Phytotherapy Research最新文献

As the global population ages, the incidence of Alzheimer's disease (AD) increases, burdening patients, families, and society. In recent years, microglia have been shown to interact with T cells, astrocytes, and other immune cells to form a complex immune microenvironment, which plays a damaging or protective role on neurons during the pathological process of AD. Herein, we review the interactions between microglia and other immune cells in the pathogenesis of AD and explore the potential of natural compounds as multi-targeted therapeutic strategies: (1) Balancing glial cell polarization status and ameliorating neuroinflammation by inhibiting core neuroinflammatory pathways such as NF-κB (nuclear factor kappa-B), MAPK, and NLRP3 inflammasome; (2) modulating the gut flora-brain axis function to inhibit central inflammation indirectly; (3) multi-targeted interventions for core AD pathology, including amyloid-beta (Aβ) clearance, tau phosphorylation, and synaptic plasticity. However, natural compounds still face clinical translation bottlenecks such as low bioavailability and poor blood-brain barrier permeability. Current studies have shown that nanocarrier systems and combination therapy strategies hold promise for addressing existing bottlenecks. However, systematic validation is still required for their clinical translation. This review systematically summarizes progress in the treatment of AD by regulating microglia and other immune cell interactions using natural compounds.

Herbal remedies are increasingly adopted as alternatives to conventional pharmacological treatments, particularly among women seeking natural approaches to managing menopausal symptoms. This interest is driven by perceptions of greater safety, affordability, and fewer adverse effects associated with medicinal plants. Vitex agnus-castus (VAC), commonly known as chaste tree, is one of the most widely utilized botanical agents for women's health. VAC is rich in diverse bioactive constituents, including flavonoids, iridoids, diterpenes, and essential oils, which collectively contribute to its complex pharmacological profile. Emerging evidence from in vitro, in vivo, and clinical studies suggests that VAC may modulate key neuroendocrine pathways involved in menopause through dopaminergic, phytoestrogenic, opioidergic, and indirect serotonergic mechanisms. These actions are proposed to influence prolactin regulation, estrogen receptor activity, mood stability, vasomotor symptoms, and overall hormonal balance during the menopausal transition. This review synthesizes current knowledge on the phytochemical composition and mechanistic pathways of VAC relevant to menopausal symptom management, alongside an evaluation of its safety and clinical tolerability. Although VAC extracts appear generally safe, effective, and well tolerated, further research is needed to clarify molecular targets, determine optimal dosing strategies, identify responsive patient subgroups, and standardize outcome measures to strengthen evidence-based clinical use.

Atherosclerosis (AS) constitutes the pathological basis of multiple cardiovascular diseases, predisposing to severe clinical complications. Isorhynchophylline (IRN), a principal bioactive alkaloid derived from Uncaria rhynchophylla, exhibits anti-inflammatory properties, yet its therapeutic potential and molecular mechanisms in AS remain unexplored. Scratch wound healing and Transwell migration assays were conducted to evaluate the effects of monomer compounds on cellular migratory and invasive capabilities. The changes in mRNA and protein expression levels of inflammation genes were determined using RT-PCR and western blot analyses, respectively. Molecular docking and drug affinity responsive target stability analyses were performed to assess the binding affinity of IRN and PP2AC. Our findings demonstrate that IRN treatment effectively ameliorates atherosclerotic plaque progression and mitigates endothelial inflammation. The underlying mechanism involves the binding of IRN to PP2AC and the subsequent regulation of YAP activity. This study underscores the therapeutic potential of IRN in alleviating inflammation and its promise as a treatment for AS.

Hepatic ferroptosis has emerged as a crucial pathogenic mechanism and severe adverse outcome in metabolic-associated fatty liver disease (MAFLD). Curcumol (CCM), a sesquiterpenoid phytochemical with potential hepatoprotective properties, remains unexplored for its therapeutic properties in MAFLD management. In this study, the effects and mechanisms of CCM on hepatic ferroptosis in MAFLD were investigated using in silico approaches and evaluated at the cellular and molecular levels using both in vivo and in vitro disease models of MAFLD. Our results showed that hepatic ferroptosis was accompanied by endoplasmic reticulum stress (ERS) in high-fat-induced MAFLD. Administration of the ERS inhibitor 4-PBA significantly alleviated ferroptosis, suggesting the pathogenic role of ERS-mediated ferroptosis in MAFLD. Notably, CCM exhibited comparable effects to 4-PBA, indicating that CCM mitigated hepatic ferroptosis through inhibiting ERS. Subsequent data showed that the therapeutic effects of CCM were achieved by targeting epidermal growth factor receptor (EGFR), as evidenced by the phenomenon that the efficacy of CCM was reversed following the administration of an EGFR agonist. In conclusion, this study highlighted the therapeutic effects of CCM on alleviating hepatic ferroptosis in high-fat-induced MAFLD by inhibiting the EGFR-ERS axis, and emphasized the promising application of CCM in MAFLD management.

Overexpression of P-glycoprotein (P-gp) in non-small cell lung cancer (NSCLC) cells is one of the primary causes of multidrug resistance (MDR), but the molecular mechanism remains obscure. Murine double minute 2 (MDM2) has been implicated in drug resistance across multiple cancer types. In this study, we investigated the potential mechanism of MDM2 on P-gp-mediated MDR of NSCLC and explored the potential therapeutic effects of 20(R)-ginsenoside Rg3 (Rg3). Western blot, RT-PCR, and immunohistochemistry (IHC) were applied to analyze the expression of critical signaling markers. The drug accumulation in resistant cells was measured using flow cytometry and confocal microscopy. Bioinformatics analysis, co-immunoprecipitation (co-IP), and immunofluorescence were conducted to confirm the protein-protein interactions. MTT, colony formation, EdU, and in vivo cell line derived xenograft (CDX) models were applied to validate therapeutic agents and molecular mechanisms. We demonstrated that MDM2 acted as a positive upstream regulator of P-gp, and the inhibition of MDM2 by Rg3 increased the sensitivity of resistant cells to taxol treatment both in vivo and in vitro. Mechanistically, we uncovered that MDM2 bound to IκB-α, facilitating its ubiquitination degradation, which subsequently promoted NF-κB pathway activation to drive the high expression of P-gp. Notably, Rg3 blocked this process by inhibiting MDM2. Moreover, interference with the NF-κB pathway reversed the regulation of P-gp expression by MDM2. Our findings elucidate the molecular mechanisms of Rg3 in the treatment of P-gp-mediated MDR in NSCLC. This study also provides a new strategy to overcome P-gp-mediated MDR by inhibiting the MDM2-IκB-α signaling axis.

Fibroblast-like synoviocytes (FLS) drive rheumatoid arthritis (RA) progression. Bacopaside I (BSI), a major component of the anti-RA herb Bacopa monnieri, demonstrates anti-arthritic effects in RA animal models; however, its precise anti-rheumatic mechanisms, especially regarding suppression of RA-FLS pathogenicity, remain unclear. Collagen-induced arthritis (CIA) rats and TNF-α-stimulated RA-FLS were used as in vivo and in vitro models of RA. We studied BSI's therapeutic potential in CIA rats and its influences on TNF-α-induced migration, invasion, and inflammation in RA-FLS, focusing on the underlying mechanism of Wnt/β-catenin pathway inhibition. BSI exhibited arthritis-alleviating activity in CIA rats, as evidenced by reductions in paw swelling, arthritis index, and histological damage to ankle joints. It also decreased serum and synovial levels of IL-1β, IL-6, and TNF-α, indicating anti-inflammatory effects in vivo. At non-cytotoxic concentrations, BSI inhibited migration, invasion, and F-actin remodeling in TNF-α-stimulated RA-FLS. Similar to its anti-inflammatory activity in vivo, BSI decreased pro-inflammatory factor production in vitro, including IL-1β, IL-6, IL-8, MMP-2, and MMP-9. Mechanistically, BSI treatment inhibited Wnt/β-catenin pathway activation in both CIA rat synovium and TNF-α-stimulated RA-FLS, as demonstrated by decreased Wnt1, p-GSK-3β (Ser9), and β-catenin protein levels, increased p-β-catenin, reduced β-catenin nuclear translocation, and a lower TOP/FOP ratio. Importantly, the critical involvement of this pathway was further confirmed by the loss of BSI's benefits following β-catenin overexpression in TNF-α-stimulated RA-FLS. BSI ameliorates arthritis severity and RA-FLS pathogenicity by suppressing the Wnt/β-catenin pathway, highlighting its promise as a novel candidate for RA treatment.

The incidence of cancer is increasing year by year, becoming a major public health problem worldwide. Tumor is a complex ecosystem, and tumor cells can escape recognition and killing by the immune system through a variety of mechanisms. Among them, adenosine (ADO) stands out as a highly immunosuppressive compound derived from the degradation of adenosine triphosphate (ATP) released by dying or stressed cells. ADO is prevalent in the tumor microenvironment of most solid tumors, promoting tumor cell proliferation, migration, invasion, angiogenesis, and chemotherapy resistance. Adenosine receptors (ARs) on tumor and immune cells, when activated by ADO, inhibit tumor antigen presentation and immune cell activation, suppressing tumor immunity. Targeting the adenosine pathway is thus a key focus in tumor immunotherapy. Natural compounds like alkaloids, flavonoids, and polyphenols show promise in modulating adenosine pathways by interfering with its production, transport, or receptor signaling, potentially reversing tumor immunosuppression. This paper reviews adenosine's metabolic pathways and its role in the tumor microenvironment, exploring how natural substances can regulate these pathways, offering new insights for cancer prevention and treatment.

Pancreatic cancer (PC) is among the deadliest malignancies, characterized by poor treatment response. Natural bioactive compounds, such as Morin, a flavonoid, have gained interest as potential therapeutic agents due to their anticancer properties but remain unexplored in PC. This study investigates the anticancer effects of Morin on PC cells, particularly its ability to induce mitophagy via the PINK1/Parkin pathway and modulate mitochondrial function and cancer stemness. PANC-1 cells were treated with Morin, and its impact on tumorigenic potential was evaluated using in vitro assays, including cell viability, colony formation, migration, invasion, and spheroid formation, as well as in vivo studies in a nude mice model. Mitochondrial function and apoptosis were assessed through flow cytometry, gene expression analysis, PCR microarrays, transmission electron microscopy (TEM), immunofluorescence, ELISA, western blotting, and molecular docking. Morin exhibited dose-dependent cytotoxicity, significantly reducing viability, colony formation, migration, and invasion in PC. It downregulated mesenchymal and stemness markers (N-cadherin, SNAI1, ZEB1, SOX2, NANOG, OCT4) while upregulating E-cadherin. Morin disrupted spheroid morphology and decreased ALDH activity, indicating reduced cancer stemness. Additionally, Morin-induced mitochondrial dysfunction, as evidenced by decreased membrane potential, ATP synthase activity, and mitochondrial mass, along with increased mitochondrial superoxide production. Upregulation of mitophagy markers (PINK1, Parkin, pAMPK, LC3A/B) and downregulation of fusion (MFN2) confirmed PINK1-mediated mitophagy. Apoptosis induction was supported by Annexin V/PI staining, TEM, elevated caspase-3/-9 levels, and cytochrome c release. Molecular docking confirmed strong Morin-PINK1 interaction. Morin induces mitophagy, promotes apoptosis, and suppresses cancer invasiveness in PC cells, highlighting its potential as an adjuvant therapeutic agent. Future clinical studies are warranted to evaluate its relevance.

Inflammatory responses and subsequent microglial polarization play a critical role in the secondary damage that follows spinal cord injury (SCI). Morusin, a natural flavonoid with anti-inflammatory properties, has therapeutic potential in SCI; however, its molecular mechanisms and direct targets remain unclear. This study aimed to elucidate both the neuroprotective effects of Morusin against SCI and the underlying mechanisms, with a particular focus on its role in modulating microglial/macrophage polarization. The therapeutic efficacy of Morusin was evaluated in a rat model of SCI using behavioral, histological, and immunofluorescence analyses. In vitro, its anti-inflammatory and polarization-modulating effects were examined in lipopolysaccharide (LPS)-stimulated BV2 microglia. Neuroprotection was assessed in a cellular co-culture system. To identify the direct target of Morusin, we integrated drug affinity responsive target stability with mass spectrometry and validated the findings using cellular thermal shift assay and siRNA knockdown. Administration of Morusin significantly improved functional recovery, attenuated neuroinflammation, and reduced tissue damage in SCI rats. In cellular assays, Morusin potently suppressed LPS-induced M1 polarization and enhanced IL-4-induced M2 polarization. Mechanistically, Morusin directly bound to RELA, inhibiting the NF-κB pathway, while concurrently activating the NRF2/HO-1 signaling axis. This study demonstrated that Morusin alleviates SCI by directly targeting RELA (p65) to inhibit NF-κB-driven M1 polarization, while simultaneously promoting NRF2/HO-1-mediated M2 polarization. These findings not only revealed a novel dual mechanism of action for Morusin but also underscored its potential as a lead compound for the targeted therapies against SCI.

Cardiomyocyte senescence contributes to the progression of multiple cardiac diseases, with oxidative stress identified as a central pathophysiological mechanism. Previous animal experiments demonstrated that citronellal (CT), administered at 200 mg/kg in rats, exerted significant cardioprotective effects. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to investigate the role of CT in mitigating myocardial senescence and to elucidate its mechanistic pathways. Doxorubicin-induced myocardial senescence mouse models and H9C2 cardiomyocyte senescence models were established. SA-β-gal staining, Western blotting, immunofluorescence, and immunohistochemistry were employed to evaluate senescence and oxidative stress markers. Network pharmacology analysis and molecular docking were conducted to predict CT targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify potential mechanisms of action. CT treatment significantly reduced myocardial oxidative stress levels, ameliorated senescent phenotypes in both in vivo and in vitro models, and enhanced mitophagy by activating the AMPKα-mediated PINK1/Parkin pathway. Bioinformatics analyses further supported the involvement of oxidative stress resistance and mitophagy regulation as central mechanisms underlying CT's cardioprotective effects. Citronellal effectively alleviates cardiomyocyte senescence by reducing oxidative stress and promoting mitophagy through activation of the AMPKα-PINK1/Parkin signaling pathway. These findings provide experimental evidence supporting CT as a promising cardioprotective agent and highlight a novel mechanism of action that may inform future therapeutic strategies for cardiac aging and related diseases.