Phytotherapy Research最新文献

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.

Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.

Random-pattern skin flaps are essential in reconstructive surgery but are frequently compromised by ischemic necrosis. Genistein (GST), a soy-derived isoflavone, possesses antioxidant and anti-inflammatory properties and has demonstrated protective effects in various ischemic disorders. However, its role and mechanism in improving flap survival remain unclear. A murine random-pattern skin flap model and bone marrow-derived macrophages (BMDMs) were used. In vivo, flaps were treated with different doses of genistein to determine the optimal concentration and to assess its effects on survival, angiogenesis, oxidative stress, and apoptosis. In vitro, BMDMs were stimulated with LPS and treated with genistein, with or without AMPK (Compound C) or SIRT1 (EX-527) inhibitors, to investigate macrophage polarization and the underlying AMPK/SIRT1 signaling pathway. Genistein administration significantly improved flap survival area, enhanced blood perfusion, promoted angiogenesis, and reduced oxidative stress and apoptosis. Mechanistically, genistein induced a phenotypic shift in macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 type. This effect was mediated by the activation of the AMPK/SIRT1 signaling pathway. Critically, the beneficial effects of genistein on both macrophage polarization and flap survival were abolished upon pharmacological inhibition of AMPK or SIRT1. Genistein enhances the survival of random-pattern skin flaps by reprogramming macrophage polarization from M1 to M2 via the AMPK/SIRT1 signaling pathway. This study reveals a novel molecular mechanism for genistein's protective effect and highlights its potential as a therapeutic strategy to improve outcomes in reconstructive surgery.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder globally, places a considerable burden on patients because of its progressive and disabling course. Although current pharmacological treatments offer only transient symptomatic relief and do not effectively arrest the underlying disease process, oxidative stress has been recognized as a pivotal contributor to PD pathogenesis and thus represents a key therapeutic target. Over the past decade, a growing body of evidence has indicated that selected natural compounds can ameliorate PD-related manifestations by modulating oxidative stress. Their putative neuroprotective actions and associated molecular mechanisms have been partially characterized in preclinical investigations, including in vitro cell models and in vivo animal studies. Nevertheless, the majority of current studies on these natural components are still confined to the preclinical setting, and their clinical efficacy has yet to be substantiated by rigorous, high-quality evidence. Robust randomized controlled trials with multicenter participation, adequate sample sizes, and extended follow-up are urgently required to facilitate their safe and effective translation into clinical practice. This review highlights natural compounds, including polyphenols, flavonoids, glycosides, terpenoids, and alkaloids, and synthesizes current knowledge regarding their neuroprotective potential and mechanisms, with the goal of informing future PD-focused research on natural products and guiding the development of novel therapeutic strategies.

Hydroxysafflor Yellow A (HSYA), the main active component of Carthamus tinctorius L., has been shown to reduce feeding efficiency and diet-induced obesity (DIO) by inhibiting GIP secretion. This study aimed to clarify the detailed mechanism through which HSYA suppresses GIP production. Diet-induced obese mice were treated with HSYA or HSYA plus antibiotics. A combination of untargeted and targeted metabolomics was performed on cecal contents to identify differential metabolites. RT-qPCR and siRNA knock down experiments were performed in mouse intestinal tissues, Caco-2 and STC-1 cells for further exploring the role of HSYA in regulating differential metabolites and its possible mechanism. HSYA could effectively reduce bodyweight and improve glucolipid metabolism in DIO mice. HSYA treatment significantly elevated N-lactoyl-phenylalanine (Lac-Phe) levels in the cecum, but not in the serum, independent of gut microbiota alterations. Carnosine dipeptidase II (CNDP2), the sole enzyme responsible for Lac-Phe production, was also upregulated by HSYA treatment in intestinal tissues and Caco-2 cells and this effect was abolished by CNDP2 knockdown. Furthermore, Lac-Phe treatment could directly inhibit GIP production in STC-1 cells. Our findings firstly revealed a host-derived pathway through which HSYA suppresses GIP production by the upregulation of CNDP2 expression and increasing Lac-Phe synthesis. This novel mechanism provided new insights into the metabolic regulation of GIP and highlights the therapeutic potential of HSYA in treatment of obesity.

Neurological disorders are leading causes of disability and death worldwide, yet many patients still face delayed diagnosis, limited disease-modifying options and substantial treatment-related adverse effects. Traditional Chinese medicine (TCM) provides holistic, multi-target interventions through acupuncture, herbal formulas and adjunctive therapies, but its mechanisms remain insufficiently defined. Metabolomics, which enables system-wide profiling of small-molecule metabolites, offers an objective way to characterise disease-related metabolic networks and quantify the global effects of TCM. We systematically searched PubMed, Web of Science and China National Knowledge Infrastructure for studies published between January 2005 and June 2025 that evaluated TCM-related interventions for neurological disorders and reported metabolomic outcomes. Peer-reviewed animal and clinical studies were included, whereas reviews, conference abstracts, methodological-only papers and non-neurological studies were excluded. Across Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischaemic stroke (IS), epilepsy and high-altitude cerebral oedema (HACE), consistent alterations were identified in amino acid, lipid and energy-related pathways, such as nicotinamide and lysophosphatidylcholine species in AD, branched-chain amino acids in PD and phenylalanine and asymmetric dimethylarginine in MS. Metabolomics studies indicate that acupuncture and herbal formulas can jointly modulate neurotransmitter balance, cerebral energy metabolism, oxidative stress, neuroinflammation and blood-brain barrier integrity. Emerging spatial metabolomics based on mass spectrometry imaging links individual TCM components, including ginsenosides and Astragalus membranaceus-Carthamus tinctorius decoctions, to region-specific metabolic reprogramming in the cortex, hippocampus and thalamus. However, most metabolite-disease associations are correlative and are constrained by small sample sizes, heterogeneous designs and lack of technical standardisation. Metabolomics therefore provides a quantitative framework to dissect the multi-target mechanisms of TCM in neurology and to connect molecular changes with functional outcomes. Standardised workflows, larger multicentre clinical studies and integration of spatial metabolomics, multi-omics and artificial-intelligence-based analysis are required to translate these findings into TCM-informed precision diagnosis and personalised treatment for neurological disorders.

The gasotransmitter hydrogen sulfide (H₂S) and its natural donor isothiocyanates have been suggested by emerging evidence to play a significant role in the therapeutic management of several conditions like metabolic syndrome, neurodegeneration, inflammation, and so forth. In particular, isothiocyanates from Moringa oleifera Lam have been found to be more stable than those from cruciferous vegetables and Alliaceae, although they are less studied. For this reason, the present review aims to conduct a systematic literature search to outline the potential clinical applications of isothiocyanates, as a source of H₂S, formed from glucosinolates present in M. oleifera. The systematic search was performed on Scopus and PubMed using wide-ranging keywords such as "Isothiocyanates" and "Moringa," "Isothiocyanates," and "Moringin," and "Moringin" alone. The selection was limited to publications written in English. All articles containing information on the biological activity of M. oleifera's isothiocyanates were considered for selecting articles for analysis. Review articles, letters, book chapters, editorials, conference papers, systematic reviews, and short surveys were not considered. This allowed the selection of 42 papers, which were analyzed per pathologies and evaluated for the risk of biases using the QUIN tool. Hence, this review gives an overview of the potential health benefits linked to M. oleifera's isothiocyanates as a natural source of H₂S.

Inflammation is known to exacerbate depressive symptoms. Loganin, a major iridoid glycoside derived from Cornus officinalis Sieb. et Zucc., exhibits antidepressant-like properties and anti-inflammatory effects; however, the mechanisms underlying these actions remain unclear. Given the involvement of the Sigma-1 receptor (Sigma-1R) in both depression and neuroinflammation, this study aimed to investigate whether loganin can ameliorate inflammation-related depression by modulating Sigma-1R. Experimental models of social isolation and lipopolysaccharide (LPS)-induced depressive-like behaviors were employed. The effects of loganin on behavioral outcomes, neurons, astrocytes, and microglia, oxidative stress levels, and the NLRP3 inflammasome were assessed. Molecular docking analysis and cellular thermal shift assay were conducted to evaluate the binding affinity of loganin to Sigma-1R. Additionally, the impact of a Sigma-1R inhibitor (BD1047) on loganin's effects was investigated. Loganin improved social isolation- and LPS-induced depressive-like behaviors. It also reduced astrocyte and microglia reactivity and decreased oxidative stress levels. Furthermore, loganin downregulated the expression of IRE1α, TXNIP, and the NLRP3 cascade. Molecular docking and cellular thermal shift assays confirmed strong binding of loganin to Sigma-1R. Loganin increased Sigma-1R expression in the hippocampus in response to LPS or social isolation. The antidepressant-like effects of loganin, as well as its inhibition of the NLRP3 inflammasome and oxidative stress, were reversed by BD1047. These findings suggest that loganin alleviates inflammation-associated depressive-like behaviors by inhibiting the NLRP3 inflammasome and oxidative stress via the Sigma-1R/IRE1α/TXNIP pathway, highlighting its potential as a therapeutic agent for inflammation-related depression.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Conventional treatments have limitations in addressing complex pathological mechanisms. This review highlights the roles of gut microbiota and phytochemicals in the prevention and treatment of CVDs, systematically summarizing recent research progress. Dysbiosis of the gut microbiota is closely associated with CVDs, and its metabolic products play a crucial role in regulating CVDs progression. Phytochemicals such as Higenamine, Paeoniflorin, Ginsenoside Rb1, Tanshinone IIA, Emodin, Irisin, and Quercetin demonstrate unique preventive and therapeutic potential against CVDs (including heart failure, diabetic cardiomyopathy, myocardial ischemia-reperfusion injury, and cardiac hypertrophy) by reshaping gut microbiota composition and modulating metabolic profiles. For example, Ginsenoside Rb1 can regulate gut microbiota abundance to alleviate myocardial fibrosis, while Paeoniflorin improves gut microbiota structure and cardiac function in mice with diabetic cardiomyopathy. Despite significant advances, challenges remain in clinical translation, long-term safety assessment, and elucidation of mechanisms. Future research should focus on clinical cohort validation, in-depth mechanistic studies integrating multi-omics technologies, and the development of innovative treatment strategies targeting the gut microbiota. These efforts hold promise for advancing precision medicine in the management of CVDs.