Phytotherapy Research最新文献

Postmenopausal metabolic syndrome and its associated liver injury have attracted considerable research interest, yet their underlying mechanisms and treatment strategies remain insufficiently elucidated. This study aimed to investigate the relationship between aberrant lipid metabolism and hepatic injury in ovariectomized (OVX) females and to evaluate the therapeutic potential of ingenol (Ing), a natural diterpenoid, via the SIRT1-LXRα signaling pathway. Data from 3047 females in NHANES (2017-2020) were analyzed to compare serum triglyceride (TG) and liver injury markers between OVX and non-OVX women. An OVX mouse model was established to examine hepatic lipid metabolism and SIRT1 expression. Molecular docking, dual luciferase assays, and SIRT1 silencing were performed to evaluate Ing-SIRT1 binding and regulation. HepG2 cells were used to assess Ing's effects on lipid levels and expression of LXRα, CYP39A1, CPT1, and ACOX1. In vivo studies in OVX mice confirmed the therapeutic effects of Ing and further investigated its mechanism via the SIRT1-LXRα pathway. NHANES data indicated that OVX women had significantly higher serum TG levels and more severe liver injury. OVX mice exhibited downregulated SIRT1 expression and disrupted lipid homeostasis. Ing showed high binding affinity to SIRT1, outperforming several known agonists. In HepG2 cells, Ing reduced intracellular TG and total cholesterol (TC), while upregulating LXRα, CYP39A1, CPT1, and ACOX1. In OVX mice, Ing treatment notably attenuated weight gain, reduced TG and TC levels, and ameliorated liver histopathological damage. These effects were mediated through the SIRT1-LXRα pathway. Ing effectively mitigates OVX-induced liver injury by activating SIRT1 and modulating downstream LXRα-mediated lipid metabolic pathways. These results support Ing as a promising therapeutic candidate for liver injury in postmenopausal or OVX women.

Vascular aging, a central feature of organismal aging, involves endothelial cell (EC) structural and functional alterations. Methylglyoxal (MGO), a key advanced glycation end product precursor, pathologically accumulates during aging. While MGO induces EC apoptosis via mitochondrial pathways and endothelial dysfunction, its role in cellular senescence remains unclear. The integrated stress response (ISR) sensor Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2 (EIF2AK2), also known as PKR, has emerged beyond its well-established antiviral role as a critical regulator of cellular senescence. This study explores the novel mechanism of berberine (BBR) on targeting EIF2AK2 dimerization to attenuate MGO-induced EC senescence and apoptosis. In vitro, MGO-treated HUVECs assessed EIF2AK2 dimerization/phosphorylation and senescence (p16, p21) and apoptosis (cleaved caspase-3) markers. In vivo, three aging models (MGO-induced aortic injury, D-gal-induced accelerated aging, natural aging) evaluated MGO accumulation and EIF2AK2 pathway activation (phospho-EIF2AK2, ATF4), demonstrating BBR's efficacy via EIF2AK2 axis modulation. Here, we present the first evidence demonstrating that EIF2AK2 dimerization and subsequent activation significantly exacerbate EC senescence and apoptosis in both in vivo and in vitro models, characterized by upregulation of pro-apoptotic markers (Cleaved caspase-3, Bax) and senescence-associated proteins (P53, P21, P16), along with downregulation of the anti-apoptotic protein Bcl-2. EIF2AK2 has been identified as a key cellular target of the natural isoquinoline alkaloid BBR. Our findings further establish that BBR ameliorates MGO-induced vascular EC senescence and apoptosis through selective inhibition of EIF2AK2 dimerization and subsequent eIF2α phosphorylation. Notably, pharmacological suppression of EIF2AK2 with C16 synergistically enhances BBR's protective effects against MGO-induced EC senescence and apoptosis. Collectively, this study reveals a novel mechanistic pathway by which MGO drives EC senescence/apoptosis via EIF2AK2 dimerization/activation and validates BBR's therapeutic potential for vascular pathologies. EIF2AK2 emerges as a promising target for developing novel vascular protection strategies.

Neointima formation, characterized by similarities to tumor-like growth, plays a pivotal role in the progression of vascular occlusive diseases. Oroxylin A (OroA), a bioactive flavonoid from Scutellaria roots, shows protective effects against cardiovascular diseases and cancers. This study explores whether OroA inhibits neointima formation caused by vascular injury and investigates the mechanisms involved. Models of carotid artery ligation and guide wire-induced injury were used to study vascular smooth muscle cell (VSMC) phenotypic switching and neointima formation. Glycolytic activity and oxidative phosphorylation were evaluated using extracellular acidification rates and oxygen consumption rates, respectively. Western blot and quantitative real-time PCR were utilized to measure the expression of contractile and proliferative markers, glycolytic enzymes, and intracellular signaling pathways. For rescue experiments, an adenovirus encapsulated in pluronic gel was used to overexpress HIF-1α in injured vascular tissue. OroA effectively inhibited VSMC phenotypic switching and neointima formation by suppressing vascular injury-induced glycolytic reprogramming. Mechanistically, the vascular injury-induced upregulation of mammalian target of rapamycin complex 1 (mTORC1)-hypoxia-inducible factor-1α (HIF-1α) signaling increases the aerobic glycolysis of VSMCs. OroA attenuated mTORC1-HIF-1α signaling-mediated aerobic glycolysis by preventing the phosphorylation of tuberous sclerosis complex 2 (TSC2) at serine 939. Notably, the overexpression of HIF-1α reversed the inhibitory effects of OroA on VSMC phenotypic switching and neointima formation. This study suggests that OroA mitigates neointima formation by inhibiting the TSC2/mTORC1/HIF-1α-dependent glycolysis pathway, indicating its potential as a therapeutic agent for vascular occlusive diseases.

Secondary bacterial infection is a major cause of severe progression and death in viral pneumonia. The excessive recruitment of neutrophils accompanied by the formation of neutrophil extracellular traps (NETs) plays an important role in excessive inflammation caused by viral-bacterial co-infection, but effective pharmacological interventions remain lacking. Our study revealed that quercitrin (QTN), a flavonoid commonly found in traditional Chinese medicine and daily diets, significantly reduced mortality, recruitment of neutrophils, the production of inflammatory cytokines, and viral and bacterial loads in H1N1 influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection-induced pneumonia in mice. Mechanistically, QTN down-regulates the interaction between Histone H3 and myeloperoxidase (MPO), thereby mitigating excessive inflammation induced by NETs. Our study demonstrates that inhibiting NETosis with QTN is one of the effective strategies for co-infection treatment.

Essential oils (EOs) are recognized for their multiple health benefits. However, their high volatility, low stability, and limited water solubility limit their effective application. This systematic review aims to assess the use of nanoemulsions as delivery systems for the topical administration of EOs, highlighting their efficacy, safety, and limitations. A literature search was conducted in the PubMed, Scopus, and Web of Science databases for studies published in English before February 2025, following the PRISMA 2020 guidelines. Studies limited to in vitro or ex vivo assays, using isolated EO components, or involving non-topical applications were excluded. Twenty-two articles were included in this review, comprising EOs from 18 plant species, and applied in animal or human in vivo models for wound healing (n = 6), anti-inflammatory/analgesic effects (n = 5), cosmetic (n = 6), and transdermal delivery/permeation enhancer (n = 5). Nanoemulsions improved EOs' bioactivities, particularly their anti-inflammatory, antioxidant, and antimicrobial effects, by enhancing skin permeation, bioavailability, and skin barrier function, reducing skin irritation, and allowing a controlled release. However, the overall risk of bias, assessed using the SYRCLE and RoB 2 tools, was considered high, and the studies' heterogeneity limited direct comparisons. Therefore, further well-designed preclinical and clinical trials are needed to validate these findings and assess the potential of the EOs nanoemulsions for topical use.

Due to its high recurrence and metastasis rates, the prognosis of pancreatic cancer (PC) patients is extremely poor. Cancer stem cells (CSCs) are the major source of occurrence and progression of PC, suggesting that targeting pancreatic CSC stemness may provide therapeutic benefits. This study aims to clarify the mechanisms by which Honokiol (HNK) inhibits the stemness of pancreatic cancer. The expression of c-Met and downstream molecules was investigated based on public databases and also confirmed by the immunohistochemistry (IHC) staining of human tissues. Colony formation assay and sphere formation assay were conducted to verify the effect of HNK on the proliferation and stemness of PC cells. A subcutaneous transplanted tumor model of BALB/c nude mice was established to explore the effect of HNK on modulating the tumor growth of PC in vivo. c-Met expression was significantly elevated in PC tissues versus normal pancreas tissues, and the high level of c-Met was positively correlated with poor prognosis of PC patients. Overexpression of c-Met significantly enhanced the proliferation and stemness of cancer cells, whereas HNK treatment reversed these effects. Critically, HNK suppressed tumor growth in vivo by downregulating c-Met. Our study reveals that HNK reduced the proliferation and stemness of PC cells via suppressing the c-Met overexpression. These findings provide a potential therapeutic method for PC, offering new hope for improving patients' outcomes.

Ashwagandha (Withania somnifera) is a herbal adaptogen which has been extensively studied for its wide-ranging medicinal properties, ranging from stress relief to neuroprotection and immune modulation. Recent studies have evoked concerns over the toxicity of the bioactive compounds, including withanolides, alkaloids, and sitoindosides. Gastrointestinal side effects, immune hypersensitivity, liver toxicity, and endocrine disruption have been reported, particularly with prolonged or excessive usage. Metabolic transformation via cytochrome P450 enzymes can form reactive intermediates, leading to oxidative stress and hepatotoxicity. The endocrine-modulating activity of Ashwagandha has been implicated in thyrotoxicosis and adrenal suppression. This review provides a comprehensive overview of the pharmacological profiles, incorporating preclinical and clinical data to illustrate the fine balance between the therapeutic and toxic effects of Ashwagandha, identifying populations that may be at increased risk of adverse reactions and interactions with prescribed drugs for specific conditions. The necessity for standardizing dosing regimens, rigorous clinical trials, improving pharmacovigilance, carrying out long-term safety assessments, and revising regulatory guidelines is emphasized to maximize clinical application of Ashwagandha while minimizing concomitant risks.

Ischemic stroke is a prevalent neurological disorder often resulting in brain tissue injury and blood-brain barrier (BBB) damage. Luteolin (LUT), a natural polyphenolic compound in grape skin, wine, and other plants, has neuroprotective properties against ischemic stroke. However, it remains unclear whether its protective effect involves alterations in BBB integrity. This study aimed to examine the BBB-protective impact of LUT in a photothrombotic (PT) mouse model and oxygen-glucose deprivation (OGD) cell model and investigate its underlying mechanism. First, we used neurofunctional scoring, 2,3,5-triphenyltetrazolium chloride staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to evaluate the neuroprotective effects of LUT in ischemic stroke. Furthermore, we assessed the impact of LUT on BBB permeability using Evans Blue staining, brain water content, transendothelial electrical resistance, FITC, and flow cytometry techniques. We also examined the expression of tight junction (TJ) proteins related to BBB integrity using Western blotting. Finally, we validated the potential mechanism of action of LUT using short hairpin RNA (shRNA) technology. LUT alleviated the cerebral infarct area and neuronal apoptosis in the PT mouse model, reduced brain water content and Evans Blue leakage, decreased bEnd.3 cell apoptosis in the OGD model, increased transmembrane resistance, and reduced FITC leakage. LUT also counteracted the degradation of TJ proteins and decreased the expression of MMP9. Furthermore, the improvement was weakened when LRP1 was interfered with using shRNA. Our study suggests that LUT has the potential to improve BBB damage and exert neuroprotective effects following ischemic stroke. The mechanism of action may involve the inhibition of LRP1 and subsequent reduction in MMP9 expression.

Pulmonary fibrosis is a chronic and irreversible pulmonary disease. At present, there are few drugs to treat pulmonary fibrosis, and effective targets are unknown. This study was aimed at exploring the mechanism of the anti-fibrosis effect of ginsenoside Re (Re). In vivo experiments determined the inhibitory effect of Re on bleomycin (BLM)-induced pulmonary fibrosis and explored whether it was related to the regulation of chemokine CX3C ligand 1 (CX3CL1)/chemokine CX3C receptor 1 (CX3CR1) axis. In vitro experiments, lentivirus transfection was employed to knock down CX3CL1 to further explore the role of the CX3CL1/CX3CR1 axis in the mode of action of Re in inhibiting pulmonary fibrosis. The pathological examination of mice lung tissues showed that Re attenuated BLM-induced pulmonary fibrosis in C57 BL/6J mice. The inhibitory effect of Re on pulmonary fibrosis was more potent in the wild-type mice than that in the CX3CL1^-/- mice. Transwell, Western Blot, and RT-qPCR results showed that Re could inhibit TGF-β1-induced epithelial-mesenchymal transition (EMT). In addition, the results showed that epithelial cells inhibited the anti-pulmonary fibrosis effect of Re after CX3CL1 knockdown. The anti-fibrosis effect of Re is related to the regulation of CX3CL1/CX3CR1, and the decreased CX3CL1 gene expression can inhibit the anti-fibrosis effect of Re.

Flavonoids are natural secondary metabolites of plants with a basic composition derived from polyphenols that can produce a plethora of different neurophysiological effects, some of which are relevant to anxiety disorders. As such, many flavonoids have been evaluated in behavioral screens in preclinical research on anxiolytics. We sought to map the potential of flavonoids as anxiolytics by bibliometric analysis and a systematic review and meta-analysis of animal tests using these compounds. Bibliometric analysis suggests that the field is highly concentrated on a few research groups mostly located in the Global South, suggesting the need to improve international collaborations. The themes which emerged in the bibliometric analysis are driven by the exploratory steps of pharmacological research, including finding anxio-selective effects and looking for dose-response patterns. This suggests that the field, as a whole, could benefit from more mechanistic and confirmatory research. The systematic review included 38 articles, with a total of k = 183 comparisons, comprising 43 different molecules. The meta-analysis showed strong evidence for an anxiolytic-like effect of flavonoids on animal tests, including assays made in rats, mice, and zebrafish (SMD = -1.457, 95% CI [-1.365 to -0.9264]). Subgroup analysis suggested that this effect is present in acute treatment (SMD = -1.0985 (95% CI: -1.31 to -0.88)), but not after chronic treatment (SMD = -1.96, 95% CI [-4.93; 1.01]). Study quality was overall moderate. We finish with a set of recommendations for preclinical research on the anxiolytic potential of flavonoids.