Abstract: Background: Positron emission tomography (PET) is a molecular imaging technique that exploits the β+ decay of selected radionuclides to enable non-invasive in vivo investigation of biochemical and physiological processes, including early and subclinical disease alterations. Radiotracers are designed to bind specific molecular targets with high affinity and selectivity. Among the targets to which PET devotes increasing attention are G protein-coupled receptors (GPCRs)—the largest class of transmembrane receptors—which orchestrate a wide spectrum of biological outcomes and are widely implicated in human disease. Objectives: This review analyzes patents published between 2020 and 2025 focusing on GPCR-targeted PET radiotracers, highlighting design strategies, radionuclide selection, and translational perspectives across oncology, central nervous system (CNS) disorders, and inflammatory diseases. Results: Patent activity shows that most GPCR-targeted PET tracers are derived from validated ligands adapted for imaging while preserving affinity and selectivity. Oncology patents mainly favor peptide-based or modular metal–chelator platforms enabling radionuclide flexibility and theranostic extension, whereas CNS tracers rely on drug-like small molecules optimized under strict ADME and blood–brain barrier constraints. Increasing emphasis on non-orthosteric, function-sensitive, and dual-targeting approaches reflects a shift toward interrogating GPCR signaling states, while inflammatory indications remain comparatively underrepresented despite clear biological foundations. Conclusions: Current patent trends consolidate GPCR-targeted PET tracers as well-established diagnostic tools while progressively expanding their clinical utility, both as platforms supporting translational research—informing mechanistic insight and drug development—and as components of emerging theranostic strategies across multiple disease areas.

Abstract: Polypharmacy presents a major challenge when caring for older adults and increasingly causes preventable health problems in both inpatient and outpatient settings. While it is often defined as taking five or more medications, it is more accurately seen as a clinical condition where medication burden surpasses physiological capacity, is unnecessary, or is incongruent with patient-centered goals. Age-related changes in drug absorption, distribution, metabolism, and excretion, along with multiple chronic conditions, fragmented care, and frequent transfers between healthcare environments, create a perfect storm for medication-related adverse effects. Falls, syncope, confusion, fatigue, low blood pressure, slow heart rate, or functional decline can be mistaken for evidence of underlying illness rather than side effects of medication. Medication reconciliation can therefore serve as a powerful diagnostic, therapeutic, and safety measure to avoid the harmful effects of polypharmacy. This review offers a practical, detailed, step-by-step approach to managing polypharmacy for internists, with a particular focus on medication reconciliation in older adults.

Abstract: The C-C motif chemokine receptor 1 (CCR1) plays key roles in guiding leukocyte movement during immune surveillance and inflammatory responses. Targeting CCR1 is a promising approach for treating autoimmune diseases and cancers. We previously developed anti-mouse CCR1 (mCCR1) monoclonal antibodies (clones C1Mab-2 and C1Mab-6) for use in flow cytometry and western blotting. However, the specific binding sites have not yet been identified. This study examined the binding epitope of C1Mab-2 and C1Mab-6. Analysis of mCCR1 mutants with altered extracellular domains showed that C1Mab-2 and C1Mab-6 bind to the N-terminal region of mCCR1. Additionally, PA-tag substitution experiments identified the epitope as comprising amino acids 1–13 of mCCR1. Further, alanine (or glycine) scanning within the N-terminal region (amino acids 2–13) was performed using flow cytometry and western blotting. The results demonstrated that Met1, Glu2, Asp5, and Phe6 are critical for recognition by C1Mab-2, while Met1, Glu2, Ile3, and Asp5 are essential for recognition by C1Mab-6. These findings enhance our under-standing of how mCCR1 interacts with C1Mabs.

Abstract: Peptides are short chains of amino acids with a unique pharmacological niche between small-molecule drugs and large proteins. Their use in sports medicine is rapidly expanding, driven by patient demand for accelerated injury recovery and performance enhancement. While numerous peptide drugs have undergone a rigorous approval process that evaluates both safety and efficacy, a parallel "gray market" of unapproved compounds has emerged, operating largely outside regulatory oversight. Our objective is to present the pharmacological mechanisms, safety profiles, and regulatory status of prominent approved and unapproved peptides marketed direct to patients, including AOD-9604 (Anti-Obesity Drug 9604), BPC-157 (Body Protection Compound 157), CJC-1295, FS-344 (Follistatin-344), GHK-Cu (Glycyl-L-histidyl-L-lysine copper), ipamorelin, MOTS-C (Mitochondrial ORF of the 12S rRNA type-c), sermorelin, SS-31 (Elamipretide), tesamorelin (Egrifta), Tβ4 (thymosin beta-4), and TB-500 (thymosin beta-4 fragment). Many unapproved peptides demonstrate favorable tissue repair and metabolic outcomes in animal models, but rigorous human safety data is scarce, and there is potential for serious harm to patients. This narrative review focuses on the utilization of peptides in sports medicine, and alternative treatments that may be considered. We provide a framework to navigate patient discussions about peptides to better facilitate evidence-based practices for musculoskeletal healing and athletic performance. We also discuss the placebo effect as a mediator of peptide efficacy, and how social media amplifies this effect.

Abstract: Immune checkpoint modulation has emerged as a promising strategy in cancer therapy, including the treatment of aggressive tumors such as glioblastoma. Among these targets, programmed death-ligand 1 (PD-L1) plays a key role in tumor immune evasion and represents an attractive target for small-molecule inhibitor development. In this study, a virtual screening approach was applied to identify potential PD-L1 modulators within a library of nucleoside-related compounds and structurally similar molecules. A dataset of 400 compounds was evaluated using molecular docking to predict their binding affinity (free energy values and binding pose) toward PD-L1. The resulting complexes were analyzed to identify non-bond interactions within the hydrophobic pocket formed at the PD-L1 dimer interface. In addition to docking results, physicochemical descriptors associated with drug-likeness and blood brain barrier penetration were calculated, including lipophilicity, molecular weight, hydrogen bond donors and acceptors, and topological polar surface area. To integrate these parameters, a multiparameter optimization (MPO) score was implemented. The analysis revealed that several top-ranked compounds exhibited favorable docking scores and physicochemical properties compatible with drug-like behavior. Interestingly BMS-1, a known PD-L1 inhibitor was identified among the highest-scoring compounds, supporting the reliability of the MPO protocol. Furthermore, multiple candidates displaying nucleoside-like scaffolds combined with reduced polarity and moderate lipophilicity emerged as promising molecules according to the MPO ranking. Overall, the results suggest that nucleoside-derived scaffolds may represent a viable starting point for the development of small-molecule PD-L1 modulators with potential applicability in glioblastoma therapy.

Abstract: Severe COVID-19 follows a cliff-edge trajectory: patients appear stable, then deteriorate rapidly and irreversibly. This paper identifies molecular oxygen as the dual control variable governing two previously unconnected biological systems: the DUOX-Lactoperoxidase-Iodine (DLI) airway antiviral defense and HIF-1α, the transcription factor that drives COVID-19 severity. Both share the same oxygen-dependent enzymes (DUOX and PHD, Km approximately 20 μM O₂ corresponding to approximately 94% SpO₂). When SpO₂ falls below this threshold via AT2 cell destruction with surfactant loss, ventilation-perfusion mismatch, and microvascular thrombosis, both systems fail simultaneously, initiating three concurrent cascade arms: (1) collapse of DLI mucosal defense through O₂ substrate depletion; (2) HIF-1α-driven Furin upregulation accelerating viral spike cleavage and entry, with a viral amplification feedback loop; and (3) IL-6-mediated cytokine storm depleting thyroid iodide reserves. These three arms interact multiplicatively, not additively. A Monte Carlo simulation across four populations demonstrates a 40.3% steeper cliff-edge signature than an additive null model. The framework generates three falsifiable clinical predictions and identifies supplemental oxygen initiated before the HIF-1α threshold (SpO₂ 94–95%) as the primary actionable intervention, suppressing all three cascade arms simultaneously.

Abstract: Geriatric pharmacotherapy is usually challenged by physiological senescence. For instance, progressive declines in organ function and alterations in body composition can complicate drug disposition. However, conventional pharmacometrics models commonly have limited capacity to map these high-dimensional, non-linear relationships. In this review, we are examining the recent shift toward integrating Machine Learning (ML) with mechanistic Pharmacokinetic (PK)/Pharmacodynamic (PD) models to improve the accuracy and precision of dosing. Machine learning approaches like Random Forest and XGBoost consistently provided more accurate exposure predictions and significantly more efficient computational workflows than conventional methods. Nevertheless, concerns such as "black box" transparency and the potential of algorithmic bias toward specific patient demographics are challenging. It is important to incorporate explainability tools like SHAP, and adopting FAIR data principles is crucial for achieving professional trust and ensuring site-specific generalizability.

Abstract: Background: Eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) are distinct conditions, yet they often exhibit overlapping clinical, endoscopic, and histological features. Aim: This study aims to assess the prevalence of GERD among patients with EoE and to identify risk factors for both typical and atypical GERD symptoms. Methods: We conducted a population-based retrospective analysis of patients diagnosed with EoE and collected data on demographics, GERD diagnosis, symptoms, comorbidities, and laboratory results. GERD symptoms were classified as typical (e.g., heartburn and regurgitaion) or atypical (e.g., hoarseness and cough). Results: Of the 2,496 patients with EoE (73.2% male), 48.5% exhibited GERD symptoms—26.2% prior to and 30.5% following the diagnosis of EoE. Typical symptoms predominated before EoE diagnosis (26% vs. 4.3% after diagnosis), whereas atypical symptoms were more frequent after diagnosis (28% vs. 0.4% before diagnosis), with cough increasing from 0.4% to 27.4%. In the multivariate analysis, allergic rhinitis (odds ratio [OR 1.40, 95% confidence interval [CI]; 1.15–1.75, p < 0.001) and hiatal hernia (OR 2.47, 95% CI 1.75–3.47, p < 0.001) predicted typical GERD symptoms, whereas asthma (OR 1.50, 95% CI 1.28–1.85), food allergy (OR 1.36, 95% CI 1.08–1.70), and elevated eosinophil counts (OR 2.00, 95% CI 1.44–2.73) were associated with atypical GERD symptoms. Conclusion: Approximately half of patients with EoE are present with GERD symptoms, with a tendency toward more atypical symptoms after EoE diagnosis. Identifying key predictors and risk factors may improve diagnostic accuracy and facilitate the development of targeted treatment strategies.

Abstract: Background: Nigeria bears a disproportionate burden of metabolic disease, with diabetes affecting an estimated 6.8-7.5% of adults and obesity prevalence among women reaching 15.7%. Despite the rich ethnobotanical tradition of using indigenous plants to manage these conditions, the molecular mechanisms by which Nigerian plant-derived phytochemicals modulate immunometabolic pathways remain poorly characterised. Objectives: This narrative review synthesises current evidence on the immunometabolic mechanisms of key phytochemicals derived from Nigerian medicinal plants, with specific focus on how these compounds regulate macrophage polarisation, inflammatory cytokine signalling, insulin sensitivity, and metabolic reprogramming in obesity and type 2 diabetes (T2D). Methods: A comprehensive narrative review was conducted using PubMed, Scopus, Google Scholar, Web of Science, and African Journals Online (AJOL). Studies reporting in vitro, in vivo, or in silico evidence for the immunometabolic activity of phytochemicals from Nigerian medicinal plants were included. Key immunometabolic targets - NF-kB, PPARgamma, AMPK, mTOR, HIF-1alpha, and macrophage M1/M2 polarisation markers - were used as mechanistic anchors for evidence synthesis. Results: Multiple phytochemicals abundant in Nigerian plants - including rutin, quercetin, luteolin, chlorogenic acid, vitexin, kolaviron, nimbolide, and 6-gingerol - demonstrate modulatory activity at immunometabolic nodes. These compounds converge on shared targets: suppression of NF-kB-driven M1 macrophage polarisation, activation of AMPK-mediated anti-inflammatory signalling, PPARgamma agonism to promote insulin sensitisation, and attenuation of HIF-1alpha-driven glycolytic reprogramming. Mechanistically, this represents a phytochemical-mediated shift from pro-inflammatory M1 immunometabolism toward an anti-inflammatory, insulin-sensitising M2 phenotype. Conclusions: Nigerian medicinal plants represent an underexplored reservoir of immunometabolic modulators. Their principal phytochemicals act on mechanistic targets directly relevant to the pathophysiology of obesity-linked T2D. Integrating ethnobotanical knowledge with network pharmacology and immunometabolic biology offers a compelling framework for rational drug discovery from Nigerian biodiversity. Future experimental validation using macrophage culture models and high-fat-diet animal systems is warranted.

Abstract: This study focuses on the multitarget biological evaluation of variously substituted 4-pyridyl thiosemicarbazones. Six compounds (C1-C6) containing chlorine atoms in different positions of the phenyl ring were synthesized, and their structures were confirmed using mass spectrometry, FTIR, and NMR spectroscopy. Biological evaluation included antioxidant activity assays (ABTS, DPPH, and ORAC-FL), antibacterial testing against Gram-positive and Gram-negative bacteria, and anticancer activity assessment against a panel of cancer cell lines (A375, G-361, LNCaP, Caco-2, and U-87 MG), as well as healthy fibroblasts (BJ) to evaluate selectivity. While the compounds exhibited limited antibacterial activity, more pronounced anticancer effects were observed, particularly for a singly chlorinated derivative, with reduced cytotoxicity toward healthy cells. No direct correlation was observed between anticancer and antioxidant activities. Finally, ADME analysis suggested favorable pharmacokinetic profiles for all six compounds.

Abstract: Sesquiterpenoids are terpenoid-derived compounds with diverse biological activities and are commonly found in plants of the Dysoxylum genus (Meliaceae). This study aimed to isolate and characterize sesquiterpenoids from the n-hexane extract of Dysoxylum acutangulum Miq. and to evaluate their antibiofilm activity against Streptococcus mutans. The extract was separated using various chromatographic tech-niques to yield one tricyclic sesquiterpenoid and one mixture of epimeric sesquiterpenoids. Structural elucidation was performed using spectroscopic analyses, including MS, IR, and NMR, and by comparison with reported data. The isolated com-pounds were identified as spathulenol (1), 10-oxo-isodauc-3-en-15-al (2a, mayor), and sinulin A (2b, minor). In vitro testing showed weak antibiofilm activity (MBIC 250–500 µg/mL) and no significant inhibition at 62.5 µg/mL compared to chlorhexidine. Molecular docking against Sortase A and GtfB revealed moderate binding affinities consistent with the experimental trend. The slightly better activity of the epimeric mixture suggests a possible additive effect. Overall, these findings provide preliminary structure–activity insights into sesquiterpenoids from D. acutangulum as potential antibiofilm candidates, warranting further mechanistic and combination-based investigations.

Abstract: Cadherin-13 (CDH13), part of the cadherin family, is attached to the plasma membrane through glycosylphosphatidylinositol. CDH13 plays essential roles in the development of the neurological and vascular systems and is a risk factor for neural and cardiovascular diseases. CDH13 is expressed on the plasma membrane in both mature and uncleaved precursor forms with the prodomain. Although several anti-CDH13 monoclonal antibodies (mAbs) are available for basic research, there have been no reports of anti-CDH13 mAbs suitable for flow cytometry that can detect both the mature form and the uncleaved precursor. In this study, we developed novel anti-human CDH13 mAbs (named Ca₁₃Mabs) using the mature form of CDH13 expressed in cells as an antigen. Among these, a clone Ca₁₃Mab-17 (IgG2b, κ) specifically recognized the CDH13-overexpressed Chinese hamster ovary-K1 (CHO/CDH13) cells with no detectable cross-reactivity toward 21 other cadherins by flow cytometry. Ca₁₃Mab-17 also detected endogenous CDH13 in human glioblastoma (LN229 and U87MG) and lung mesothelioma (NCI-H2052) cell lines. The dissociation constant (KD) value of Ca13Mab-17 for LN229 was estimated at 3.2 × 10^⁻8 M. Furthermore, Ca₁₃Mab-17 detected both the mature form and the uncleaved precursor of CDH13 in western blotting. It also identified new blood vessels and glioblastoma cells by immunohistochemistry. Overall, these findings suggest that Ca13Mab-17 is a versatile tool for detecting whole CDH13 and has potential for tumor diagnosis and therapy.

Abstract: Background: Oroantral communication (OAC) represents an accidental opening of the maxillary sinus during oral surgery in the absence of pre-existing inflammation. Despite being considered a rare complication; however, it remains clinically significant due to the risk of chronic sinus pathology. Methods: This study was conducted within the "Arsenie Guțan" Department of Oral and Maxillofacial Surgery at "Nicolae Testemitanu" State University of Medicine and Pharmacy. We evaluated a cohort of 31 patients with OAC treated in an outpatient setting at the Municipal Dental Center in Chisinau during 2022. Results: The first molar was the most frequently involved tooth (45.16%), with molars accounting for 83.88% of cases. Immediate post-extraction diagnosis was achieved in 90.32% of patients. Imaging was required in selected cases, with orthopantomography (OPG) used in 83.87% and computed tomography (CT) in 9.67% of patients. Conclusions: Early diagnosis based on combined clinical and radio-graphic assessment remains essential for successful management of OAC. Prompt intervention reduces the risk of maxillary sinus infection and chronic fistula formation.

Abstract: Background: Atopic dermatitis (AD) is a chronic inflammatory disease characterized by profound dysbiosis, Staphylococcus Aureus colonization, and a compromised epidermal barrier. Current therapies often face safety and compliance limitations, necessitating proactive, steroid-sparing ecological restorations. Methods: This pharmacological review evaluates a synergistic framework combining Lactobacillus and Saccharomyces postbiotic lysates with innovative Perilla frutescens plant-derived exosomes, analyzing their molecular impact on skin homeostasis. Results: Our analysis demonstrates that Lactobacillus enhances innate immunity, while Saccharomyces ferments support the microbial ecosystem, showing an 87% increase in elastin secretion and a 41% increase in collagen type I synthesis, essential for barrier repair. Furthermore, Perilla frutescens exosomes modulate the JAK-STAT pathway, reducing Interleukin-6 (IL-6) by 40% and downregulating CYP1A1 expression by up to 49%, thereby mitigating oxidative stress and pruritus. Conclusions: By integrating these components into a "Triple-Action Therapy"—focusing on immunomodulation, structural restoration, and precision anti-inflammatory signaling—this review provides a comprehensive evidence-based roadmap for next-generation dermo-cosmetic interventions in atopic skin management.

Abstract: Increasing use of intrauterine devices (IUDs) makes effective pain management essential for high‑quality reproductive care. Yet gaps between patient and clinician pain perceptions, along with limited training in managing IUD‑related acute pain, contribute to barriers in IUD uptake and patient‑provider mistrust. This narrative review (1) summarizes current approaches to IUD‑related pain management, (2) evaluates the emphasis on pain education and the management of acute and chronic pain, including IUD insertion pain, across undergraduate medical education (UME), graduate medical education (GME), and residency training, and (3) examines how gaps in pain education may affect clinicians’ preparedness to manage both chronic pain broadly and IUD‑related acute pain specifically. Relevant literature was identified through keyword searches across major databases and national organizations. Evidence highlights limited and inconsistent strategies for managing IUD insertion pain and a persistent lack of comprehensive pain‑medicine training in medical school and residency. Variability in clinicians’ approaches to IUD‑related pain likely reflects gaps between national guidelines and insufficient pain‑management education across UME and GME. A structured, longitudinal pain medicine curriculum spanning pre-clerkship, clerkship, and residency is needed to strengthen clinicians’ competence in pain management and improve patients' experiences with IUD care.

Abstract: Drug repurposing provides a rational strategy to expand therapeutic applications of compounds with established toxicological and pharmacological backgrounds. Cutaneous injury and inflammatory dermatoses are driven by interconnected oxidative stress, inflammatory signaling, and cellular repair pathways rather than single-target dysregulation. The present review evaluates the potential repositioning of the sulphur-mustard countermeasure candidate DRDE-07 using a structure-guided comparative framework against established cytoprotective agents such as aminothiol radioprotectants and endogenous polyamines.A narrative literature-based analysis was performed integrating published mechanistic information for reference cytoprotective molecules with physicochemical descriptors and in-silico drug-likeness parameters of DRDE-07. Comparative assessment focused on structural backbone similarity, translational feasibility, and compatibility with biological stress-response pathways relevant to skin injury.The evaluation indicates that DRDE-07 retains functional chemical features associated with indirect cytoprotection while exhibiting physicochemical characteristics more consistent with conventional small-molecule therapeutics, including balanced lipophilicity and predicted bioavailability. Mechanistic comparison suggests potential compatibility with pathways involved in oxidative stress adaptation and inflammatory regulation rather than high-affinity single-target inhibition.The analysis supports a hypothesis-generating framework in which DRDE-07 may represent a structurally suitable candidate for repurposing in cutaneous protection research. Rather than asserting therapeutic activity, the comparison suggests compatibility with biological pathways implicated in tissue stress adaptation and barrier homeostasis. Accordingly, DRDE-07 is proposed as a candidate for further experimental evaluation in dermatological contexts. This review therefore outlines a hypothesis-generating framework based on structural analogy and pathway convergence, highlighting how countermeasure molecules may be systematically assessed for repurposing into cutaneous protective strategies.

Abstract: Background: A new-concept of non-osteotomy implant is advantageous in not only performing a surgery by applying the tensile force to the growth plate without osteotomy but also achieving a prompt recovery; it is expected to be effective in correcting the leg length discrepancy and angular deformity. Objectives: This animal experiment was performed to assess the effectiveness of a new-concept of non-osteotomy implant in correcting the leg length discrepancy and angular deformity by promoting the growth without suppressing it. Methods: To compare differences in changes in anthropometric measurements between preoperatively and postoperatively, the right and left sides of the femur served as the experimental group and the control group, respectively. In the right femur, two screws each were placed in the upper and lower part of the growth plate. For bilateral distraction, a spring was applied to both sides of the femur (experimental animals 9 and 10). For unilateral distraction, a spring was applied to the external side of the femur only (experimental animals 5, 7, 8 and 11). A CT was performed at a 4-week interval and CT scans were reconstructed 3-dimensionally the MimicsÒ Innovation Suite (Mimics and 3-matic; Materialize, Leuven, Belgium). The anatomical axis of the femur (AAF) is considered as a line that passes through the long axis of the femur through the medullary canal. The mechanical axis of the femur (MAF) is the line drawn through the centers of the femoral head and the intercondylar fossa. This was followed by measurement of time-dependent changes in the line and angle formed by the AAF and the MAF. In more detail, a 3-D registration was performed for CT scans of the femur at each time point, for which the lower part of the growth plate was matched and both the AAF and the MAF were used to form the plane. This was followed by 3-D orthogonal projection of both the AAF and the MAF on the plane postoperatively. Results: With bilateral distraction at a tensile force of 50 N and 100 N, the degree of changes in the length of the AAF at 1 month from baseline was higher on the right side as compared with the left side. This was also seen in the length of the MAF. Moreover, with unilateral distraction at a tensile force of 25 N and 50 N, the degree of changes in the angle formed by the AAF at 1, 2, 3, 4, 5 and 6 months from baseline was significantly higher on the right side as compared with the left side (P<0.05). This was also seen in the angle formed by the MAF. Conclusions: The current results confirm the biomechanical effectiveness of a new-concept of non-osteotomy implant in promoting the bone growth. But this deserves further prospective randomized controlled trials.

Abstract: Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one), a bioactive flavonoid, has been reported to exercise anti-inflammatory, anti-neoplastic, and antioxidant effects, and may also possess lifespan-extending properties. However, any modifications of transmembrane ionic currents produced by corylin remain largely unknown. In pituitary GH3 somatolactotrophs, we found that the presence of corylin concentration-dependently augmented the magnitude of M-type K⁺ current (I_K(M)) with effective EC50 of 3.8 μM; concurrently, a shortening in activation time constant of the current was observed in its presence. Further addition of linopirdine (10 μM), an inhibitor of IK(M), but still in the presence of 10 μM corylin, almost fully suppressed I_K(M) amplitude. Application of this compound induced a leftward shift in the steady-state activation curve of I_K(M). The amplitude of I_K(M) elicited during pulse train stimulation was enhanced in its presence. The exposure to corylin could augment hysteretic strength of I_K(M) evoked by the long-lasting triangular ramp pulse; and corylin-enhanced strength was attenuated by further addition of linopirdine. Corylin-stimulated I_K(M) failed to be altered by subsequent addition of either carvedilol or iberiotoxin, but it was attenuated by dapagliflozin. The depolarization-activated I_K(M) was not affected by the presence of 17β-estradiol alone. Under cell-attached current recordings, the corylin application to bath increased the activity of M-type K⁺ (K_M) channels with minimal change in single-channel amplitude; however, the mean open time of the channel became lengthened in its presence. Corylin-stimulated K_M-channel activity was reversed by subsequent addition of either linopirdine or dapagliflozin. The erg-mediated current in GH₃ cells was slightly inhibited by exposure to corylin. The docking analysis showed the ability of corylin to bind to certain residues in KCNQ2 or KCNH2 by using hydrogen bond and hydrophobic contact. Collectively, the present findings provide evidence that corylin modulates ionic currents, with K_M (or KCNQ/KV7) channels serving as a key target underlying its in-vivo actions, as well as those of structurally related flavonoids. The ability of corylin or similar compounds to regulate ionic currents may contribute to their effects on the functional activities of neuronal, neuroendocrine or endocrine cells.

Abstract: Background/Objectives: Empagliflozin is an SGLT2 inhibitor prescribed for the management of type 2 diabetes mellitus, lowering blood glucose by increasing urinary glucose excretion (UGE) through inhibition of renal glucose reabsorption. PK/PD responses vary substantially across patient populations, complicating dose selection under altered organ function. Here, we developed a whole-body PBPK/PD digital twin integrating absorption, distribution, metabolism, and excretion with explicit modeling of renal glucose handling via the renal threshold for glucose. Methods: The model represents empagliflozin and its glucuronide metabolite, is implemented in SBML, and was calibrated and evaluated against curated PK/PD data from 27 clinical studies spanning healthy individuals, patients with type 2 diabetes, and cohorts with renal or hepatic impairment. Results: The model accurately captured observed clinical PK/PD data across all 27 studies, spanning a wide range of doses, dosing regimens, and patient populations. Good agreement between simulations and observations was obtained under normal and impaired renal and hepatic function, as well as under fasted and fed conditions, demonstrating the model's ability to reproduce empagliflozin disposition and pharmacodynamic response across clinically relevant scenarios. Conclusions: This SBML-based PBPK/PD digital twin provides quantitative insight into empagliflozin dose dependency and the impact of renal impairment, hepatic impairment, and food intake on PK/PD across clinically relevant populations. All model files, simulation scripts, and curated datasets are openly available in accordance with FAIR principles.

Abstract: Counter-current flow in channels separated by a membrane was studied by several scientists and researchers. The current study aims to analytically simulate and describe the distribution of pressure, volume flow rate, and velocity in square channels separated by a membrane. Consequently, the current study was executed using 1-D analytical solutions to achieve several significances: avoiding the experimental tests’ execution, reducing the effort of module design for expensive and time-consuming tasks, and easy observation of the variations in pressure, volume flow rate, and velocity. The 1-D analytical solution directly simulated the flow in square channels separated by a membrane to solve the continuity and Darcy’s Law, where pressure, volume flow rate, and velocity are calculated. The experiment module results were used to validate the results of the 1-D analytical solutions. The results of the current study found that the pressure decreases from the inlet to the outlet of the channel, and the horizontal velocity decreases from the inlet to the middle of the channel length and increases to the outlet of the channel. The result of the 1-D analytical solutions is characterized by acceptance accuracy compared with experimental module results. Consequently, the 1-D analytical solutions can be used to explore and display the distribution of pressure, volume flow rate, and velocity in square channels separated by a membrane with acceptance accuracy to examine the hemodialysis prototype module efficiency and performance before fabrication.