Securidaca inappendiculata (SI) Hassk. is a traditional Chinese herbal medicine commonly used in Southern China for the treatment of rheumatoid arthritis (RA). However, its exact mechanism of action remains unclear. In this study, we evaluated the therapeutic effects of the SI-derived compound 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) in a collagen-induced arthritis (CIA) rat model by measuring paw thickness, joint morphology, and histopathological changes. In vitro, cytotoxicity of XAN on RAW 264.7 macrophages was assessed using the Cell Counting Kit-8 (CCK-8) assay. Additional experiments, including real-time PCR, immunofluorescence, glycolytic metabolism analysis, Western blotting, and dual-luciferase reporter assays, were conducted to investigate the mechanisms underlying the anti-inflammatory effects of XAN. Results showed that XAN significantly alleviated arthritis severity in CIA rats. In RAW 264.7 cells, lipopolysaccharide (LPS) enhanced glycolysis and upregulated NAMPT and HIF-1α expression, whereas SIRT1 levels were reduced. XAN treatment reversed these effects by suppressing glycolysis in LPS-induced macrophages, indicating that its anti-inflammatory activity involves modulation of cellular energy metabolism. Further mechanistic studies revealed that XAN attenuates inflammation by regulating the SIRT1/HIF-1α/glycolysis signaling axis in macrophages. These findings underscore the role of energy metabolism in macrophage polarization and suggest that targeting this pathway may represent a promising therapeutic strategy for RA.
Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed but are associated with adverse drug reactions (ADR), including angioedema, which is typically reported in 0.1%-0.7%. Data from sub-Saharan Africa are limited. This study aimed to estimate the incidence and risk factors of enalapril-associated ADRs in a Zambian cohort, with particular focus on angioedema. We conducted an ambispective cohort study of 400 adults initiating enalapril at two tertiary hospitals in Lusaka, Zambia. Enalapril was the only ACEI available to the participants, and the primary outcome was the occurrence of enalapril-associated ADRs requiring treatment discontinuation or modification. Kaplan-Meier methods were used to estimate event-free survival, and Cox proportional hazards regression was used to identify factors associated with ADR occurrence. Angioedema occurred in 19/400 participants (4.8%). Overall, 22% (88/400) of participants experienced at least one ADR impacting treatment. The most frequent ADRs were cough (10.3%) and dizziness (5.0%). In multivariable analysis, male sex was independently associated with a lower risk of ADR (adjusted hazard ratio [aHR] 0.59, 95% CI 0.37-0.93). No significant associations were identified for the high rate of angioedema. The incidence of enalapril-associated angioedema in this cohort was substantially higher than that reported in global as well as African American populations. These findings have clinical relevance for prescribing and monitoring ACEIs in sub-Saharan African populations. Further studies are needed to confirm this signal and explore underlying mechanisms.
Contemporary pharmacotherapy has improved disease-specific outcomes, but prescribing for multimorbidity remains largely guideline-driven, endpoint-focused, and insufficiently sensitive to cumulative treatment burden in patients with limited physiological reserve. Mitochondrial dysfunction and redox imbalance are shared biological processes that shape disease vulnerability, adaptive capacity, and susceptibility to drug-related toxicity; however, they are rarely operationalized in medication review or deprescribing. This mechanism-informed narrative review integrates mechanistic, translational, and clinical literature on redox-mitochondrial biology, drug-class-specific mitochondrial liabilities, polypharmacy, frailty, and deprescribing, with searches conducted through 2024 and targeted updates through June 2026. Primary clinical and preclinical examples are used to illustrate pharmacological plausibility for selected drug classes, and structured tables and a prioritization algorithm translate these concepts into pragmatic medication-review signals. We propose redox-mitochondrial reasoning as a complementary lens for interpreting treatment intolerance, functional decline, and cumulative medication burden as possible evidence of mismatch between pharmacological exposure and a patient's adaptive capacity. The proposed framework is explicitly conceptual: its vulnerability strata, algorithm, and decision categories are heuristic aids rather than validated clinical prediction instruments. It should therefore be used only alongside established deprescribing tools, individualized benefit-harm assessment, and shared decision-making.
Metabolic associated fatty liver disease (MAFLD) has high morbidity and tragically lacks effective therapeutic remedies. Tormentic acid (TA) has been shown to have therapeutic effect on liver fibrosis, but its role in MAFLD remains unknown. Therefore, we employed multi-omics analyses to investigate the effects of TA on MAFLD. In this study, male C57BL/6J mice were fed a methionine- and choline- deficiency (MCD) diet to induce MAFLD and subsequently treated with TA for 4 weeks. The therapeutic efficacy of TA was then evaluated through histopathological examination and biochemical analysis. In addition, multi-omics analyses including transcriptomics, proteomics and metabolomics were conducted to identify potential pathways associated with TA treatment. Finally, key genes and proteins in the identified pathways were validated by qPCR and Western blot. Our results showed that TA significantly alleviated liver damage and excessive lipid accumulation. Importantly, our integrative multi-omics analyses identified tryptophan metabolism and glycolysis as pivotal pathways associated with TA treatment in our fatty liver mouse model. Subsequent validation demonstrated the TA-induced upregulation of IDO2 and HAAO, suggesting engagement of tryptophan metabolism. Concurrently, TA treatment downregulated HK2, PFKP, and PKM2, indicative of altered rate-limiting glycolytic enzyme expression. These findings suggest that TA alleviates MCD diet-induced MAFLD, potentially involving modulation of enzyme expression in tryptophan metabolism and glycolysis.
ABSTRACT Hyperuricemia (HUA) is primarily driven by hepatic overproduction of urate, mediated by xanthine dehydrogenase (XDH). This preclinical study evaluates YJH‐012‐D, a N ‐acetylgalactosamine (GalNAc)‐conjugated small interfering RNA (siRNA) targeting hepatic XDH . Functional assays demonstrated that YJH‐012‐D potently suppressed both XDH mRNA and protein expression in primary hepatocytes. In mice, a single subcutaneous dose of 8 mg/kg significantly reduced serum uric acid levels and suppressed hepatic XDH expression for more than 42 days. In cynomolgus monkeys, administration of YJH‐012‐D at 10 mg/kg lowered serum uric acid for up to 180 days, with sustained XDH inhibition observed for 120 days. Pharmacokinetic analysis revealed a high liver‐to‐plasma area under the curve (AUC) ratio (2000–6100) and a hepatic half‐life exceeding 10 days, consistent with prolonged pharmacological activity. Comprehensive toxicity assessments—including clinical biochemistry, histopathology, and RNA sequencing (RNA‐seq)‐based off‐target profiling—identified no significant adverse effects. Collectively, YJH‐012‐D exhibits potent, durable urate‐lowering efficacy and a favorable safety profile, underscoring its potential as a novel therapeutic candidate for HUA.
ABSTRACT Hyperuricemia, characterized by elevated serum uric acid (SUA) levels, is increasingly recognized as a pathological contributor to renal injury through oxidative stress, inflammation, and apoptosis. Hirudin, a thrombin inhibitor derived from leech saliva, has recently been noted for its anti‐inflammatory properties, yet its role in hyperuricemia remains unclear. This study aimed to investigate the protective effects and underlying mechanisms of hirudin in a uric acid (UA)‐induced renal tubular epithelial injury model. Using HK‐2 cells, we found that hirudin enhanced cell viability and reduced apoptosis in UA‐treated conditions. Mechanistically, these protective effects were mediated through downregulation of TNFRSF6B, a decoy receptor involved in inflammatory and apoptotic signaling. TNFRSF6B knockdown potentiated hirudin's cytoprotective effects, whereas its overexpression reversed them. Hirudin treatment attenuated UA‐induced expression of urate transporters (URAT1, GLUT9, and OAT4) and pro‐inflammatory cytokine IL‐1β, both at the transcriptional and protein levels. Moreover, hirudin suppressed activation of the NF‐κB signaling pathway, a critical mediator of inflammation and apoptosis in hyperuricemia, with transcriptomic and immunoblotting data confirming downregulation of NF‐κB‐associated targets. Co‐treatment with JSH‐23, an NF‐κB inhibitor, further reinforced these findings and highlighted a TNFRSF6B/NF‐κB axis as a key regulatory mechanism. Collectively, these findings reveal a novel protective role for hirudin in UA‐induced renal injury, mediated via modulation of TNFRSF6B and suppression of NF‐κB signaling. This study provides new insight into the potential therapeutic application of hirudin in hyperuricemia‐associated kidney damage.
ABSTRACT Hematological malignancies remain one of the leading causes of morbidity and mortality despite advances in targeted therapies, immunotherapy, and stem cell transplantation. Emerging evidence indicates that treatment efficacy and toxicity depend not only on the choice of therapy but also on its timing relative to the patient's internal circadian rhythm. The circadian clock orchestrates fundamental processes in hematopoiesis and immunity, such as stem‐cell proliferation, leukocyte trafficking, DNA repair, and drug metabolism, while its disruption promotes malignant transformation, therapeutic resistance, and systemic toxicity. This narrative review synthesizes current understanding of circadian regulation in hematopoietic and immune systems, the mechanistic and preclinical foundations of chronotherapy in blood cancers, and the limited but growing body of clinical evidence linking treatment timing with outcome in leukemia, lymphoma, and transplantation. The review also examines practical challenges, including inter‐individual variability, disease‐induced circadian disruption, and hospital workflow constraints, while highlighting emerging technologies, such as transcriptomic clocks, wearable biosensors, and AI‐driven scheduling algorithms, that are poised to enable personalized, time‐aware therapy. By integrating temporal precision into existing therapeutic frameworks, chronotherapy may represent a promising investigational dimension of precision medicine in hematological oncology. However, its clinical value remains to be defined through prospective studies that incorporate validated circadian biomarkers, predefined timing windows, and clinically meaningful efficacy and toxicity endpoints.
ABSTRACT CD148 is the primary receptor‐type protein tyrosine phosphatase (PTP) regulating platelet activation, and its inhibition has been proposed as a novel anti‐thrombotic strategy with potentially lower bleeding risk than current therapies. However, selective and potent inhibitors of CD148 are currently lacking. AKB‐9778 (razuprotafib), a potent inhibitor of the closely related vascular endothelial‐PTP (VE‐PTP), has also been reported to inhibit CD148. This study investigated the effect of AKB‐9778 on in vitro whole‐blood thrombogenicity, examined the molecular basis of its interaction with the CD148 catalytic domain using molecular docking, and assessed inhibitor selectivity with an in vitro phosphatase assay. In a total‐thrombus formation analysis system (T‐TAS), AKB‐9778 partially inhibited thrombus formation, reducing AUC 10 by 28%, without significantly affecting occlusion start time or occlusion time. The inhibitor did not alter collagen‐stimulated CD62P platelet surface expression or PAC‐1 binding to the activated integrin αIIbβ3. Molecular docking using CB‐Dock predicted a binding configuration in which the phenylsulfamic acid group of AKB‐9778 is orientated towards the catalytic cysteine, with additional conformations reflecting ligand flexibility. Site‐directed mutagenesis of Tyr1071, Gln1283, His1206, and Asn1073 to alanine reduced the inhibitory effect in phosphatase assays, supporting interaction with these residues. Notably, the IC 50 of AKB‐9778 against CD148 was approximately 300‐fold higher than previously reported values, consistent with the wide variability across studies. Despite this reduced potency, these findings support the concept of CD148 inhibition as a potential anti‐thrombotic strategy and suggest that AKB‐9778 may serve as a useful prototype for developing more selective and efficacious CD148 inhibitors.
ABSTRACT Liver fibrosis is the common consequence of liver injury caused by a variety of chronic liver disorders. This condition leads to the development of more severe complications, particularly cirrhosis and hepatocellular carcinoma. Despite abundant studies, the fundamental cell and molecular mechanisms of liver fibrosis are still unknown. There are many key players involved in the initiation and progression of liver fibrosis. Thus, the specific type of underlying disease and the study's objectives should be considered while choosing suitable models for liver fibrosis. Numerous in vitro and in vivo models have been generated to investigate liver fibrosis and proposed for drug screening and toxicology; however, there are no ideal in vitro models for drug discovery yet. In this review, we introduced the available in vitro models and highlighted certain platforms such as organoids and liver‐on‐a‐chip for investigating liver fibrosis. Furthermore, we discussed the current challenges and potential application of each model.
ABSTRACT Despite advances in targeted and immunotherapy for melanoma, resistance to treatment and severe adverse effects pose significant challenges. This necessitates the development of new treatment strategies, and cannabinoids, because of the extensive preclinical evidence for their cytotoxic action on carcinoma cells in a variety of cancers, can offer a novel therapeutic option when used appropriately. Indeed, the potential therapeutic benefits of cannabinoids were formally recognized in the world and much more recently in the United Kingdom when cannabis‐based medicinal products were moved from Schedule 1 of the Misuse of Drugs Regulations 2001 to Schedule 2 in 2018. This move further encouraged scientists to look at more applications of cannabinoids in different disorders. Although the potential psychoactivity of cannabis as a Schedule 1 drug hinders research, more research could focus on non‐psychoactive components such as cannabidiol (CBD) and cannabigerol (CBG). This review summarizes some past and current research on the relationship between the cannabinoid system and the microbiome in patients with metastatic melanoma who undergo immunotherapy. The review also provides a comprehensive background on the function of the cannabinoid system in normal and diseased skin, as well as future directions in using cannabinoids as an adjunct to chemotherapeutics in the treatment of the disease.
ABSTRACT The FDA has mandated a Boxed Warning for glatiramer acetate (GA) due to the risk of serious anaphylactic reaction. This study aimed to characterize the reported features of GA‐associated anaphylaxis. Data mining was performed using the Reporting Odds Ratio (ROR) in the FDA Adverse Event Reporting System (FAERS) database (Q1 2004–Q1 2025) and the Canadian Vigilance Adverse Reaction (CVAR) database (Q1 1996–Q1 2025). Demographic characteristics, time‐to‐onset (TTO), and case seriousness were compared using the Mann–Whitney U test or the Chi‐squared ( χ 2 ) test. In the FAERS database, 9816 reports were identified with 29 significant disproportionality signals. Younger age ( p < 0.01) was significantly associated with a higher proportion of serious reports. The association between GA and anaphylactic AEs remained statistically significant after stratification by age, body weight, sex, and reporter types. Twenty AEs demonstrated significantly higher reporting rates in serious cases ( p < 0.05). Clinical prioritization identified 9 moderate‐priority and 20 weak‐priority signals. The median TTO was 197 days for moderate‐priority signals versus 153 days for weak‐priority signals. All signals exhibited early failure‐type patterns, indicating that reported anaphylactic events were more frequently observed earlier after treatment initiation than later in treatment. In the CVAR database, 711 reports were identified. A total of 17 PTs overlapped with FAERS, with respiratory arrest uniquely present in CVAR. Three PTs were rated as moderate priority in the CVAR database but weak priority in FAERS. This large‐scale pharmacovigilance analysis of the FDA and Canadian databases characterizes the safety signals derived from GA‐associated reports of anaphylaxis, providing a hypothesis‐generating foundation for future pharmacovigilance validation.
SLC15A4 is a member of the solute carrier superfamily that has been strongly linked to the pathogenesis of the auto-immune disease SLE. The endo-lysosomally localized SLC15A4 has traditionally been considered a proton-dependent histidine and peptide transporter, but has also been shown to facilitate TLR7, 8, and 9 induced IFN-alpha signaling in B cells and pDCs. New research has shown that SLC15A4 facilitates endo-lysosomal TLR signaling through a scaffolding interaction with a newly identified signal transducer, termed TASL. This interaction enables TLR7, 8, and 9 induced IRF5 activation, which is a crucial pathway in the pathogenesis of lupus. SLC15A4 is therefore an attractive target for the development of drugs for the treatment of SLE, and several small molecule SLC15A4 binders have now been reported which are capable of inhibiting TLR7, 8, or 9 signaling. This review summarizes the SLC15A4:TASL complex, its link to SLE, existing evidence for the transporter activity of SLC15A4, the current small molecule binders, and tools available for further drug discovery efforts.
ABSTRACT The pregnane X receptor (PXR) gene encodes a ligand‐activated protein involved with the metabolism and excretion of drugs, toxins, and other xenobiotics. The PXR protein is also an orphan nuclear receptor with a broad spectrum of potential ligands, including common prescription drugs, that can act as agonists or antagonists. Once activated, PXR upregulates several target genes involved in xenobiotic metabolism and can influence lipid and glucose metabolism, as well as the metabolism of commonly used drugs. In this review we searched the primary literature for articles reporting on drugs that regulate PXR and discuss potential clinical implications. Using the databases CINAHL, Embase, Medline, Scopus and Web of Science, we searched for terms related to PXR, following PRISMA guidelines. We screened 12 236 studies, 101 of which met the inclusion criteria, and included a further 46 research and review articles. We identified 42 studies reporting on prescription medications and 40 on non‐prescription medications that regulate PXR as agonists or antagonists, and 47 studies reporting both beneficial and detrimental PXR‐mediated effects of drugs on specific diseases, including different cancers, metabolic diseases, and inflammatory conditions, among others. We conclude that PXR is regulated by a broad range of drugs. Downstream effects of this regulation affect different diseases, leading to clinically relevant outcomes, such as altered efficacy of drugs or changes to the pathophysiology of a disease. Understanding and managing the agonist or antagonist role of drugs on PXR holds great potential to improve the health outcomes of different diseases. However, more information is needed about the potency of known PXR regulators.
ABSTRACT Opioids, most intravenous anesthetics and various illicit substances can cause fatal respiratory depression by depressing central respiratory networks. ENA‐001, a ventilatory modulator targeting the carotid bodies, has emerged as a potential countermeasure without impairing analgesia or hypnosis. We conducted a literature review to evaluate the efficacy and safety of ENA‐001. This scoping review summarizes the current evidence base for ENA‐001 from in vitro, animal experiments, and human volunteer studies. A comprehensive search was conducted across several electronic databases to identify all available literature describing its effects as a respiratory stimulant and as a reversal agent of drug‐induced respiratory depression. We identified eight relevant publications, four describing data in humans and four using animal models (mice, rats, and non‐human primates). ENA‐001 increased ventilation and attenuated respiratory depression induced by morphine and the combination of xylazine and fentanyl. The primary site of action was localized to the carotid bodies, specifically the pore‐forming α‐subunit of the KCa1.1 (BK) channel. In humans, ENA‐001 increased minute ventilation and reduced end‐tidal carbon dioxide under poikilocapnic conditions. In experimental human models of alfentanil‐ and propofol‐induced respiratory depression, ENA‐001 significantly improved isohypercapnic minute ventilation and fully restored the hypoxic ventilatory response, respectively, without impairing sedation or analgesia. Across all studies, the safety profile was favorable, with no serious adverse events reported. In conclusion, ENA‐001 is a first‐in‐class, peripherally acting respiratory stimulant that effectively reverses drug‐induced respiratory depression. These findings support its continued clinical development for opioid‐ and anesthetic‐induced respiratory compromise.
ABSTRACT Pharmacokinetics is fundamental to drug discovery, therapeutic optimization, and patient safety. Despite its importance, students consistently demonstrate limited mastery of pharmacokinetic core concepts. Studies reveal that students have persistent misconceptions of pharmacokinetic core concepts, difficulty applying mathematical principles, and challenges in transferring theoretical knowledge to medical and biomedical practices. Contributing factors include mathematical skill deficits upon entering university programs, fragmented curricular integration, and limited opportunities for active application of knowledge. These gaps raise concerns about the preparedness of graduates entering health professions and drug design/discovery fields, where pharmacokinetic competence directly impacts the fundamentals of drug discovery, therapeutic optimization, and patient safety. In addition to student challenges with learning pharmacokinetics, this commentary highlights innovative teaching strategies for educators to support student comprehension and application of pharmacokinetic core concepts. Approaches such as team‐based learning, case‐based exercises, simulations, games, and prerequisite review tutorials have shown promise in strengthening conceptual understanding and bridging theory with practice. These strategies have largely been studied in isolated contexts, underscoring the need for broader evaluations examining how course design, delivery methods, and teaching strategies shape student learning of pharmacokinetic core concepts. Future research could explore pharmacology educator and student perspectives on pharmacokinetics to develop an international framework for pharmacokinetics education. Such a framework would ensure progressive reinforcement of core concepts, integration across curricula, and alignment of teaching practices with real‐world application, ultimately preparing students for diverse careers where pharmacokinetics proficiency is essential.
ABSTRACT Medication errors, often arising from insufficient pharmacology knowledge, can have serious consequences, highlighting the importance of effective pharmacology education for health care students. This study hypothesized that virtual reality (VR) could improve student engagement, motivation and perceived learning of core concepts in pharmacology. A mixed‐method approach was employed. Students who had completed a course in basic pharmacology were recruited from five international study sites to view a VR animation, explaining drug absorption and bioavailability. The students responded to an online questionnaire exploring their experience and understanding. In addition, 13 medical students from the University of Bergen participated in focus group interviews to further explore their perceptions of VR in pharmacology education. A total of 133 students participated in the VR session and completed the questionnaire, with approximately half reporting that the VR animation changed their understanding of drug absorption. Thematic analysis of the focus group interviews produced three themes descriptive of the students' learning experiences, each pivoting tensions between: (1) The role of VR in integrating pharmacology with other medical disciplines; (2) striking a balance between engaging and overwhelming learning experiences; (3) in‐depth learning under the weight of assessment. The technical solution appears satisfactory, and students found the 360° VR animation engaging and useful for visualizing the complex concepts of absorption and bioavailability. VR animation shows potential to enhance integration of pharmacology to other medical disciplines. However, careful design is required to support self‐paced learning and minimize cognitive overload.
ABSTRACT Pharmacology education, often reputed as complex, overtly didactic and decontextualised, may benefit from artificial intelligence‐supported strategies. However, current guidance is fragmented across disciplines and contexts, thus weakening evidence‐based curricular implementation. This scoping review mapped existing research to identify applications, strengths, limitations, and areas for future development. A double‐blinded screening process facilitated by Covidence yielded 17 eligible studies from four databases. Studies mostly comprised cross‐sectional studies from high‐income countries in the medical context, with generative artificial intelligence being predominant (ChatGPT‐3.5 and ChatGPT‐4.0). Research comprised assessment ( n = 12), paedagogy ( n = 4), curriculum design ( n = 1), and programme evaluation ( n = 1). Most studies assessed tools' ability to answer examinations, with mixed success depending on the version, question type, and inclusion of context in prompt engineering. Few studies incorporated students, limiting insights into learning impact. Zero‐shot prompting was mostly used, limited further by unclear design frameworks, which may bias outcomes considering downstream inefficiencies. Current research prioritises the performance of artificial intelligence, rather than its integration or impact in learning, which reduces its applicability for curriculum design and competency development. Although promising, the impact is limited, requiring clearer instructional design and rationalisation within the education ecosystem. Although there is considerable potential for pharmacology education, research requires greater structure, longitudinal design, and incorporation of students to inform clear impact. Purposeful, context‐aligned implementation and continuous evaluation are needed to ensure ethical, valid, and meaningful use in pharmacology education. To support future research, recommendations are provided for practical reporting, scientific design, and impact measurement.
