Antibiotics have played a crucial role in the reduction of TB incidence globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline of antibiotic development, and different economic and social conditions. In this review, we summarise recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasise that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throught the community.

Still, the most common in vitro model for absorption, distribution, metabolism and excretion (ADME) purposes is the Caco-2 cell line. However, clear differences in gene- and protein expression towards the small intestine and an at best fair prediction accuracy of intestinal drug absorption restrict the usefulness as model for intestinal epithelial cells. To overcome these limitations, we evaluated a panel of low-passaged patient-derived colorectal cancer cell lines of the HROC collection concerning similarities to small intestinal epithelial cells and their potential to predict intestinal drug absorption. After initial screen of a larger panel, ten cell lines with confluent outgrowth and long-lasting barrier forming potential were further characterized in close detail. Tight junctional complexes and microvilli structures were detected in all lines, differentiated epithelial cells were abundant in 7/10. All lines expressed multiple transporter molecules, with expression levels in three lines being close to those of small intestinal epithelial cells. Compared to the Caco-2 model, three HROC lines demonstrated both higher similarity to jejunal epithelial tissue cells and higher regulatory potential of relevant drug transporters. In sum, these lines would be better suited human small intestinal epithelium models for basic and translational research; especially for ADME studies.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Firocoxib is a non-steroidal anti-inflammatory drug specifically formulated for veterinary medicine and selectively acts on inhibiting the cyclooxygenase 2 enzyme(COX-2). This study aimed to evaluate the possible adverse effects of administering oral therapeutic firocoxib on gastric mucosa, hematological parameters, coagulation cascade, and hepatic and renal biochemistry in healthy horses. Nine clinically healthy Arabian horses, approximately nine years old, received 0.1mg/kg of oral firocoxib for 14 days. Before beginning treatment, a gastroscopic examination was conducted, and venous blood samples were obtained for laboratory tests on D0. Follow-up blood samples and gastroscopic examinations were taken on D7 and D14 after starting treatment and one week after completing treatment on D21. No changes were found in the gastroscopic and hematological tests. Additionally, coagulation and serum biochemistry levels remain between normal values for this particular species. However, the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) indicate reduced blood coagulation capacity, which contradicts the expected effect of treatment with selective COX-2 inhibitors, as these drugs theoretically promote coagulation. Administering Firocoxib to horses is safe as it does not cause any significant adverse reactions. Therefore, it is a suitable option for managing inflammatory conditions in these animals.

In the first wave of COVID-19, up to 20% of patients had skin lesions with variable characteristics. There is no clear evidence of the involvement of the SARS-CoV-2 virus in all the cases; some of these lesions may be secondary to drug hypersensitivity. To analyze the possible cause of the skin lesions, we performed a complete allergology study on 11 patients. One year after recovery from COVID-19, we performed a lymphocyte transformation test (LTT) and Th1/Th2 cytokine secretion assays of PBMC. We included 5 nonallergic patients treated with the same drugs without lesions. Except for one patient who had an immediate reaction to azithromycin, all patients had a positive LTT to at least one of the drugs tested (azithromycin, clavulanic acid, hydroxychloroquine, lopinavir, and ritonavir). None of the nonallergic patients had a positive LTT. We found mixed Th1/Th2 cytokine secretion (IL-4, IL-5, IL-13, and IFN-γ) in patients with skin lesions corresponding to mixed drug hypersensitivity type IVa and IVb. In all cases, we identified a candidate drug as the culprit for skin lesions during SARS-CoV-2 infection, although only three patients had a positive drug challenge. Therefore, it would be reasonable to recommend avoiding the drug in question in all cases.

Background Coronary artery disease (CAD) is a widely recognized cardiovascular disease that is considered the leading cause of death worldwide, affecting people on a global scale. Percutaneous coronary intervention (PCI), which involves procedures such as balloon angioplasty or stenting, plays an important role in opening blocked arteries and minimizing damage to the cardiac muscle. While the use of drug-eluting stents (DESs) has significantly reduced the occurrence of coronary restenosis, the problem of in-stent restenosis (ISR) continues to pose a significant clinical challenge. Gaining a deeper understanding of the clinical predictors associated with ISR is vital for early detection and appropriate treatment. Hence, this study aimed to evaluate the clinical predictors of ISR specifically in Taiwanese patients. Methods We conducted a single-center, retrospective case-control study, enrolling 517 CAD patients undergoing previous coronary stenting and stable angina with positive stress test or acute coronary syndrome (ACS) during follow-up between January 2019 and December 2022 at National Taiwan University Hospital. The patients were categorized into two groups: the ISR group, consisting of individuals who received drug-coated balloon (DCB) treatment (n=177), and the non-ISR group, comprising patients who did not receive DCB treatment (n=340). To gather relevant data, we meticulously reviewed the medical records and analyzed the findings from coronary angiography to assess the clinical characteristics of the patients. Results Patients with three-vessel disease (3VD) exhibited a higher prevalence of underlying diseases and were more likely to be taking aspirin and clopidogrel. Moreover, our analysis revealed that age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00 - 1.04, p = 0.037) and the presence of 3VD (adjusted odds ratio [aOR] 2.15, 95% confidence interval [CI] 1.03 - 4.46, p = 0.039) were significantly associated with an increased risk of coronary ISR. Conclusions Older age and 3VD were the independent predictors of coronary ISR in CAD patients receiving coronary stent implantation.

The growing worldwide cancer incidence, coupled to the increasing occurrence of multidrug cancer resistance, requires a continuous effort towards the identification of new leads for cancer management. In this work, two C-scorpionate complexes, [FeCl2(κ3-Tpm)] (1) and [Co(κ3-TpmOH)2] (2), (Tpm = hydrotris(pyrazol-1-yl)methane and TpmOH = 2,2,2-tris(pyrazol-1-yl)ethanol), are studied as potential scaffolds for future anti-cancer drug development. Their cytotoxicity and cell migration inhibitory activity are analyzed, and an untargeted metabolomics approach is em-ployed to elucidate the biological processes significantly affected by these two complexes, using two tumoral cell lines (B16 and HCT116) and a non-tumoral cell line (HaCaT). While [FeCl2(κ3-Tpm)] did not display a significant cytotoxicity, [Co(κ3-TpmOH)2] was particularly cy-totoxic against the B16 cell line. While [Co(κ3-TpmOH)2] significantly inhibited cell migration in all tested cell lines, [FeCl2(κ3-Tpm)] displayed a mixed activity. From a metabolomics perspective, exposure to [FeCl2(κ3-Tpm)] is associated with changes in various metabolic pathways involving tyrosine, where iron-dependent enzymes are particularly relevant. On the other hand, [Co(κ3-TpmOH)2] is associated with dysregulation of cell adhesion and membrane structural pathways, suggesting its antiproliferative and anti-migration properties can be due to changes in the overall cellular adhesion mechanisms.

Small molecules that can modulate or stabilize cell-cell interactions are valuable tools for investigating the impact of collective cell behavior on various biological processes such as development/morphogenesis, tissue regeneration and cancer progression. Recently, we showed that budesonide, a glucocorticoid widely used as anti-asthmatic drug, is a potent regulator of stem cell pluripotency. Here we tested the effect of different budesonide derivatives and identified CHD-030498 as a more effective analogue of budesonide. CHD-030498 was able to prevent stem cell pluripotency exit in different cell-based models, including embryonic stem-to-mesenchymal transition, spontaneous differentiation and 3D gastruloid development, and at lower doses compared to budesonide.

To reveal the relationship between metallodrugs and cancer malignancy, molecular networks of anti-cancer drugs were analyzed. Molecular networks in several types of cancers were analyzed in Ingenuity Pathway Analysis (IPA). Analysis of carboplatin revealed the causal network in diffuse large B-cell lymphoma. Analysis of 12 analyses of cisplatin treatment identified causal networks including camptothecin and NUPR1. The causal network of camptothecin, which includes PTEN, FAS, and IRF1, was inactivated in diffuse-type GC and activated in intestinal-type GC. Upstream regulator analysis of cisplatin revealed an increase in FAS, BTG2, SESN1 and CDKN1A, and the involvement of the tumor microenvironment pathway. Upstream regulators of cisplatin-treated lung adenocarcinoma included a histone deacetylase inhibitor, trichostatin A (TSA). Causal network of arsenic was inactivated in diffuse-type GC and activated in intestinal-type GC, and included ERK, EGFR, SRC, IKK and TP53. Prediction of RNA-RNA interactions with the causal network of arsenic identified 10 microRNAs including mir-101, mir-103, and mir-22. The results revealed the involvement of EMT in arsenic treatment. Analysis of oxaliplatin, a platinum drug, revealed that the SPINK1 pancreatic cancer pathway is inactivated in ischemic cardiomyopathy. The study showed the importance of the relationship between platinum drugs or arsenic trioxide and the tumor microenvironment in the treatment of resistant cancer in humans.

Acute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody-drug conjugates,chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients.

The multidrug-resistant fungal pathogens belonging to the Candida haemulonii complex and the phylogenetically related species Candida auris are well-known for causing infections that are difficult to treat due to their multidrug-resistance profile. C. auris is even more worrisome due to its ability to cause outbreaks in healthcare settings. These emerging yeasts produce a wide range of virulence factors that facilitate the development of the infectious process. In recent years, the aggregative phenotype has been receiving attention, as it is mainly associated with defects in cellular division and its possible involvement in helping the fungus to escape from host immune responses. In this study, we initially investigated the aggregation ability of 18 clinical isolates belonging to the C. haemulonii species complex and C. auris. Subsequently, we evaluated the effects of physicochemical factors on the fungal aggregation competence. The results demonstrated that cell aggregation was a typically time-dependent event, in which almost all studied fungal isolates exhibited high aggregation after 2 h of incubation at 37°C. The aggregation was not impacted by pH, temperature, -mercaptoethanol (a protein-denaturing agent) and EDTA (a chelator agent). Conversely, proteinase K, trypsin and sodium dodecyl sulfate significantly diminished the aggregation. Collectively, our results demonstrated that the aggregation ability in these opportunistic yeast pathogens is time-dependent, and surface proteins and hydrophobic interactions seem to mediate cell aggregation, since the presence of proteases and anionic detergent affected the aggregation ability. However, further studies are necessary to better elucidate this phenomenon.

Gene therapy has seen major progress in recent years. Viral vectors have made a significant contribution through efficient engineering for improved delivery and safety. A large variety of indications such as cancer, cardiovascular, metabolic, hematological, neurological, muscular, ophthalmological, infectious diseases, and immunodeficiency have been targeted. Viral vectors based on adenoviruses, adeno-associated viruses, herpes simplex viruses, retroviruses including lentiviruses, alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, picornaviruses, reoviruses, and polyomaviruses have been used. Proof-of-concept has been demonstrated for different indications in animal models. Therapeutic efficacy has also been achieved in clinical trials. Several viral vector-based drugs have been approved for the treatment of cancer, and hematological, metabolic, and neurological diseases. Moreover, viral vector-based vaccines have been approved against COVID-19 and Ebola virus disease.

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of ovarian tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable to treatment with PARP inhibitors such as olaparib. Recent studies have shown that TGFβ can induce “BRCAness” in BRCA wild-type cancer cells. Given that TGFβ is a known driver of epithelial to mesenchymal transition (EMT), and the con-nection between EMT and metastatic spread in EOC and other cancers, we asked if TGFβ and EMT alter susceptibility of EOC to PARP inhibition. Epithelial EOC cells were transiently treated with soluble TGFβ and their clonogenic potential, expression and function of EMT and DNA repair genes, and response to PARP inhibitors compared with untreated controls. A second epithelial cell line was compared to its mesenchymal derivative for EMT and DNA repair gene expression and drug responses. We found that TGFβ and EMT resulted in downregulation of genes responsible for homologous recombination (HR) and sensitized cells to olaparib. HR efficiency was reduced in a dose-dependent manner. Furthermore, mesenchymal cells displayed sensitivity to olaparib, cis-platin, and the DNA-PK inhibitor Nu-7441. Therefore, treatment of disseminated, mesenchymal tumors may represent an opportunity to expand clinical utility of PARP inhibitors and similar agents.

The emergence of drug resistant pathogenic bacteria is increasingly challenging conventional antibiotics. Plant derived flavonoids are considered as potential alternatives to antibiotics due to their antimicrobial properties. However, the mechanisms by which flavonoids modulate pathogenic microorganisms’ growth are not fully understood. In our previous studies we found that Rutin, a kind of flavonoids showed inhibition against Klebsiella pneumoniae strains. In order to better understand its inhibitory mechanism on strain growth, we used both Rutin and Luteolin as treatments to incubate K. pneumoniae ATCC700603 strain. After incubation for 4 hours, the homogenous and differential effects of two different flavonoids on the growth of K. pneumoniae were evaluated. The integrated metabolomic and transcriptomic analysis was performed. The expression levels of 5,483 genes and the contents of 882 metabolites were measured. The differentially expressed genes (DEGs) and metabolites (DEMs) were screened and analyzed. The correlation between DEGs and DEMs were also studied. Our results showed that Rutin could inhibit the strain growth by changing metabolic pathways and ABC transporters pathways. Our study also revealed FU841_RS17580 and FU841_RS19145 as functional genes that played vital roles in the strain growth.

Antimicrobial peptides (AMPs) are a promising alternative to antibiotics to combat drug resistance in pathogenic bacteria. However, the development of AMPs with high potency and specificity remains a challenge, and new tools to evaluate antimicrobial activity are needed to accelerate the discovery process. As a step toward direct prediction of the experimental minimum inhibitory concentration (MIC) of AMPs, we proposed MBC-Attention, a combination of a multi-branch CNN architecture and attention mechanism. Using a curated dataset of 3929 AMP against Escherichia coli, the optimal MBC-Attention model achieved an average Pearson correlation coefficient of 0.775 and an RMSE of 0.533 (log μM) in three independent tests of 393 sequences each. This results in a 5–12% improvement in PCC and 7–13% improvement in RMSE compared with RF and SVM models. Ablation studies confirmed that both attention mechanisms contributed to performance improvement.

The topography and chemical composition modification of the titanium (Ti) implants play a decisive role in improving biocompatibility and bioactivity, accelerating osseointegration, and, thus, determining clinical success. In spite of the development of surface modification strategies, bacterial contamination is a common cause of failure. The use of systemic antibiotic therapy does not guarantee action at the contaminated site. In this work, we proposed a surface treatment for Ti implant that aim to improve its osseointegration and reduce bacterial colonization in surgery site due to local release of antibiotic. The Ti disks were hydrothermally treated with 3M NaOH solution to form a nanostructured layer of titanate on the Ti surface. Metronidazole was impregnated on these nanostructured surfaces to allow its local release. The samples were coated with poly(vinyl alcohol) - PVA films with different thickness to evaluate a possible control of drug release. Gamma irradiation was used to crosslink the polymer chains leading to a hydrogel layer formation and to sterilize the samples. The samples were characterized by XRD, SEM, FTIR, contact angle measurements, “in vitro” bioactivity, and drug release analysis. The alkaline hydrothermal treatment successfully produced intertwined, web-like nanostructures on the Ti surface, providing wettability and bioactivity to Ti samples (Ti+TTNT samples). Metronidazole was successfully loaded and released from Ti+TTNT samples coated or not with PVA. Although the polymeric film acted as a physical barrier to drug delivery, all groups reached the minimum inhibitory concentration for anaerobic bacteria. Thus, the surface modification method presented is a potential approach to improve the osseointegration of the Ti implant and to associate local drug delivery to dental implants, preventing early infections and bone failure.

Plantago major L. is a worldwide available plant that has been used traditionally for several medical application due to its properties such as wound healing, anti-inflammatory, antimicrobial etc. This work aimed to develop and evaluate nanostructured PCL electrospun dressing with P. major extract encapsulated in nanofibers for application in wound healing. The extract from leaves was obtained by extraction in a mixture of water:ethanol= 1:1 of the freeze-dried extract presented a minimum inhibitory concentration (MIC) for Staphylococcus Aureus susceptible and resistant to methicillin of 5.3 mg/mL, a high antioxidant capacity, but a low content of total flavonoids. Electrospun mats without defects were successfully produced using two P. major extract concentrations based on MIC value. The extract incorporation in PCL nanofibers was confirmed by FTIR and contact angle measurements. The PCL/P. major extract was evaluated by DSC and TGA demonstrating that incorporation of the extract decreases the thermal stability of the mats as well as the degree of crystallinity of PCL-based fibers. The P. major extract incorporation on electrospun mats produced a significant swelling degree (more than 400%) and increased the capacity of adsorbing wound exudates and moisture, important characteristics for skin healing. The extract-controlled release evaluated by in vitro study in PBS (pH, 7.4) shows that P. major extract delivery from the mats occurs in the first 24 h, demonstrating their potential capacity to be used in wound healing.

The human serotonin transporter (hSERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process plays an important role in depression. In addition to substrate serotonin, hSERT is also the target of drugs of abuse like cocaine and clinically used antidepressants such as escitalopram and paroxetine. To date, few studies attempt to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of hSERT. The high-resolution X-ray structure of hSERT resolved recently enables us to theoretically study the unbinding of the above four ligands against the S1 or S2 site of hSERT, by means of molecular docking, molecular dynamics (MD) and potential of mean force (PMF) simulations. We proved that for either the S1 or S2 site, the other three ligands (cocaine, escitalopram and paroxetine) are much more favorable than the original substrate serotonin, whether in kinetics along the unbinding pathways or in thermodynamics at the equilibrium states. Furthermore, the S1 site is much more favorable than the S2 site, for each ligand. Interestingly, inspection revealed that there are ~ 3Å lengths between the allosteric site of serotonin and cocaine, and an unseen un-binding pathway for escitalopram at the S1 site except for verification of the broadest trail.

Mental health issues can have significant impacts on individuals and communities and hence on social sustainability. There are several challenges facing mental health treatment, however, more important is to remove the root causes of mental illnesses because doing so can help prevent mental health problems from occurring or recurring. This requires a holistic approach to understanding mental health issues that are missing from the existing research. Mental health should be understood in the context of social and environmental factors. More research and awareness are needed, as well as interventions to address root causes. The effectiveness and risks of medications should also be studied. This paper proposes a big data and machine learning-based approach for the automatic discovery of parameters related to mental health from Twitter data. The parameters are discovered from three different perspectives, Drugs & Treatments, Causes & Effects, and Drug Abuse. We used Twitter to gather 1,048,575 tweets in Arabic about psychological health in Saudi Arabia. We built a big data machine learning software tool for this work. A total of 52 parameters were discovered for all three perspectives. We defined 6 macro-parameters (Diseases & Disorders, Individual Factors, Social & Economic Factors, Treatment Options, Treatment Limitations, and Drug Abuse) to aggregate related parameters. We provide a comprehensive account of mental health, causes, medicines and treatments, mental health and drug effects, and drug abuse, as seen on Twitter, discussed by the public and health professionals. Moreover, we identify their associations with different drugs. The work will open new directions for social media-based identification of drug use and abuse for mental health, as well as other micro and macro factors related to mental health. The methodology can be extended to other diseases and provides a potential for discovering evidence for forensics toxicology from social and digital media.

Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides’ fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest methods to analyze the lipids in biological samples. Finally, we discuss the drug development strategies focusing on the ceramide synthases and ceramides as future therapeutic approaches in cancer therapy.

Lyme disease (LD) is a tick-transmitted infection caused by Borrelia burgdorferi sensu lato species which includes B. burgdorferi, B. afzelii, and B. garinii. The majority of patients with early LD can be cured by standard treatment, yet some still suffer from post-treatment Lyme disease syndrome (PTLDS). The presence of Borrelia persisters has been proposed as a contributing factor, which cannnot be completely killed by the currently used antibiotics for Lyme disease. Finding new pharmaceuticals targeting Borrelia persisters is crucial in developing more effective treatment. Here, we first confirmed the existence of persisters in cultures of B. garinii and B. afzelii and then conducted high-throughput screening of a custom drug library against persister-rich stationary-phase cultures of B. garinii and B. afzelii. Among 2427 compounds screened, hypocrellin A (HA), anthracycline class of drugs, and topical antibiotics along with some other natural compounds were identified to have strong potential in killing persisters of B. garinii and B. afzelii. HA was the most active anti-Borrelia compound, capable of eradicating stationary-phase Borrelia persisters, in particular when combined with doxycycline and/or ceftriaxone. Liposoluble antioxidant vitamin E was found to antagonize the activity of HA, indicating HA’s target is the cell membrane where HA-triggered reactive oxygen species (ROS) generation took place in the presence of light. HA was found to have distinct bactericidal activity against Borrelia species but had poor or no activity against Gram-positive and Gram-negative bacteria. Identification of the above-mentioned drug candidates may help to develop more effective therapies for LD.

Magnetic Nanoparticles (MNPs) is a promising technique to cure brain diseases. On the one hand, by serving as drug carriers, they can bypass the blood-brain barrier and deliver drug molecules to the brain parenchyma; on the other hand, their transport trajectory can be manipulated by applying an external magnetic field. However, due to the complex microstructure of brain tissues, e.g. the anisotropy of white matter (WM), how to achieve desired drug distribution patterns, e.g. uniform distribution, by tuning the drug delivery system is largely unknown. Here, in this study, by adopting a mathematical model capable of capturing the diffusion trajectories of MNPs in the microstructures, we systematically investigated the effects of key parameters in the MNPs delivery system on the equivalent diffusion coefficient of MNPs in the microenvironment of brain WM. The results show that uniform distribution of MNPs in anisotropic tissues can be achieved by adjusting the particle size and magnetic field. We have not only obtained a deeper understanding on how to optimise the MNPs delivery system, it can also be anticipated that an improved mathematical model could even help to achieve complex drug distribution patterns in the complicated brain environment by designing an appropriate combination of the key parameters.

One of the most frequent brain diseases, Alzheimer's is defined by poor cognitive function brought on by the build-up of Beta Amyloid plaques and the gradual death of neurons. Glucose metabolism and the development of amyloid plaques are being studied together. Under physiologically normal circumstances, glucose is the primary substrate for the adult human brain. The prodromal phases of AD are significantly influenced by glucose hypometabolism. Hypometabolism of glucose in the brain is a clear sign of mitochondrial dysfunction and bioenergetic system impairment. By regulating energy synthesis and cell death, mitochondria play a crucial role in the functioning of cells. Increased formation of reactive oxygen species (ROS) and oxidative stress are a result of mitochondrial dysfunction, which also accelerates the development of Alzheimer's disease. For the maintenance of balance, autophagy is crucial because it selectively destroys damaged mitochondria. AD affects this route for mitochondrial breakdown. Targeting specific mitochondrial ligands by interventions along this pathway might be a useful therapeutic approach. Due to a number of biological obstacles, this method has significant limitations. As a result, many nanocarriers have been created to improve drug delivery effectiveness. All potential nanotechnology-based treatments for AD have been examined in this study, with a particular emphasis on medication delivery to the mitochondria

This study examines demographic factors which may influence opinions concerning medical students’ self-care and substance use behaviors as a means of providing insights into how future doctors view these issues compared to Australian doctors and members of the public. We conducted national, multicenter, prospective, on-line cross-sectional surveys using hypothetical scenarios to three cohorts- Australian medical students, medical doctors, and the public. Participants’ responses were compared for the different contextual variables within the scenarios and the participants’ demographic characteristics. In total 2,602 medical students, 809 doctors and 503 members of the public participated. Compared with doctors and the public, medical students were least tolerant of alcohol intoxication, and most tolerant of using stimulants to assist with study, and cannabis for anxiety. Doctor respondents more often aligned with the public’s opinions on the acceptability of the medical students’ behaviors. Although opinions are not equivalent to behaviour, Australian students’ views on the acceptability for cannabis to help manage anxiety, and inappropriate use of prescription-only drugs are concerning; these future doctors will be responsible for prescribing drugs and managing patients with substance abuse problems. However, if current Australian medical student’s opinions on alcohol misuse persist, one of the commonest substance addictions amongst doctors may decrease in future.

In this work, polyacrylic acid-functionalized MCM-41 was synthesized, which was further interacted with calcium ions, to realize enhanced pH-responsive nanocarrier for sustained drug release. First, mesoporous silica nanoparticles (MSNs) were prepared by the sol-gel method. Afterward, (3-trimethoxysilyl)propyl methacrylate (TMSPM) modified surface was prepared by using the post-grafting method, then polymerization of acrylic acid was proceeded. After adding calcium chloride solution, polyacrylic acid-functionalized MSNs with calcium-carboxyl ionic bonds in the polymeric layer, which can prevent the cargo from leaking out of the mesopore, were prepared. The structure and morphology of the modified nanoparticles (PAA-MSNs) were characterized by X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), and N2 adsorption-desorption analysis, etc. The controlled release of guest molecules was studied by using 5-fluorouracil (5-FU). The drug molecules-incorporated nanoparticles showed different releasing rates under different pH conditions. It is considered that our current materials have the potential as pH-responsive targeted nanocarriers in the field of medical treatment.

The low water solubility of any pharmacoactive molecules limits their pharmacological potential but the solubility parameter cannot compromise, so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, the oral dosage forms cover more than 50 %, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry screening programs identified that around 40% of new chemical entities (N.C.E.s) face various difficulties at the formulation and development step. These pharmaceuticals are attributed to their less solubility and bioavailability. The bioavailability and drug solubility enhancement are significant challenges in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibits poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of the poorly water-soluble drug, for example, complexation of active molecules, utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelles preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, by some appropriate research reports.

Lipid nanoparticles have an interesting part of drug delivery system. In this study, the modification of the convention nano-lipid based soybean lecithin was demonstrated. Ginger oil derived Zingiber officinale was used along with lecithin, cholesterol and span 80 to fabricate nano-lipid (GL nano-lipid) using thin-film method. Through TEM and confocal microscope, GL nano-lipid exposes the liposome- like morphology. The average size of the resultant nanoparticles was 249.1nm with monodistribution (PDI= 0.021). The ζ-potential of GL nano-lipid was negative as similar to as prepared nano-lipid based lecithin. GL nano-lipid express the highly stable over 60 days of storage at room temperature in term of size, ζ-potential. A shift of pH value from alkaline to acid was detected in lecithin nano-lipid, while with the incorporation of ginger oil, pH value of nano-lipid dispersion was around 7.0. Furthermore, due to the rich of shogaol-6 and other active compounds in ginger oil, the GL nano-lipid is endowed with intrinsic antibacterial feature. In addition, the sulforhodamine B (SRB) assay and live/dead imaging revealed the excellent biocompatibility of GL nano-lipid. Notably, GL nano-lipid was capable to carry the hydrophobic agents as curcumin and perform a pH-dependent release profile. A subsequent characterization are a suitable potential for drug delivery system.

The adaptive immune system in vertebrates comes in two flavors. Historically, adaptive immunity focused on the study of immunoglobulins (also referred to as Ig-based antibodies herein); more recently, jawless vertebrates were found to use an entirely different class of proteins for their adaptive immunesystem. Specifically, these organisms express variable lymphocyte receptors (so called VLR antibodies) that create diversity based on the rearrangement of leucine-rich repeats. Meanwhile, various, naturally occurring repeat motifs have been used as building blocks for the design of artificial binding scaffolds which, among others, include designed ankyrin repeat proteins (DARPins). Such binding scaffolds are also referred to as non-Ig-based antibodies or non-Ig scaffolds herein). DARPins display several benefits such as a low molecular weight (~15 kDa), high thermal stability, high specificity and affinity, versatility (e.g., in terms of valency and multi-specificity), speedy preclinical development, low production costs and, thus, bear the potential to not only complement existing therapeutic Ig-based antibodies but also open up novel therapeutic strategies. The first generation DARPin therapeutic abicipar pegol has completed two Phase III studies in 2020 while several other DARPin drug candidates are currently undergoing clinical validation. Most recently, the rapid development of tri-specific SARSCoV-2 DARPin therapeutics showcases the immense potential of recombinant repeat proteins in adopting quickly e.g., new forms of target neutralization that a single Ig-based antibody cannot afford. Here, we highlight the design principles of repeat proteins in general and summarize in detail the continuous advancements of the DARPin scaffold that made it one of the most promising antibody mimetics to date. This review provides an overview of current and emerging applications of DARPins as both a research tool and therapeutic drug that can match or even surpass Ig-based antibody applications.

Rheumatoid arthritis (RA) is a chronic, systemic, abnormal inflammatory immune response. It is characterized by the involvement of the synovium and multiple organs and the destruction of joints and articular cartilage. Over the past 30 years, several promising novel compounds and antibodies have been developed for the treatment of RA. The introduction of new drugs and precision medicine for all forms of RA raises several issues related to access to novel treatments by patients, optimal regimen selection, cost-effectiveness, prognosis monitoring and outcome surveillance, particularly with regarding to the development of low drug response rates, drug resistance and adverse side effects. Tremendous attention has been given to the identification of optimized drug combinations for the treatment of RA, particularly in early high-risk vulnerable and early individuals. Addressing these issues requires novel therapeutic approaches with new mechanisms and the establishment of accurate guidelines for drug selection, drug recombination, and non-chemical therapeutic efforts. In this study, we reviewed the most exciting recently established or ongoing novel drugs and methods according to the clinical trial database maintained by the United States National Library of Medicine and discussed the trends in RA drug development and challenges in the treatment, providing a reference significant for the accurate treatment of RA and the research direction in the future.

The aim of this review is to present the Quality by Design (QbD) model as a suitable methodology to perform research in the academic Costa Rican institutions that teach Pharmacy. Pubmed, Science Direct, and Google Scholar databases were screened for original and review papers, as well as short communications published not more than 10 years ago. Publications were screened by title and abstract. Relevant references were used to develop three important themes: The University’s Research Model in Costa Rica, QbD Model, and QbD as a Research Methodology for Industrial Pharmacy in the Academy. In this sense, the QbD model is a great methodology for carrying out research projects regarding Pharmaceutical Sciences but especially for Drug Development. Academic research based on this model enables training and developing practical, scientific, and leadership skills in pharmacy students. The generated knowledge can be shared in the classrooms, which represents an ideal environment to communicate their research results and to foster collaborative work between researchers, professors, and students. The participation of all these actors allows a high level of commitment to research work, which benefits the scientific advancement of the university and society. It is important to visualize the student body as potential key actors in the research process, encouraging in them the desire to become trained scientific researchers who want to pursue a career in the academy, giving continuity to it.

Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by five dry powder inhalers under realistic inhalation and exhalation conditions. The active respiratory system model (xPULM™) was used as a model of the human respiratory system and to simulate a patient undergoing inhalation therapy. A mechanical upper airway model was developed, manufactured and introduced as a part of the xPULM™ to represent the human upper respiratory tract with high fidelity. Integration of optical aerosol spectrometry technique into the setup allowed for evaluation of pharmaceutical aerosols. The results show that the upper airway model increases the resistance of the overall system and act as a filter for bigger particles (>3 µm). Furthermore, there is a significant difference (p < 0.05) in mean particle diameter between inhaled and exhaled particles with the majority of the particles depositing in the lung. The minimum deposition is reached for particle size of 0.5 µm. The mean particle number concentrations exhaled are 2.94% (BreezHaler®), 2.66% (Diskus®), 10.24% (Ellipta®) 2.13% (HandiHaler®) and 6.22% (Turbohaler®). In conclusion, the xPULM™ active respiratory system model is a viable option for studying interactions of pharmaceutical aerosols and the respiratory tract in terms of applicable deposition mechanisms. The model can support the reduction of animal experimentation in aerosol research and provide an alternative to experiments with human subjects.

Virtual screening - predicting which compounds within a specified compound library bind to a target molecule, typically a protein - is a fundamental task in the field of drug discovery. Doing virtual screening well provides tangible practical benefits, including reduced drug development costs, faster time to therapeutic viability, and fewer unforeseen side effects. As with most applied computational tasks, the algorithms currently used to perform virtual screening feature inherent tradeoffs between speed and accuracy. Furthermore, even theoretically rigorous, computationally intensive methods may fail to account for important effects relevant to whether a given compound will ultimately be usable as a drug. Here we investigate the virtual screening performance of the recently released Gnina molecular docking software, which uses deep convolutional networks to score protein-ligand structures. We find, on average, that Gnina outperforms conventional empirical scoring. The default scoring in Gnina outperforms the empirical AutoDock Vina scoring function on 89 of the 117 targets of the DUD-E and LIT-PCBA virtual screening benchmarks with a median 1% early enrichment factor that is more than twice that of Vina. However, we also find that issues of bias linger in these sets, even when not used directly to train models, and this bias obfuscates to what extent machine learning models are achieving their performance through a sophisticated interpretation of molecular interactions versus fitting to non-informative simplistic property distributions.

Chitosan arouses large interest due to its properties and possible applications. Every year the number of publications and patents based on this polymer increases. Chitosan exhibits poor solubility in neutral and basic media limiting its use in such conditions. Another serious obstacle is directly related to its natural origin. Chitosan is not a single polymer with a defined structure but a family of molecules with differences in their composition, size, and monomer distribution. These properties have a fundamental effect on the biological and technological performance of the polymer. Moreover, some of the biological properties claimed are discrete. In this review, we discuss how chitosan chemistry can solve the problems related to its poor solubility and can boost the polymer properties. We focus on some of the main biological properties of chitosan and the relationship with the physicochemical properties of the polymer. Then, we visit two polymer applications related to green processes: the use of chitosan in the green synthesis of metallic na-noparticles and its use as support in biocatalyst. Finally, we briefly describe how making use of the technological properties of chitosan it is possible to develop a variety of systems for drug delivery

Melatonin is a hormone used for treating several disorders. However, its oral administration is problematic due to the variable absorption and extensive first-pass metabolism. The topical application of this drug does not present these disadvantages and can be used for therapeutic and skin protection purposes. The adsorption and release of melatonin in the montmorillonite clay was investigated experimentally and theoretically. The drug-clay interaction products were prepared and characterized, showing a modified and improved diffusion and release of melatonin. The crystal structure and spectroscopic properties of melatonin and melatonin-water-mineral materials were studied by molecular modeling, finding that the adsorption of this drug is energetically favourable, and the results were consistent with the experimental data. Ab initio molecular dynamics simulations with the metadynamics methodology showed the release of melatonin from the confined interlayer nanospace of montmorillonite to the liquid bulk water with a 20 kcal/mol free energy barrier.

In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictory inhibitory activities falling within the low nanomolar concentration range.

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 150 million individuals and killed 3 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccines development, COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

In this work, we designed and fabricated a multifunctional nanocomposite system which consists of chitosan, raspberry-like silver nanoparticles and graphene oxide. Room temperature atmospheric pressure microplasma (RT-APM) process provides a rapid, facile, and environment-friendly method for introducing silver nanoparticles into the composite system. By loading different drugs onto the polymer matrix and/or graphene oxide, our composite can achieve a pH controlled dual drug release with release profile specific to the drugs used. In addition to its strong antibacterial ability against E. coli and S. aureus, our composite also demonstrates excellent photothermal conversion effect under irradiation of near infrared lasers. These unique functionalities point to it’s the potential of nanocomposite system in multiple applications areas such as multimodal therapeutics in healthcare, water treatment, and anti-microbial, etc.

Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephrotoxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients' recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostructures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010-2020. Numerous publications have been reviewed to provide an essential summation of the nanopolymer types and their essential properties, mechanisms towards efficient drug delivery, as well as active targeting stimuli-responsive strategies that are currently utilized in the doxorubicin transportation field.

The morbidity and mortality caused by invasive fungal infections is increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is an effective way of expanding the application of existing drugs. In the last years, various existing drugs have been shown to be useful in the prevention and treatment of the invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up to date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field.

The study aimed to assess the prevalence and correlates of hazardous, harmful or dependent alcohol use (HHDA) and drug use among persons 15 years and older in South Africa. In a national cross-sectional 2017 survey, 39,210 persons 15 years and older (Median=34 years) responded to a questionnaire on substance and health variables. Logistic regression was used to assess the determinants of HHDA and any drug use. Results indicate that (10.3%) engaged HHDA, 16.5% among males and 4.6% among females, and past 3-month drug use was 8.6%, 13.3% among males and 4.1% among females. In adjusted logistic regression analysis, among men, middle age (25-34 year olds), higher education, urban residence, drug use, and psychological distress were positively and Indian or Asian and White population groups were negatively associated with HHDA. Among women, middle age (25-34 year olds), Coloureds, residing on rural farms and urban areas, drug use and psychological distress were positively and older age (55 years and older), and Indians or Asians were negatively associated with HHDA. In adjusted logistic regression analysis, among men, having Grade 8-11 education, Coloureds, being unemployed, and HHDA were positively and middle and older age (25 years and older) and being a student or learner were negatively associated with past 3-month any drug use. Among women, Coloureds, Indians or Asians, and HHDA were positively and older age (45 years and older) was negatively associated with past 3-month and drug use. About one in ten participants engaged HHDA and any drug use, and several sociodemographic and health indicators were identified associated with HHDA and any drug use.

Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.

Community-level mass treatment with azithromycin has been associated with a mortality benefit in children. However, antibiotic exposures result in disruption of the gut microbiota and repeated exposures may reduce recovery of the gut flora. We conducted a nested cohort study to examine associations between mass drug administration (MDA) with azithromycin and the gut microbiota of rural Malawian children aged between 1-59 months. Fecal samples were collected from the children prior to treatment and 6 months after two or four biannual rounds of azithromycin treatment. DNA was extracted from fecal samples and V4-16S rRNA sequencing used to characterize the gut microbiota. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. There were no associations between azithromycin treatment and changes in alpha diversity, however, four biannual rounds of treatment were associated with increased abundance of Prevotella. The lack of significant changes in gut microbiota after four biannual treatments supports the use of mass azithromycin treatment to reduce mortality in children living in low- and middle-income settings.

Polyhydroxyalkanoate (PHA) co-polymers show relatively higher in vivo degradation rate compared to other PHAs thus they received a great deal of attention for a wide range of medical applications. Nanoparticles (NPs) loaded with poorly water soluble anticancer drug docetaxel (DCX) were produced using poly 3-hydroxybutyrate-co-4-hydroxybutyrate, P(3HB-co-4HB), co-polymers biosynthesised from Cupriavidus sp. USMAA1020 isolated from Malaysian environment. Three co-polymers with different molar proportions of 4-hydroxybutirate (4HB) were used: 16% (PHB16), 30% (PHB30) and 70% (PHB70) 4HB-containing P(3HB-co-4HB). Blank and DCX loaded nanoparticles were then characterized for their size and size distribution, surface charge, encapsulation efficiency and drug release. Pre-formulation studies showed that an optimised formulation could be achieved through the emulsification/solvent evaporation method using PHB70 with the addition of 1.0% PVA, as stabilizer and 0.03% VitE-TPGS, as surfactant. DCX-loaded PHB70 nanoparticles (DCX-PHB70) gave the desired particle size distribution in term of average particles sizes around 150 nm and narrow particle size distribution (PDI below 0.100). The encapsulation efficiencies result showed that at 30% w/w drug-to-polymer ratio: DCX- PHB16 NPs were able to encapsulate up to 42% of DCX; DCX-PHB30 NPs encapsulated up to 46% of DCX and DCX-PHB70 NPs encapsulated up to 50% of DCX within the nanoparticles system. Approximately 60% of DCX was released from the DCX-PHB70 NPs within 7 days for 5%, 10% and 20% of drug to polymer ratio while for the 30% and 40% drug to polymer ratios, an almost complete drug release (98%) after 7 days of incubation was observed.

Background: Extraintestinal pathogenic Escherichia coli (ExPEC) is the most common cause of urinary tract infections (UTIs). They are often multidrug-resistant (MDR), making them challenging to treat. Additionally, virulence mechanisms as biofilm formation are associated with persistent UTIs. Aims: To reveal a possible association between patients’ risk factors and UTIs caused by MDR or biofilm-forming ExPECs and characterize ExPECs causing asymptomatic bacteriuria, community- (CA), or hospital-acquired (HA) UTIs in hospitalized patients in Brazil. Methods: Bacterial DNA was extracted from the urine of 63 hospitalized patients and sequenced using short-read sequencing. Antibiotic susceptibility was evaluated using VITEK-2, and the biofilm-forming, adhesion, and invasion abilities were quantitatively assessed. Results: Antibiotic resistance rates were high, and the majority of UTIs were complicated CA-UTIs. Most MDR- and ESBL-producing E. coli isolates belonged to high-risk lineages and were associated with UTIs in patients with comorbidities and over 60 years of age. The mortality rate of patients infected with MDR-isolates was higher than of those infected with non-MDR isolates. Most isolates were biofilm-forming, but no association with patients’ risk factors was found. Conclusions: Complicated UTIs caused by MDR- and biofilm-forming bacteria are frequently found in hospitalized patients in Brazil suffering from a UTI and are associated with high-risk lineages.

Despite the surge in the research of cannabis chemistry and its biological and medical activity, only a few cannabis-based pharmaceutical-grade drugs have been developed and marketed to date. Not many of these drugs are Food and Drug Administration (FDA)-approved and some are still going through regulation processes. Active compounds including cannabinergic compounds (i.e., molecules targeted to modulate the endocannabinoid system) or analogs of phytocannabinoids (cannabinoids produced by the plant) may be developed into single-molecule drugs. However, since in many cases treatment with whole plant extract is preferred over treatment with a single purified molecule, some more recently developed cannabis-derived drugs contain several molecules. Different combinations of active plant ingredients (API) from cannabis with proven synergy may be identified and developed as drugs to treat different medical conditions. However, possible negative effects between cannabis compounds should also be considered, as well as the effect of the cannabis treatment on the endocannabinoid system. FDA registration of single, few or multiple molecules as drugs is a challenging process and certain considerations that should be reviewed in this process, including issues of drug-drug interactions, are also discussed here.

Objectives: The aim of this study was to assess the knowledge, attitude and practice of healthcare professionals regarding adverse drug reaction [ADR] monitoring and pharmacovigilance [PV] in India. Materials and Methods: It was a questionnaire based cross sectional observational study. Data was collected with the help of data collection Google form that included the demographics and twenty two survey based questions. Data were analysed by using Microsoft Excel sheet, further analysed for results, including frequency, percentage, mean and standard deviation. Result: The questionnaire was filled by two hundred ten healthcare professionals in which 52.9 % were male and 47.10% of female. Most of the respondents were pharm d students (50.47%). Out of the total 91.4% responded to the definition of pharmacovigilance correctly. 87.6% participants said all ADR should be reported. 86.20% participants think Pharmacovigilance should be taught in detail to healthcare professionals. Most of the respondents (43.8%) always informed the patients about ADR while prescribing the medicines. Conclusion: Study revealed most of the participants have good knowledge about ADR and pharmacovigilance. Difficult to decide whether ADR occur or not and extra work load being major factors responsible for under reporting.

Barcode medication administration (BCMA) is advocated as a technology that reduces medication errors relating to incorrect patient identity, drug or dose. Little is known, however, about the impact it has on nursing workflow. Our aim was to investigate the impact of BCMA on nursing activity and workflow. A comparative study was conducted on two similar surgical wards within an acute UK hospital. We observed nurses during drug rounds on a non-BCMA ward and a BCMA ward. Data were collected on drug round duration, timeliness of medication administration, patient identification, medication verification and general workflow patterns. BCMA appears not to alter drug round duration, although it may reduce the administration time per dose. Workflow was streamlined, with a reduction in use of the medicines room. The rate of patient identification increased from 74% (of 47) patients to 100% (of 43), with 95% of 255 scannable medication doses verified using the system. This study suggests that BCMA does not affect drug round duration; further research is required to determine the impact it has on timeliness of medication administration. There was reduced variability in the medication administration workflow of nurses, along with an increased patient identification rate and high medication scan rate, representing potential benefits to patient safety.

During the current COVID-19 pandemic caused by SARS-CoV-2, clinicians and scientists are working assiduously to unravel its pathophysiology and find effective treatments. An impressive number of papers has been published on SARS-CoV-2, exposing the complexity of the disease, the tendency of scientists to form hypotheses within their area of expertise, and the lack of orchestration of research. Hypotheses and research findings mainly complement each other, though sometimes controversies can be discerned among various theories and study results. Our overview aims to portray the ‘big picture’ of COVID-19, visualising the interwovenness of different pathophysiological pathways, with a focus on cytokine-induced pathology, the sequelae of ACE2 downregulation, and thrombosis associated with microvascular injury. It aids in overseeing the effects of repurposed drugs on intended targets, but also alerts to the (adverse) effects on interacting pathways. The overview shows how comorbidities probably increase susceptibility to (severe) COVID-19 and provides the possible pathophysiological origin of signs, symptoms, and biochemical abnormalities.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding, and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are freely available online, either through web applications or public code repositories.

The new pandemic coronavirus disease 2019 (COVID-19) is a worldwide threatening health issue. Early progression of this disease starts in the lung airways with an exaggerated inflammation, triggered by the viral infection and characterized by a “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs, Thalidomide, a historically emblematic controversial molecule that harbors an FDA approval for treating Erythema Nodosum Leprosum (ENL) and multiple myeloma (MM). Based on only one-case report of positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Conversely, the absence of any substantial, promising evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases might cause a significant obstacle for carrying on clinical studies. In this review, we will discuss the theoretical effectiveness of this drug in attenuating inflammatory complications that are encountered in patients with COVID-19 while pinpointing the lack of evidence that is needed to move forward with this drug.

There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. In mouse, knockout of tmprss2 led to protection against SARS-CoV-1 with no deleterious phenotypes, and in human populations genetic loss of TMPRSS2 does not appear to be selected against. Here, we mined publicly available gene expression data to identify several compounds that down-regulate TMPRSS2. Recognizing the need for immediately available treatment options, we focused on FDA-approved drugs. We found 20 independent studies that implicate estrogenic and androgenic compounds as transcriptional modulators of TMPRSS2, suggesting these classes of drugs may be promising therapeutic candidates for clinical testing and observational studies of COVID-19. We also note that expression of TMPRSS2 is highly variable and skewed in humans, with a minority of individuals having extremely high expression. Combined with literature showing that inhibition of TMPRSS2 protease activity reduces SARS-CoV-2 viral entry in human cells, our results raise the hypothesis that modulation of TMPRSS2 expression is a promising therapeutic avenue for COVID-19.

The high mutation rate of human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance from the development of vaccines to long-lasting drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10-5 - 10-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the location of these mutations can be further analyzed for their potential allosteric effects to reveal potentially new inhibitors with different pharmacodynamics that can be used to circumvent fast occurring HIV drug resistance. Given that HIV is one of the fastest mutating viruses, it is a good model for comprehensive study of its mutations that can give rise to much horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

Ubiquitin-specific protease 14 (USP14) is a member of the Deubiquitinating enzymes (DUBs) involved in disrupting the regulation of the ubiquitin-proteasome system, responsible for the degradation of impaired and misfolded proteins which is an essential mechanism in eukaryotic cells. The involvement of USP14 in cancer progression and neurodegenerative disorders has been reported. Thereof USP14 is a prime therapeutic target; hence, designing efficacious inhibitors of USP14 is central in curbing these conditions. Herein, we relied on structural bioinformatics methods incorporating molecular docking, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), Molecular dynamics simulation (MD simulation) and ADME to identify potential allosteric USP14 inhibitors. A library of over 733 compounds from the PubChem repository with >90% match to the IU1 chemical structure was screened in a multi-step framework to attain prospective drug-like inhibitors. Two potential lead compounds (CID 43013232 and CID 112370349) were shown to record better binding affinity compared to IU1, but with subtle difference to IU1-47, a 10-fold potent compound when compared to IU1. The stability of the lead molecules complexed with USP14 was studied via MD simulations. The molecules were found to be stable within the binding site throughout the 50ns simulation time. Moreover, the protein-ligand interactions across the simulation run time suggest Phe331, Tyr476, and Gln197 as crucial residues for USP14 inhibition. Furthermore, in silico pharmacological evaluation revealed the lead compounds as pharmacological sound molecules. Overall, the methods deployed in this study revealed two novel candidates that may show selective inhibitory activity against USP14, which could be exploited to produce potent and harmless USP14 inhibitors.

Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Attenuation of virulence by QS inhibition could be an alternative and effective approach to control infections. Therefore, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. E-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs due to their higher binding affinity to LasR receptor (-7.53 to -10.32 kcal/mol compared to -7.43 kcal/mol of native ligands). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed good binding stability and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections.

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Re-purposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), human immunodeficiency virus 1 (HIV-1), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FluAV), niclosamide against HSV-2, brequinar against HIV-1, and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vivo tests.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered of adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline, dextromethorphan, and diltiazem when co-administered an oral drug cocktail. After 7-days of feeding with an ABO-containing diet, plasma concentrations of theophylline and chlorzoxazone were increased after oral administration of drug cocktail. The major CYP enzyme activities in liver and intestinal were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

In recent years, polyureas with dynamic hindered urea bonds (HUBs), as a class of promising biomedical polymers, have attracted attention as a benefit of their controlled hydrolytic property. The effect of the chemical structures on the properties of polyureas and their assemblies was rarely reported. In this study, four kinds of polyureas with different chemical groups have been synthesized, and the polyurea from cyclohexyl diisocyanate and tert-butyl diamine showed the fastest hydrolytic rate. The amphiphilic polyurea composed of hydrophobic cyclohexyl-tert-butyl polyurea and hydrophilic poly(ethylene glycol) was synthesized for controlled delivery of antitumor drug paclitaxel (PTX). The PTX-loaded PEGylated polyurea micelle more effectively entered into the murine breast cancer 4T1 cells and inhibited the corresponding tumor growth in vitro and in vivo. Therefore, the PEGylated polyurea with adjustable degradation might be a promising polymer matrix for drug delivery.

Mycobacteria are a large family of over 100 species, most of which do not cause diseases in humans. The majority of the mycobacterial species are referred to as nontuberculous mycobacteria (NTM), meaning they are not the causative agent of tuberculous (TB) or leprosy, i.e. Mycobacterium tuberculous complex and Mycobacterium leprae, respectively. The latter group is undoubtedly the most infamous, with TB infecting an estimated 10 million people and causing over 1.2 million deaths in 2017 alone (1). TB and leprosy also differ from NTM in that they are only transmitted from person to person and have no environmental reservoir, whereas NTM infections are commonly acquired from the environment (2) (3). It took until the 1950's for NTM to be recognised as a potential lung pathogen in people with underlying pulmonary disease and another 3 decades for NTM to be widely recognised by the medical community when NTM, particularly Mycobacterium avium complex (MAC) was recognised as the most common group of opportunistic pathogens in AIDS patients (4). This review focusses on an emerging NTM called Mycobacterium abscessus (M. abs). M. abs is a rapidly growing (RGM) NTM that is responsible for opportunistic pulmonary infections in patients with structural lung disorders such as cystic fibrosis (CF) and bronchiectasis (5), as well as a wide range of skin and soft tissue infections (SSTIs) in humans (6) (7). M. abs is a weakly staining Gram-positive mycobacterium that is neverand is, like other NTM, most often seen in soil and aquatic environments (8). The bacillus-shaped bacterium is 1-6µm long and 0.2-0.5µm in diameter, with curved ends and the presence of cord factor, or trehalose 6-6'-dimycolate, a glycolipid found in the cell wall of virulent species of mycobacteria that results in "serpentine cord" cell morphology is sometimes observed (8) (9). On solid growth medium, M. abs can display either a rough (M. abs-R) or smooth (M. abs-S) morphotype, with the rough morphotype displaying a more virulent phenotype than its smooth variant (10). The rough morphotype is characterised by irregular parallel filaments that form ridges across the colony, whereas a smooth morphology is displays a wet, smooth colony with no filaments or ridges (79). This morphology is driven by cell wall glycopeptidolipid (GPL); a loss of GPL results in the reversion from rough to smooth morphotype (80) (81). Moreover, it has been shown using human tissue culture models of infection that M. abs-R is able to persist and multiply within the host macrophage whereas M. abs-S lacks this capacity, hence its role in virulence (82). Like all other mycobacteria, M. abs are aerobic, non-motile and acid-fast organisms with a characteristically thick, lipid-rich cell wall that is hydrophobic. Due to their unusually impermeable, thick cell wall, mycobacteria are notoriously resistant to many antibiotics, disinfectants and heavy metals (11). When the genome of M. abs became available in 2009, elucidation of the resistance mechanisms of M. abs became an area of focus for scientific research, as the considerable threat it poses to public health became more apparent (12) (13) (14). In this review we will discuss how we came to understand the pathogen, how it is currently treated, as well as a discussion of drug resistance mechanisms and novel treatments currently in development.

Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. Approximately, 1.7 billion people are latently infected with TB and on reactivation many of these infections are drug resistant. As the current treatment is ineffective and diagnosis remains poor, millions of people have the potential to reactivate into active TB disease. The immune system seeks to control the TB infection by containing the bacteria in a granuloma, where it is exposed to stressful anaerobic and nutrient deprived conditions. It is thought to be these environmental conditions that trigger the NRP state. A number of in vitro models have been developed that mimic conditions within the granuloma to a lesser or greater extent. These different models have all been utilised for the research of different characteristics of NRP Mycobacterium tuberculosis, however their disparity in approach and physiological relevance often results in inconsistencies and a lack of consensus between studies. This review provides a summation of the different NRP models and a critical analysis of their respective advantages and disadvantages relating to their physiological relevance.

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

Molecular dynamics(MD) simulations are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals the solvent structure and preferential interaction sites (hot spots) on the protein surface. This information is largely transferable across all classes of protein ligands (from water to drugs) and can be used very effectively to understand ligand recognition and improve the predictive capability of well-established methods such as molecular docking. MD simulations for protein and drug or drug-like compounds are now being used but are still computationally expensive and can only be applied to specific cases. On the other hand, MDmix simulations can now be used in SBDD and we will describe the latest developments and implementations. We expect to see an increase in the application of these techniques to a plethora of protein targets to identify new drug candidates with the advent of new tools and faster computers.

Our study aims to implement a strategy to reduce the carbon steel corrosion rate in sulfuric acid solution, using an expired drug with adsorption affinity on the metal surface. To investigate the corrosion protection efficiency of an environmental friendly inhibitor, namely neomycin sulfate (NMS), the electrochemical measurements were applied on carbon steel immersed in 1.0 M H₂SO₄ solution with and without NMS. The protective layer formed on the steel surface was studied by atomic force microscopy (AFM). The potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) showed that the presence of the neomycin sulfate in acid solution leads to the decrease in corrosion current density (i_corr) and the increase of polarization resistance (R_p). The mixed mechanism between physical and chemical adsorption of NMS molecules on the steel surface was proposed according to the Langmuir adsorption isotherm. The Atomic Force Microscopy (AFM) indicated that the NMS molecules contributed to a protective layer formation by their adsorption on the steel surface. The AFM parameters such as: root-mean-square roughness (R_q); average roughness (R_a) and maximum peak to valley height (R_p-v) revealed that in the presence of NMS a smoother surface of carbon steel was obtained, compared to the steel surface corroded in sulfuric acid blank solution.

Chagas disease, caused by Trypanosoma cruzi, presents a significant challenge in global health due to the parasite's complex life cycle and its persistence in human tissues. In contrast, advances in treating Trypanosoma brucei infections, notably through the use of irreversible enzyme inhibitors like eflornithine, offer valuable insights into therapeutic strategies. This article explores how artificial intelligence (AI) can aid in identifying crucial metabolic and biochemical pathways in T. cruzi that could serve as targets for irreversible enzymatic inhibitors, drawing parallels to the successful inhibition of T. brucei’s ornithine decarboxylase. By employing AI for data mining, drug-target interaction prediction, pathway modelling, and drug repurposing, researchers can accelerate the discovery of novel treatments. We compare the biological and biochemical differences between T. cruzi and T. brucei, highlighting how AI can bridge the gap in drug discovery and offer new possibilities for Chagas disease treatment.

BackgroundThe present review summarizes the state-of-the-art of in silico methods and techniques that are the most useful in drug discovery, their relationship with data science, as well as the successful application of data science, machine learning (ML) and artificial intelligence (AI) applications. A meta-analysis of the various technologies available is furthermore proposed as a guideline for the non-expert, reader relative to the several subject areas is also discussed in this article. The scope of this meta-analysis is to rank the enlisted technologies by their field of applications and to depict the latter according to knowledge accessibility, from students to experts.Method The search strategy utilized for this review first produced a general collection of 900 papers without duplications, which were subsequently streamlined and divided into two independent collections: the top 300 most-cited papers of all time (since 2000) and the papers with the highest interest for a systematic review analysis (high-impact exciting papers). Results In Part 1, we discuss the most cited and quality 97 articles in these top 300 papers most relevant to the field of in silico drug discovery. The different disciplines are listed according to their industrial and economic incurred to society, independently from the “metric” results of how many new drug approvals (NDAs) each discipline has generated to date.ConclusionBig data, the ensemble of known items stored in publicly available databases, has improved our understanding of the many fates of a potential drug candidate during its development and even after its commercialization. Moreover, the combination of new screening techniques and “omics” with old drugs has led to a new paradigm in which the unknown knowledge of any biological molecule and its cellular structure, now plays an important role as a target for a series of yet-to-be-developed drugs: the chemical space. Furthermore, leveraging big data, data science, ML, and AI can revolutionize drug discovery by swiftly analyzing massive datasets, predicting efficacy and safety profiles, streamlining development, cutting costs, and boosting success rates for new drugs. AI also speeds up the search for promising drug candidates, advancing innovative therapies.

Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications, formed by reducing sugars and carbonyl products of their degradation. Resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied in respect of glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in dramatic suppression of primary seed metabolism, although secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.

Acute pancreatitis (AP) is a potentially fatal organ disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that generating urate and also responsible to produce reactive oxygen species (ROS). Considerable clinical and mechanical research has been conducted over many decades to explore the function of XO in AP and its promising therapeutic applications. Unquestionably, XO is a key part of starting and progressing AP by ROS production. Not fully known, though, are XO's many other functions besides ROS resource in both local and global processes, such as its role in cellular signaling or metabolism regulation. This review seeks to summarize the function of XO in AP pathophysiology by analyzing the inherent biological and chemical properties of XO, and lastly provide fresh concepts for future research.

The global burden of drug-resistant tuberculosis (DR-TB) continues to challenge healthcare systems worldwide. There is a critical need to tackle DR-TB by enhancing diagnostics and drug susceptibility testing (DST) capabilities, particularly for emerging DR-TB drugs. This endeavor is crucial to optimize the efficacy of new therapeutic regimens and prevent the resistance and overuse of these invaluable weapons. Despite this urgency, there remains a lack of comprehensive review on public health measures aimed at improving the diagnostics and DST capabilities. In this review, we outline strategies to enhance the capabilities especially tailored to address the challenges posed by resistance to new DR-TB drugs. We discuss the current landscape of DR-TB drugs, existing diagnostic and susceptibility testing methods, notable gaps and challenges in these methods, and explore strategies for ensuring fair access to DST while narrowing these disparities. The strategies include public health interventions aimed at strengthening laboratory infrastructure, workforce training, and quality assurance programs, technology transfer initiatives, involving drug developers in the DST development, establishing national or regional referral hubs, fostering collaboration and resources pooling with other infection control efforts, extending testing access in underserved areas through public-private partnerships, advocating for lowering costs or loans at low-interest, remote technical support, and implementing mandatory molecular surveillance monitoring. This review underscores the urgent need to enhance DST capacities for new DR-TB drugs and identifies opportunities for innovation and improvement. Assessing the extent of the global health impact of these measures is crucial to ensure their effectiveness in combating DR-TB.

The widespread clinical application of collagen sponge-delivered recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion currently remains limited. This limitation is due to potential adverse events associated with the rapid release of excessively high doses. This study aimed to investigate the impact of varying PGmatrix 3D Shape peptide hydrogel (PepGel) formulations on the release kinetics of rhBMP-2 in vitro. Three PepGel formulations were assessed: 1) 50% v/v PepGel, where solution A (crosslinking reagent) was mixed with solution B (synthetic peptides) and rhBMP-2 solution, making a 50% v/v (solution B volume/total volume) PepGel; 2) 67% v/v PepGel; 3) 80% v/v PepGel. Each sample was loaded with 12 µg of rhBMP-2 and incubated in PBS. The incubation solution containing released rhBMP-2 was collected at 1 hour, 6 hours, and 1, 2, 4, 7, 10, 14, and 21 days, and released rhBMP-2 was quantified using a BMP-2 ELISA kit. To explore how PepGel formulations influence rhBMP-2 release, the gel porosities, swelling ratios, and mechanical properties of the three PepGel formulations were quantitatively analyzed. The results showed that rhBMP-2 encapsulated with 50% v/v PepGel exhibited a sustained release over the 21-day experiment. Between days 7 and 21, the 50% v/v PepGel demonstrated significantly higher rhBMP-2 release rates compared to the 67% and 80% v/v formulations. Higher histological porosity of PepGel was significantly correlated with increased rhBMP-2 release rates. Conversely, the swelling ratio and elastic modulus at 1.0 Hz of the 50% v/v PepGel was significantly lower than that of the 67% and 80% v/v formulations. In conclusion, this study indicates that varying the formulation of crosslinked PepGel can control rhBMP-2 release rates in vitro by modulating gel porosity, swelling ratio, and mechanical properties. Encapsulation with 50% v/v PepGel offers a sustained rhBMP-2 release pattern, which could mitigate the adverse effects associated with burst release of rhBMP-2 if replicated in vivo.

Plants are continuously exposed to environmental challenges, including pollutants, pesticides, and heavy metals, collectively termed xenobiotics. These substances induce oxidative stress by generating reactive oxygen species (ROS), which can damage cellular components such as lipids, proteins, and nucleic acids. To counteract this, plants have evolved complex metabolic pathways involving both enzymatic and non-enzymatic mechanisms to detoxify and process these harmful compounds. Oxidative stress in plants primarily arises from the overproduction of ROS, including hydrogen peroxide (H2O2), superoxide anions (O2•−), singlet oxygen (1O2), and hydroxyl radicals (•OH), by-products of metabolic activities such as photosynthesis and respiration. Exposure to xenobiotics significantly elevates ROS levels, causing cellular damage and disrupting metabolism. Plants employ a robust antioxidant defense system featuring enzymatic antioxidants like catalase (CAT), superoxide dismutase (SOD), and various peroxidases (POD). These enzymes collaborate to scavenge ROS, minimizing their detrimental effects. Additionally, plants produce numerous non-enzymatic antioxidants, such as flavonoids, phenolic acids, vitamins C and E, which neutralize ROS and regenerate other antioxidants, providing comprehensive protection against oxidative stress. Xenobiotic metabolism in plants involves three phases: Phase I (modification), Phase II (conjugation), and Phase III (compartmentalization), facilitated by enzymes like cytochrome P450 monooxygenases (CYPs), transferases such as glutathione S-transferases (GSTs), and ATP-binding cassette (ABC) transporters. Plant secondary metabolites, including alkaloids, terpenoids, and flavonoids, significantly contribute to detoxification and antioxidant defense. Understanding these oxidative processes and xenobiotic metabolism pathways in plants is crucial, as it offers insights into developing plant-based strategies to mitigate environmental pollution impacts and improve human health through enhanced detoxification and antioxidant mechanisms, as we discuss in this review.

Self-assembling peptides have emerged as promising materials for pharmaceutical and biomedical applications due to their unique biocompatibility, biodegradability, and multifunctionality. These properties make them ideal candidates for addressing the challenges posed by biofilm-associated infections linked to implanted medical devices. Additionally, these peptides can form a variety of nanostructures, including nanotubes, hydrogels, and nanosheets, which facilitate targeted drug delivery and enhance therapeutic efficacy. The successful translation of peptide-based materials into clinical applications is exemplified by products like RADA16 and lanreotide, which improve therapeutic outcomes and enhance patient compliance. Furthermore, the development of peptidomimetics extends the versatility of these materials across various biomedical applications. This review highlights the potential of peptide-based biomaterials as effective tools in combating infections and as innovative platforms for drug delivery, emphasising their significance in modern medical therapies.

Interferons (IFNs) are cytokines involved in the immune response with synergistic regulatory action. They are therapeutics for various viral and proliferative conditions, with proven safety and efficacy. Their clinical application presents difficulties due to the molecules' size, degradation, and pharmacokinetics. We developed a controlled release system for viral respiratory tract infections. A core-shell nanoparticle was prototyped, which hydrolyzed the shell (polyvinylpyrrolidone), releasing the active ingredients IFN-α and IFN-γ. The core (chitosan) degraded slowly, with a controlled release of IFN-α. The primary and rapid effect of the combination of interferons ensured an antiviral and immunoregulatory response from day one, induced by IFN-α and enhanced by IFN-γ. The multilayer design demonstrated an optimal toxicity profile. This formulation is an inhaled dry powder targeted for the non-invasive intranasal route. This prototype would ensure greater bioavailability, controlled release, fewer adverse effects, and robust biological action thanks to the simultaneous impact of both molecules.

Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Antibody drug conjugates (ADCs) are novel anti-cancer therapies designed to minimise challenges of systemic drug distribution and are currently being investigated in multiple types of malignancies, after failure of standard therapeutic options. This review outlines the mechanism of action of ADCs and the current research in this field in various cancer types, including BTCs.

Effective pain management in laboratory animals is crucial for both animal welfare and the reliability of scientific research. We retrospectively examined the effects of carprofen as post-operative analgesia in Sprague Dawley rats following stereotactic surgery. Our data indicate that administering carprofen twice daily (5 mg/kg), as currently recommended by GV-SOLAS, led to adverse effects such as reduced food and water intake, disrupted fecal excretion, and abdominal bloating consistent with peritonitis. Continued administration exacerbated these symptoms, with post-mortem findings of intestinal obstructions and ulcers. However, when the frequency was reduced to once daily, such adverse symptoms were not observed. These results are based on incidental data collected from various neuroscientific experiments, resulting in small and uneven sample groups across various experimental cohorts. The inherent imbalances in these groups present challenges for statistical interpretation. While the findings suggest that less frequent carprofen use may reduce adverse effects, the surgical interventions and concurrent use of other drugs in these experiments likely exacerbated these outcomes. Further investigation into the interactions between carprofen, surgical stress, and other perioperative factors is needed to refine analgesia protocols in laboratory animals. Despite these limitations, these observations contribute to understanding analgesia protocols and may assist in improving animal welfare practices.

Certain species of Mucorales have been identified as causative agents of mucormycosis, a rare yet often lethal fungal infection. Notably, these fungi exhibit intrinsic resistance to common azole drugs, which target lipids. Given the pivotal role of lipids in drug resistance and their contribution to the innate resistance to azoles, this study provides a comprehensive overview of key lipid classes, including sphingolipids (SLs), glycerophospholipids(GPLs), and sterols, in Rhizopus delemar 99-880, a well-characterized reference strain among Mucorales. Through high-throughput analysis involving the identification and quantification of intermediates, we have elucidated the biosynthetic pathways of SLs, PGLs, and sterols. Notably, the acidic SLs were not found probably because the acidic branch of the SL biosynthesis pathway terminates at α-hydroxy phytoceramides as evident by their high abundance. Intermediates in the neutral SL pathway incorporated higher levels of 16:0 fatty acid compared to other pathogenic fungi. A strikingly high phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio was observed among GPLs. Ergosterol remains the major sterol, similar to other fungi, and our analysis confirms the existence of alternate ergosterol biosynthesis pathways. The total lipidomic profile of R. delemar 99-880 offers insights into its lipid metabolism and potential implications for studying pathogenesis and drug resistance mechanisms.

Significant advancements have been made in controlled drug delivery systems in recent years, especially for oral administration. Conventional methods, although groundbreaking, encounter significant constraints when handling drugs with weak acidity or alkalinity because of their solubility being influenced by pH. The release rates of these ionizable drugs are subject to variability, which is influenced by factors such as the pH of the gastrointestinal tract (GIT), patient-specific conditions, and whether the patient is in a fed or fasted state. As a result, there is often a lack of correlation between in vitro and in vivo data. Therefore, it is imperative to develop drug delivery systems that are not affected by changes in pH in order to address these limitations. This review delves into different strategies that have been developed to achieve drug release that is not affected by changes in pH. These strategies include the utilisation of Diffucaps technology, the incorporation of pH modifiers and surfactants, the combination of non-ionic and ionic polymers, the implementation of supersaturating techniques with nucleation inhibitors, and the utilisation of osmotic drug delivery systems. We assess the efficacy of these methods in reducing the influence of pH fluctuations on the solubility and release rates of drugs. In addition, we explore the potential of these innovative techniques to enhance the reliability and predictability of drug delivery, ultimately leading to better therapeutic results. This review provides an in-depth information of various pH independent controlled drug delivery based formulation and By summarizing the existing technologies and looking into the future, the importance of innovation in pH independent delivery systems is emphasised, laying a good foundation for the future design of simple drug delivery systems, which will be conducive to achieving a wider range of applications in oral drug delivery system.

Long COVID, characterized by persistent symptoms lasting from weeks to several months following initial infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), significantly impacts individuals' quality of life and poses a potential long-term burden on global healthcare systems. Clinical manifestations of Long COVID are diverse, affecting multiple systems including respiratory, cardiovascular, neurological, and gastrointestinal. While the precise mechanisms underlying Long COVID remain unclear, emerging evidence suggests involvement of various bodily pathways. This study employs bioinformatics tools to investigate the mechanisms of Long COVID and identify potential drug targets associated with key pathways, including inflammation, cytokines, immune response, coagulation, mitochondrial function, oxidative stress, and autonomic dysfunction. Tools such as the National Center for Biotechnology Information (NCBI) database, PubChem, UniProt, and iGEMDOCK were utilized for pathway analysis and molecular docking. The analysis aimed to identify drug molecules that may interact with target proteins to regulate or inhibit pathway activity, yielding several potential drug candidates for further investigation.

In Burkina Faso, there is lack of awareness of antibiotics use at community level. In this study, we generate information on the commonly used antibiotics along with the reasons for which they have been used, in rural Burkina Faso. The ‘drug bag’ method, was employed to collect information from 423 households, in the health district of Nanoro. Descriptive analyses were performed using R software version 4.2.1. The number of self-reported antibiotic use on a regular basis was estimated at 3401 of which amoxicillin was reported 367 times (10.8 %), oxytetracycline was reported 288 times (8.5 %), ampicillin, 245 times (7.2 %), metronidazole, 239 times (7 %), and norfloxacin 223 times (6.6 %). Among the health complaints for which amoxicillin was used, wounds accounted for 28.5% (88/309) and gastrointestinal disorders 17.1% (53/309). For oxytetracycline, gastrointestinal disorders accounted for 57.1% (121/212) and wounds 22.64% (48/212). The study highlights the use of antibiotics for a range of health problems within the community, as well as antibiotics that appeared to of importance in people’s life. Further research is essential to elucidating the rationalities and logic reasoning underlying such use of antibiotics.

Venous thromboembolism (VTE) is a serious health condition and represents an important cause of morbidity and, in some cases, mortality. According to the latest estimates from the Centers for Disease Control and Prevention, 3 out of 10 people with VTE will have recurrence of clotting event within 10 years. The American Heart Association reports that VTE is more common in people over 40 years of age, and that risk doubles with each decade. The World Health Organization advises that the world’s population of people aged 60 years is going to be doubled by 2050. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the two main conditions that make up VTE. People with VTE are initially treated with anticoagulants to prevent conditions such as stroke and to reduce the recurrence of VTE. However, thrombolytic therapy is used for people with PE experiencing with low blood pressure or in severe cases of DVT. Despite the approval of direct anticoagulants in 2010, there is clear evidence that the search for new drugs that are more effective or safer than the current antithrombotic treatments continues. Thrombin plays a crucial role in regulating hemostasis and maintaining blood coagulation, and therefore serves as a major target for the treatment of hemostatic disorders such as thromboembolic syndromes, disseminated intravascular coagulation, thrombocytopenia, and acquired hemostatic disorders such as platelet dysfunction and excessive anticoagulation, among other pathologies. This review focuses on the progress in research on new anticoagulants and novel delivery systems for antithrombotic targeting to vascular embolisms.

The article "Ensuring Quality Medicine is Not a Single Event but a Combined Effort of a Pharmaceutical Company" explores the multifaceted approach required to maintain high standards in pharmaceutical manufacturing. It emphasizes that quality assurance in medicine production is not an isolated event but a continuous, integrated process involving multiple departments and stages. The article highlights the roles of research and development, rigorous clinical trials, regulatory compliance, and robust manufacturing practices in ensuring the efficacy and safety of medicines. It also discusses the importance of quality control measures, such as stringent testing protocols and regular audits, to detect and mitigate potential issues early. The collaboration between different teams within a pharmaceutical company, including scientists, engineers, and quality assurance professionals, is crucial for sustaining quality throughout the product lifecycle. Moreover, the article addresses the necessity of adhering to global standards and guidelines, such as Good Manufacturing Practices (GMP), to ensure consistency and reliability in drug production. By fostering a culture of continuous improvement and vigilance, pharmaceutical companies can effectively safeguard public health and maintain trust in their products. This holistic approach underscores that delivering quality medicine is an ongoing commitment requiring coordinated efforts across the entire organization.

Bacillus Calmette-Guérin (BCG) immunotherapy has been a cornerstone treatment for non-muscle invasive bladder cancer for decades and still faces challenges, such as severe immune adverse reactions, which reduce its use as a first-line treatment. This review examines BCG therapy’s history, mechanisms, and current status, highlighting how nanotechnology and bioengineering are revitalizing its application. We discuss novel nanocarrier systems aimed at enhancing BCG's efficacy while mitigating specific side effects. These approaches promise improved tumor targeting, better drug loading, and enhanced stimulation of anti-tumor immune responses. Key strategies involve using functional BCG cell wall components and co-delivering BCG with chemotherapeutics to achieve synergistic effects. While most studies remain experimental, this research direction offers hope for overcoming BCG's limitations and advancing bladder cancer immunotherapy. Further elucidation of BCG's mechanisms and rigorous safety evaluations of new delivery systems will be crucial for translating these innovations into clinical practice.

(1) Background: We aimed to determine the prevalence of hepatitis B virus (HBV) resistance-associated mutations (RAMs) in people with HBV and human immunodeficiency virus (HBV/HIV) in Botswana. (2) Methods: We sequenced HBV from participants with HBV/HIV from the Botswana Combination Prevention Project study (2013-2018) using the Oxford Nanopore GridION platform. Consensus sequences were analyzed for genotypic and mutational profiles. (3) Results: Overall, 98 HBV sequences had evaluable reverse transcriptase region coverage. The median participant age was 43 years (IQR: 37, 49) and 66/98 (67.4%) were female. Most participants, 85/97 (87.6%) had suppressed HIV viral load (VL). HBV RAMs were identified in 61/98 (62.2%) participants. Most RAMs were in positions 204 (60.3%), 180 (50.5%) and 173 (33.3%), mostly associated with lamivudine resistance. The triple mutations, rtM204V/L180M/V173L and was the most predominant (17/61 [27.9%]). Most participants (96.7%) with RAMs were on antiretroviral therapy for a median duration of 7.5 years (IQR: 4.8, 10.5). Approximately 27.9% (17/61) of participants with RAMs had undetectable HBV VL, 50.8% (31/61) had VL &lt;2000IU/mL and 13/61 (21.3%) had VL ≥2000 IU/mL. (4) Conclusions: The high prevalence of lamivudine RAMs discourages the use of ART regimens with 3TC as the only HBV-active drug in people with HIV/HBV.

For 80 years high-intensity focused ultrasound (HIFU) has been a significant area for medical research. It is a non-invasive procedure which causes cell death in a highly localised area at a defined distance from the transducer. Since 2000, the clinical indications have broadened considerable as the technology has improved. This review looks back at the history of HIFU and the current clinical indications.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavourable drugs properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use as inhalable formulations. Particulate-solid HA-VAN25 complex by spray drying from an aqueous dispersion was obtained. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern by X-ray was observed. The powder density, geometric size and morphology showed a suitable aerosolization and aerodynamic performance of the powder, indicating the capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 hours. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus, showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

The current study was formulated with the aim of assessing the impact of the Extent of Drug addiction on the Family environment and interventions for drug-addicted youth in rural areas of Dir Lower Khyber Pakhtunkhwa, Pakistan. The study comprised a dependent variable (Extent of Drug addiction) and an independent variable (Family Environment). A sample size of 266 was randomly selected for primary data collection through structured interviews. The collected information was evaluated through descriptive analysis (frequency and percentage distribution) and inferential analysis, specifically utilizing the Chi-square Statistical Test. The study concluded that drug addiction among youth has an adverse impact on the family environment, leading to instability and violent behavior. Further, families of drug-addicted youth experience a high level of dissatisfaction in relationships, often culminating in divorce. Similarly, the families of drug-addicted are characterized by low cohesion, role conflict, and tolerance. Thus, the government should formulate polices and strategies for the prevention of drug addiction, with speedy implementation across all institutional dynamics, including family. Moreover, It is also crucial to rehabilitate the lifeblood of a nation (youth) in terms of socio-economic, emotional and psychological growth. These recommendations were put forward in the light of the current study.

(1) Background: Since the pandemic, adolescent girls have increasingly faced mental health challenges. We examined prevalence trends and associated risk factors for depression among adolescent girls. 2) Methods: Data for girls aged 12 to 17 years (N=4346) from the 2021 cross-sectional National Survey on Drug Use and Health were analyzed. Factors associated with depression were examined using multiple regression analysis. (3) Results: Rates of severe depression were significantly higher (p&lt;.001) in older girls (adjusted odds ratio [AOR]: 1.63, 1.61, those who did not have authoritative parents (AOR: 3.40), and those with negative school experiences (AOR: 4.03). Black and Asian/Native Hawaiian or other Pacific Islanders were less likely to report severe depression than white girls. As previously reported, non-White girls were significantly less likely to receive treatment for depression (p&lt;.05). Parents’ characteristics and school experiences had no effect on the likelihood of receiving mental health treatment. (4) Conclusion: Depression has become increasingly common among American adolescent girls, who are now three times as likely as adolescent boys to have had recent experiences with depression. Our results show that family structure, parenting style, and negative school experiences significantly contribute to the rate of depression and that treatment disparities exist with regard to race and ethnicity.

Nanoencapsulation has emerged as a recent improvement in the delivery of drugs, offering and improving stability and bioavailability, and allowing for the controlled and targeted delivery of substances to specific cells or tissues. However, traditional nanoparticle delivery faces challenges such as short circulation time and immune recognition. To address these issues, cell membrane-coated nanoparticles have been proposed as a promising alternative. The production of cell membrane-coated nanoparticles involves three key stages: cell lysis and membrane fragmentation, membrane isolation, and nanoparticle coating. Typically, cell membranes are fragmented using hypotonic lysis in combination with homogenization or sonication. Subsequent membrane fragments are isolated through multiple centrifugation steps. The coating of nanoparticles can be achieved through extrusion, sonication, or a combination of both methods. This analysis shows the absence of a universally applicable method for nanoparticle coating, as the three stages exhibit notable differences in their procedures. Here we review ongoing developments and approaches to cell membrane-coated nanoparticles that position this technology as a promising alternative for effective targeted drug delivery and many other therapeutic applications.

Antimicrobial resistance is a major public health concern. Rodents and shrews live in closer proximity to humans and animals and serve as reservoirs for the transmission of several diseases, including AMR pathogens. There is no data available from India on surveillance of AMR bacteria in rodents and shrews. In this study, bacterial pathogens viz, Staphylococcus sp, Escherichia coli and Salmonella sp were isolated from rodents and shrews and genetic elements conferring antimicrobial resistance in the pathogens were screened by PCR. Bacterial pathogens in the oropharyngeal and anal swabs collected from the rodents and shrews trapped (n=100) were cultured on selective media such as Mannitol salt, Mac Conkey and Xylose lysine deoxycholate media to isolate Staphylococcus sp., E. coli and Salmonella sp. respectively. A total of 76 (80%) S. aureus and 19 (20%) Staphylococcus non aureus were isolated. E. coli was isolated in 89 samples and among the Salmonella sp (n=59), 16 (27%) were S. enteritidis and 29 (49.1%) were S. typhimurium. In S. aureus isolates, mec A and mec C (MRSA) were detected in 40 (52.6%) and 6 (7.9%) isolates respectively. Also, 7 (36.84%) and 1 (5.3%) Staphylococcus non aureus isolates were tested to harbour mec A and mec C genes. A total of 77 (86.5%) E. coli isolates had genes encoding ESBL [TEM in 21 (23.59%), SHV in 45 (50.6%) and CTXM in 11 (12.4%)]. Among the 45 pathogenic Salmonella sp, 44 (97.78%) harboured AMR genes [tet in 13 (28.9%), sul3 & sul4 in 20 (44.4%) and qnrA in 11 (24.4%)]. Thirty-eight animals harboured more than one zoonotic pathogen and 21 with multi-drug resistant genes. Our findings signify that these rodents and shrews may serve as sentinels to screen environment spillover of AMR pathogens and also act as reservoir to transmit MRSA, ESBL, Salmonella sp. human/animals. Also these animals aid in the transfer of antimicrobial resistance genetic elements to non-pathogenic organisms.

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The obtained compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 3.47 μM for MAO-B and 43.3 μM for MAO-A. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for development anti-Parkinson’s disease agents.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following Death Receptors (DRs) activation by the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. Inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify, new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These compounds selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these 9 molecules using the human lung cancer cell line H1703 overexpressing c-FLIP. Our results showed that 6 of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC Immunoprecipitation assay. Overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis, however, combination of TRAIL with these selected molecules signifi-cantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical compounds efficiently prevent c-FLIP recruit-ment into the DISC complex, thus restoring caspase-8 dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory compounds that may serve as anticancer agents in tumors overexpressing c-FLIP.

Transdermal drug delivery systems have become an intriguing research topic in healthcare technology and one of the most frequently developed pharmaceutical products in the global market. In recent years, researchers and pharmaceutical companies have made significant progress in developing new solutions in the field. This study sheds light on current trends, collaboration patterns, research hotspots, and emerging frontiers of transdermal drug delivery. Herein, a bib-liometric and patent analysis of data recovered from Scopus and The Lens databases, respectively, is reported over the last 20 years. From 2000 to 2022, the annual global publications increased from 131 in 2000 to 659 in 2022. Researchers in the United States, China, and India produced the highest number of publications. Likewise, most patent applications have been filed in the USA, China, and Europe. The recovered patents are 7,275, grouped into 2,997 patent families, of which 314 were granted. This study could support the work of decision-makers, scientific managers, or scientists to create new business opportunities or save money, time, and intellectual capital, thus, defining when a research or technology project should be a priority or not.

2,4-dichlorophenoxyacetic acid (2,4-D) is a globally used herbicide and is frequently found in water samples. This fact has prompted studies on its effects in non-target organisms, revealing significant alterations on liver structure and function. In this review, we evaluated the literature on the hepatotoxicity of 2,4-D, focusing on morphological damages, biomarkers of toxicity and affected liver functions. Searches were conducted on PubMed, Web of Science and Scopus and 83 articles were selected after curation. Among the studies, 72% used in vivo models and 30% used in vitro models. Additionally, 48% used the active ingredient, and 35% used commercial formu-lations in exposure experiments. The most affected biomarkers were related to a decrease in an-tioxidant capacity, including alterations in the activities of catalase and superoxide dismutase, and in the levels of malondialdehyde. Changes in energy metabolism, lipids, liver function, and xenobiotic metabolism were also identified. Furthermore, we found studies about the effects of 2,4-D in mixtures with other pesticides, as well as hepatoprotection trials. The reviewed data in-dicate that the reduction in antioxidant capacity and oxidative stress play an important role in 2,4-D-induced hepatotoxicity. However, the mechanism of action of the herbicide is still not ful-ly understood and further research in this area is needed.

Toxoplasma gondii, a protozoan parasite with the ability to infect various warm-blooded vertebrates, including humans, is the causative agent of toxoplasmosis. This infection poses significant risks, leading to severe complications in immunocompromised individuals and potentially affecting the fetus through congenital transmission. A comprehensive understanding of the intricate molecular interactions between T. gondii and its host is pivotal for the development of effective therapeutic strategies. This review emphasizes the crucial role of proteomics in T. gondii research, with a specific focus on host-parasite interactions, post-translational modifications (PTMs), PTM crosstalk, and ongoing efforts in drug discovery. Additionally, we provide an overview of recent advancements in proteomics techniques, encompassing interactome sample preparation methods such as BioID, APEX, and Y2H, as well as various proteomics approaches, including single-cell analysis, DIA, targeted, top-down, and plasma proteomics. Furthermore, we discuss the integration of proteomics with other omics technologies, highlighting its potential in unraveling the intricate mechanisms of T. gondii pathogenesis and identifying novel therapeutic targets.

This article discusses the fabrication of pullulan/polyvinyl alcohol (PVA) and PVA blends as carrier polymers for drug delivery. This study utilized coaxial electrospinning to encapsulate doxorubicin (DOX), a common anticancer drug, within nanofibers, which helped mitigate the adverse effects of DOX on normal cells. The study also demonstrated that the coaxial electrospinning technique using PVA/pullulan cores was effective in inhibiting the attachment and proliferation of HeLa cells, a type of cervical cancer cell. The use of pullulan/PVA and PVA blends as carrier polymers in conjunction with coaxial electrospinning could provide a safe and effective drug delivery system for the treatment of cervical and other solid malignancies. The study concluded that nanofibers showed promising results in inhibiting the growth of HeLa cells, indicating their potential as safe and effective drug delivery systems for treating cervical cancer and other solid malignant tumors.

The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction with tyrosine kinase inhibitors. Coupled with this, the research leverages molecular contrastive learning and protein language modeling to examine interactions between small molecule inhibitors and FLT3 activation loop mutants. Utilizing the ConPLex platform, over 5.7 million unique FLT3 activation loop mutants-small molecule pairs were analyzed. The binding free energies of three inhibitors were assessed, and cellular apoptotic responses were evaluated under drug treatments. Notably, the introduction of the Xepto50 scoring system provides a nuanced metric for drug efficacy. The findings underscore the modulation of molecular interactions and cellular responses by Y842 mutations in FLT3-KD, highlighting the need for tailored therapeutic approaches in FLT3-ITD-related malignancies.

Worldwide, hypoxia-related conditions, including cancer, COVID-19, and neuro-degenerative diseases, often lead to multi-organ failure and significant mortality. Oxygen, crucial for cellular function, becomes scarce as levels drop below 10 mmHg (<2% O2), triggering mitochondrial dysregulation and activating hypoxia-induced factors (HiFs). Herein, Oxygen nanoBubbles (OnB), an emerging versatile oxygen de-livery platform, implies to offer a novel approach to address hypoxia-related pathologies. This review explores OnB oxygen delivery strategies and systems, including diffusion, ultrasound, photodynamic, and pH-responsive nanobubbles. It delves into the nanoscale mechanisms of OnB, elucidating their role in mitochondrial metabolism (TFAM, PGC1alpha), hypoxic responses (HiF-1alpha), and their interplay in chronic pathologies including cancer and neurodegenerative disorders, amongst others. By understanding these dynamics and underlying mechanisms, this article aims to contribute to our accruing knowledge of OnB and the developing potential in ameliorating hypoxia- and metabolic stress-related conditions and fostering innovative therapies.

Background: Although triptorelin acetate (TA) is generally considered a safe medication, severe adverse drug reactions (ADRs) to triptorelin have occurred. In this study, we present the largest retrospective analysis of ADRs related to TA during the treatment of pediatric central precocious puberty. Methods: We describe a total of 38 suspected cases of TA-induced ADRs reported to the pharma-covigilance center of Shenzhen Children’s Hospital from September 2015 to December 2022. Causality assessment was carried out using the validated Kramer’s algorithm. The severity of ADRs was evaluated using the Modified Hartwig and Siegel Scale. Results: The most common ADRs attributed to TA were damage to the cutaneous tissues (29.3%) and reactions affecting the systemic and digestive systems (20.7%). The majority (61.1%) of ADRs occurred within 2 hours of administration. Among the 12 patients with severe ADRs, the three most frequent symptoms were anaphylactic reactions, hip synovitis, and arthralgia. Additional-ly, six patients experienced ADRs due to a change in the manufacturing process. Conclusion: The majority of ADRs observed in pediatric cases were type I anaphylactic reactions, which are rare but life-threatening. It is advisable to perform skin prick tests and intradermal tests when switching pharmaceutical manufacturers.

Infection with Ebola virus (EBOV) is responsible for haemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention are required to tackle highly variable RNA viruses, whose infections often lead to outbreaks. Here, we have screened the 2P2I3D chemical library using a nanoluc-based protein complementation assay (NPCA) and isolated two compounds disrupting the interaction of the EBOV protein fragment VP35IID with the N terminus of the dsRNA-binding proteins PKR and PACT, involved in IFN response and/or intrinsic immunity, respectively. The two compounds inhibited EBOV infection in cell culture as well as infection by measles virus (MV) independently of IFN induction. Consequently, we propose the compounds are antiviral by restoring intrinsic immunity driven by PACT. Given that PACT is highly conserved across mammals, we support further testing of the compounds in other species, as well as against further negative sense RNA viruses.

While biologic originators’ patents are expiring, biosimilars are emerging to take their place, offering significant cost savings to healthcare systems. Many challenges still need to be addressed in the clinical practice of inflammatory bowel disease (IBD). A global survey was organized to highlight physicians’ current knowledge and beliefs and to gain insight about their practical management and remaining concerns and obstacles associated with starting a biosimilar, switching from an originator to a biosimilar, or switching from one biosimilar to another (multiple switches and reverse switching). Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. Consensus was reached on 10 statements regarding biosimilar effectiveness, safety, indications and rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching and future perspectives.

BMAP-18, derived from the N-terminal region of bovine myeloid antimicrobial peptide BMAP-27, demonstrated potent antimicrobial activity without cytotoxicity. This study aimed to compare the antibacterial, antibiofilm, and anti-inflammatory properties of BMAP-18, rich in aromatic phenylalanine residues, with its aliphatic analogue, BMAP-18-FL. Both aromatic BMAP-18 and aliphatic BMAP-18-FL exhibited equally potent antimicrobial activities against Gram-positive and Gram-negative bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Mechanistic investigations employing SYTOX green uptake, DNA binding, and FACScan analysis revealed that both peptides acted by inducing membrane permeabilization and subsequent intracellular targeting. Moreover, both BMAP-18 and BMAP-18-FL effectively prevented biofilm formation and eradicated existing biofilms of MRSA and MDRPA. Notably, BMAP-18-FL displayed superior anti-inflammatory activity compared to BMAP-18, significantly reducing the expression levels of pro-inflammatory cytokines in lipopolysaccharide-stimulated macrophages. This study emphasizes the similarities and differences in the antimicrobial, antibiofilm, and anti-inflammatory properties between aromatic BMAP-18 and aliphatic BMAP-18-FL, providing valuable insights for the development of multifunctional antimicrobial peptides against drug-resistant bacteria.