Phytotherapy Research最新文献

Paraquat (PQ) causes acute lung injury in part via mitochondrial respiratory dysfunction. We evaluated whether Glycyrrhiza uralensis. extract (LE) confers holistic protection and whether liquiritin (LQ) is a key mitochondria-targeting constituent. A PQ lung-injury model was established in KM mice by a single oral dose of PQ (20 mg/kg). LE was gavaged after PQ exposure for in vivo assessment; LQ was used as pretreatment in A549 and HPAEpic cells. Outcomes included lung function, pulmonary microcirculation, histopathology, and oxidative-stress markers (MDA, SOD). UPLC-Q/TOF-MS profiled LE composition. Differential genes and pathway enrichment were derived from integrated transcriptomics (GSE171625 plus our RNA-seq). Mitochondrial superoxide, membrane potential (Δψm), mtDNA leakage, and respiratory-chain proteins were measured. Rotenone and antimycin A were used as pharmacological probes, and molecular docking was employed to assess target engagement. Eighteen major LE constituents were identified; enrichment linked them to oxidative stress, inflammation, fibrosis, and metabolism pathways. Transcriptomics converged on mitochondrial pathways. LE treatment improved clinical appearance and lung function, enhanced microcirculation, reduced alveolar wall thickening, inflammation, and early fibrosis, lowered MDA levels, and restored SOD levels in PQ-exposed mice. In vitro, LQ restored mitochondrial function, increasing Δψm and respiratory activity while limiting PQ-induced damage. Perturbation with rotenone/antimycin A supported Complex I as a core target, consistent with docking. This work establishes a prediction-to-validation chain from LE's multi-component holistic efficacy to LQ's mitochondria-targeted mechanism, validating Complex I as a mechanistic node and supporting LE/LQ as candidates against PQ-induced lung injury.

Worldwide, diabetes and its consequences pose a significant threat to public health. The pathogenesis, molecular mechanisms, and complications are well identified, but their permanent cure is unknown. Plants have various compounds like flavonoids, alkaloids, and phytosterols, which work efficiently in anti-diabetic roles. Flavonoids (flavanones, flavones, flavonols, isoflavones, anthocyanins, etc.) are a diverse group of polyphenolic compounds abundant in vegetables, fruits, and medicinal plants, demonstrating significant potential in glycemic control through a multifaceted mechanism. Current evidence demonstrates that flavonoids exert multifaceted antidiabetic effects through various mechanisms, including enhancement of insulin sensitivity, glucose uptake stimulation, and pancreatic β-cell protection. Compounds such as quercetin, catechin, naringenin, and epicatechin have shown significant improvements in glycemic parameters and antioxidant enzymes in both preclinical and clinical studies. The compounds also show promise in preventing diabetic nephropathy through their anti-inflammatory and antioxidant properties. Due to the adverse effects of various anti-diabetic medications, researchers are looking for effective organic, plant-based medicinal products that have negligible side effects. However, challenges remain regarding bioavailability, optimal dosing, and safety profiles, particularly in vulnerable populations, including pregnant women. Future directions should prioritize nano-formulations to improve pharmacokinetics. The integration of multi-omics approaches could further elucidate flavonoid-mediated epigenetic modifications in chronic diabetic complications. More rigorous and larger-scale clinical trials are required to validate their efficacy, determine appropriate dosing, and assess long-term safety.

Bone cancer pain (BCP) is a chronic and debilitating condition often accompanied by neuroinflammation, microglial activation, and neuronal damage, which are difficult to manage with current therapies. Cycloastragenol (CAG), a bioactive compound from Astragalus membranaceus, exhibits anti-inflammatory and neuroprotective activities, yet its potential in BCP remains unclear. This study aimed to investigate the analgesic effects and underlying mechanisms of CAG in a rat model of BCP. In this study, we induced BCP in rats and administered CAG to evaluate its therapeutic effects. Behavioral testing, Western blotting, immunofluorescence, and molecular docking were employed to assess pain behaviors, inflammation, microglial polarization, and ferroptosis markers. CAG treatment significantly attenuated BCP-related pain and suppressed inflammation, promoting a shift from pro-inflammatory M1 to anti-inflammatory M2 microglial phenotypes, while inhibiting ferroptosis in spinal cord neurons through activation of the Sirt1-Nrf2 pathway. Sirt1 knockdown via siRNA abolished these beneficial effects, and cellular thermal shift assays confirmed a direct interaction between CAG and Sirt1. These findings demonstrate that CAG alleviates BCP by modulating microglial polarization and inhibiting neuronal ferroptosis via Sirt1 activation, suggesting its promise as a multi-targeted therapeutic strategy for BCP and other neuroinflammatory pain disorders.

Cordyceps sinensis is a traditional medicinal fungus known for its immunomodulatory properties. Its bioactive sphingolipids (SPLs) exhibit antitumor potential, though their mechanisms remain poorly understood. This study aimed to identify the active SPLs from C. sinensis and investigate their synergistic effects with αPD-1 (anti-programmed death-1 antibody) therapy. SPLs were isolated from C. sinensis via UPLC-MS/MS-guided purification. The antitumor efficacy and immunomodulatory synergy with αPD-1 were assessed using a Lewis lung carcinoma (LLC) tumor-bearing mouse model and in vitro co-culture systems. Mechanisms involving sphingosine kinase 1 (SphK1) were explored through cellular thermal shift assays, enzymatic activity tests, surface plasmon resonance, molecular docking, and molecular dynamics simulations. The combination of SPLs and αPD-1 enhanced antitumor immunity by promoting CD8⁺ T-cell infiltration and suppressing PD-L1 expression in the tumor microenvironment. Metabolomic and transcriptomic analyses revealed that SPLs shifted the sphingolipid balance by targeting the SphK1-mediated ceramide/sphingosine-1-phosphate (Cer/S1P) axis, promoting antitumor immunity. A novel ceramide, cordysinamide A, was identified as a key bioactive constituent and shown to bind directly to SphK1 (IC₅₀ = 28.45 μM; KD = 14.4 μM), stabilizing its structure and inhibiting S1P production. This shift increased IL-2 and IFN-γ levels and sensitized tumors to αPD-1 treatment. This study identifies C. sinensis-derived SPLs as key bioactive components that overcome αPD-1 resistance by targeting the SphK1-mediated Cer/S1P balance. Our findings propose a natural product-based strategy to change immunosuppressive metabolism in non-small cell lung cancer.

Carotid intima-media thickness (CIMT), measured by ultrasound, is a validated marker of subclinical atherosclerosis and an early predictor of cardiovascular and cerebrovascular disease. Increasing evidence links vascular aging and oxidative stress to cognitive decline, particularly among older adults and individuals with neurodegenerative disorders. Dietary antioxidants and polyphenols-abundant in fruits, vegetables, olive oil, tea, and red wine-exert protective effects on vascular and brain health through anti-inflammatory, antioxidant, and endothelial-supportive mechanisms. This narrative review synthesizes current evidence on the influence of dietary antioxidants and polyphenols on ultrasound-measured CIMT and cognitive function, with emphasis on aging and early neurodegenerative disease. A narrative review of clinical trials, cohort studies, and mechanistic investigations published between 2000 and 2024 was conducted. Studies exploring antioxidant-rich diets and individual polyphenols (e.g., resveratrol, epigallocatechin gallate, punicalagin) and their effects on CIMT, oxidative stress, neuroinflammation, and cognitive outcomes were included. Evidence from randomized controlled and observational studies shows that polyphenol-rich interventions-such as the Mediterranean diet and pomegranate juice-are associated with reductions in CIMT and improvements in cognitive domains, including memory, attention, and executive function. These benefits are mediated through reduced oxidative stress, suppression of pro-inflammatory cytokines, improved lipid metabolism, and enhanced nitric oxide bioavailability. Some studies also demonstrate favorable changes in brain imaging biomarkers and cerebrovascular perfusion. Dietary antioxidants and polyphenols show potential to mitigate vascular aging and cognitive decline. These nutritional strategies may serve as safe, cost-effective adjuncts in preventing atherosclerosis and neurodegenerative disorders. However, further long-term, high-quality studies are needed to define optimal doses, formulations, and personalized dietary approaches.

Right heart failure is a major cause of mortality in patients with pulmonary arterial hypertension (PAH). This study aimed to evaluate the preventive anti-remodeling effect of a natural phenolic compound, caffeic acid phenethyl ester (CAPE), on pressure-overloaded right hearts. PAH was induced in Sprague-Dawley rats by intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). The rats were randomly treated with CAPE (30 mg/kg/day, i.p.) or vehicle for 28 days. Right ventricular (RV) function was assessed, and remodeling was examined using both ex vivo and in vitro analyses. Chronic CAPE treatment in MCT rats attenuated right heart hypertrophy, fibrosis, and oxidative stress. CAPE improved RV function and normalized the elevated RV pressure and QTc interval in anesthetized animals. It also restored the prolonged QT interval and ventricular refractory period and reduced arrhythmia vulnerability in perfused hearts. CAPE normalized the prolonged action potential duration in right heart tissues. In RV myocytes, the delayed kinetics of Ca²⁺ transients and cell contraction were also corrected. Furthermore, CAPE reversed the PAH-induced downregulation of sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) and restored the densities of transient outward, steady-state outward, and inward rectifier K⁺ currents, along with the expression of their corresponding channel proteins. CAPE also significantly mitigated RV remodeling induced by PA banding, a model of fixed PA stenosis. These results indicate that CAPE ameliorates structural and electromechanical abnormalities in pressure-overloaded right hearts, likely through inhibition of oxidative stress. CAPE may represent a potential therapeutic candidate in PAH-related cardiac remodeling and dysfunction. Trial Registration: NCT03049046.

Osteoarthritis (OA) is a chronic low-grade inflammatory and degenerative disease involving the destruction of joint structures. Its pathogenesis involves multiple factors such as inflammatory responses, cartilage metabolic disorders, and abnormal mechanical stress. Current pharmacological interventions primarily offer symptomatic relief. Non-steroidal anti-inflammatory drugs (NSAIDs), whereas commonly used, do not arrest disease progression and are associated with potential cardiovascular and renal adverse effects when used long-term. Historically, natural herbs have been employed in the management of OA for millennia and are increasingly recognized as promising candidates for the development of disease-modifying therapies. This review provides a systematic overview of the research advancements concerning 14 natural herbs in the context of OA treatment. It highlights the capacity of these herbal medicines to concurrently influence pathways associated with inflammation and cartilage metabolism. The bioactive constituents of these herbs are classified based on structural characteristics into categories such as polysaccharides, flavonoids, and terpenoids. Importantly, the review identifies mechanistic similarities among compounds within the same category. Additionally, it addresses studies related to the organ toxicity of these natural herbs, with the objective of offering insights into strategies for mitigating the progression of OA.

Macrophage polarization between pro-inflammatory M1 and anti-inflammatory M2 phenotypes is pivotal in chronic inflammatory diseases, offering a key therapeutic target. Natural polyphenols exhibit promising immunomodulatory capacity. This review illustrates how polyphenols target key signaling pathways (NF-κB, JAK/STAT, PI3K/Akt, and Notch) to subsequently direct macrophage polarization, and reveals their potential therapeutic effects in chronic inflammatory diseases. The literature was collected from the Web of Science and PubMed databases using relevant search terms, such as "natural polyphenols," "macrophage polarization," "natural products," "signaling pathways," "chronic inflammation," "anti-inflammatory," and "pharmacokinetics." Polyphenols exert their effects by modulating core signaling pathways, with the resultant reprogramming of macrophage polarization being a key consequential event. These compounds primarily promote M2 polarization, thereby resolving chronic inflammatory-related diseases, including atherosclerosis, metabolic diseases, and neurodegenerative diseases. Meanwhile, their ability to induce M1 polarization also provides new intervention strategies for cancer therapy. In addition to overcome the limitations of low bioavailability and low toxicity of polyphenols, this review proposes innovative approaches including nanotechnology, synthetic biology, and artificial intelligence. Polyphenols modulate macrophage polarization via signaling pathways, demonstrating therapeutic duality: promoting M2 polarization to resolve chronic inflammation while inducing M1 polarization for cancer immunotherapy. This insight positions them as promising immunomodulators.

Osteoporosis is a common metabolic bone disorder characterized by reduced bone mass and compromised skeletal microstructure, increasing fracture risk. Current therapies, such as bisphosphonates and hormone replacement, have limitations and side effects, highlighting the need for safer alternatives. Flavonoids, bioactive compounds in traditional Chinese medicine, show promise due to their antioxidant, anti-inflammatory, and estrogen-mimetic properties. However, their complex interactions with bone metabolism pathways require systematic exploration. This review evaluates the regulatory effects of flavonoids on osteoporosis, focusing on their ability to enhance osteoblast-mediated bone formation while inhibiting osteoclast-driven resorption. We categorize major flavonoid subfamilies (flavones, flavonols, flavanones, and isoflavones) and detail their molecular mechanisms and signaling pathways contributing to clinical efficacy. Additionally, we address challenges related to flavonoid bioavailability, explore strategies for optimizing drug delivery, and highlight the integration of advanced technologies-such as network pharmacology and artificial intelligence-to uncover synergistic mechanisms in herbal formulations. These discussions provide a mechanistic framework supporting the role of flavonoids as multitarget modulators in osteoporosis therapy, offering insights for future pharmacological research and clinical applications.

Melanoma, a formidable adversary in the realm of cancer, poses a significantly deadly public health challenge globally. Eukaryotic elongation factor 2 kinase (eEF2K), as a promising and attractive therapeutic target for cancer, was reported to be related to poor patient survival and prognosis. Bavachinin (BVC), a natural compound isolated from Psoralea corylifolia L., was reported to have an anti-cancer effect. However, the effect and underlying mechanisms of BVC on the metastasis of melanoma are certainly unclear. In this experiment, the aim was to investigate the suppressive action of BVC on melanoma growth and metastasis, as well as the underlying mechanisms. The proliferation, cell migration, and invasion, cell cycle, and cell apoptosis in vitro were determined using CCK8, EdU staining, transwell assays, and Western blotting, respectively. The amount of eEF2K signaling-related proteins was detected by Western blotting and immunofluorescence. The interaction between BVC and eEF2K was performed by molecular docking and molecular dynamics. The eEF2K lentivirus transfection was conducted to overexpress eEF2K and explore its function in BVC's anti-melanoma action. Finally, using mouse allograft melanoma models, the action of BVC on melanoma growth was validated in vivo. BVC suppressed cell proliferation, caused cell cycle arrest, promoted cell apoptosis, and restrained migration and invasion. Interestingly, BVC induced autophagy, and suppressing autophagy partially enhanced the anti-tumor effect of BVC. Of note, BVC directly bound to eEF2K and inhibited the eEF2K/eEF2 signaling pathway in melanoma cells. In addition, eEF2K overexpression by lentivirus partly limited the antitumor effects of BVC. Finally, the allograft mouse models ulteriorly validated that BVC impaired tumor growth and inhibited eEF2K signaling in vivo. Collectively, the present study demonstrated that BVC inhibited melanoma metastasis by targeting eEF2K/eEF2 signaling, and the inhibition of autophagy caused by BVC could further contribute to the anti-melanoma potency of BVC.