Phytotherapy Research最新文献

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.

Knee osteoarthritis (KOA) is a widespread chronic osteoarticular condition, with pain constituting a critical clinical symptom necessitating prompt intervention. Persistent pain substantially diminishes patients' quality of life. Glycyrrhiza, a component of traditional Chinese medicine, has shown effectiveness in the treatment of KOA. Liquiritin (LQ), a principal active compound in licorice, demonstrates therapeutic potential; however, its mechanisms of action have yet to be comprehensively understood. This study aims to investigate the underlying pharmacological mechanisms by which LQ alleviates KOA nociceptive sensitization by establishing in vivo and in vitro KOA models and integrating transcriptomic analyses. In vivo, a KOA mice model was established via destabilization of the medial meniscus (DMM) surgery. The ameliorative effects of LQ on mechanical allodynia were assessed. We established an in vitro coculture model of bone marrow-derived macrophages (BMDM) and dorsal root ganglion (DRG) to investigate the effects of various treatments on TRP channels in mouse DRG neurons and further elucidated the mechanism of LQ action on BMDM through transcriptomic analysis. In vivo findings demonstrated that inflammatory conditions reduced M2 macrophage infiltration in DRG tissues while concurrently elevating transcriptional and protein expression levels of TRPA1, TRPV1, TRPM8, NGF, and Substance P. LQ intervention significantly increased M2 macrophage infiltration in DRG tissues and simultaneously suppressed transcriptional and protein expression of TRPA1, TRPV1, TRPM8, NGF, and Substance P. This result is consistent with the findings from mice behavioral assessments, indicating that LQ effectively alleviates KOA-induced nociceptive sensitization. In vitro experiments revealed that LQ alleviates KOA nociceptive sensitization by promoting M2 macrophage activation. Integrated transcriptomic analysis further demonstrated that LQ likely facilitates M2 macrophage polarization by suppressing the Rap1/PI3K/Akt signaling pathway in BMDMs. LQ alleviates nociceptive sensitization in KOA mice by modulating the Rap1/PI3K/Akt signaling pathway to promote M2 macrophage polarization in DRG tissues.

Mailuoning oral liquid (MLN O) has been used clinically to alleviate inflammatory and thrombotic illnesses, such as thromboangiitis obliterans (TAO), which often present with pulmonary injury in the early stage. However, the mechanisms of action of MLN O and its active ingredients remain unclear. This study aimed to explore the protective effects and mechanisms of MLN O and its effective components against pulmonary injury caused by lipopolysaccharide (LPS) and cigarette smoke extract (CSE). LPS- and CSE-induced rats and HUVECs or HUVECs stimulated by TGF-β1 were used in vivo and in vitro. The components of MLN O in rat plasma were detected with UPLC-QTOF-MS/MS and UPLC-QqQ-MS/MS. Western blotting was used to screen for the most promising and effective ingredient of MLN O. Masson and H&E stainings, immunohistochemistry, ELISA, western blotting, qRT-PCR, and immunofluorescence assays focused on the research of inflammation, fibrosis, and thrombosis. The mechanisms of action of MLN O and luteolin (LUT) were explored using siRNA transfection, ChIP, qRT-PCR, western blotting, immunofluorescence, molecular docking, cellular thermal shift, molecular dynamics simulation, and microscale thermophoresis assays. In total, 35 compounds of MLN O were detected in plasma using UPLC-QTOF-MS/MS. Furthermore, 18 components with higher contents were screened using UPLC-QqQ-MS/MS. The most promising effective ingredient, LUT, was identified by western blotting assay. MLN O and LUT significantly improved inflammation, epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), fibrosis, and thrombosis by inactivating the cGAS-STING pathway. siRNA transfection and ChIP assays showed that PAI-1 may be a downstream molecule of IRF3 in the cGAS-STING pathway. Most importantly, molecular docking, cellular thermal shift, molecular dynamics simulation, and microscale thermophoresis assays indicated that LUT might directly interact with cGAS. This study is the first to suggest that MLN O and its effective ingredient, LUT, significantly improved LPS- and CSE-induced pulmonary injury by regulating the cGAS-STING-IRF3-PAI-1 pathway, and that LUT may serve as an inhibitor of cGAS in this process. Our study provides a new therapeutic strategy for pulmonary injury and a solid theoretical basis for the clinical application of MLN O.

Cordyceps, known as "winter-worm summer-grass", has been used as a medicinal mushroom to boost energy levels and immune activity. Among cordyceps types, Cordyceps militaris (CM) is the most commercially useful owing to its ease of artificial cultivation for mass production. In contrast, other types, such as Ophiocordyceps sinensis, are expensive and difficult to collect. Therefore, numerous studies have explored the therapeutic potential and active constituents of CM. The therapeutic use of CM is based on its various pharmacological activities, including immunomodulatory, anti-tumor, antioxidant, anti-diabetic, anti-obesity, and neuroprotective activities, of which the immunomodulatory effects have been the most studied. CM contains active constituents such as nucleosides (cordycepin and adenosine), polysaccharides, peptides, proteins, sterols, glycolipids, and carotenoids. Recent studies show that CM extract, cordycepin, and polysaccharides exert immunomodulatory effects in response to the immune environments. They enhance innate and cell-mediated adaptive immunity not only under normal conditions but also in immunosuppressed states induced by cyclophosphamide, interleukin-4, tumor culture supernatant, methotrexate, cancer cell-line-xenografts, influenza virus, and severe acute respiratory syndrome coronavirus 2. Meanwhile, they suppress an overactivated immune system stimulated by factors such as angiotensin II ± vascular endothelial growth factors, concanavalin A, 2,4-dinitrophenyl (DNP)-serum albumin ± DNP-specific immunoglobulin E, lipopolysaccharide (LPS), lipoteichoic acid, phytohemagglutinin, phorbol myristate acetate plus calcium ionophore A23187, calcium chloride, cecal ligation and puncture ± LPS, dextran sodium sulfate, monosodium iodoacetate, ovalbumin, myelin oligodendrocyte glycoprotein 25-35, monosodium urate, and Western diet by ameliorating innate and humoral adaptive immune responses. This study reviewed recent and notable literature evaluating the immunomodulatory potentials of CM extract, cordycepin, and polysaccharides. In vitro, in vivo, and clinical trial results indicate that CM is safe for administration and shows promise for developing functional foods having various efficacies such as immunomodulation, anti-tumor, and neuroprotection.

Background and aim: Restoring mitochondrial homeostasis to inhibit apoptosis in renal tubular epithelial cells (RTECs) has emerged as a promising therapeutic strategy for diabetic kidney disease (DKD). This study focuses on the therapeutic effect and mechanism of the triterpenoid compound cycloastragenol (CAG) from Astragali Radix in the treatment of DKD.

Experimental procedure: The DKD model was established in C57BL/6J^db/db mice and AGEs-induced HK-2 cells. Various biological techniques such as WB and RT-PCR revealed that CAG enhanced mitophagy via TFEB, reducing apoptosis in RTECs. Mechanistic studies combining CETSA, molecular docking, and molecular dynamics simulations confirmed the CAG-ERK interaction.

Key results: CAG improved renal function and reduced renal tubular injury in db/db mice. CAG effectively reduced the accumulation of mitoROS, enhanced mitochondrial membrane potential, promoted mitophagy and mitochondrial biogenesis, and restored mitochondrial homeostasis. Mechanistically, CAG enhanced mitophagy in db/db mice and AGEs-induced HK-2 cells by stimulating the autophagic flux via regulating TFEB. Moreover, CAG inhibited AGEs-induced HK-2 apoptosis, which was reversed by autophagy inhibitor chloroquine (CQ) and siRNA-TFEB. Importantly, after mutating the valine (VAL) at position 39 of the ERK to alanine (ALA), the binding effect between CAG and ERK was significantly reduced, revealing that CAG directly bound ERK at 39VAL, inhibiting its phosphorylation, thus preventing the phosphorylation of the S142 site of TFEB and enabling TFEB to translocate into the nucleus.

Conclusions and implications: CAG ameliorated renal tubule damage in DKD by regulating mitochondrial quality though targeting ERK to regulate TFEB. This research advances drug development and proposes lifestyle interventions (e.g., dietary supplements).

Glucocorticoids and beta2-agonists are the main treatments for asthma in modern medicine. They are significantly restricted in clinical usage due to its drug tolerance and certain side effects. As an important pathological feature of asthma, it is not currently targeted by any frontline treatments, targeting oxidative stress mechanisms may represent a novel therapeutic intervention for asthma. Icariin is a prenylated flavonol glycoside from the chinese herb Epimedium, which has been shown to have anti-oxidative stress activities. Our previous study showed that Icariin effectively inhibits airway inflammation of asthmatic mice, but the mechanism is still not fully understood. This study was to determine whether Icariin can play an anti-oxidative stress role in asthmatic airway epithelium and inhibits NF-κB signaling by promoting the expression of Nrf2. The oxidative stress status of asthmatic patients were observed. OVA was used for induction of mouse allergic asthma models, and the human bronchial epithelial cell line HBE was used for in vitro studies. The potential mechanism of Icariin was explored by in vivo and in vitro studies. Our results showed that there is an imbalance of oxidative/antioxidant factors in both asthmatic patients and mice. Icariin alleviated airway inflammation while reversing oxidative/antioxidant factors in asthmatic mice. Mechanically, Icariin significantly promoted the expression of Nrf2 in asthmatic mice and airway epithelial cells, while significantly inhibited the expression of NF-κB signaling. Further, the inhibitory effect of Icariin on phosphorylated NF-κB p65 was significantly weakened after knockdown of Nrf2. However, Icariin had no effect on the methylation of the DNA promoter regions of Keap-1 or Nrf2. Overall, the study demonstrated that Icariin could inhibit NF-κB signaling by promoting the activation of Nrf2 signaling, thereby exerting an anti-asthmatic effect. However, this promoting effect of ICA on Nrf2 activation is independent of DNA-methylation of Keap-1 or Nrf2. Icariin might be a promising intervention for the treatment of asthma by activating Nrf2 signaling to inhibit NF-κB signaling, targeting oxidative stress mechanisms.

Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis and has a high prevalence, with limited clinical treatment options available. Saikosaponin D (SSD) is a major component of the traditional Chinese medicine compound Chaihuang Yishen Granules (CHYS) and exhibits favorable anti-fibrotic effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. To elucidate the protective effects of SSD on CKD-induced renal fibrosis and investigate the underlying mechanism by which SSD alleviates renal fibrosis through regulating hexokinase-2 (HK2)-mediated Smad3 activation, CKD models were established using unilateral ureteral obstruction (UUO) and adenine (ADE) induction. Subsequently, SSD was administered via oral gavage as a therapeutic intervention to observe its protective effects against CKD-induced renal fibrosis. Mechanistically, in vitro experiments involving HK2 overexpression and knockdown, as well as the use of SIS3 to inhibit Smad3 activation, evaluated the regulatory role of HK2 on glycolysis and Smad3. The results demonstrated that SSD treatment significantly improved the abnormal serum creatinine (CRE) and blood urea nitrogen (BUN) levels in CKD mice, alleviated renal pathological damage, and reduced the expression of fibrosis-related proteins (Col-I, FN, α-SMA). HK2 was found to promote glycolysis-related enzymes and Smad3 activation. Inhibition of Smad3 activation with 4 μM SIS3 significantly attenuated TGF-β-induced fibrosis in tubular cells but had no effect on HK2 expression or glycolysis. Direct suppression of LDHA-mediated lactate production using 25 mM oxamic acid sodium (OX) markedly reduced HK2-induced Smad3 activation and tubular cell fibrosis. This study reveals that SSD significantly alleviates CKD-induced renal fibrosis by inhibiting HK2-mediated Smad3 activation. Lactate, not only as the end product of HK2-driven glycolysis, but also acts as a signaling mediator in HK2-regulated Smad3 activation, facilitating its activation.

Curcumin (CUR), a major active compound in Curcuma longa Linn., exhibits various bioactivities, but its potential in treating gastric precancerous lesions (GPL) and the underlying mechanisms remain unexplored. To investigate the effect and possible mechanism of CUR on GPL both in vitro and in vivo, an N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced rat model of GPL and a malignant transformation model of human gastric epithelial cells (MC cells) were employed. The results showed that CUR treatment reversed intestinal metaplasia and dysplasia in GPL rats. Furthermore, CUR treatment led to decreased levels of gastrin 17 and increased levels of pepsinogen I (PG I) and prostaglandin E2 (PGE2) in the rat model. Compared to normal controls, GPL rats exhibited elevated levels of interleukin 1β (IL-1β), IL-4, IL-6, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ), along with decreased levels of IL-10. CUR treatment reduced the levels of IL-1β and IL-4. Immunohistochemical analysis revealed that protein expressions of Yes-associated protein 1 (YAP1) and TEA domain transcription factor 1 (TEAD1) were significantly upregulated in human GPL tissues, while p-YAP1 expression was downregulated. CUR treatment downregulated YAP1 and TEAD1, and upregulated p-YAP1 and apoptosis-related proteins both in vivo and in vitro. In conclusion, CUR could alleviate gastric mucosal inflammation and prevent the occurrence and progression of GPL, potentially via modulation of the YAP/TEAD axis in the Hippo signaling pathway.