2026-04-02
Yejiang Tang, Ahmad Alhaskawi, Bing Ruan, Zhenli Yuan
Tendon injuries are increasingly recognized as conditions driven not only by mechanical overload but also by complex molecular imbalances, particularly involving oxidative stress. Recent evidence highlights the central role of reactive oxygen species (ROS), originating primarily from mitochondrial respiration and NADPH oxidase activation, in regulating cellular responses during tendon injury and repair. Mechanical loading and calcium signaling further influence ROS dynamics, exacerbating oxidative damage or modulating adaptive responses depending on context. Tendon cells counteract oxidative insults through a coordinated antioxidant defense network, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins. However, in pathological states such as tendinopathy or diabetes, this redox balance is often disrupted, leading to sustained inflammation, extracellular matrix degradation, and impaired healing. This review synthesizes current findings on ROS generation, redox-sensitive signaling pathways, and the functional consequences of oxidative stress in tendon biology. Furthermore, it explores therapeutic strategies targeting redox imbalance, including pharmacological antioxidants and bioengineered scaffolds with antioxidant properties. Understanding these mechanisms provides critical insights into tendon pathophysiology and highlights promising avenues for redox-based regenerative therapies.
DOI: 10.3389/fphar.2026.17524912026-04-02
Xing Chen, Shu Yang, Srilatha Sakamuru, Chainarong Sukhawanit, Savannah Wood, Masato Ooka, Ruili Huang, Menghang Xia
The Wnt/β-catenin signaling pathway plays an important role in development and tissue homeostasis, and its dysregulation is implicated in various pathologies, including cancer, fibrosis, and neurodegeneration. However, the discovery of small-molecule modulators of this pathway remains challenging due to the pathway’s inherent complexity, characterized by ligand redundancy, overlapping receptor usage, and compensatory downstream signaling. In this study, we optimized a cell-based LEF/TCF-β-lactamase reporter assay for quantitative high-throughput screening in a 1536-well format. Screening 1280 compounds from the Library of Pharmacologically Active Compounds alongside 88 compounds from the Tox21 collection identified twelve potential antagonists of Wnt/β-catenin signaling. Follow-up studies confirmed the activity of 10 compounds, demonstrating consistent activity across two independent reporter systems (β-lactamase and luciferase). Western blot analysis showed that all compounds except for cytosine-1-beta-D-arabinofuranoside and PMEG reduced accumulation of both non-phosphorylated β-catenin (active) and total β-catenin, providing orthogonal validation of pathway inhibition. The identification of known Wnt inhibitors such as emetine, tyrphostin A9, niclosamide, ouabain, and podophyllotoxin further validated the assay’s robustness. Collectively, this study establishes a robust 1536-well screening platform for identifying Wnt pathway modulators and identifies topotecan, amsacrine, brefeldin A, and tyrphostin AG 879 as candidate small-molecule antagonist, thereby expanding the chemical tools for investigating Wnt/β-catenin signaling.
DOI: 10.3389/fphar.2026.17880412026-04-02
Riyasat Ali, Tahmid Faisal, Kalyani Kulkarni, Sanket Patel, Tahir Hussain
IntroductionAcute kidney injury (AKI) is marked by infiltration of immune cells, particularly macrophages and T cells, and their expansion as inflammatory and anti-inflammatory mediators to create a microenvironment critical for kidney injury/repair. As the angiotensin type 2 receptor (AT2R) is emerging as reno-protective and anti-inflammatory, this study aimed to analyze the phenotypes of macrophages and helper T cells (CD4) in response to AT2R activation in ischemia-reperfusion (IR)-induced AKI.MethodsSprague Dawley rats were subjected to 30 min IR without and with AT2R agonist C21 administration. Rats were euthanized at 2 h, 3 d, and 5 d post IR. Flow cytometry of kidney digested cells was performed to analyze kidney infiltrating immune cells. For in-vitro polarization, mouse CD4 T cells were cultured in presence of various stimulus and characterized by flow cytometry and western blot analysis.ResultsOn day 3, there was a massive increase in macrophage/monocytes (CD68+) and M1 (CD68+CD86+) cell accumulation and a modest increase in M2 (CD68+CD163+) cell accumulation. The AT2R activation reduced CD68+ and M1 cells accumulation without affecting M2. Accumulation of CD4+CD25+ cells increased on day 3, and Tregs (CD4+CD25+FoxP3+) and Tregs-IL-10 increased at 2 h and 3 d post-IR. The AT2R agonist C21 further increased these phenotypes at all-time points. Th-17 cell accumulation increased at early time points (2 h and 3 d) but returned to normal on day 5 and was not affected by C21 treatment. Ex vivo studies revealed that AT2R agonist promoted CD4+ cell expansion into Tregs, which was blocked by the AT2R antagonist PD123319, PP2A inhibitor okadaic acid, or NO synthase inhibitor L-NAME, suggesting the direct involvement of AT2R-PP2A-NOS pathways.DiscussionOverall, AT2R activation reduces M1 and promotes Tregs accumulation in IR-AKI, thus shifting the kidney microenvironment towards anti-inflammation and presents a potential mechanism to limit kidney injury and promote repair.
DOI: 10.3389/fphar.2026.17966872026-04-02
Linlin Zhao, Xing Yang, Sijing Su, Jihang Xie, Qian Zhang, Yusen Hou, Jiaxin Li, Xianzhe Li, Mingkun Meng, Ting Wang, Tingting Yan, Tong Xu, Yi Zhang
BackgroundThe genus Salvia L. constitutes a core medicinal resource in China’s diverse ethnic medical systems. However, a systematic and comparative understanding of how ecological adaptation-particularly among high-altitude ethnomedicinal species-translates into specific ethnomedicinal value remains lacking.ObjectiveTo address this gap, we developed and validated a “habitat-phytochemistry-pharmacological effect” linkage model, testing the hypothesis that environmental stressors driven by altitudinal gradients induce chemical differentiation among Salvia species, which in turn underlies their distinct pharmacological properties and traditional therapeutic uses.MethodsWe conducted a multidimensional analysis of 32 Salvia species documented in the Dictionary of Chinese Ethnic Medicine. This integrated systematic literature review, verification of altitudinal distributions using the Global Biodiversity Information Facility (GBIF), phenological characterization based on the Flora of China, and phytochemical profiling cross-referenced with the Human Metabolome Database (HMDB) and PubChem.ResultsThese species are used by 17 ethnic minority groups in China, primarily for cardiovascular and cerebrovascular diseases, gynecological disorders, and wound healing, guided by the principles of “activating blood circulation to resolve stasis” and “clearing heat and detoxifying.” Our findings support the habitat-adaptation hypothesis: biologically, species diverge into spring-flowering types (low-altitude, used predominantly by Miao and Zhuang communities) and summer-flowering types (high-altitude; widely employed in Tibetan medicine). Chemically, this divergence corresponds to marked compositional differences-low-altitude species are enriched in flavonoids, whereas high-altitude species accumulate higher levels of phenolic acids, consistent with adaptive responses to intense UV radiation at elevation. Functional compartmentalization was also observed: roots preferentially accumulate lipophilic diterpenoid quinones (associated with antitumor and antiplatelet effects) and hydrophilic phenolic acids (linked to antioxidant and antifibrotic activities), while aerial parts are rich in flavonoids (antibacterial and antitussive) and triterpenoids (immunomodulatory). Pharmacologically, Salvia species exhibit broad bioactivities - including anticancer, anti - inflammatory, hepatoprotective, and cardioprotective effects - mediated by multiple compound classes (terpenoids, phenolic acids, polysaccharides) acting through diverse pathways. Clinical evidence further corroborates a direct alignment between traditional efficacy concepts and molecular mechanisms: “activating blood circulation to resolve stasis” corresponds to diterpenoid quinone–mediated antitumor activity, and “clearing heat and detoxifying” aligns with phenolic acid-driven anti-inflammatory effects.ConclusionThis study successfully validates the “habitat-phytochemistry-pharmacological effect” linkage model, demonstrating a strong correlation between the ethnomedicinal value of Salvia species and their ecological traits, phytochemical profiles, and pharmacological actions. The model provides a robust framework for ethnopharmacology-guided natural product discovery. Future work should prioritize mechanistic studies of key active constituents and rigorous pharmacological validation of their traditional uses.
DOI: 10.3389/fphar.2026.17172612026-04-02
Shuwei Weng, Jinjxiu Lin, Dajun Chai
This review examines how olanzapine drives metabolic injury beyond the brain and why an organ-resolved perspective is needed. We synthesize clinical signals of early weight gain, insulin resistance, dyslipidemia, and steatotic liver disease, and integrate translational evidence across liver, adipose tissue, skeletal muscle, pancreatic β-cells, and the gut–liver axis. Mechanistic strands include disordered hepatic lipid handling, suppression of brown-fat thermogenesis, β-cell endoplasmic-reticulum stress with impaired secretion, and skeletal-muscle insulin-signaling defects with altered epigenetic programs that blunt glucose disposal. We summarize modifiers of risk across life stage, treatment exposure, genetic variation, smoking status, and pregnancy, and distill a pragmatic pathway that prioritizes early reassessment, MASLD-aligned liver evaluation, targeted lifestyle treatment, metformin for early deterioration, and GLP-1 receptor agonists when required. We advance the view that weight-independent extra-cerebral mechanisms are central to olanzapine’s metabolic liability and that psychiatric practice should adopt metabolic frameworks used in hepatology and endocrinology. We propose an agenda for organ-specific human phenotyping and exposure-aware designs that integrate therapeutic drug monitoring with microbiome, metabolomics, and bile-acid profiling, alongside comparative trials that test stepped algorithms within psychiatric care. This perspective outlines a path to preserve antipsychotic efficacy while reducing preventable systemic metabolic harm.
DOI: 10.3389/fphar.2025.17292642026-04-01
Min Liu, Yanxia Li, Bing Han, Ni Zeng, Xiuhua Wei, Xiaoli Xing, Zhongmin Jiang, Xiaozhi Liu, Chunyan Zhang
IntroductionPlatinum-based chemotherapy remains a cornerstone for advanced non-small cell lung cancer (NSCLC), but its efficacy is often compromised by chemoresistance, necessitating strategies to restore drug sensitivity. Ginsenoside Rg3, an active component of Panax ginseng, exhibits anti-tumor and potential chemosensitizing properties, though its mechanisms in clinically relevant models are not fully understood.MethodsWe successfully established and characterized three lung adenocarcinoma patient-derived organoid (PDO) lines that faithfully recapitulated the histopathological and molecular features of the parental tumors. The chemosensitizing effect of Rg3 on cisplatin was evaluated by assessing organoid viability, half-maximal inhibitory concentration (IC50), intracellular reactive oxygen species (ROS) levels, and apoptosis via TUNEL assay.ResultsPharmacodynamic evaluation revealed that the combination of Rg3 and cisplatin exerted superior inhibitory effects on organoid viability compared to either agent alone, with a pronounced reduction in IC50. Furthermore, the combination treatment significantly increased intracellular ROS levels and induced apoptosis, as evidenced by TUNEL assay.DiscussionThis study provides preclinical evidence for Rg3 as a promising chemosensitizer in lung adenocarcinoma and highlights the value of PDOs as a robust platform for personalized drug response profiling. These findings support further exploration of Rg3 as an adjunct to platinum-based chemotherapy in overcoming chemoresistance.
DOI: 10.3389/fphar.2026.17911702026-04-01
Yi Luo, Xijie Wu, Wenjing Chen, Ziao He, Yan Yang, Linjie Ma, Hongqiang Chen, Sicheng Zhang, Chao Li
Oral cancer remains a major global health burden. Current therapies are often limited by recurrence, drug resistance, and systemic toxicity. Natural bioactive metabolites, particularly those derived from medicinal plants used in Traditional Chinese Medicine are increasingly investigated as multitarget anticancer leads. In this review, we integrated evidence from studies published between January 2010 and June 2025. We summarize representative flavonoids, terpenoids, phenolic metabolites, alkaloids, polysaccharides, and quinones evaluated in oral cancer models. Reported activities include suppression of proliferation, induction of apoptosis and autophagy, inhibition of epithelial–mesenchymal transition and angiogenesis, and modulation of tumor metabolism and immune pathways. However, the current evidence base remains largely preclinical and frequently relies on simplified in vitro assays. Pharmacokinetic bridging, toxicity evaluation, and clinically relevant validation are still limited. Importantly, several polyphenolic metabolites exhibit pan-assay interference (PAINS) liabilities, requiring cautious interpretation of pathway-level findings. Advances in nano-delivery systems, rational structural optimization, and combination strategies may improve exposure and selectivity. Future work should emphasize PAINS-aware pharmacological rigor, orthogonal target validation, advanced translational models, and biomarker-driven clinical trials to support the development of genuinely druggable natural metabolite candidates for oral cancer management.
DOI: 10.3389/fphar.2026.17942852026-04-01
Xiaoyi Liu, Xiaochuan Huang, Xiaobin Song
Symphytum officinale: L. (S. officinale), commonly known as comfrey, has been used in traditional medicine for over 2,000 years to treat wounds, fractures, and inflammatory conditions. This review is the first comprehensive ethnopharmacological synthesis that systematically integrates cross-cultural traditional knowledge with the latest evidence on its phytochemical profile, pharmacological mechanisms, clinical efficacy, and toxicological risks. Unlike previous fragmented reviews that addressed only isolated aspects, we followed PRISMA guidelines to analyze selected studies, with a strong emphasis on developing safe, pyrrolizidine alkaloid (PA)-depleted topical formulations that translate the plant’s classic “knitbone” reputation into modern evidence-based phytotherapy. Key bioactive constituents—allantoin, rosmarinic acid, polysaccharides, and lignans—exert anti-inflammatory, tissue-regenerative, and bone-repair effects primarily by inhibiting NF-κB and MAPK pathways and suppressing pro-inflammatory cytokines. Randomized controlled trials demonstrate that topical S. officinale preparations significantly outperform placebo in acute back pain, knee osteoarthritis, ankle sprains, and myalgia, while showing non-inferiority to diclofenac and an excellent safety profile. However, the presence of hepatotoxic PAs (intermedine and lycopsamine) strictly limits internal use. Topical application remains safe owing to minimal systemic absorption. By bridging historical wisdom with rigorous contemporary data and spotlighting PA-depletion strategies, this review offers a balanced framework for safe clinical application and future formulation optimization.
DOI: 10.3389/fphar.2026.17930842026-04-01
Florina-Diana Goldiş, Sabina-Oana Vasii, Sebastian-Mihai Ardelean, Mihai Udrescu-Milosav, Lucreția Udrescu
IntroductionPsychiatric outpatients frequently receive complex, long-term regimens where polypharmacy, drug-drug interactions (DDIs), QT interval risk, anticholinergic load, and serotonergic exposure co-occur. Clinicians must triage drug lists quickly, yet most tools address a single risk domain. We developed the PsychoPharm Aggregated Risk Score (PARS), a visit-level composite score that integrates multiple pharmacological risk domains into a single, clinically interpretable signal.MethodsWe analyzed 2,666 visits from 680 adults in ambulatory psychiatry. For each visit, we computed the risk components: DDI score from DrugBank, AZCERT QT risk, anticholinergic cognitive burden (ACB), serotonergic exposure, and polypharmacy (≥5 drugs). Using z-standardized components, we created the PARS composite as their equal-weight mean, and report it as PARS rescaled on a 0–10 scale for clinical communication. We trained a logistic regression to estimate the probability of High-risk PARS, defined as PARS ≥75th percentile, using only prescribed drugs, age, and sex as features (explicitly excluding the engineered components to prevent leakage), then compared with additional stratifications by age and sex, as well as a 5-fold GroupKFold. A fixed decision threshold of 0.30 was set to favor recall and F1 for the positive class. A drug-only model was also used to identify drugs associated with High-risk visits.ResultsThe prevalence of high-risk cases was observed in 25.2% of visits. Across validation schemes, the primary 80–20 patient-level split achieved the best accuracy, precision, and F1 at the 0.30 operating point. In the primary 80–20 split stratified by High-risk status, the logistic model achieved an AUC of 0.931 (patient-bootstrap 95% CI 0.875–0.971). Discrimination was similar with additional age and sex stratification (AUC of 0.938) and 5-fold GroupKFold (pooled out-of-fold AUC 0.939), indicating robustness to partitioning. In the drug-only model, positive associations included drugs such as quetiapine, haloperidol, clozapine, and amiodarone. The highest-ranked visits combined central nervous system-heavy regimens and polypharmacy.ConclusionAs an exploratory tool, PARS integrates DDIs, QT risk, anticholinergic cognitive burden, serotonergic exposure, and polypharmacy into a single probability that reliably discriminates High-risk visits and supports screening at a 0.30 operating threshold. Our approach highlights actionable drug combinations and patient profiles for drug review and deprescribing.
DOI: 10.3389/fphar.2026.17829682026-04-01
Wenxin Xu, Lisha Shang, Xue Li, Jie Yu, Jinyi Shen, Yujin Li, Qiongyao He, Liang Chen, Deqiang Wang, Yelin Wei, Siqiang Niu
Carbapenem-resistant Enterobacterales (CRE) have been identified by the World Health Organization as critical-priority pathogens, posing a severe global public health threat due to limited therapeutic options and high mortality rates. In response, this review provides a comprehensive assessment of current antimicrobial strategies against CRE, covering the efficacy and limitations of traditional antibiotics (e.g., polymyxins, tigecycline), novel agents (e.g., cefiderocol, ceftazidime-avibactam), and diverse combination therapies. Despite recent advances, major gaps persist, including the lack of effective regimens for pan-drug-resistant (PDR) strains, insufficient large-scale clinical evidence for many novel agents, and disparities in global access to newer therapeutics. Future priorities should including conducting high-quality randomized controlled trials (RCTs) to optimize treatment strategies, integrating rapid molecular dianostics into routine clinical practice to facilitate precision therapy, and continuing the development of novel agents and synergistic combination approaches. Simultaneously, establishing a global antimicrobial resistance surveillance network is indispensable for mitigating the ongoing spread of CRE.
DOI: 10.3389/fphar.2026.17965572026-04-01
Xianting Liang, Junning He, Qiuting Wu, Lixiang Fu, Yongfang Liu
Alcohol-associated liver disease (ALD), a significant cause of chronic liver disease worldwide, is strongly linked to gut microbiome dysregulation. Heavy alcohol use disrupts the gut bacterial equilibrium and damages the intestinal barrier, making it more permeable to microbial toxins (e.g., endotoxins) that trigger liver inflammation. Many studies have investigated ALD, but no single microbial marker has yet been identified as diagnostic. Results from microbiome studies on this condition have been inconsistent; consequently, scientists are developing new microbiome-based indices and multi-omics approaches to improve their ability to predict diseases. The review evaluates current findings on how disturbances in the gut microbiome and deterioration of the intestinal barrier contribute to the development of ALD. The assessment includes microbiome-based treatments such as probiotics, fecal microbiota transplantation (FMT), and bacteriophage therapy. Research indicates that probiotics and FMT treatments may enhance liver function and reduce inflammation in patients with ALD. The studies present conflicting results because researchers used different methods and worked with limited numbers of participants. Bacteriophage therapy exists as an experimental treatment method. The development of personalized microbiome treatments, along with biomarker standardization and solutions to technical and ethical challenges, will enable these strategies to enter medical practice. The review integrates existing knowledge of the gut-liver axis in ALD to demonstrate the clinical potential of microbiome-based treatments while highlighting the need for additional research to enhance treatment outcomes.
DOI: 10.3389/fphar.2026.17708332026-04-01
Yao Chen, HuLi Li, WenJie He
Diabetic wound (DW) healing impairment is one of the most common and serious complications of diabetes. DW is characterized by a complex pathogenesis involving hyperglycemia, oxidative stress, persistent inflammation, mitochondrial dysfunction, impaired angiogenesis, and neuropathy. Recent studies have revealed that mitochondria are not only the cellular powerhouses but also key organelles regulating inflammatory responses, redox balance, and cell fate. This review summarizes how mitochondrial dysfunction exacerbates inflammation and impedes the healing process in DW through mechanisms such as excessive reactive oxygen species (ROS) production, mitochondrial DNA (mtDNA) leakage, and aberrant inflammasome activation. Furthermore, it comprehensively outlines innovative therapeutic strategies targeting mitochondria, including mitochondria-specific antioxidants, metabolic reprogramming techniques, nanomaterial-based delivery systems, genetic engineering approaches, and natural product applications. These strategies are discussed from molecular mechanisms to clinical applications, aiming to provide new insights and a theoretical basis for the clinical management of DW. Systematic analysis indicates that therapeutic strategies targeting the mitochondria-inflammation axis hold significant potential and may represent a critical breakthrough in addressing the challenge of DW healing.
DOI: 10.3389/fphar.2026.17866932026-04-01
Qian Sun, Jiani Ji, Jingqi Chen, Ting Jiang, Shiyan Zhang, Hongli Yang
BackgroundOvarian cancer ranks fourth in terms of incidence among gynecological malignancies and third as a cause of cancer death in the gynecological field, with oral contraceptives (OCs) exhibiting a potential relationship to ovarian cancer chemoprevention. This meta-analysis aimed to investigate the association between exposure to OCs and the incidence of ovarian cancer.MethodsFollowing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, Web of Science, Embase, and the Cochrane Library were searched for cohort studies on OCs and ovarian cancer incidence, covering the period from the establishment of each database to May 2025. Hazard ratio (HR) and 95% confidence interval (95% CI) were applied to assess the association between OCs and ovarian cancer incidence, with subgroup analyses performed for duration of use, time since OCs discontinuation, and geographical region.ResultsThis meta-analysis included a total of 11 cohort studies. The results revealed that the OCs exposure group had a significantly lower ovarian cancer incidence than the control group (HR: 0.80, 95% CI: 0.71–0.89; P < 0.001; I2 = 53.6%). However, no significant difference in incidence was noted between both groups for individuals with an OCs exposure duration of less than 5 years (HR: 0.98, 95% CI: 0.84–1.16; P = 0.857), and a lower incidence was exclusively observed in the OCs exposure group with use lasting more than 5 years (HR: 0.66, 95% CI: 0.58–0.76; P < 0.001). Subgroup analysis revealed that in both European (HR: 0.74, 95% CI: 0.61–0.91; P = 0.004) and American (HR: 0.83, 95% CI: 0.68–1.01) cohorts, the incidence of ovarian cancer in the exposed group was lower than that in the control group. However, the difference in the latter did not reach statistical significance (P = 0.064), while no difference in ovarian cancer incidence was observed between the two groups in the Asian cohort (HR: 0.93, 95% CI: 0.71–1.23; P = 0.628).ConclusionThis study demonstrated that OCs exposure can exert a preventive effect on ovarian cancer, but such prevention necessitates a duration of use of more than 5 years, and the effect is impacted by geographical factors. In the future, OCs may emerge as one of the potential measures for ovarian cancer prevention.
DOI: 10.3389/fphar.2026.17327192026-04-01
Xi Liu, Lulu Xu, Xue Zhong, Jie Zhang
BackgroundRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe condition with an unclear pathogenesis. Here, we investigated the effects of baricitinib on lung fibrosis progression.MethodsA collagen-induced arthritis (CIA) mouse model was established. Lung tissues were analyzed using Western blotting, immunofluorescence staining, immunohistochemical staining, Masson’s trichrome and hematoxylin and eosin staining. Protein expression was assessed in vitro using Western blotting and immunofluorescence staining. The cytokine levels in supernatants were measured using ELISA, and macrophage-derived exosomes were identified using transmission electron microscopy and Western blotting, followed by microRNA sequencing analyses. miR-126a-3p-regulated genes were identified using dual-luciferase reporter assays.ResultsIn vivo, baricitinib reduced iNOS, CD206 and MerTK levels and collagen deposition in the lungs of CIA mice through the JAK/STAT pathway. In vitro, baricitinib downregulated the expression of arginase-1, CD206 and MerTK in macrophages and TGF-β and IL-10 in supernatants. Baricitinib also increased miR-126a-3p expression in macrophage-derived exosomes. miR-126a-3p exerted antifibrotic effects by regulating apoptosis and autophagy via the PI3K/AKT1/mTOR pathway. Silencing JAK1 reduced JAK1 and JAK2 expression.ConclusionBaricitinib targets the JAK/STAT signaling pathway in macrophages, thereby exerting dual anti-inflammatory and anti-fibrotic inhibitory effects on CIA-ILD mice. Meanwhile, it increases miR-126a-3p secretion by suppressing M2 polarization, further contributing to its anti-fibrotic activity in vitro using NIH3T3 cell.
DOI: 10.3389/fphar.2026.1747540