Frontiers in Pharmacology最新文献

Background: Systematically evaluate the effects of Kang'ai Injection (KAI) combined with platinum-based chemotherapy on immune function, clinical efficacy, and safety in patients with advanced non-small cell lung cancer.

Materials and methods: Relevant literature published from the inception of each database through September 2025 will be identified through systematic searches of Chinese and English electronic databases. Randomized controlled trials (RCTs) evaluating Kang'ai injection combined with chemotherapy for advanced non-small cell lung cancer will be screened against predefined inclusion and exclusion criteria. Two investigators will independently perform data extraction and quality assessment. Meta-analyses will be conducted using RevMan 5.3 and Stata 18.0 software. Publication bias will be assessed using funnel plots and Egger's test, while the robustness of findings will be examined through trial sequential analysis (TSA). The quality of evidence for critical outcomes will be evaluated using the GRADE approach.

Results: A total of 14 randomized controlled trials involving 1,214 patients were included. The meta-analysis demonstrated that compared with chemotherapy alone, KAI combined with chemotherapy significantly improved the objective response rate and enhanced immune function parameters, including increased CD3⁺ and CD4⁺ T-cell counts, elevated CD4⁺/CD8⁺ ratio, and higher natural killer cell percentage, while reducing CD8⁺ T-cell percentage. The combination therapy group also showed superior outcomes in reducing tumor marker and vascular endothelial growth factor levels compared to the chemotherapy-alone group. Furthermore, combination treatment significantly reduced the incidence of chemotherapy-related adverse reactions including leukopenia, myelosuppression, nausea and vomiting, and gastrointestinal reactions.

Conclusion: As an adjunctive therapy, KAI can enhance immune function (low-quality evidence), improve the objective response rate to chemotherapy (moderate-quality evidence), and alleviate chemotherapy-related toxicities (predominantly moderate-quality evidence) in patients with advanced NSCLC, providing an evidence-based reference for comprehensive clinical management.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251168090.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by a lipid overload-induced pathological cascade featuring hepatocyte injury, inflammation, and progressive fibrosis. This study aims to systematically investigate the role of EMMPRIN in MASH progression, and to elucidate its mechanisms in reprogramming the hepatic metabolic microenvironment.

Methods: Murine models induced by methionine-choline -deficient diet, hepatocyte-specific EMMPRIN overexpression and knockout mice models were used to evaluate EMMPRIN' roles in steatohepatitis. Parallel in vitro studies were conducted in corresponding cellular models. Proteomic sequencing, mass spectrometry, co-immunoprecipitation, Western blotting, quantitative PCR, and immunofluorescence were employed to identify downstream targets and characterize ubiquitination modifications.

Results: EMMPRIN overexpression significantly exacerbated MASH phenotypes, including hepatic steatosis, inflammatory infiltration, and collagen deposition. Conversely, EMMPRIN knockout conferred substantial protection against these pathological changes both in vivo and in vitro. Mechanistically, EMMPRIN downregulated UBA52 expression, resulting in reduction in the free ubiquitin pool and subsequent decrease in K63-linked polyubiquitination of monocarboxylate transporter 1 (MCT1). This ubiquitination defect led to destabilization of MCT1 and was associated with a global increase in protein lactylation in EMMPRIN-deficient models. Furthermore, EMMPRIN suppression inhibited several signaling pathways critically involved in MASH pathogenesis, including PPAR signaling, Notch signaling, and TGF-β-mediated fibrotic response.

Conclusion: Our findings demonstrate that EMMPRIN promotes MASH progression through the UBA52-MCT1 regulatory axis, which modulated ubiquitin-dependent protein stability and induced metabolic reprogramming, thereby driving lipid accumulation, inflammation, and fibrosis. These results position EMMPRIN as a promising therapeutic target for MASH intervention.

The increasing use of extended kidney grafts to bridge organ shortage has led to delayed and impaired graft function, warranting the development of new preservation strategies. In addition to hypothermic machine perfusion, the addition of pharmacological agents to preservation solutions has been primarily investigated, with a few promising agents making their way into clinical trials. This review aimed to identify and summarize current literature studies on pharmacological treatment additives for hypothermic kidney graft preservation. A scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive literature search was performed using Medline and Cochrane Library databases until 1 December 2023. All studies published in English reporting on pharmacological supplementation of preservation solutions to improve hypothermic kidney graft preservation were included. A total of 67 records were retrieved, all of which were preclinical except one. Of these, 8 were conducted on cellular models, 21 on ex vivo kidneys, and 38 on animal kidney transplantations. A total of 40 pharmacological agents were evaluated based on the key markers of ischemia-reperfusion injury (IRI) pathophysiology, most of them showing promise in kidney preservation. Although promising, with numerous preclinical studies identifying various effective additives, the pharmacological treatment additive strategy to improve hypothermic kidney preservation has still not been translated into clinical practice. Clinical investigations should be promoted to support few ongoing trials offering encouraging outcomes.

Background: The relationship between oral iron preparation-related gastrointestinal adverse events (AEs) and medication adherence in female patients with iron deficiency anemia (IDA) remains unclear.

Objective: To assess gastrointestinal AEs linked to oral iron preparations via the US FDA Adverse Event Reporting System (FAERS), evaluate medication adherence levels in female IDA patients, and analyze the impact of gastrointestinal AEs and other factors on their medication adherence.

Methods: Reporting odds ratio (ROR) and Proportional Reporting Ratio (PRR) were used to analyze oral iron preparation-related gastrointestinal AEs. The Medication Adherence Report Scale-5 (MARS-5) was used to assess patients' medication adherence, while logistic regression analyzed the impact of factors (gastrointestinal AEs, medication beliefs, illness perception, doctor-patient relationship, social support) on medication adherence.

Results: FAERS recorded 2,624 reports of gastrointestinal AEs following oral iron supplementation in female patients with IDA (January 2000-March 2025). Disproportionality analysis indicated that ferrous fumarate exhibited the weakest gastrointestinal AE disproportional reporting signal (ROR = 0.36, 95% CI 0.27-0.48; PRR = 0.44), with no positive signals detected, whereas ferrous gluconate displayed the strongest signal (ROR = 2.62, 95% CI 2.05-3.34; PRR = 1.90) and the most prominent positive signals. No significant gastrointestinal AE disproportional reporting signals were found for ferrous sulfate or iron polysaccharide complex. A cross-sectional study (148 patients) showed that adherent patients and non-adherent patients accounted for 64.86% and 35.14%, respectively. Multivariate logistic regression analysis indicated that gastrointestinal AEs were not significantly associated with medication adherence, while medication concern beliefs, doctor-patient relationship, and hemoglobin level were important factors affecting medication adherence in female IDA patients.

Conclusion: Gastrointestinal AEs are not a key factor affecting medication adherence. Reducing patients' medication concerns, improving the doctor-patient relationship and reinforcing counseling to avoid premature medication withdrawal due to elevated hemoglobin levels are beneficial to enhancing medication adherence in female IDA patients.

Neglected tropical diseases (NTDs) are a distinct group of illness that are primarily prevailing in the tropical regions. NTDs are caused by diverse pathogens including viruses, bacteria, parasites, fungi and toxins, resulting in adverse health, social and economic outcomes. Currently, more than one billion people globally are affected with NTDs, therefore, precise and rapid diagnostic mechanisms are integral for detection and control of NTDs. However, the NTDs programs are underinvested in the progression and enhancement of diagnostic tools. Due to this reason, WHO has released a new road map for NTD 2021-2030 and has pinpointed diagnostics as one of the precedence areas that require concrete action. In order to achieve the 2030 targets, WHO has also established Diagnostic Technical Advisory Group (DTAG) which will help in initiating collaboration among nations to drive advancement in this area. In this review, we explored the epidemiology and burden of NTDs, the challenges in their mitigation, and the available therapeutic interventions for managing these diseases. We have also highlighted the need to holistic approach like "One health" for an effective elimination of NTDs in affected areas. Elimination of NTDs will enhance the socioeconomic levels of the affected regions, thereby assisting in the accomplishment of few sustainable development goals. Thus, there is a need for worldwide commitment for funding to develop fast and safe therapeutic and diagnostic strategies for NTDs.

Background: With the development of cardiac rehabilitation (CR), the advantages of combined Chinese and Western medicine cardiac rehabilitation for the treatment of stable coronary artery disease (SCAD) have become increasingly prominent.

Purpose: This study was aimed to evaluate the effect of Zhenyuan capsule (a Chinese patented medicine consisting of ginseng berry saponins extracted from the mature berry of Panax Ginseng) on cardiorespiratory fitness (CRF) in patients with SCAD, and explore possible potential candidate molecule.

Study design and methods: Using a randomized, double-blind, placebo-controlled trial design, 100 patients with SCAD were enrolled and randomly divided into the group taking Zhenyuan capsules (test group, n = 50) and the group taking placebo (control group, n = 50). In both groups, patients were treated with secondary prevention medication for CHD, with the addition of 2 capsules of Zhenyuan capsule 3 times a day for 12 weeks in the test group and 2 capsules of placebo 3 times a day for 12 weeks in the control group, with a follow-up of 1 month after the end of treatment. Subjects completed symptom-limited maximal cardiopulmonary exercise test (CPET) on a bicycle ergometer at 3 time points before enrollment, after 12 weeks of treatment, and after 1 month of follow-up. The main outcome was the increase in metabolic equivalent.

Results: Both at anaerobic threshold (AT) level and at maximal level, the results of between-group comparisons showed that the test group was significantly better than that of the control group after treatment (AT level: 0.58 ± 0.89 Mets vs. 0.15 ± 1.06 Mets; maximal level: 0.69 ± 0.92 Mets vs. 0.19 ± 0.93 Mets) (P < 0.05). No serious adverse events occurred in patients in both groups. Serum proteomics studies suggested that insulin-like growth factor II (IGF2) was downregulated in a minority of responders, potentially related to cholesterol metabolism and the PI3K-Akt pathway.

Conclusion: Zhenyuan capsule can significantly improve the CRF of patients with SCAD, and the downregulation of IGF2 observed in a minority of responders suggests IGF2 may be a potential candidate molecule of interest associated with cholesterol metabolism and the PI3K-Akt pathway.

Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=53361, identifier ChiCTR2000032818.

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease. Statins are the first choice LDL-C-lowering drugs, but often associated with musculoskeletal disorders (MSDs), limiting adherence. Bempedoic acid (BA) is a newer LDL-C-lowering prodrug acting upstream of statins with limited muscle tissue activation, offering an alternative to statin-intolerant patients. However, recent evidence suggests a higher-than-expected rate of muscle-related adverse drug reactions (ADRs). This study compares muscle-related ADRs for BA and atorvastatin (ATO) using the European spontaneous reporting system.

Methods: ADRs reports were extracted from the earliest available date to 30 June 2024 and categorized by patient demographics and ADR type. Disproportionality analysis via Reporting Odds Ratios (RORs) was performed to assess differences in muscle-related ADRs between BA and ATO.

Results: A total of 78,930 ADR reports, respectively 2,667 for BA-only, 76,137 for ATO-only and 126 for coadministration, were analysed. MSDs were the most frequently reported events, significantly higher in BA-only than ATO-only recipients (ROR 2.25, 95% CI 2.08-2.43). Musculoskeletal and muscle discomfort showed the highest odds of association with BA (6.97, 95% CI 4.46-10.91 and 6.37, 95% CI 4.58-8.85, respectively). Conversely, more severe conditions such as creatine phosphokinase increase (ROR 0.44, 95% CI 0.34-0.57) and rhabdomyolysis (ROR 0.05, 95% CI 0.02-0.10) were more frequently reported for ATO-only recipients. Overall, muscle-related ADRs reported for BA showed lower severity.

Conclusion: Using a Registry-based approach, we found increased odds of muscle-related ADR reports in BA recipients compared to ATO, although characterized by more favourable clinical outcomes. It is suggested to pay increased attention to consider drug-related causes of muscle symptoms when BA is used, particularly when in combination with statins.

Background: Hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), are characterized by high relapse rates due to intrinsic and acquired drug resistance. Resistance mechanisms often involve dysregulation of apoptosis pathways, such as B-cell lymphoma 2 (BCL2) family overexpression, and immune evasion through microenvironment modulation.

Purpose: This review synthesizes recent advances (2020-2025) in therapeutic strategies targeting these mechanisms, focusing on BCL2 inhibition and immunomodulatory approaches to overcome resistance and improve outcomes.

Methods: We systematically reviewed literature from PubMed, Nature, and other databases, emphasizing clinical trials, mechanistic studies, and emerging combinations published between 2020 and 2025. Main Findings: BCL2 inhibitors like venetoclax have achieved high response rates (ORR >70%) in CLL and AML but face resistance via MCL1/BCL-XL upregulation. Next-generation agents (e.g., sonrotoclax) and combinations address this. Immunomodulatory therapies, including immunomodulatory imide drugs (IMiDs) and chimeric antigen receptor T-Cell immunotherapy (CAR-T cells), enhance T/NK cell activity, with objective response rate (ORR) up to 90% in relapsed MM. Integrated strategies combining BCL2 inhibition with immunotherapy show synergistic effects, improving progression-free survival (PFS) by 30%-40%.

Conclusion: These strategies represent a paradigm shift toward precision medicine, but challenges like toxicity and biomarker-driven resistance persist. Future directions include AI-guided predictions and novel degraders like proteolysis-targeting chimeras (PROTACs).

Background: Ershiyiwei Lvronghao Concentrated Pills (ESYWLRHW) is the concentrated pill developed and prepared based on the classical prescription in Xizang: Ershiwuwei Lvronghao Pills (ESWWLRHW). However, its effect on nonalcoholic fatty liver disease (NAFLD) remains unclear. The aim of this study is to clarify the therapeutic effect and mechanism of ESYWLRHW on NAFLD.

Methods: High-Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry/Mass Spectrometry (HPLC-Q-TOF-MS/MS) was used to analyze the components of ESYWLRHW. The NAFLD model was established by feeding Sprague-Dawley (SD) rats with high-fat diet (HFD) for ten consecutive weeks, and different doses of ESYWLRHW and positive drugs were given for intervention treatment in the last 6 weeks. The pathological and molecular changes of rats in each group were determined after the whole experimental procedure with pathological sections and ELISA experiments, and the metabolomics, proteomics and transcriptomics were used to investigate the possible mechanism.

Results: In this study, 206 compounds of ESYWLRHW were identified. In vivo experiments, ESYWLRHW administration significantly ameliorated the pathological manifestations in NAFLD model rats, including attenuating the abnormal body weight gain, reducing the accumulation of hepatic and peripheral fat, and improving dyslipidemia, liver function, and systemic inflammatory response. Metabolomic analysis further revealed that ESYWLRHW treatment upregulated the levels of specific metabolites, such as 12-keto-leukotriene B4 (12-keto-LTB4), 20-COOH-LTB4, glycocholate (GCA), and dehydroepiandrosterone sulfate (DHEAS). Integrated multi-omics analysis and subsequent verification indicated that the therapeutic effects of ESYWLRHW might be mediated by modulating the expression of Peroxisome Proliferator-Activated Receptors (PPARs), which in turn regulated downstream signaling pathways including nuclear factor erythroid 2-related factor 2 (Nrf2) and the Nuclear Factor-kappa B (NF-κB)/NOD-like receptor family, pyrin domain-containing 3 (NLRP3)/Caspase-1 axis.

Conclusion: In summary, ESYWLRHW can regulate the three metabolic pathways: arachidonic acid metabolism, primary bile acid biosynthesis and steroid hormone biosynthesis, and improve oxidative stress and inflammation in NAFLD rats by regulating the expression of PPARs protein, and ultimately alleviate NAFLD.

Objective: This study aimed to evaluate the availability, price levels, affordability, and utilisation of targeted drugs for pulmonary arterial hypertension (PAH) in China.

Methods: This study utilized a retrospective longitudinal design, based on drug procurement data from 859 public hospitals in China, covering the period from January 2019 to December 2023. Accessibility of 11 PAH-targeted therapies was evaluated across three key dimensions: availability (proportion of hospitals stocking the drug), price level (the Defined Daily Dose cost, namely, DDDc = Total annual drug expenditure/DDDs of the drug), and affordability (out-of-pocket expenses as a percentage of household disposable income).

Results: While there was a significant overall improvement in the accessibility of PAH-targeted drugs, structural disparities in accessibility were evident across different drug types, hospital tiers, and between urban and rural areas, as well as among income groups. Availability data showed that tertiary hospitals had significantly better access to NMI-negotiated drugs than secondary hospitals (p = 0.006). Among all drugs, treprostinil had the highest availability (56.1% across hospitals), while newer drugs such as selexipag had very low availability (<10%). Price analysis revealed that the DDDc for most drugs had significantly decreased, including sildenafil (-91.0%) and macitentan (-95.2%), while iloprost remained costly (>3,700 CNY). In terms of affordability, in 2023, all drugs were affordable for the highest-income urban groups, while no drugs were affordable for the lowest-income rural groups, with the cost burden of iloprost accounting for 8,454.8% of the disposable income of the rural population. Drug accessibility exhibited significant structural imbalances, with some drugs being "affordable but hard to obtain" (e.g., riociguat) and others "highly burdensome and poorly accessible" (e.g., treprostinil).

Conclusion: The findings demonstrate significant improvements in the affordability and availability of PAH-targeted therapies over the study period; however, notable inequalities persist in accessibility improvements across urban and rural areas and income groups. Future policies should be tailored to address specific accessibility challenges for different drug categories and focus on overcoming medication access barriers for low-income rural populations to foster health equity.