Phytotherapy Research最新文献

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, characterized by severe impairment of osteoblast function and increased bone fragility. Current therapeutic options inadequately address glucocorticoid (GC)-induced osteoblast apoptosis and suppress osteogenesis, highlighting the need for novel targeted interventions. To explore the molecular pathogenesis of GIOP and identify therapeutic targets, we performed integrated transcriptomic analysis, bioinformatics approaches, and multiple experimental validation methods. We demonstrate that dexamethasone (DEX), a prototypical GC, robustly upregulates osteoglycin (OGN) expression in both cellular and animal models. Crucially, the transcription factor ELF5 functions as a critical transcriptional repressor of OGN, counteracting DEX effects. ELF5-mediated OGN repression is essential for maintaining pro-survival PI3K/AKT/mTOR signaling integrity in osteoblasts. Molecular docking confirmed stable, high-affinity binding between the natural compound chrysophanol and OGN. Functionally, chrysophanol effectively antagonized DEX-induced OGN elevation and mitigated osteoblast apoptosis. This work is the first to define a role for the DEX-OGN-ELF5 axis in PI3K/AKT/mTOR signaling as critical for osteoblast survival in GIOP. Chrysophanol, as a novel natural compound targeting this OGN-centric axis, presents a promising and potentially safer therapeutic alternative to bisphosphonates, which are associated with risks like atypical femoral fractures and osteonecrosis of the jaw. Our findings offer novel insights into the molecular pathogenesis of GIOP, identify a potential druggable ELF5/OGN/PI3K/AKT/mTOR signaling axis, and establish a basis for future translational research in GC-induced bone diseases.

Postmenopausal osteoporosis (PMOP) results from estrogen deficiency, oxidative stress, and impaired bone formation, yet effective treatments remain limited. In this study, we identify the natural isoflavone ononin as a potent antiosteoporotic compound and uncover its mechanism through activation of aldehyde dehydrogenase 2 (ALDH2). Using an ovariectomized (OVX) mouse model and bone marrow-derived mesenchymal stem cells (BMSCs), we evaluated the in vivo and in vitro effects of ononin. An integrated approach combining network pharmacology, molecular docking, enzymatic assays, and ALDH2 knockout (Aldh2^-/-) models was employed to verify its molecular target. Ononin significantly alleviated OVX-induced trabecular bone loss and promoted osteogenic differentiation of BMSCs in a dose-dependent manner. Mechanistically, network pharmacology and docking analyses identified ALDH2 as the primary target. Enzymatic assays confirmed that ononin robustly enhances ALDH2 activity, reduces reactive oxygen species, lowers 4-hydroxynonenal and malondialdehyde levels, and maintains mitochondrial integrity. These beneficial effects were largely abolished in Aldh2^-/- mice, confirming the dependence on ALDH2 activation. Collectively, these findings demonstrate that ononin protects against PMOP by promoting ALDH2-mediated osteogenesis and restoring redox balance, highlighting its potential as a natural therapeutic agent for postmenopausal osteoporosis.

Immune checkpoint inhibitors (ICIs) have prolonged cancer survival but exacerbated atherosclerotic cardiovascular disease (ASCVD). This research aims to interrogate the underlying mechanism of ICIs-related atherosclerotic progression and the potential protective effect of Red Yeast Rice (RYR) on it. A tumor-bearing atherosclerotic (TB-AS) mouse model was established by subcutaneously injecting MC38 cells in male ApoE^-/- mice fed a high-fat diet (HFD). Intraperitoneal anti-PD-1 antibody (αPD-1) with/without dietary RYR supplementation was administered during the model. Serum was separated for lipid and inflammation evaluation. Plaque assessment was quantified by histological staining. Bone marrow-derived macrophages (BMDMs) were isolated, incubated in growth medium containing 5% serum from the mice model, and treated with ox-LDL and RYR. Cell viability was accessed by CCK8 assay. Lipid staining was employed to assess lipid droplet accumulation. The apoptosis and polarization of BMDMs were analyzed using flow cytometry. Cytokine levels were determined by luminex multiplex assay. And finally, western blot was conducted for mechanism investigation. αPD-1 significantly increased atherosclerotic lesion area, plaque lipid content, and macrophage/T-cell infiltration versus untreated TB-AS controls. These effects coincided with elevated pro-inflammatory cytokines/chemokines and reduced anti-inflammatory mediators. RYR co-treatment attenuated these αPD-1-induced pro-atherogenic changes. In vitro, compared with serum from TB-AS mice, BMDMs cultured with serum from αPD-1-treated TB-AS mice exhibited reduced cell viability, elevated pro-inflammatory cytokine levels in culture supernatants, enhanced M1 polarization, and increased apoptosis levels. All these phenotypic changes were reversed by RYR treatment. Mechanistically, RYR significantly inhibited the RhoA-mediated activation of NF-κB and MAPK signaling, thereby suppressing the αPD-1-induced inflammatory response in BMDMs. αPD-1 promotes ASCVD progression by enhancing macrophage inflammation and T-cell recruitment within plaques. RYR mitigates these effects through RhoA inhibition, suggesting its therapeutic potential for improving cardiovascular outcomes in ICIs-treated cancer patients with ASCVD.

Obesity is a global metabolic disorder in which gut microbiota has emerged as a pivotal regulator. Chlorogenic acid (CGA) has been reported to improve lipid metabolism and mitigate obesity; however, its microbiota-mediated mechanisms remain unclear. Here, we established a diet-induced obesity (DIO) mouse model by high-fat diet feeding and integrated serum metabolomics, liver transcriptomics, and fecal microbiota transplantation (FMT) to elucidate the effects of CGA. CGA supplementation alleviated obesity-related phenotypes, reduced intestinal inflammation, and preserved mucosal barrier integrity, thereby restoring microbial homeostasis. Combined 16S rRNA sequencing and untargeted metabolomics revealed that CGA reshaped gut microbiota (suppressing Desulfovibrio and Allobaculum, enriching Oscillospira), accompanied by altered serum metabolites (elevated linoleic acid, reduced hexadecanoic and tetradecanoic acids). Transcriptomic analysis demonstrated that CGA downregulated genes related to hepatic lipid synthesis (FASN, ACACA, SCD1) and lipid uptake (FABP4, SCP2, CD36), which was further validated by qRT-PCR. Importantly, FMT from CGA-treated mice reproduced the metabolic improvements, confirming that the beneficial effects of CGA are closely associated with gut microbiota modulation. Collectively, these findings indicate that CGA ameliorates obesity through modulation of the gut microbiota-serum metabolite-liver axis.

Osteoporosis is a prevalent skeletal disorder characterized by imbalanced bone remodeling, leading to excessive bone loss. Cannabinoid receptor 2 (CB2) has emerged as a promising therapeutic target in bone metabolism due to its peripheral expression and dual regulation of osteoblast and osteoclast activity. Desmethoxyyangonin (DMY) has demonstrated CB2 agonist activity, yet its therapeutic efficacy and molecular mechanisms in bone remain incompletely understood. Here, we investigated the anti-osteoporotic effects of DMY and its mechanistic insight on CB2 signaling. An ovariectomized (OVX) mouse model was used to assess the in vivo effects of DMY on trabecular bone microarchitecture and biomechanical properties. The impact of DMY on osteoblast and osteoclast differentiation was examined in vitro using MC3T3-E1 cells and bone marrow-derived macrophages (BMMs), respectively. Molecular docking and molecular dynamics simulations were conducted to investigate the potential interactions between DMY and CB2. Untargeted metabolomics was performed to explore metabolic alterations associated with DMY treatment. Western blot studies evaluated key osteogenic and signaling markers. DMY treatment significantly restored bone mineral density and improved trabecular microarchitecture. In vitro, DMY promoted osteoblast differentiation and mineralization while concurrently suppressing osteoclast formation and function. Pharmacological blockade of CB2 with its antagonist (SR144528) abrogated DMY's effects on both cell types, indicating CB2-mediated action. Molecular docking and dynamics simulations predicted a stable interaction between DMY and CB2. Untargeted metabolomics revealed DMY-induced shifts in metabolic pathways related to bone remodeling. Mechanistically, DMY upregulated osteogenic markers and activated PI3K/Akt and Wnt/β-catenin signaling cascades. Collectively, these findings demonstrate that DMY exerts bone-protective effects via CB2-dependent modulation of bone formation and resorption, offering a dual-target strategy for osteoporosis intervention.

Curcuminoids are dietary polyphenols that can improve health indices through various mechanisms, such as anti-inflammatory, antioxidant, and other clinical properties. Due to the lack of evidence on the efficacy of curcuminoids in critically ill patients, this meta-analysis was conducted. The aim of this study was to assess and quantify the influence of curcumin supplementation on markers of inflammation, liver function, and clinical outcomes in critically ill patients. In this study, relevant randomized clinical trials were identified via electronic database searches, including MEDLINE, Scopus, and Web of Science, up until January 2025. The Cochrane risk-of-bias tool was utilized to assess the quality of the studies. Standardized mean differences (SMDs) and risk ratio (RR) in changes between intervention and placebo groups were calculated. Both random-effects and fixed-effects models were applied, and pre-specified stratified analyses were performed to explore potential sources of heterogeneity. Out of a total of 691 studies screened, seven trials met the inclusion criteria, encompassing data from 571 participants. The pooled analysis demonstrated that curcumin supplementation significantly lowered alanine transaminase (ALT) levels (SMD: -0.4, 95% CI: -0.8 to -0.001, p = 0.03), total bilirubin levels (SMD: -0.4, 95% CI: -0.9 to -0.07, p = 0.01), Sequential Organ Failure Assessment (SOFA) scores (SMD: -0.8, 95% CI: -1.2 to -0.4, p < 0.001), the duration of intensive care unit (ICU) stays (SMD: -0.3 days, 95% CI: -0.6 to -0.1, p = 0.01), compared to placebo. Furthermore, curcumin supplementation was associated with significant increases in albumin (SMD: 0.3, 95% CI: 0.001 to 0.6, p = 0.004) and alkaline phosphatase levels (SMD: 0.4, 95% CI: 0.02 to 0.8, p = 0.01). This meta-analysis demonstrates that curcumin supplementation improves liver function, albumin levels, SOFA scores, and ICU stay duration in critically ill patients, suggesting its potential role in mitigating organ dysfunction in this population.

Crohn's disease (CD), a chronic inflammatory bowel disease, is frequently complicated by intestinal fibrosis, a process driven by extracellular matrix remodeling. Current therapies lack efficacy in controlling or reversing fibrotic progression, underscoring the need for novel treatments. Here, we found that garlic-derived exosomes (GDE) significantly reduced hydroxyproline production and inhibited the expression of fibrosis-related proteins such as COL1A2, COL3A1, and α-SMA in TGF-β1-treated intestinal fibroblasts. Administration of GDE significantly improved the lesions of the muscular mucosa, the colon shortening, and bowel wall thickness, while also decreasing the expression of COL1A2, COL3A1, and α-SMA in the colon tissues of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mice. Meanwhile, GDE significantly attenuated phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) expression in TGF-β1 treated intestinal fibroblasts and colon tissue of TNBS-induced mice. Both Pfkfb3 gene interruption and PFK-015 (a PFKFB3 inhibitor) markedly prevented the role of GDE in the expression of fibrosis-related biomarkers by blocking the glycolysis pathway and triggering metabolic reprogramming in TGF-β-treated intestinal fibroblasts. Furthermore, fibroblast-specific Pfkfb3 deficiency significantly reduced the fibrosis in the colon tissues of TNBS-induced mice. Taken together, this study reveals the anti-fibrotic mechanism of GDE by regulating Pfkfb3 expression to inhibit the metabolic reprogramming of fibroblasts, which is expected to provide new strategies and targets for the treatment of intestinal fibrosis in patients with CD.

Background: ALDH1A3 is a key factor associated with tumor stemness and chemotherapy resistance, making it a promising therapeutic target. Screening various compounds with potential inhibition of cancer stem cells led to the discovery of a naturally occurring Dioscin as a novel ALDH1A3 inhibitor. However, the precise mechanism underlying its action remains unexplored.

Experimental procedure: Immunohistochemical analysis of 90 ovarian serous tumor samples revealed the clinical significance of ALDH1A3 in tumor progression. TCGA data was used to identify genes highly correlated with ALDH1A3 in ovarian cancer. Using CRISPR/Cas9-generated ALDH1A3 knockout (KO) cell lines, we investigated its oncogenic influence in ovarian and gastric cancers. The anti-tumor effects of Dioscin were assessed through MTT, scratch, and 3D spheroid formation assays. In vivo efficacy of Dioscin was assessed using a xenograft mouse model. Mechanistic investigations of Dioscin with ALDH1A3 were predicted by molecular docking and assessed through ALDH1A3 enzymatic activity and retinoic acid (RA) metabolism analyses.

Results: ALDH1A3 expression correlates with early-stage ovarian cancer progression. Genetic ablation of ALDH1A3 significantly suppressed cell proliferation, migration, and stemness properties. ALDH1A3 is significantly associated with ECM-related genes in ovarian cancer. Dioscin exhibited an ALDH1A3-dependent anti-tumor effect by inhibiting ALDH1A3 enzymatic activity, disrupting RA metabolism, and downregulating the expression of stemness- and migration-associated proteins (CD44 and MMP2). Furthermore, Dioscin effectively delays tumor growth without obvious signs of toxicity.

Conclusion: Our study provides the first evidence that Dioscin inhibits ALDH1A3-mediated RA metabolism and cancer stemness. Our data will further support its potential as a therapeutic agent for cancer treatment.

Lung cancer (LC) remains the leading cause of global cancer-related death due to delayed diagnosis, poor therapeutic efficacy, and drug resistance. Traditional therapeutic methods like radiation, chemotherapy, and targeted medicines are often associated with high toxicity and often result in minimal survival improvements. Phytochemicals from medicinal plants are increasingly being considered as potential LC treatment agents due to their multi-targeted action, safety, and accessibility. These have anticancer properties by regulating key molecular signaling pathways like PI3K/Akt/mTOR, MAPK/ERK, NF-κB, STAT3, and apoptotic cascades. These compounds also promote apoptosis, increase chemotherapeutic medication sensitivity, and prevent tumor cell growth, angiogenesis, invasion, and metastasis. Phytochemicals have shown potential in reducing therapy-induced side effects and combating multidrug resistance, potentially enhancing treatment effectiveness. Despite promising discoveries, challenges such as low bioavailability, limited pharmacokinetic stability, and lack of extensive clinical validation inhibit their widespread use. This review provides clinical insights into phytochemical-based LC preventive and treatment approaches, focusing on their role in addressing molecular signaling pathways. It demonstrates the potential medicinal benefits, potential disadvantages, and potential applications of phytocompounds as supplementary or alternative treatments for LC.