Phytotherapy Research最新文献

Gastric cancer, the fifth most prevalent cancer globally, presents a significant challenge for effective treatment. Despite advancements, chemotherapy is often hindered by severe side effects and drug resistance, whereas targeted immunotherapy exhibits inconsistent efficacy. Amidst these challenges, plant secondary metabolites or phytochemicals have emerged as promising agents for the prevention and treatment of gastric cancer. The aim of this review is to perform a comprehensive evaluation of the gastric cancer preventive and therapeutic effects of various phytochemicals with an understanding of related mechanisms of action. A structured literature search was followed to collect preclinical and clinical data on the effects of phytochemicals in combating gastric cancer. Results have indicated that alkaloids, glycosides, polyphenols, sulfur-containing compounds, and terpenoids inhibited gastric cancer cell proliferation in vitro and suppressed gastric tumor growth in vivo. These effects are driven by mechanisms such as alterations of pro-apoptotic and anti-apoptotic proteins, induction of cell cycle arrest, and promotion of apoptosis and autophagy. Additionally, alkaloids and terpenoids influence cancer progression through epigenetic modifications, such as alterations in DNA methylation and histone modifications, as well as through regulating inflammatory pathways, such as the nuclear factor-κB pathway. Moreover, glycosides, polyphenols, and sulfur-containing compounds modulate critical signaling pathways related to cancer cell survival, proliferation, progression, and metastasis, including rat sarcoma/mitogen-activated protein kinase, wingless-related integration site/β-catenin, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signal transduction pathway. Despite promising preclinical results, further detailed studies, including clinical trials, are crucial to validate the clinical utility of phytochemicals in gastric cancer prevention and therapy.

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.

Withania somnifera , commonly known as Ashwagandha, is a widely recognized medicinal plant in India, belonging to the family Solanaceae, used in Ayurveda due to its diverse therapeutic properties. The roots of Ashwagandha are considered the most active part of the plant, for its biological and pharmacological effects. However, very little scientific evidence regarding its safety assessment has been published. Thus, the objective of the present study was to assess the safety of the standardized extract of Ashwagandha, known as Shagandha, which is prepared from the roots of Ashwagandha containing 2.5% Withanolides, analysed using a USP method (HPLC). The GLP studies for acute, subacute, subchronic, reproductive, bacterial reverse mutation assay, and mammalian erythrocyte micronucleus test were conducted following the test guidelines established by the Organization for Economic Cooperation and Development (OECD). Treatment with Shagandha (Ashwagandha Root Extract-ARE) did not result in any toxicologically significant changes regarding abnormal clinical signs or behavioral changes, body weight, reproductive and developmental parameters, or gross and histopathological changes. Additionally, the results of genotoxicity as evaluated by the in vitro reverse mutation assay and in vivo micronucleus test in mice demonstrated that ARE did not induce any genotoxic effects. These findings indicate that the oral administration of ARE is safe in rodents, non-mutagenic, with no adverse effects under experimental conditions.

Tumors progress within a complex intricate territory consisting of tumorigenic cancer cells with heterogeneous stromal, cellular and non-cellular soluble constituents. The tumor microenvironment (TME) continuously crosstalks with the tumor cells, which helps the tumor cells in achieving different malignant phenotypes and later aids in tumor initiation, progression, and metastasis. Cancer associated fibroblasts (CAFs) constitute a chief component of the TME that is often corroborated with unfavorable disease outcomes, therapy resistance and distant metastasis. CAFs are essential components of TME which facilitate intricate communication between cancer cells, release numerous regulatory factors, thereby aiding tumor growth, synthesize and remodel the extracellular matrix providing drug resistance and regulating immune cell infiltration into TME. Thus, inspecting new therapeutic approaches for targeting CAFs may reverse the current landscape of cancer therapy. Recently, several phytochemicals, such as curcumin, resveratrol, quercetin, silibinin and others, have been studied to demonstrate several regulatory effects on TME. These phytochemicals often target different oncogenic signaling pathways orchestrated within TME components like cancer cells, CAFs, immune cells, cancer stem cells, and endothelial cells crucial for tumor development and progression. Several research findings have demonstrated that different anti-fibrotic phytochemicals in combination with chemotherapeutics have shown better therapeutic efficacy by modulating CAFs in TME. However, despite promising preclinical outcomes, challenges such as poor bioavailability, low solubility, hydrophobicity and obscure target specificity restrict their therapeutic applications in the clinic. There has been acontinually increasing interest to formulate phytonanomedicine, the integration of phytochemicals and nanotechnology using various nanocarriers like liposomes, micelles, and nanoemulsions to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have highlighted the mechanistic pathways through which phytonanomedicine interacts with CAFs, addresses current challenges in clinical translation, and suggests future research directions to optimize the use of natural-product-based nanotherapeutics in anti-CAF strategies for cancer treatment.

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.

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.

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.

Stigmasterol glucoside (SG), a phytosterol glycoside derived from plants, is widely distributed in numerous natural sources-particularly medicinal and edible plants-and is recognized to possess potential anti-inflammatory properties, although its mechanisms of action remain incompletely understood. Experimental results demonstrated that SG significantly attenuated lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages. In a murine model of systemic inflammatory response syndrome (SIRS) established by LPS challenge, SG effectively mitigated systemic inflammation and ameliorated LPS-induced hepatic dysfunction. Integrated network pharmacological analysis and transcriptomic sequencing revealed that SG primarily exerts its anti-inflammatory activity through modulation of the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, thereby conferring protection against liver injury and systemic inflammation. These findings highlight SG as a promising therapeutic candidate for inflammation-related disorders.

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.

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.