synthesized supramolecular amphiphile is an efficient nanocarrier to enhance the oral bioavailability of lipophilic drugs

Rottlerin(R) is a natural extract from Mallotus philippensis with antiviral properties. Feline Infectious Peritonitis (FIP) is a fatal disease characterized by systemic granulomatous inflammation and high mortality, with no established prevention or cure. We investigated antiviral effect of liposome loaded R, Rottlerin-liposome(RL) against Feline infectious peritonitis virus (FIPV), the causative agent. We demonstrated that R and RL inhibited FIPV replication in dose dependently with a PKCδ related manner, not only in the early endocytosis step but also in the late step of replication. RL resolved the low solubility issue of rottlerin and improved its inhibition efficacy at the cellular level. Based on these findings, we suggest that RL has a value for further research as a potential antiviral agent against FIPV.

Hydrogel microneedles are a promising technology for the delivery of different types of medicines locally and painlessly, as well as ISF extraction. As the hydrogel microneedles are inserted into the tissue, they swell and release drugs. To improve the effectiveness of this technology in delivering medicine at controlled and desirable doses and intervals, a deep understanding of the mechanism of drug delivery inside the microneedles is required. In this work, drug diffusion inside a tapered microneedle is investigated using numerical simulation. The microneedle is divided into many small elements, and the mass transfer equation of meloxicam is solved in each element over time. The skin is simulated as the sink in the microneedle surface for drug absorption. Simulations are performed for different sizes of microneedles. For a microneedle with a height of 500 µm and a base diameter of 250 µm, the drug completely penetrates the skin within 3.2 seconds. The rate of drug diffusion from the tip of the microneedle is higher than diffusion from the side area near the microneedle base. The obtained data demonstrate that in addition to the height and the base diameter, the microneedle’s aspect ratio, h/d, also affects the time of drug diffusion. We present a nonlinear equation to predict the time of complete drug diffusion as a function of the microneedle geometrical parameter, including the height and base diameter. The proposed equation calculates the total drug diffusion time with an error of less than 7% for all studied cases. Predicting drug diffusion patterns inside microneedles can be helpful in the biomedical field, especially in the drug-controlled release system for the optimization of drug delivery.

The emergence of drug-resistant tuberculosis forced the development of new drugs and screnning of more effective or less toxic analogs. Mycolic acids biosynthesis is targeted by several antituberculosis drugs toped by the isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in FAS-II cycle, received official approval and was included in the Russian national clinical guidelines. Using the serial dilution method on agar 7H10 plates for perchlozone and Sensititre MYCOTB microdilution plate we analyzed the phenotypic properties of primary M. tuberculosis clinical isolates and analyzed the molecular determinants of resistance to isoniazid, ethionamide and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between the ethionamide and the perchlozone was driven by mutations in ethA gene encoding monooxygenase responsible for activation of both drugs. Presumably susceptible to perchlozone wild-type strains had MICs ranged 2–4 mg/L, and the breakpoint estimated to be at 4 or 8 mg/L. In conclusion, susceptibility to perchlozone retained for a part of MDR strains, as does suceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.

The proportion of human cells to the microbial cell is 1:1. These procaryotes use efflux pumps and enzymes to prevent cellular intoxication of ions and compounds respectively. There is promising evidence on the role of the gut microbiome and its enzymes in metabolizing xenobiotics. The genetic potential of oral bacteria in drug and xenobiotic metabolism is yet to be unveiled. This study aimed to characterize the bacteriome associated with oral fibroepithelial polyps (FEP) and to predict the genetic potential. A representative sub-sample of 22 clinically diagnosed oral FEP (the control group) was selected from a main case-control study. Amplification of nucleotides of extracted DNA from frozen tissues was performed for the V1 to V3 region and sequencing of the amplicon with Illumina’s 2 X 300–bp chemistry. Classification of high-quality nonchimeric merged reads was done to the species level with a prioritized BLASTN-based algorithm. Downstream compositional analysis was performed with QIIME (Quantitative Insights into Microbial Ecology). Functional prediction of bacteriome was obtained by PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States). Rothia mucilaginosa, Streptococcus mitis, Gamella haemolysans, Streptococcus sp. oral taxon 431, and Rothia dentocariosa accounted for the top five taxa among 810 bacterial species according to the percentage of average relative abundance. Rothia mucilaginosa was elevated statistically significantly (p< 0.05). The genetic potential of xenobiotics and drug metabolism catalyzed by the P450 enzymes was observed for the first time as an attribute of bacteriome associated with oral FEP tissues dominated by R. mucilaginosa. This finding needs further investigation.

Nanomedicine holds great potential to devise better drug delivery systems (DDSs). However, many reported nanomedicines still fall short of commercial requirements including specific targetability, scale-up manufacturing and safety. Cell/tissue based carriers, including cell membrane vehicle and exosome, are biocompatible and targeting platforms but usually suffered from low yields and unstable reproducibility. Here in this study, we proposed the concept and preparation of reconstituted lipid nanoparticles (rLNPs) to develop highly reproducible cell/tissue based lipid nanoparticles (LNPs) for drug delivery, which holds the potential as a versatile drug delivery platform. The whole lipids of cell or tissue were firstly extracted and then prepared into rLNPs using solvent diffusion method. In this way, the preparation of ultra-small (~20 nm) rLNPs can be easily applied to both cell (mouse breast cancer cell line, 4T1) and tissue (mouse liver tissue). Our results demonstrated that mouse liver tissue derived rLNPs can be further labeled/modified with imaging, targeting or other functional moieties. Furthermore, rLNPs were highly biocompatible and capable of loading different drugs including doxorubicin hydrochloride (Dox) and curcumin (Cur). Most importantly, Dox loaded rLNPs (rLNPs/Dox) showed preferable in vitro and in vivo anticancer performance. Therefore, rLNPs might be a versatile drug delivery platform for future application in the treatment of a variety of diseases.

There are various biomaterials in nature, but none fulfills all the requirements. Cellulose, eco-friendly material-based biopolymers, have been advanced biomedicine to satisfy most market demand and circumvent many ecological concerns. This review aims to present an overview of the state of the art in cellulose's knowledge and technical biomedical applications. It included an extensive bibliography of recent research findings for fundamental and applied investigations. The chemical structure of cellulose allows modifications and simple conjugation with several materials, including nanoparticles, without tedious efforts. Cellulose-based materials were used for biomedicine applications such as antibacterial agents, antifouling, wound healing, drug delivery, tissue engineering, and bone regeneration. They advanced the applications to be cheap, biocompatible, biodegradable, easy for shaping and processing into different forms, with suitable chemical, mechanical and physical properties.

Molecularly imprinted polymers (MIPs) have been widely used in nanomedicine during the last few years. However, their potential is limited by their intrinsic properties resulting, for instance, in lack of control in drug release processes or complex detection for in vivo imaging. Recent attempts in creating hybrid nanomaterials combining MIPs with inorganic nanomaterials succeeded in providing a wide range of new interesting properties suitable for nanomedicine. Through this review, we aim to illustrate how hybrids molecularly imprinted polymers may improve patient care with enhanced imaging, treatments and combination of both.

This review revisits clinical use of antibiotics for most common acute oro-dental conditions; we aim to provide evidence governing antibiotics use when access to oral healthcare is not available, as during the ongoing outbreak of the severe acute respiratory syndrome coronavirus 2. In this rapid review, articles were retrieved after conducting a search on PubMed and Google Scholar. Relevant publications were selected and analyzed. Most recent systematic reviews with/without meta-analyses and societal guidelines were selected. Data were extracted, grouped, and synthesized according to the respective subtopic analysis. There were evidence supporting the use of antibiotics in common oro-dental conditions as temporary measure when immediate care is not accessible, such as in case of localized oral swellings as well as to prevent post-extraction complications. No sufficient evidence could be found in support of antibiotic use for pain resulting from pulpal origin. Consequently, antibiotic use may be justified to defer treatment temporarily or reduce risk of complications in case of localized infection and tooth extraction, when no access to immediate dental care is possible.

Among various metal-based nanoparticles, silver nanoparticles (AgNPs) manifest superior inhibitory effect against several microorganisms. In fact, the AgNPs based therapy has been reported to inhibit both sensitive as well resistant isolates of bacteria and other disease causing microbes with equal propensity. Keeping this fact into consideration, we executed bio-mediated synthesis of AgNPs employing Hibiscus rosa sinensis flower extract. The as-synthesized AgNPs were evaluated for their potential to inhibit Streptococcus mutans (S. mutans), one of the main causative bacteria for dental caries. Beside several other reasons, orthodontic appliances have also been reported to facilitate infliction of oral cavity with a range of microbes including S. mutans. To determine the growth inhibitory and anti-adherence activity of AgNPs on orthodontic appliance, we performed microbiological assays employing AgNPs adsorbed on to the orthodontic wires. Topographic analysis of orthodontic wires was executed by scanning electron microscopy. In addition to antimicrobial and antibiofilm activity against oral S. mutans, the as-fabricated AgNPs demonstrated significant inhibitory and anti-biofilm properties against other biofilm forming bacteria such as Escherichia coli and Listeria monocytogenes as well.

Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 65 million cases and one point five million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We created a novel computational pipeline aimed to speed up the process of repurposable candidate drug identification. Compared with current drug repurposing methodologies, our strategy is centered on filtering the best candidate among all selected targets focused on the introduction of a mathematical formalism motivated by recent advances in the fields of algebraic topology and topological data analysis (TDA). This formalism allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib among others. To our knowledge, it is the first time that a TDA based strategy has been used to compare a massive amount of protein structures with the final objective of performing drug repurposing

Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most of normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.

Background: Most modern studies about human marijuana use have been made under a set of arbitrary cultural standards and policies not related to drug harm potential, loosely called Prohibition. Here we asked if potential health hazards generated by Prohibition are addressed in research design and analysis. Methods: For this, we have searched PubMed database (from inception to December 2017) for citations of prevalent contaminants of illegal street cannabis: fungi and pesticides. In addition, we performed full text evaluation of 23 studies selected from, and including, 2 meta-analysis reviews investigating potential health hazards from cannabis use. Results: Different combinations of the keywords cannabis, prohibition, pesticides, fungi, contaminants, cancer, schizophrenia, psychosis, show that these words coincide in less than 1% of the cannabis human studies within the database. In the scope of 141 abstracts in which the terms, cannabis and pesticides coincide, none is directed to distinguish cannabis and pesticide adverse effects on CNS. A similar picture emerges when fungi is the paired word. Full text evaluation shows that all but one of the studies analyzed, completely neglect or comment on the nature of cannabis source, legal status, or contamination as a confounding factor. Discussion: Our results show a potential bias on scientific investigation that may affect data reliability in informing about the health hazards of cannabis use. This finding suggests that other aspects of the Prohibition environment may also go unacknowledged. Conclusion: Prohibition related health risks usually go unacknowledged and unaccounted for in biomedical research on Cannabis.

A novel coronavirus called 2019-nCoV was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. 2019-nCoV spreads more rapidly than SARS-CoV. Unfortunately, there is no drug to combat the virus. It is of high significance to develop a drug that can combat the virus effectively before the situation gets worse. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In this paper, we first collected virus RNA sequences from the GISAID database, translated the RNA sequences into protein sequences, and built a protein 3D model using homology modeling. Coronavirus main protease is considered to be a major therapeutic target, thus this paper focused on drug screening based on the modeled 2019-nCov_main_protease structure. The deep learning based method DFCNN, developed by our group, can identify/rank the protein-ligand interactions with relatively high accuracy. DFCNN is capable of performing virtual screening quickly since no docking or molecular dynamic simulation is needed. DFCNN identifies potential drugs for 2019-nCoV protease by performing drug screening against 4 chemical compound databases. Also, we performed drug screening for all tripeptides against the binding site of 2019-nCov_main_protease since peptides often show better stability, more bio-availability and negligible immune responses. In the end, we provided the list of possible chemical ligands and peptide drugs for experimental validation.

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as Sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of Sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. A diverse set of fragments is required to maximise the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

Japanese encephalitis is a zoonotic disease caused by Japanese encephalitis virus (JEV). It is mainly epidemic in Asia with an estimated 69,000 cases occurring per year. However, no approved agents are available for the treatment of JEV infection, and existing vaccines cannot resist various types of JEV strains. Drug repurposing is a new concept for finding new indication of existing drugs, and recently, it has been used to discover new antiviral agents. Identifying host proteins involved in the progress of JEV infection and using these proteins as targets are the center of drug repurposing for JEV infection. In this study, based on the gene expression data of JEV infection and the phenome-wide association study (PheWAS) data, we identified 286 genes participating in the progress of JEV infection using the systems biology methods. The enrichment analysis of these genes suggested that the genes identified by our methods were predominantly related to viral infection pathways and immune response-related pathways. We found that bortezomib which can target these genes may have potential effect on the treatment of JEV infection. Subsequently, we evaluated the antiviral activity of bortezomib using the JEV-infected mice model. The results showed that bortezomib can lower JEV-induced lethality in mice, alleviate suffering in JEV-infected mice and reduce the damage in brains caused by JEV infection. This work provides a new method for the development of antiviral agents.

Introduction Pharmacovigilance may detect safety issues after marketing of medications, and this can result in regulatory action such as direct healthcare professional communications (DHPC). DHPC can be effective in changing prescribing behaviour, however the extent to which prescribers vary in their response to DHPC is unknown. This study aims to explore changes in prescribing and prescribing variation among GP practices following a DHPC on the safety of mirabegron, a medication to treat overactive bladder (OAB). Methods This is an interrupted time series study of English GP practices from 2014-2017. NHS Digital provided monthly statistics on aggregate practice-level prescribing and practice characteristics (practice staff and registered patient profiles, Quality & Outcomes Framework indicators, and deprivation of the practice area). The primary outcome was monthly mirabegron items as a percentage of all OAB drug items. The exposure was a DHPC issued by the European Medicines Agency in September 2015. Variation between practices in mirabegron prescribing before and after the DHPC was assessed using the systematic component of variation (SCV). Multilevel segmented regression with random effects quantified the change in level and trend of prescribing after the DHPC. Practice characteristics were assessed for their association with a reduction in prescribing following the DHPC. Results This study included 7,408 practices. During September 2015, 88.9% of practices prescribed mirabegron and mirabegron composed a mean of 8.2% (SD 6.8) of OAB items. Variation between practices was classified as very high and the median SCV did not change significantly (p=0.11) in the 6 months after the September 2015 DHPC (12.4) compared to before (11.6). Before the DHPC, there was a monthly trend of 0.294 (95%CI, 0.287, 0.301) percentage points increase in mirabegron percentage. There was no significant change in the month immediately after the DHPC (-0.023, 95% CI -0.105 to 0.058) however there was a significant reduction in trend (-0.036, 95% CI -0.049 to -0.023). Higher numbers of registered patients and patients aged ≥65 years, and practice area deprivation were associated with having a significant decrease in level and slope of mirabegron prescribing post-DHPC. Conclusion Variation in mirabegron prescribing was high over the study period and did not change substantively following the DHPC. There was no immediate prescribing change post-DHPC, although the monthly growth did slow. Knowledge of the degree of variation in and determinants of response to safety communications may allow those that do not change prescribing to be provided with additional supports.

2017 was an excellent year in terms of new drugs (chemical entities and biologics) approved by the FDA, with a total of forty-six. In turn, one of the highlights was the number of peptides (six) included in this list. Here, the six peptides are analysed in terms of chemical structure, synthetic strategy used for their production, source, biological target, and mode of action.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

The drug delivery systems receive more and more attention for the control and treatment of many diseases due to their increased number in recent years. The main aims of this study were to develop and to characterize a polyurethane drug delivery system that it is intended to be used for the transmembrane transport of nucleosides. Three different samples have been synthesized based on aliphatic diisocyanates (hexamethylene diisocyanate, isophorone diisocyanate and lysine diisocyanate) as organic phase, respectively a mixture of polyethylene glycol, polycaprolactone diol and low molecular weight diols as aqueous phase. The samples were characterized by pH, refractivity index and solubility measurements, drug loading efficacy and release investigations, thermal behavior, Zetasizer, cells viability and irritation tests on mice skin. The results indicate the obtaining of different populations of neutral acido-basic particles with size between 132 and 190 nm; the Zeta potential values and SEM images show a medium tendency to form clusters, while UV-Vis evaluations indicate an almost 70% encapsulation efficacy, a prolonged release (45% of encapsulated substance is released in the first 5 days) and around 70% of particles have penetrated an artificial membrane in the first 24h. The synthesized products can be tested in further clinical trials, the currently tests on cells culture and mice skin revealing no side effects.

Background: Several studies recently confirmed the emergence of resistance to antimalarial drugs in sub-Saharan Africa. Multiple first-line treatment (MFT) is one of the measures envisaged to respond to the emergence and spread of this resistance. The aim of this study was to identify perceived advantages and disadvantages of several MFT deployment strategies and to better understand potential implementation drivers and barriers. Methods: A qualitative survey was conducted in seven sub-Saharan countries amongst key opinion-leaders, national decision-makers, and end users. A total of 200 individual interviews were conducted and findings were analyzed following a thematic inductive approach. Results: From a policy perspective, the new MFT intervention would require endorsement at the global, national, and regional levels to ensure its inclusion in guidelines. Funding of the MFT intervention could be a bottleneck due to costs associated with additional training of healthcare workers, adaptation of drug delivery mechanisms, and higher costs of drugs. Concerning the MFT deployment strategies, a slight preference for the segmentation strategy was expressed over the rotation and geographic approaches, due to the perception that a segmentation approach is already in place at country level. Conclusions: The findings highlighted the need for a collective approach to MFT deployment through the engagement of stakeholders at all levels of malaria management.

High rates of resistance to antibiotics are associated with healthcare-related infections, thus appealing for the urgent need for effective antimicrobials against these maladies. The present study aims to determine the chemical composition of essential oil (EO) from Clausena anisata leaves, and evaluate their antibacterial activity against selected nosocomial bacteria. Fresh leaves of Clausena anisata were subjected to a steam distillation using a Clevenger apparatus to afford the essential oil. The phytochemical composition of this oil was analyzed using gas chromatography-mass spectrometry (GC-MS). The essential oil was further tested against selected nosocomial bacteria, including Staphylococcus and Klebsiella species, among others, using a microdilution method. As a result, 0.77% of essential oil was extracted from fresh leaves of Clausena anisata. The GC-MS analysis revealed that the as-prepared essential oil contain E-anethole (70.77%), methyl isoeugenol (13.85%), estragole (4.10%), γ-terpinene (3.33%), myrcene (2.82%) and sabinene (0.77%), with E-anethole being the major constituent. Meanwhile, twenty two compounds were identified in the EO of Clausena anisata leaves through gas chromatography. Upon antibacterial test against selected nosocomial pathogens, the E-anethole-rich essential oil exhibited minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranging from 3.91 to 125 µg/mL and 7.81 to 125 µg/mL, respectively, indicative of a bactericidal orientation of the plant’s essential oil (MIC/MBC ratio: 4). This novel contribution highlights the scientific validation of the use of Clausena anisata leaves in the traditional treatment of various infectious diseases. However, toxicity and pharmacokinetic studies, mechanistic basis of the antibacterial action, and in vivo antibacterial experiments of the E-anethole-rich essential oil of Clausena anisata should be investigated to successfully use this plant in the treatment of infectious diseases.

Human serum albumin (HSA) is multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. Formulating anticancer drugs with HSA is a clinically validated approach to improve the pharmacological properties and provide targeted delivery (passive and active) of cytotoxic payload to the tumor (such as in Abraxane). A number of receptors facilitating HSA uptake from systemic circulation have been characterized. What is interesting, such uptake may differ depending on the nature and quantity of ligands bound to HSA. Based on this, one might like to modify the HSA in a way that its distribution is more favorable for certain therapeutic purposes, thus ensuring more efficient delivery of the therapeutic cargo to disease site. E.g. Levofloxacin (LV), broad spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interaction with plasma proteins could be useful for this purpose. We have engrafted monomeric or polymeric CDs on the surface of HSA molecules to strengthen the LV adsorption (CD-LV dissociation constant is three orders of magnitude lower than that for HSA-LF). We have found that (HSA-HPolS)conj+LV exhibited the highest activity against E. coli, whereas (HSA-HPCD)conj+LV was the most effective against B. subtilis; and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution, and thus a more favorable risk/benefit ratio.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated to somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in non-Hodgkin B-cell lymphoma. Furthermore, we aim to present in close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have greatest potential to improve the prognosis of lymphoma patients.

Management of resistant Tuberculosis (TB) can be extremely difficult, especially in case of novel unpredicted complications. In this report, we present a case of a 48-year-old patient with pre-extensive-drug-resistant-(XDR)-TB who received a treatment regimen including Pretomanid, Bedaquiline, Linezolid, Cycloserine and Amikacin and died due to myocarditis. Acquired resistance to first- and second-line drugs developed due to previous poor adherence to medication. The clinical presentation of the patient, along with her initial ultrasonographical, electrocardiogram (ECG) and laboratory examinations, were typical for acute myocarditis, however, the patient was considered unstable and further investigation with Magnetic Resonance Imaging (MRI), pericardiocentesis and endomyocardial biopsy were not performed. To our knowledge, this is the first case of myocarditis in such a patient, the clinical features of which set a high suspicion of drug-induction that could be attributed to the treatment regimen that was administered. Clinicians who manage cases of drug-resistant TB should be aware of this, newly reported, potentially lethal, adverse event.

Background: The ever-growing emergence of antibiotic resistance associated with tuberculosis (TB) has become a global challenge. In 2012, USFDA has given expedited approval to bedaquiline (BDQ), as a new treatment for drug-resistant TB in adults when no other viable options are available. BDQ is a diarylquinoline derivative and exhibits targeted action on mycobacterium tuberculosis but due to poor solubility desired therapeutic action is not achieved. Objective: To develop a QbD-based self-nanoemulsifying drug delivery system of Bedaquiline using various oils, surfactants, and co-surfactants. Methods: The quality target product profile (QTPP) and critical quality attributes (CQAs) were identified with a patient-centric approach which facilitated the selection of critical material attributes (CMAs) during pre-formulation studies and initial risk assessment. Caprylic acid as a lipid, propylene glycol as a surfactant and Transcutol-P as a co-surfactant were selected as CMAs for the formulation of Bedaquiline fumarate SNEDDS. Pseudo-ternary phase diagrams were constructed to determine the optimal ratio of oil and Smix. To optimize the formulation, a Box-Benkhen design (BBD) was used. The optimized formulation (BDQ-F-SNEDSS) was further evaluated for parameters such as droplet size, polydispersity index (PDI), percentage transmittance, dilution studies, stability studies, and cell toxicity through the A549 cell. Results: Optimized BDQ-F-SNEDDS showed well-formed droplets of 98.88±2.1 nm with a zeta potential of 21.16 mV. In vitro, studies showed enhanced drug release with a high degree of stability at 25 ± 2 ºC & 60 ± 5 % and 40 ± 2 ºC & 75± 5 %. Furthermore, BDQ-F-SNEDDS showed promising cell viability in A549 cells indicating BDQ-F-SNEDDS as a safer formulation for oral delivery. Conclusion: Finally, it was concluded that the utilization of a QbD approach in the development of BDQ-F-loaded SNEDDS offers a promising strategy to improve the biopharmaceutical properties of the drug, resulting in potential cost and time savings.

Waddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical system theory represents a high-dimensional cell state space, in which each cell phenotype is considered as an “attractor” that is determined by interactions among multiple variables (molecular players), and is buffered against environmental fluctuations. Further, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss these phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors” – hidden stable states of the underlying regulatory network that are not occupied by normal cells. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of drug/hormone resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to drug/hormone treatment. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes ‘recanalization’, i.e. the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.

HIV incidence remains alarmingly high among female sex workers (FSWs) in low- and middle-income countries, with Uganda being no exception. The elevated risk of HIV transmission among this vulnerable population can be attributed to a complex interplay of factors, including engaging in sexual activities with multiple partners, inconsistent condom usage, substance use, and structural barriers, such as legal criminalization and pervasive stigmatization by healthcare providers. To combat this epidemic, various HIV prevention interventions have been devised, targeting these multi-faceted challenges. This study involved conducting focus groups among FSWs and healthcare providers in Uganda, with the overarching objective of informing the development of a tailored HIV prevention intervention aimed squarely at FSWs. Through these discussions, valuable insights were gained into FSWs’ perceptions of their HIV risk, their attitudes regarding HIV prevention strategies, and their recommendations regarding the content and delivery of future interventions.

Tyrosine Kinase Inhibitors work by blocking the tyrosine kinases responsible of the dysregulation of intracellular signalling pathways in tumour cells. This study looked at the impact of age and sex on the levels of imatinib, dasatinib, nilotinib, and ponatinib in plasma and cerebrospinal fluid samples of patients with chronic myeloid leukaemia. Imatinib and dasatinib were used to treat the majority of the enrolled patient and most of them were paediatrics. The 82.4% of patients were men; however, sex-related differences in drugs pharmacokinetics were not found. Age and imatinib plasma concentration were found to be inversely correlated: as patients ages increased, drug levels decreased. The dasatinib concentrations in plasma were found to be substantially lower than those found in cerebrospinal fluid, particularly in paediatrics. Analysing the obtained data, we can state that Therapeutic Drug Monitoring is a useful method for adjusting a patient treatment schedule depending on drug concentrations in biological fluids. The use of Therapeutic Drug Monitoring in conjunction with Tyrosine Kinase Inhibitors for the treatment of chronic myeloid leukaemia is supported by a number of sources of evidence. As a result, as the research develops, Tyrosine Kinase Inhibitors Therapeutic Drug Monitoring classification needs to be refined in terms of factors like sexes and ages.

The recent outbreak of the new virus in Wuhan city, China from the sea food market has led to the identification of a new strain called the corona virus and named as novel corona virus (2019-nCoV) belonging to Coronaviridae family. This has created major havoc and concern due to the mortality of 250 persons and affecting more than 10,000 people. This virus causes sudden fever, pneumonia and also kidney failure. In this study a computational approach is proposed for drug and vaccine design. The spike protein sequences were collected from a protein database and analysed with various bioinformatics tools to identify suitable natural inhibitors for the N-terminal receptor binding domain of spike protein. Also, it is attempted to identify suitable vaccine candidates by identifying B-Cell and T-cell epitopes. In the drug design, the tanshinone Iia and methyl Tanshinonate were identified as natural inhibitors based on the docking score. In the vaccine design, B-cell epitope VLLPLVSSQCVNLTTRTQLPPAYTN was found to have the highest antigenicity. FVFLVLLPL of MHC class-I allele and FVFLVLLPL of MHC class-II allele were identified as best peptides based on a number of alleles and antigencity scores. The present study identifies natural inhibitors and putative antigenic epitopes which may be useful as effective drug and vaccine candidates for the eradication of novel corona virus.

Small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have got interest following the recent publication of their pharmacologically beneficial effects. Recently it comes out that FABP4 is an attractive molecular target for the treatment of type 2 diabetes, other metabolic diseases, and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized and discovered but, unfortunately, none of them is in the clinical research phase. The field of computer-aided drug design seems to be promising and useful for the identification of FABP4 inhibitors; hence, different structure- and ligand-based computational approaches were already performed for their identification. In this paper, we searched for new potentially active FABP4 ligands in the Marine Natural Products (MNP) database. 14,492 compounds were retrieved from this database and filtered through a statistical and computational filter. Seven compounds were suggested by our methodology to possess a potential inhibitory activity upon FABP4 in the range of 79–245 nM. ADMET properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives; from these analyses, three molecules resulted as excellent candidates for becoming new drugs.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the chief concern of the international community in almost no time. As of May 9th, 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. Hence, many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed. Pregnant women, fetuses, and infants are known high-risk populations that are threatened during disease outbreaks. Therefore, this article reviews the safety of potential drugs for COVID-19 patients during pregnancy and breastfeeding.

This narrative review delves into the evolving landscape of fertility preservation techniques with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

Biomaterials have been the subject of extensive research, with their applications in medicine and pharmacy expanding rapidly. Collagen and its derivatives stand out as valuable biomaterials due to their high biocompatibility, biodegradability, and lack of toxicity and immunogenicity. This review comprehensively examines collagen from various sources, its extraction and processing methods, and its structural and functional properties. Preserving the native state of collagen is crucial for maintaining its beneficial characteristics. The challenges associated with chemically modifying collagen to tailor its properties for specific clinical needs are also addressed. The review discusses various collagen-based biomaterials, including solutions, hydrogels, powders, sponges, scaffolds, and thin films. These materials have broad applications in regenerative medicine, tissue engineering, drug delivery, and wound healing. Additionally, the review highlights current research trends related to collagen and its derivatives. These trends may significantly influence future developments, such as using collagen-based bioinks for 3D bioprinting or exploring new collagen nanoparticle preparation methods and drug delivery systems.

Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene which has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds: doxorubicin (Dox) and the triterpene BeA using an oil-water-like micro-emulsion method. Spectrophotometric assays were performed to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h, at pH 6.8, while less drug was released at pH 7.4 in this time period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against the non-small cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed cellular internalization of the DDS and nucleus accumulation of the Dox. We determined the mechanism of action of the BSA(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of the epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC.

Background: In the present study, cisplatin, artemisinin and oleanolic acid were evaluated alone and in combination, on human ovarian A2780, A2780ZD0473R and A2780cisR cancer cell lines with aim of overcoming cisplatin resistance and side effects. Methods: Cytotoxicity was assessed by MTT reduction assay. CI values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Results: Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism and biosynthetic processes and drug resistance and detoxification. Conclusion: Results indicate that appropriately sequenced combinations of cisplatin with ART and OA may provide a means to reduce side effects and circumvent platinum resistance.

Background: This study aimed to estimate the prevalence of sexualized drug use (SDU) in gay, bisexual, and other men who have sex with men living with HIV (HIV+GBMSM) in Madrid during 2019/2020 and compare it with data from 2016/2017. Methods: We analysed the frequency of SDU in a sample of HIV+GBMSM attending HIV clinics, who participated in an anonymous online survey regarding sexual behaviour and recreational drug use. The association between SDU, sexual risk behaviours, and STIs was evaluated. The methodology employed in the present study(U-SEX-2) in 2019/2020 was consistent with that of a previous study(U-SEX-1) in 2016/2017. Results: The study included 424 HIV+GBMSM, with a mean age of 40(10.43) years. Overall, 94% (396) reported being sexually active. Additionally, 33% (140) had been diagnosed with an STI within the previous year. Moreover, 54% (229) had used drugs in the last year, 25% (107) engaged in SDU, and 15% (17) reported engagement in slamsex. After adjusting for confounding factors, SDU was associated with STIs, fisting, unprotected anal intercourse, and having &gt; 24 sexual partners in the last year. According to the DUDIT test scores, 76% (81) probably had problematic drug use (≥6 points), and 5% (8) probable drug dependence (≥25 points). When comparing the U-SEX-1(2016/2017) data with the U-SEX-2(2019/2020) data, no significant differences were found in the proportion of participants practicing SDU or slamsex. Conclusion: The prevalence of SDU among HIV+GBMSM has remained high in recent years and without significant changes. We observed a clear association between SDU, high-risk sexual behaviors, STIs, and the risk of drug related problems.

Background: The Government of Bangladesh is currently providing COVID-19 vaccines free of cost, but for a massive population, the free vaccination program’s sustainability is challenging. In this regard, assessing willingness to pay can help to explore vaccine pricing, subsidizing strategy, and vaccine demand. The study aimed to evaluate the prevalence of willingness to pay (WTP) for the COVID-19 vaccine and its associated factors to ensure the sustainability of the vaccination program. Methods: A cross-sectional research design was adopted to collect data from 1497 respondents through online and face-to-face interviews. Data were analyzed using the chi-square test and point-biserial correlation for descriptive statistical analysis, and multiple logistic regression analysis was also used to identify the factors associated with the dependent variable in the study. Results: The prevalence of WTP towards a COVID-19 vaccine was 50.9 %, and mean and median WTP were respectively 754.55 BDT (US$ 8.93), 300 BDT (US$ 3.55). WTP of other religions was significantly higher than Muslims (aOR=1.5, P=0.037). WTP was also higher among Graduate (aOR=2.2, P=0.007), Masters & MPhil/PhD (aOR=2, P=0.030), higher family income group (aOR=1, P=0.039) and respondents with higher knowledge about the vaccine (aOR=1.1, P=0.003), behavioral practice (aOR=1.1, P< 0.001), higher subjective norms (aOR=1.2, P=0.009), higher anticipated regret (aOR=1.2, P=0.005) and higher perceived benefits from the vaccine (aOR=1.1, P=0.029). On the contrary, WTP is lower among respondents who had a higher negative attitude toward vaccines (aOR= 0.9, P<0.001) and higher behavioral control (aOR=0.9, P=0.006). The participants who had experienced severe morbidity and who belonged to a higher income group, they have highly tended to WTP's highest amount of money for the COVID-19 vaccine. Conclusion: The study found that nearly half of the respondents were not interested in paying for the COVID-19 vaccine. It emphasizes higher education, proper knowledge dissemination about the COVID-19 vaccine, positive behavioral practice, reducing negative attitudes towards it, and higher household income to increase WTP for the COVID-19 vaccine. Health promotion materials should be developed to improve COVID-19 vaccine knowledge and reduce negative attitudes regarding vaccines. A subsidized scheme for lower-income groups should be initiated to minimize the catastrophic income challenge regarding WTP for the COVID-19 vaccine.

Introduction: Transforming growth factor beta receptor 2 (Tgfbr2) signaling regulates odontoblast differentiation, dentin mineralization, and the paracrine signaling that guides sensory innervation in developing mouse molars. We hypothesized that Tgfbr2 also regulates the neuro-pulpal responses to injury to activate axon sprouting and tertiary dentin secretion. Methods: We per-formed a timed deletion of Tgfbr2 using tetracycline-responsive Osterix-Cre;Tgfbr2f/f (Tgfbr2^cko) mice, which allowed them to develop normally. At 3 months, we drilled a shallow hole on the mesial side of the first mandibular molar (M1) in both control and Tgfbr2^cko mice. Hemi-mandibles were collected 4, 8, 21, and 56 days post-injury (dpi). In situ hybridization (ISH) for Sp7 was performed to confirm Osterix-Cre transcription. Microcomputed tomography (micro-CT) imaging and histology were used to examine the tertiary dentin, and immunofluorescence was used to visualize CGRP+ axons following the injury. Results: Tgfbr2 deletion was inferred by Sp7 ISH. Micro-CT and histology indicated a lower dentin volume in 21 dpi Tgfbr2^cko M1s compared to WT M1s, but the volume was comparable by 56 dpi. The duration of axon sprouting was longer in injured Tgfbr2^cko M1s compared to WT M1s. Conclusions: These results suggest that sensory afferents may support dentin repair in Tgfbr2-deficient odontoblasts.

In this case series, we examine the impact of the Titan-iR Pro® deep spectrum biotherapeutic device on brain function in healthy individuals. Here we present 15 participants, aged 26-68 years, who enrolled in this open-label study, designed to assess the effect of a single 15-minute course of deep spectrum biotherapy on brain function. Although symptom-free upon enrollment, participants had diverse medical histories with some displaying early signs of cognitive decline. As part of the evaluation, all participants engaged in electroencephalogram (EEG) recording sessions that focused on assessing event-related potential (ERP) evaluations, including audio P300 amplitudes and latencies (speeds), neurocognitive testing, and physical reaction times. Following the Titan-iR Pro intervention an improvement in EEG-based cognitive markers was observed. These results underscore the importance of further investigation into the potential of advanced and deep spectrum photobiomodulation in the prevention and treatment of cognitive decline and other neurological disorders.

We report the first correction by Prime editing of a mutation in the RYR1 gene, paving the way to gene therapies for RYR1-related myopathies. The RYR1 gene codes for a calcium channel named Ryanodine receptor 1, which is expressed in skeletal muscle fibers. The failure of this channel causes muscle weakness in patients, which degenerates into motor disabilities. Currently, there are no effective treatments for these diseases, which are mainly caused by point mutations. Prime editing allows the modification of precise nucleotides in the DNA. Our results showed a 59% correction rate of the T4709M mutation in the RYR1 gene in human myoblasts by RNA delivery of the Prime editing components. It is to be noted that the T4709M is recessive, and thus, persons having a heterozygous mutation are healthy. These results are the first demonstration that it is possible to correct mutations in the RYR1 gene.

Biological, environmental, behavioral, and social factors can influence sleep and lead to sleep disorders or diseases. Sleep disorders are common, numerous and heterogeneous in terms of their etiology, pathogenesis, and symptomatology. Management of sleep-wake circadian disorders (SWCD) includes education to sleep hygiene, behavioral strategies, psychotherapy (cognitive behavioral therapy (CBT), particularly), instrument-based treatments (i.e. positive airway pressure therapy, hypoglossal nerve stimulation), and pharmacotherapy. Depending on the disease, therapy varies and is executed sequentially, or can be a combination of several forms of therapy. Drugs used for SWCD include traditional sleep or wake-promoting agents, chronotherapeutic agents. Recently, novel medications, which are more precisely acting on specific neurochemical systems (i.e. orexin system) important for sleep and wake, are also increasingly being used. In this review, the pharmacotherapy of common sleep disorders (insomnia, sleep-related breathing disorder, central disorders of hypersomnolence, circadian rhythm sleep wake disorders, parasomnias, and sleep-related movement disorders) embedded in the overall therapeutic concept of each disorder is presented. There is also an outlook on possible future pharmacotherapies.