Phytotherapy Research最新文献

Phyllanthus species have been known for their medicine and food homology properties in the management of diabetes and related metabolic disorders. This review provides the scientific insights supporting the potential in diabetes prevention and intervention. Descriptions of the geographical distribution and traditional usage highlight the similarities and differences among selected Phyllanthus species, that is, Phyllanthus niruri L., Phyllanthus urinaria L. and Phyllanthus acidus (L.) Skeels, known for their extensive conventional usage in Southeast Asia, particularly Malay Peninsula. Their rich phytochemical profiles, well-documented antidiabetic properties and abundant existing research necessitate a review for potential sustainable food and clinical applications. Metabolomics unlocked the therapeutic avenues of Phyllanthus species for a more sustainable and natural option for diabetes remedies. The overview of phytochemical fingerprints and bioactive compounds in Phyllanthus plants, and the elucidation of biomarker pathways deepened the understanding of antidiabetic properties of these medicinal plants. Additionally, the toxicological data revealed that lower dosages of Phyllanthus species are safe for consumption without significant adverse effects. Data from 2010 to 2025 for in vitro and in vivo antidiabetic studies demonstrated the capability of Phyllanthus species as anti-hyperglycemic agent. Nevertheless, limited clinical trials have shown prominent antidiabetic properties. Standardized polyherbal marketed products and patents incorporating Phyllanthus species in various formulations have been abundantly filed. Overall, this review offers a comprehensive insight into the role of bioactive phytoconstituents in Phyllanthus species and enhance the prospects in the advancement of functional food ingredients and drug discovery for diabetes management.

Chronic alcoholic encephalopathy (CAE) is a condition induced by alcohol consumption, with a huge demand for research on its prevention and treatment drugs. Puerarin, the principal active compound found in Pueraria lobata, has been traditionally utilized in ethnopharmacology to mitigate alcoholic brain injury and rectify imbalances in intestinal flora. The study was aimed to investigate the mechanism by which puerarin exerts its anti-CAE effect. The CAE mice model induced by alcohol were treated with oral administration of puerarin. First, the effects of puerarin on cognitive function, motor ability, and hippocampal tissue pathology along with the expression of TLR4, Myd88, NF-κB, IL-1β, and IL-6 of brain and fecal LPS were investigated. Finally, the composition of the gut microbiome of fecal and TJs (Claudin-1 and Occludin) in the intestine and colon, focusing on the production and transporter of LPS, were measured. The findings revealed that puerarin administration significantly ameliorated motor deficits, anxiety-like behaviors, and cognitive impairments in CAE mice. Histopathological analysis revealed puerarin reduced hippocampal damage and decreased Iba1 immunoreactivity, indicating attenuated neuroinflammation. Puerarin treatment downregulated the protein expression of IL-1β, IL-6, TLR4, Myd88, and NF-κB in brain. Notably, puerarin restored intestinal barrier integrity by upregulating Claudin-1 and Occludin expression. Intestinal flora analysis demonstrated that puerarin treatment increased the abundance of beneficial bacteria (e.g., norank_f_Eubacterium_coprostanoligenes_group) while reducing pathogenic bacteria (e.g., Escherichia-Shigella). The study showed that puerarin exerts a treatment CAE effect, which may be related to modulation of the "microbiota-gut-brain axis" LPS/TLR4/NF-κB inflammatory pathway.

Doxorubicin (Dox)-induced cardiomyopathy (DIC) is characterized by significant myocardial damage that can progress to dilated cardiomyopathy and potentially lead to heart failure. The rate of mortality due to heart disease in patients undergoing cancer chemotherapy has even surpassed that caused by tumor recurrence. However, there is a lack of effective treatments for DIC in clinical practice. Lithospermic acid (LA), a polycyclic phenolic carboxylic acid isolated from the traditional Chinese herb Salvia miltiorrhiza, exhibits superior efficacy in inhibiting oxidative stress damage across various diseases. This study aimed to assess the therapeutic potential of LA in alleviating cardiac injury and elucidate its potential molecular mechanisms in DIC. Male C57BL/6J mice were randomly divided into four groups: saline control, saline with LA, Dox, and LA combined with Dox. A mouse cardiomyocyte cell line HL-1, along with human embryonic stem cells-derived cardiomyocytes, was utilized to investigate the therapeutic potential of LA on Dox-induced cardiomyocyte injury in vitro. Supplementation with exogenous LA mitigated Dox-induced cardiac atrophy, cardiac fibrosis, and ventricular remodeling while preserving cardiac function. LA reduced Dox-induced abnormal cardiomyocyte apoptosis and excessive oxidative stress both in vitro and in vivo. Dox promoted the acetylation of p53 by decreasing the expression of sirtuin-3 (SIRT3), which triggered continuous oxidative stress and apoptosis. LA enhanced the deacetylation of p53 and subsequently inhibited the activation of the p53 signaling pathway by directly targeting SIRT3. Knockdown of SIRT3 eliminated the beneficial effects of LA against Dox. LA serves as a beneficial treatment for Dox-induced pathological cardiac injury and remodeling by targeting SIRT3, thereby enhancing the deacetylation of p53. This study provides novel insights into the potential of LA as a promising drug candidate for cardio-protection.

Diabetic liver injury (DLI) is a chronic complication of the liver caused by diabetes mellitus, and its pathomechanism has not been fully elucidated. Punicalagin (PU), a polyphenol extracted from pomegranate peel, has physiological activities such as anti-inflammatory. In this study, the effects of PU on DLI and its molecular mechanisms were investigated. In vitro and in vivo studies were conducted using streptozotocin-induced diabetic mouse models and high glucose-induced HepG2 cells. After PU intervention, the effects of PU on DLI were assessed by histopathology, immunohistochemistry, western blot, immunofluorescence and transmission electron microscopy. The results showed that PU improved the pathological damage of liver tissue in diabetic mice, reduced the levels of inflammatory factors such as TNF-α, IL-18 and IL-1β in serum and liver, down-regulated the protein levels of NEK7, NLRP3 and Caspase1 in liver and HepG2 cells, and attenuated the fluorescence co-localization of NEK7 and NLRP3 in HepG2 cells. Additionally, PU up-regulated the expression of mitochondrial fusion-related proteins OPA1 and Mfn2 and their transfer to mitochondria, and inhibited the expression of mitochondrial fission-related proteins Drp1 and p-Drp1 (Ser616). The mitochondrial fusion inhibitor MYLS22 reversed the inhibitory effect of PU on NEK7-NLRP3 complex. In conclusion, the present study shows that PU inhibits NEK7-NLRP3 complex activation by regulating mitochondrial dynamics, thereby reducing liver inflammation and alleviating DLI.

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.