Front Pharmacol [JOURNAL]
Sun
200 papers
The role of mitochondria in the gut-kidney axis: implications for kidney health.
Hu Q, Jin H, Hu L … +1 more , Li X
Front Pharmacol · 2026 · PMID 42394968 · Full text
Mitochondria, multifunctional organelles that regulate cellular energy metabolism and signaling pathways, play a pivotal role in maintaining the physiological functions of the gut and kidneys, as well as influencing the...
Mitochondria, multifunctional organelles that regulate cellular energy metabolism and signaling pathways, play a pivotal role in maintaining the physiological functions of the gut and kidneys, as well as influencing the progression of chronic kidney disease (CKD). Through the gut-kidney crosstalk, gut microbiota modulate gut and renal pathophysiology and also influence mitochondrial activity in intestinal and renal cells. This review explores the regulatory roles of mitochondria in preserving epithelial barrier integrity, regulating intestinal metabolism, and maintaining gut microbiota homeostasis. It also examines the contributions of mitochondrial biogenesis, dynamics, autophagy abnormalities, and mitochondrial DNA (mtDNA) damage to renal pathological progression. Moreover, we highlight the bidirectional interactions between intestinal and renal mitochondria via the microbiota-mitochondria-kidney axis and mechanisms involving inflammation, oxidative stress, and ferroptosis. Therefore, targeting mitochondrial regulation through non-pharmacological interventions such as dietary adjustments, probiotic supplementation and fecal microbiota transplantation (FMT) emerges as a promising therapeutic strategy for maintaining renal health by optimizing mitochondrial function. In conclusion, elucidating the mechanisms of mitochondrial involvement in the gut-kidney axis will lay the foundation for novel therapeutic approaches to CKD and other gut-kidney axis-related disorders.
Association of blood-activating commercial Chinese polyherbal preparation with clinical outcomes in older patients with ischemic cardiovascular or cerebrovascular diseases: a real-world cohort study.
Su S, Dong X, Wang M … +4 more , Li B, Xing X, Gao P, Zhang L
Front Pharmacol · 2026 · PMID 42389288 · Full text
BACKGROUND: Commercial Chinese polyherbal preparation for activating blood and resolving stasis (CPABRS) were widely used in combination with guideline-directed antiplatelet agents (AA). However, real-world evidence on t...
BACKGROUND: Commercial Chinese polyherbal preparation for activating blood and resolving stasis (CPABRS) were widely used in combination with guideline-directed antiplatelet agents (AA). However, real-world evidence on the effectiveness and safety of this combination remains limited, particularly among older patients with ischemic cardiovascular and cerebrovascular diseases (ICCD). METHOD: This retrospective cohort study used data from the Beijing Municipal Medical Insurance Database (BMMID). Patients aged ≥65 years with ICCD were categorized into three groups: AA + CPABRS, CPABRS alone, and AA alone. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for major adverse cardiac and cerebrovascular events (MACCEs) and bleeding outcomes. Cox proportional hazards regression, inverse probability of treatment weighting (IPTW) based on propensity scores, subgroup and sensitivity analyses were performed to examine the robustness of the findings. RESULTS: A total of 12,113 patients were included (median age, 77 years); 78.2% received AA + CPABRS, 11.5% received CPABRS alone, and 10.4% received AA alone. Compared with AA alone, AA + CPABRS was associated with a lower risk of MACCEs (OR 0.687, 95% CI 0.544-0.876) without a statistically increase in the risk of bleeding (OR 0.734, 95% CI 0.417-1.399). CPABRS monotherapy was associated with a non-significant reduction in MACCEs (OR 0.820, 95% CI 0.597-1.126) and a numerically higher but imprecise bleeding risk (OR 1.831, 95% CI 0.895-3.866). The Cox, IPTW-propensity scores analysis, subgroup and sensitivity analyses yielded consistent results. CONCLUSION: In older ICCD patients, adjunctive CPABRS combined with antiplatelet therapy was associated with lower risk of MACCEs without statistically significant increase in bleeding events during short-term follow-up. These findings suggest that CPABRS may be a potentially useful complementary strategy for secondary prevention in this population.
Targeting FAP/CAFs to rewire immune-excluded and resistant tumor niches.
Wang Y, Zhao Y, Zhou C … +1 more , Wang Y
Front Pharmacol · 2026 · PMID 42389287 · Full text
Immune checkpoint blockade (ICB) has reshaped cancer therapy, yet many solid tumors remain immune-excluded, with cytotoxic T cells trapped in stromal regions and unable to access malignant nests. In these settings, cance...
Immune checkpoint blockade (ICB) has reshaped cancer therapy, yet many solid tumors remain immune-excluded, with cytotoxic T cells trapped in stromal regions and unable to access malignant nests. In these settings, cancer-associated fibroblasts (CAFs) and their extracellular matrix programs act as active ecosystem regulators that impose physical transport barriers, chemokine "gating" (notably CXCL12-CXCR4), and stromal exclusion signals such as TGF-β, collectively sustaining resistance to both immunotherapy and targeted agents, and contributing to treatment intolerance and rehabilitation-relevant functional burden. Building on this mechanistic blueprint, we review clinically relevant strategies that use fibroblast activation protein (FAP), when sufficiently expressed and spatially relevant, as a tractable stromal address label to rewire resistant niches, ranging from FAP-targeted immunocytokines and conditional costimulation to regional FAP-CAR-T approaches and FAPI-PET-enabled stratification/theranostics. We highlight key safety constraints and failure modes that can limit not only efficacy but also functional recovery, and propose a trial-ready roadmap centered on state-guided selection, mechanism-matched combinations, early pharmacodynamic verification of rewiring, and pragmatic functional endpoints.
Fraxini cortex (Qinpi): reframing a traditional heat-clearing botanical drug as a systemic immune-metabolic regulator.
Xin P, Fan YH, Xu JY … +4 more , Mao SJ, Zhang JW, Luo ZL, Zhou X
Front Pharmacol · 2026 · PMID 42389286 · Full text
Fraxini Cortex (Qinpi), a traditional Chinese medicine used for millennia for "Qingre" (heat-clearing), is now being re-evaluated in the context of modern immunology and systems pharmacology. Its traditional applications...
Fraxini Cortex (Qinpi), a traditional Chinese medicine used for millennia for "Qingre" (heat-clearing), is now being re-evaluated in the context of modern immunology and systems pharmacology. Its traditional applications in treating inflammatory conditions hint at a broader, systemic regulatory capacity. This review proposes that Fraxini Cortex functions as a systemic immune-metabolic regulator. We aim to synthesize existing evidence through this novel lens, hypothesizing that its therapeutic potential stems from the synergistic ability of its constituents to target pivotal hubs at the interface of immune response and cellular metabolism. We conducted a comprehensive literature review encompassing the phytochemistry, pharmacology, pharmacokinetics, and clinical evidence of Fraxini Cortex. Phytochemically, Fraxini Cortex is rich in coumarins (e.g., esculetin, esculin), secoiridoids, and phenylethanoid glycosides. Pharmacologically, its mechanisms extend beyond mere anti-inflammation. Crucially, we propose that its constituents reprogram tumor metabolism by targeting the glycolytic enzyme GPI (e.g., oleuropein); execute an anti-virulence strategy against MRSA by inhibiting Sortase A (e.g., esculetin); and correct uric acid and glucose-lipid metabolic disorders by modulating urate transporters (URAT1/GLUT9/ABCG2) and insulin signaling (e.g., fraxin and esculin). This hypothesis is based on the convergence of evidence showing that these multi-target actions are integrated by its capacity to suppress core inflammatory pathways (NF-κB, MAPK) while activating antioxidant defenses (Nrf2), thereby promoting the resolution of inflammation and tissue homeostasis. Pharmacokinetic challenges, notably low oral bioavailability of key coumarins, are being addressed by novel drug delivery systems. Preliminary clinical studies support its benefits in psoriasis and gouty arthritis. In conclusion, we propose that Fraxini Cortex exemplifies how a traditional "heat-clearing" botanical drug can be reinterpreted as a multi-target regulator of immune-metabolic homeostasis. Future research should focus on validating this paradigm using omics technologies, developing bioavailability-enhanced formulations, and conducting rigorous clinical trials for immune-metabolic diseases. This shift in perspective may accelerate the translation of Fraxini Cortex and similar botanical drugs into standardized, evidence-based immunomodulatory therapies.
Dose-dependent protective effects of theophylline on testicular endocrine function in a rat model of ischemia-reperfusion injury.
Demiriz Gulmez D, Apan A, Cuvas Apan O … +2 more , Usta M, Cinar E
Front Pharmacol · 2026 · PMID 42389285 · Full text
INTRODUCTION: Testicular torsion (TT) induces ischemia-reperfusion (I/R) damage, frequently resulting in inflammatory responses, oxidative stress, and compromised spermatogenesis. This study investigated the potential th...
INTRODUCTION: Testicular torsion (TT) induces ischemia-reperfusion (I/R) damage, frequently resulting in inflammatory responses, oxidative stress, and compromised spermatogenesis. This study investigated the potential therapeutic role of theophylline-a methylxanthine with established antioxidant and anti-inflammatory properties-on testicular I/R outcomes in a rat model. METHODS: Thirty-two pubertal Wistar-Albino rats were categorized into four cohorts (n=8 per group): Control, I/R, and I/R treated with either 10 mg/kg or 50 mg/kg theophylline. RESULTS: While plasma biochemical markers (tumor necrosis factor-alpha (TNF-α), glutathione, myeloperoxidase, ischemia-modified albumin, inhibin B, caspase-3, and testosterone) and histopathological Johnsen tubular biopsy scores remained statistically comparable across groups, significant intergroup variations were observed in testicular tissue TNF-α (p = 0.017), testicular testosterone (p = 0.003), and Cosentino histopathological grades (p < 0.05).Although high-dose theophylline showed a downward trend in tissue TNF-α, this specific pairwise difference did not reach statistical significance. DISCUSSION: These results indicate that while acute structural protection was limited within a 4-hour reperfusion window, high-dose theophylline demonstrates a promising capacity to preserve testicular testosterone levels and modulate local inflammatory markers. This suggests a dose-dependent supportive effect on Leydig cell function and endocrine recovery following ischemic insult.
Hyper-inflammation and immunosuppression: redefining sepsis therapy using modern approaches.
Prajapati M, Singh V, Mishra A … +3 more , Khatua D, Rana M, Jyoti A
Front Pharmacol · 2026 · PMID 42389284 · Full text
BACKGROUND: Sepsis is a life-threatening condition characterized by simultaneous hyperinflammation and immunosuppression, which leads to organ dysfunction and mortality. It is a global health concern, which is estimated...
BACKGROUND: Sepsis is a life-threatening condition characterized by simultaneous hyperinflammation and immunosuppression, which leads to organ dysfunction and mortality. It is a global health concern, which is estimated to be approximately 166 million cases and 21.4 million global deaths in 2021. AIM: This review aimed to analyze sepsis epidemiology, pathophysiology, current therapeutic approaches and challenges, and assess the transformational role of modern therapeutic approaches, including precision medicine, and Artificial Intelligence (AI)/Machine Learning (ML) in sepsis. METHODOLOGY: A literature search was carried out across multiple databases, including PubMed, Web of Science, and Scopus. The search was focused on hyperinflammation, immunosuppression in sepsis, current therapy, and future advances. RESULT: The review integrated the search data from original articles, review papers, and clinical trials. After careful analysis, we observed that the efficacy of current therapy is limited due to the heterogeneity of sepsis patients, the lack of patient selection based on immune status, timing, and validated biomarkers. Precision methods based on classifying patient genotypes and multi-omics-based biomarkers suggest a potential approach to risk stratification and therapeutic guidance. Concurrently, AI/ML models exhibit improved predictive accuracy and early clinical diagnosis, facilitating early identification and risk stratification. CONCLUSION: The integration of AI/ML and precision medicine into sepsis care has the potential to reduce mortality in clinically significant endotypes and allow focused immunomodulatory treatments fulfilling Sustainable Development Goal 3.
Comparing the effects of propofol and sevoflurane anesthesia on cognitive dysfunction in elderly patients after abdominal surgery: a systematic review and meta-analysis of randomised controlled trials.
Guo N, Wen X, Wang X … +3 more , Wang Y, Su Y, Zhang T
Front Pharmacol · 2026 · PMID 42389283 · Full text
OBJECTIVES: To conduct a systematic review and comparison of the effects of propofol and sevoflurane anesthesia on cognitive dysfunction in elderly patients following abdominal surgery. METHODS: Comparative studies publi...
OBJECTIVES: To conduct a systematic review and comparison of the effects of propofol and sevoflurane anesthesia on cognitive dysfunction in elderly patients following abdominal surgery. METHODS: Comparative studies published in PubMed, Web of Science, EBSCOhost, Cochrane Library, EMBASE, and Medline databases as of 08 Jun 2025 were searched. The final extracted data was analyzed using Review Manager 5.4. RESULTS: The 7 randomized controlled studies included a total of 802 patients who had undergone abdominal surgery, of whom 402 were anesthetized with propofol and 400 were anesthetized with sevoflurane. The outcomes of the meta-analysis showed that there were no statistically significant differences in operating time, anesthesia time, incidence of hypotension, the incidence of postoperative cognitive dysfunction (all P > 0.05), between the propofol and sevoflurane groups. Moreover, there was no significant difference in the severity of cognitive dysfunction between the two groups of patients on the 1st, 3rd, and 7th day after surgery (all P > 0.05). CONCLUSION: The meta-analysis results showed that there was no significant difference in the severity of cognitive dysfunction between the he propofol and sevoflurane groups of patients on the 1st, 3rd, and 7th day after surgery. This conclusion still does not prove that either one is more suitable for anesthesia in elderly patients, and more samples and clinical studies are needed to confirm. TRIAL REGISTRATION: PROSPERO registration number is: CRD42022324055.
Multidimensional targeting of ischemia-reperfusion injury by genistein: from molecular crosstalk to clinical translation.
Wang R, Ya C, He W … +4 more , Pan Y, Shi C, Lin Y, Xing X
Front Pharmacol · 2026 · PMID 42389282 · Full text
Ischemia-reperfusion injury (IRI) is a convergent pathology driven by oxidative stress, sterile inflammation, mitochondrial dysfunction, and regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis), yet val...
Ischemia-reperfusion injury (IRI) is a convergent pathology driven by oxidative stress, sterile inflammation, mitochondrial dysfunction, and regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis), yet validated pharmacotherapies remain scarce. Genistein, a soy-derived isoflavone phytoestrogen, has demonstrated multi-organ protection in preclinical IRI models through coordinated regulation of the Nrf2/HO-1 antioxidant axis, SIRT1/p53 deacetylation-dependent anti-apoptotic signaling, and NF-kappaB/JAK2-STAT3/alpha7nAChR/NLRP3 inflammasome cascades, but systematic mechanistic integration is lacking. A narrative review with systematic literature identification was conducted using PubMed/MEDLINE, Web of Science, and Scopus (2010-2024). Studies on genistein or its structurally defined derivatives in established IRI models with mechanistic endpoints were included; soy extracts, biochanin A, and non-IRI studies were excluded. Genistein engages multiple cytoprotective pathways with organ-dependent evidence strength. Causal validation (Level A: genetic deletion, siRNA, or pharmacological inhibitor with rescue) has been achieved for Nrf2/HO-1 in cerebral IRI and for SIRT1/p53, ADORA2A-cAMP-PK, and PI3K/Akt in renal IRI, whereas hepatic and intestinal evidence remains correlative (Level C). SIRT1-mediated deacetylation concurrently suppresses both p53-dependent apoptosis (Bax/PUMA) and NF-kappaB p65 subunit transcriptional activity at Lys310, integrating anti-apoptotic and anti-inflammatory effects. Genistein inhibits NLRP3 inflammasome activation at the priming level (NF-kappaB-dependent NLRP3/pro-IL-1beta transcription) and assembly level (ROS/ASC/caspase-1), linking oxidative stress sensing to gasdermin D-mediated pyroptosis. Emerging evidence (2023-2025) suggests genistein may attenuate ferroptosis via iron chelation and Nrf2-driven GPX4 preservation. Translational gaps include concentration disconnect between effective doses (10-100 μM) and free aglycone levels (<0.1 μM), unaddressed PAINS assay-interference liability, predominance of pretreatment-only rodent models, undefined drug interaction profiles, and absence of comorbidity-rich and large-animal studies. Genistein-3'-sodium sulfonate demonstrates improved aqueous solubility and post-treatment efficacy in cerebral IRI, but human pharmacokinetic data in IRI contexts are absent. Genistein's multi-target, cross-pathway pharmacology aligns with IRI pathophysiology, yet the evidence base is insufficiently rigorous for clinical deployment. This review identifies SIRT1-mediated dual p53/NF-kappaB suppression as a mechanistic nexus, highlights pyroptosis and ferroptosis as underexplored therapeutic dimensions, and proposes a translational roadmap prioritizing causal pathway validation with orthogonal PAINS-controlled assays, pharmacokinetic characterization, sex- and comorbidity-stratified preclinical models, and early-phase clinical investigation in elective surgical settings where prophylactic administration is feasible.
Neutrophil extracellular traps contribute significantly to vascular dysfunction in sepsis.
Zhang P, An Y, Liu H … +1 more , Wang D
Front Pharmacol · 2026 · PMID 42389281 · Full text
Sepsis is a systemic inflammatory condition triggered by severe infection, frequently resulting in multi-organ dysfunction. Vascular dysfunction, as its core pathological mechanism, involves a vicious cycle of inflammati...
Sepsis is a systemic inflammatory condition triggered by severe infection, frequently resulting in multi-organ dysfunction. Vascular dysfunction, as its core pathological mechanism, involves a vicious cycle of inflammation, coagulation, and endothelial injury. The mechanism of vascular damage caused by sepsis is widely studied, and neutrophils play a significant role in this process. Neutrophil extracellular traps (NETs) are an important mechanism. While NETs are designed to entrap pathogens, their excessive formation or impaired degradation directly drives vascular injury. NETs contribute to the exacerbation of vascular dysfunction through mechanisms including the induction of endothelial injury, the promotion of coagulation abnormalities, and the enhancement of vascular permeability. Nonetheless, the precise signaling pathways and regulatory networks governing these processes remain incompletely understood. This article seeks to systematically review the fundamental mechanisms through which NETs contribute to sepsis-associated vascular dysfunction, in addition to evaluating their potential utility as biomarkers and therapeutic targets. This review seeks to elucidate novel insights into the mechanisms underpinning vascular dysfunction in sepsis and associated clinical interventions, thereby contributing a theoretical foundation for the development of targeted therapeutic strategies to mitigate related pathophysiological damage.
Comparative efficacy of botulinum toxin and surgical treatment for acute acquired concomitant esotropia: a systematic review and meta-analysis.
Shi Y, Nie K, Tian M … +2 more , Lv H, Huang J
Front Pharmacol · 2026 · PMID 42389280 · Full text
OBJECTIVES: This meta-analysis aimed to compare the efficacy of botulinum toxin (BTX) injection versus surgery for acute acquired concomitant esotropia (AACE). METHODS: PubMed, Embase, Web of Science, China Biomedical Si...
OBJECTIVES: This meta-analysis aimed to compare the efficacy of botulinum toxin (BTX) injection versus surgery for acute acquired concomitant esotropia (AACE). METHODS: PubMed, Embase, Web of Science, China Biomedical Sinomed, and the Cochrane Library were systematically searched for studies comparing BTX and surgery in AACE. The primary outcome was motor success rate, and secondary outcomes included stereopsis recovery and incidence of permanent exotropia. Random-effects models were applied. Sensitivity analyses, subgroup analyses, meta-regression, and publication bias assessment were performed. RESULTS: Fourteen studies involving 1027 patients were included. At 6 months, motor success rates did not differ significantly between BTX and surgery (OR 0.45, 95% CI: 0.20-1.03, P = 0.06); however, this result was sensitive to the inclusion of a single study, and exclusion of this study favored surgery (OR 0.36, 95% CI: 0.17-0.77, P = 0.008). Subgroup analyses showed that comparable outcomes were observed between BTX and surgery in pediatric patients (OR 1.14, 95% CI: 0.45-2.89, P = 0.78) and in studies using bilateral medial rectus injection (OR 0.98, 95%CI: 0.35-2.70, P = 0.97), with stable sensitivity analyses in both subgroups. Stereopsis recovery at 6 months was similar between the two treatments (near: OR 0.61, 95% CI: 0.32-1.19, P = 0.15; distance: OR 1.05, 95%CI: 0.42-2.61, P = 0.92). CONCLUSION: The pooled short-term motor outcome showed substantial heterogeneity and sensitivity to individual studies. More consistent findings were observed in pediatric populations and in studies using bilateral medial rectus injections, where BTX may achieve short-term outcomes comparable to surgery. Stereopsis recovery at 6 months was also similar between the two treatments. However, given the limited number of available studies and the predominance of retrospective designs, adequately powered RCTs and prospective studies are needed to establish more definitive conclusions. SYSTEMATIC REVIEW REGISTRATION: Identifier: CRD420245127395.
Circadian rhythm disruption impairs time-dependent dentine regeneration and reprograms the late-stage dental proteome in a mouse pulp injury model.
Guvendi M, Yelkenci HE, Ozbay E … +6 more , Koc HI, Tok OE, Altunay S, Kilic E, Gundogar M, Beker MC
Front Pharmacol · 2026 · PMID 42389279 · Full text
Circadian rhythms coordinate metabolic and regenerative programs, yet their contribution to pulp healing and tertiary dentinogenesis remains unclear. Here, we investigated whether chronic circadian rhythm disruption (CRD...
Circadian rhythms coordinate metabolic and regenerative programs, yet their contribution to pulp healing and tertiary dentinogenesis remains unclear. Here, we investigated whether chronic circadian rhythm disruption (CRD) alters time-dependent dentine repair and proteomic remodeling after dental pulp injury (DPI) in male BALB/c mice. Animals were maintained either under a stable 12:12 h light-dark cycle or under a chronic jet-lag model with a daily 2 h phase advance. DPI was induced in the maxillary first molars, followed by immediate direct pulp capping with mineral trioxide aggregate and sealing with glass ionomer cement. Histological and histomorphometric analyses were performed at days 7, 28, and 56 post-injury, while open-field and light/dark transition tests were conducted on day 56. Untargeted LC-MS/MS proteomics was additionally performed on day-56 dental tissues to define injury-, circadian-, and dual-regulated molecular signatures. CRD produced a behavioral phenotype characterized by reduced locomotor activity and increased anxiety-like behavior. Histology revealed a canonical reparative pattern after DPI, with peripheral tertiary dentine formation surrounding a central connective tissue core; however, CRD consistently attenuated newly formed dentine area at all time points, indicating compromised odontoblast-like differentiation and mineral deposition. Proteomic profiling identified extensive remodeling of the dental proteome, with injury- and CRD-dependent signatures converging on metabolic regulation, cytoskeletal dynamics, immune pathways, and extracellular matrix organization. Integrated analyses delineated 204 injury-specific proteins, 128 CRD-specific proteins, and 86 co-regulated proteins, resolving the response into injury-dominant, circadian-dominant, dual-regulated, and condition-independent modules. Collectively, these results demonstrate that chronic circadian misalignment impairs dentine regenerative capacity and reprograms the dental proteome, suggesting that circadian status may be an underappreciated determinant of outcomes in vital pulp therapy and regenerative endodontic procedures.
A mitochondrial regulatory network of ferroptosis defense in HPV-positive cervical cancer: therapeutic implications of the mitoSTAT3-DHODH axis.
Feng S, Huang Y, Li Z … +2 more , He Z, Gao Y
Front Pharmacol · 2026 · PMID 42389278 · Full text
Human papillomavirus (HPV)-positive cervical cancer develops under persistent metabolic, replicative, and oxidative stress and frequently exhibits limited sensitivity or acquired resistance to cisplatin-based concurrent...
Human papillomavirus (HPV)-positive cervical cancer develops under persistent metabolic, replicative, and oxidative stress and frequently exhibits limited sensitivity or acquired resistance to cisplatin-based concurrent chemoradiotherapy (CCRT). In this context, ferroptosis represents a potential therapeutic vulnerability, yet the regulatory networks that sustain ferroptosis resistance in HPV-positive tumors remain incompletely defined. This review proposes a mitochondria-centered framework in which mitochondrial STAT3 (mitoSTAT3), electron transport chain (ETC)-dependent coenzyme Q (CoQ) redox turnover, and dihydroorotate dehydrogenase (DHODH) may form a context-dependent regulatory axis of ferroptosis defense. We first summarize how HPV E6 and E7 oncoproteins impose chronic biosynthetic, replicative, and oxidative pressures that increase tumor dependence on mitochondrial redox and bioenergetic control. We then discuss STAT3 not only as a canonical nuclear transcription factor but also as a stress-adaptive signaling node with mitochondria-associated functions. Current evidence suggests that mitoSTAT3 may support ETC efficiency, limit electron leakage, and help maintain CoQ cycling, whereas DHODH may contribute to localized CoQH-dependent radical-trapping activity within the inner mitochondrial membrane. Together, these mechanisms may restrain mitochondrial lipid peroxidation and thereby reduce susceptibility to ferroptotic injury. Finally, we discuss the translational implications of this framework, including ferroptosis-sensitizing strategies, DHODH inhibition, STAT3-directed interventions, biomarker-guided patient stratification, rational combinations with chemoradiotherapy or immunotherapy, and nanomedicine-enabled delivery. Overall, this review identifies the mitoSTAT3-DHODH axis as a mechanistically plausible regulatory network of ferroptosis resistance and a potential therapeutic vulnerability in HPV-positive cervical cancer.
Gut-bone axis: mechanisms and intervention effects of Chinese botanical drugs in osteoporosis management.
Li S, Liu H
Front Pharmacol · 2026 · PMID 42389277 · Full text
Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mass, impaired bone microarchitecture, and elevated fracture risk. With global population aging, OP has become a major public health burde...
Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mass, impaired bone microarchitecture, and elevated fracture risk. With global population aging, OP has become a major public health burden worldwide. The gut-bone axis, a critical regulatory network connecting gut microbiota (GM) and bone metabolism, has emerged as a frontier in OP pathogenesis and intervention. GM dysbiosis disrupts bone homeostasis through metabolic, endocrine, and immune pathways, including short-chain fatty acids, estrogen/parathyroid hormone signaling, and Th17/Treg balance. Chinese botanical drugs (CBDs) exert unique advantages in OP management via holistic and multi-target effects, particularly by regulating GM to restore gut-bone axis balance. This review systematically elaborates the mechanisms by which GM contributes to OP, and summarizes advances in CBDs that regulate bone metabolism by remodeling GM composition, improving intestinal barrier function, and modulating gut-bone axis signaling. This work provides theoretical support for the clinical application and innovative research of CBDs, and lays a foundation for developing novel GM-targeted anti-OP therapeutic strategies.
The METOD study: exploring metabolism, emotional blunting and treatment outcomes in depression - A naturalistic, two-phase observational protocol.
Krupa AJ, Kania MJ, Podkowa K … +3 more , Krawczyk E, Plencler-Turakiewicz I, Siwek M
Front Pharmacol · 2026 · PMID 42389276 · Full text
INTRODUCTION: Major depressive disorder (MDD) constitutes a substantial global health burden, profoundly undermining psychosocial functioning and quality of life, and the persistent limitations of treatment efficacy-desp...
INTRODUCTION: Major depressive disorder (MDD) constitutes a substantial global health burden, profoundly undermining psychosocial functioning and quality of life, and the persistent limitations of treatment efficacy-despite advances in neurobiology and pharmacotherapy-underscore its considerable clinical complexity. Recent research increasingly delineates the heterogeneity of depressive symptomatology, particularly emotional blunting, and emerging evidence further implicates metabolic and inflammatory pathways processes in shaping treatment response Insulin resistance (IR), immune dysregulation, individual circadian preference, and trait-level vulnerabilities associated with neurodevelopmental or trauma-related characteristics may contribute to reduced responsiveness to standard therapies and limited adherence to antidepressant treatment. Taken together, these converging findings emphasize the need for individualized interventions rather than continued reliance on broad diagnostic categories. OBJECTIVES: The study consists of two phases with distinct hypotheses: phase I) evaluating emotional blunting along other clinical/psychopathological variables as potential predictors of treatment non-response to SSRI/SNRI in MDD, and phase II) assessing relationships between IR and treatment non-response to vortioxetine in MDD. Further exploratory objectives encompass assessment of: links between psychopathological and metabolic predictors of health status; longitudinal association between emotional blunting and both sexual and cognitive functioning. MATERIALS AND METHODS: The METOD study is an open, non-randomized two-phase observational study conducted in accordance with clinical standards and with all required ethical approvals. The protocol was prepared in line with STROBE recommendations. In Phase I, MDD patients meeting eligibility criteria and initiating antidepressant treatment with one of the first-line SSRIs or SNRIs are observed, whereas in Phase II, individuals showing an inadequate response are switched to vortioxetine as a second-line option. Validated clinical assessment tools are administered alongside anthropometric and laboratory evaluations. EXPECTED IMPLICATIONS/SIGNIFICANCE: By examining these interrelations within a naturalistic cohort treated in accordance with current clinical standards, this innovative study-with its strong emphasis on patient-reported outcomes-may increase insight into the lived experience of depression, enhance understanding of the pathophysiological mechanisms shaping its diverse symptomatology, and provide a foundation for more precisely targeted therapeutic approaches.
Role of gut microbiota in melanosis coli: from anthraquinone biotransformation to mucosal homeostasis dysbiosis.
Zhang P, Zhuang YD, Lv WW … +4 more , Zhao Y, Wang JH, Zhang JY, Wu LL
Front Pharmacol · 2026 · PMID 42389275 · Full text
Melanosis coli (MC) is a benign and usually reversible condition characterized by brownish-black pigmentation of the colonic mucosa and is commonly associated with chronic exposure to anthraquinone laxatives (ALs). The b...
Melanosis coli (MC) is a benign and usually reversible condition characterized by brownish-black pigmentation of the colonic mucosa and is commonly associated with chronic exposure to anthraquinone laxatives (ALs). The best-established histopathological sequence involves AL-related epithelial apoptosis, phagocytosis of apoptotic bodies by macrophages, and subsequent lipofuscin deposition. Emerging evidence suggests that the gut microbiota (GM) may contribute to this process by converting pharmacologically inactive anthraquinone glycosides into active anthrone metabolites, including rhein anthrone. This narrative review summarizes available MC-specific findings and clearly distinguishes them from mechanistic hypotheses extrapolated from constipation, intestinal barrier, and microbiome literature. We discuss microbial β-glucosidases and reductases involved in AL biotransformation, reported changes in microbial diversity and SCFA-producing taxa in MC or constipation-associated cohorts, and plausible links with barrier dysfunction, bile-acid metabolism, tryptophan-derived metabolites, and LPS-TLR4 signaling. We therefore present the "Microbiota-Apoptosis Axis" as a proposed framework rather than a validated causal pathway. Finally, we review GM-targeted strategies, including probiotics, synbiotics, and fecal microbiota transplantation, while emphasizing that direct clinical evidence in MC remains limited and that cessation of anthraquinone laxatives remains the primary management strategy.
Integrative network pharmacology, molecular dynamics simulation, and single-cell RNA sequencing strategies reveal the multi-target mechanisms of oridonin against cervical cancer.
Xu M, Lu T, Lv Q … +2 more , Mo K, Liu Y
Front Pharmacol · 2026 · PMID 42389274 · Full text
INTRODUCTION: Cervical cancer remains a major threat to women's health worldwide, and effective therapeutic strategies with clear molecular mechanisms are still needed. Oridonin (Ori), a natural diterpenoid compound, has...
INTRODUCTION: Cervical cancer remains a major threat to women's health worldwide, and effective therapeutic strategies with clear molecular mechanisms are still needed. Oridonin (Ori), a natural diterpenoid compound, has shown antitumor activity in multiple malignancies; however, its regulatory mechanisms in cervical cancer, particularly at the single-cell level, remain incompletely understood. METHODS: In this study, an integrative strategy combining network pharmacology, bulk transcriptomic analyses, single-cell RNA sequencing (scRNA-seq), molecular docking, molecular dynamics simulations, and experiments was employed to systematically investigate the pharmacological effects and mechanisms of oridonin in cervical cancer. Differentially expressed genes were identified from multiple Gene Expression Omnibus datasets, and core targets were screened through protein-protein interaction analysis. Immune infiltration patterns were evaluated using CIBERSORT, while cell-type-specific pathway activities were inferred based on scRNA-seq data. The predicted mechanisms were further validated by molecular simulations and functional assays in cervical cancer cell lines. RESULTS: Network pharmacology and transcriptomic analyses identified 25 core EMT-related targets of oridonin, with enrichment primarily in the PI3K/AKT signaling pathway. Immune infiltration analysis revealed that oridonin-associated targets were closely correlated with macrophages and T-cell subsets. Single-cell analysis demonstrated that PI3K/AKT and EMT-related pathways were predominantly enriched in epithelial tumor cells, suggesting cell-type-specific regulatory effects. Molecular docking and dynamics simulations indicated favorable binding potential between oridonin and AKT1. experiments confirmed that oridonin significantly inhibited cervical cancer cell proliferation, migration, and invasion, induced apoptosis, and suppressed epithelial-mesenchymal transition progression via downregulation of the PI3K/AKT pathway. CONCLUSION: This study provides a systematic and multi-level characterization of the antitumor mechanisms of oridonin in cervical cancer. By integrating network pharmacology with single-cell transcriptomic analysis, our findings highlight the cell-type-specific modulation of the PI3K/AKT-EMT axis by oridonin, offering mechanistic insights and establishing a theoretical pharmacological basis that warrants future preclinical evaluation.
Omega-3 polyunsaturated fatty acids are associated with microbiota-related 18β-glycyrrhetinic acid alterations and M2 macrophage polarization in type 1 diabetes mellitus.
Guo Y, Hu F, Zhao AZ … +5 more , Zeng Y, Chen H, Wang A, Li X, Cong L
Front Pharmacol · 2026 · PMID 42389273 · Full text
INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFAs) have been widely reported to exert beneficial effects in type 1 diabetes mellitus (T1DM). However, the mechanisms by which Omega-3 PUFAs influence pancreatic isle...
INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFAs) have been widely reported to exert beneficial effects in type 1 diabetes mellitus (T1DM). However, the mechanisms by which Omega-3 PUFAs influence pancreatic islet function through the gut-islet axis remain incompletely understood. This study aimed to investigate whether Omega-3 PUFAs-associated alterations in gut microbiota composition and their metabolites are involved in the modulation of the pancreatic islet microenvironment in T1DM, and to explore the potential immunological mechanisms underlying these effects. METHODS: Fecal microbiota transplantation (FMT) was performed to evaluate the effects of Omega-3 PUFAs-associated gut microbiota in non-obese diabetic (NOD) mice. Immune cell composition and inflammatory status within pancreatic islets were analyzed using transcriptomic profiling, flow cytometry, and immunohistochemistry. Metabolomics analysis was performed to investigate the association among Omega-3 PUFAs, gut microbiota, and microbiota-related metabolites. co-culture systems were further established to evaluate the effects of selected metabolites on macrophage polarization and insulin production and secretion in pancreatic β-cells. RESULTS: Omega-3 PUFAs treatment and FMT were associated with reduced islet inflammation and a marked enrichment of the (). Enhanced M2 macrophage polarization was observed in the islet microenvironment of FMT mice. Among gut microbiota metabolites, 18β-glycyrrhetinic acid (18β-GA) showed a strong association with , and experiments suggested a potential involvement of in the metabolic conversion process related to 18β-GA. In co-culture systems, 18β-GA promoted macrophage polarization toward an M2-like phenotype, which was accompanied by increased insulin production and secretion in pancreatic β-cells. CONCLUSION: These findings suggest that Omega-3 PUFAs-associated alterations in gut microbiota composition and 18β-GA-related metabolic changes may contribute to the modulation of the pancreatic immune microenvironment and β-cells function in T1DM. This study provides additional insights into lipid-microbiota-immune interactions relevant to T1DM and supports further investigation of microbiota-associated immune regulation.
GLP-1 receptor agonists in obesity-related knee osteoarthritis: from weight loss to therapeutic pathway reconstruction.
Wu J, Lei Y, Sa R … +2 more , Zhong Y, Lu Y
Front Pharmacol · 2026 · PMID 42389272 · Full text
Obesity is a major modifiable contributor to knee osteoarthritis (KOA), but excess adiposity has often been managed as a background risk factor rather than as a therapeutic target. In obesity-related KOA, adiposity may a...
Obesity is a major modifiable contributor to knee osteoarthritis (KOA), but excess adiposity has often been managed as a background risk factor rather than as a therapeutic target. In obesity-related KOA, adiposity may aggravate pain and disability through increased joint loading, low-grade inflammation, metabolic dysfunction, impaired physical activity, and reduced rehabilitation tolerance. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have created a new opportunity to achieve clinically meaningful weight loss in selected patients with obesity-related KOA. However, current evidence should be interpreted cautiously. Human data most strongly support weight-loss-mediated improvements in pain, function, and rehabilitation feasibility, whereas direct cartilage-, synovium-, subchondral bone-, or structure-modifying effects remain unproven. In this narrative review, we summarize the rationale, receptor biology, pharmacological mechanisms, inflammatory signaling hypotheses, clinical evidence, safety concerns, and implementation challenges related to GLP-1RA use in obesity-related KOA. We also position GLP-1RAs within a broader obesity-treatment continuum that includes lifestyle intervention, exercise-based rehabilitation, multidisciplinary weight management, other anti-obesity medications, bariatric surgery, symptom-bridging treatments, and arthroplasty when indicated. Particular attention is given to gastrointestinal intolerance, dehydration, gallbladder and pancreatitis-related concerns, lean-mass loss, perioperative management, treatment discontinuation, affordability, access, and long-term adherence. Overall, GLP-1RAs may become a useful component of integrated obesity-directed KOA care, but they should be regarded as part of a proposed framework rather than as validated disease-modifying therapy.
Pharmacological mechanisms and clinical impacts of antidiabetic drugs on colorectal cancer risk: a systematic review.
Yang Y, Wang K
Front Pharmacol · 2026 · PMID 42389271 · Full text
Type 2 diabetes mellitus (T2DM) significantly increases colorectal cancer (CRC) risk, driven by shared metabolic and inflammatory pathways. As lifelong glucose-lowering medications are routinely used in T2DM, their pharm...
Type 2 diabetes mellitus (T2DM) significantly increases colorectal cancer (CRC) risk, driven by shared metabolic and inflammatory pathways. As lifelong glucose-lowering medications are routinely used in T2DM, their pharmacological activities and associated oncological effects have become critical for safety and repurposing. This review systematically summarizes the pharmacological mechanisms, epidemiological evidence, and clinical outcomes of eight antidiabetic drug classes in modulating CRC risk. We highlight drug-specific effects: metformin may act via AMPK/mTOR and immune reprogramming; SGLT-2 inhibitors may exert direct cytotoxicity and indirect metabolic benefits; GLP-1 RAs show class-wide neutrality except high-dose semaglutide; DPP-4 inhibitors display dual pro- and anti-tumor effects; insulin and most secretagogues elevate CRC risk via hyperinsulinemia; while TZDs and AGIs offer modest chemopreventive effects. We conclude that antidiabetic drugs possess pharmacological properties that can inform CRC risk stratification and drug repurposing. Future research should prioritize mechanistic validation and precision pharmacology to translate these findings into clinical practice.
Polyphenol-enriched fraction of Delile (Mimosaceae) inhibits human triple-negative breast cancer cells and exhibits anticancer and immunomodulatory effects in a DMBA-induced breast cancer model.
Tueche AB, Kamdem MHK, Tonga JL … +4 more , Mmutlane EM, Ndinteh DT, Zingue S, Njamen D
Front Pharmacol · 2026 · PMID 42389270 · Full text
INTRODUCTION: Breast cancer killed 665,684 patients globally in 2022 despite government efforts and conventional therapies. The hydro-ethanolic extract of Acacia seyal, a sub-Saharan African ethnomedicinal plant, showed...
INTRODUCTION: Breast cancer killed 665,684 patients globally in 2022 despite government efforts and conventional therapies. The hydro-ethanolic extract of Acacia seyal, a sub-Saharan African ethnomedicinal plant, showed moderate cytotoxicity, significant anti-migration and in vivo preventive effects against breast cancer cells. The aim of this study was to propose an improved traditional extract and to evaluate its efficacy and potential mechanism of action. METHODS: To achieve this, A. seyal hydro-ethanolic extract (ASHE) was fractionated in polyphenol-enriched (ASpo), polysaccharides (ASsu) and residue (ASre) fractions. Fractions along with the crude extract were tested for their ability to inhibit cell growth (MTT) and proliferation (CCK-8). The promising fraction (ASpo) was further investigated on clone formation, caspase-3, wound healing, chemotaxis and cell adhesion to understand its underlying mechanisms of action. Moreover, ASpo at 18.75 and 37.5 mg/kg, compared to standard drugs (tamoxifen and letrozole) and control (distilled water) were assessed in a 20-week preventive study of DMBA (50 mg/kg, )-induced breast cancer by considering tumor incidence, tumor volume, organ mass, histopathological, hematological, antioxidant and anti-inflammatory/immunomodulatory markers. RESULTS: Among the 3 fractions, ASpo compared to control, inhibited ( < 0.01) MDA-MB 231 cells growth, proliferation and clone formation at 50 μg/mL. It increased caspase-3 and inhibited cell migration and invasion ( < 0.01) with increase ( < 0.01) adherence to collagen and fibronectin. , comparable to reference drugs, ASpo reduced tumor incidence (50%), and tumor volume from 7827.30 mm3 (adenocarcinoma SBRIII, 10% lymphocytes infiltration) in DMBA to 804.32 mm3 (adenocarcinoma SBRII, 30% lymphocytes infiltration) at 37.5 mg/kg. It increased femur and thymus'mass, lymphocytes and monocyte levels ( < 0.001) in serum, reduced ( < 0.001) TNF-α, IL-6, IL-12, EGF, nitrites levels whereas increased SOD, catalase and major IFN-γ cytokine ( < 0.001). ASpo additionally showed a safety profile on toxicity organs. CONCLUSION: Overall, ASpo mainly contributed to anti-breast cancer activities of total crude extract and involved immunomodulatory effects to consider with optimized bioactivity to further investigate it as a promising natural and inexpensive alternative to costly and efficient current immunotherapy.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe