Phytomedicine最新文献

Background: Platelet adhesion to collagen, a critical initial step in thrombus formation, remains an underexplored therapeutic target in thrombosis. Current disease treatment strategies primarily focus on platelet activation and aggregation, often overlooking the crucial initial adhesion phase. Reynoutria japonica (Huzhang, HZ), utilized in traditional Chinese medicine to enhance blood circulation and resolve blood stasis, lacks comprehensive insights into its active components and their anti-thrombotic mechanisms.

Purpose: This study investigated the antithrombotic effects and mechanisms of polydatin, a stilbene derived from HZ, with a focus on its effect on platelet adhesion.

Methods: An acute pulmonary infection model was used, along with metabolomic and proteomic analyses, to investigate the antithrombotic efficacy of the active component polydatin and identify its targets. Chemical biology, protein mass spectrometry analyses, and molecular interaction analysis were performed to investigate its mechanism. Multiple models of circulatory disorders, including disseminated intravascular coagulation (DIC) and atherosclerosis in mice, with or without targeted gene knockdown, were employed to assess the role of polydatin in modulating platelet adhesion.

Results: Our investigation revealed that polydatin targets prolyl hydroxylase 2 (PHD2), thereby inhibiting hydroxylation of proline residues on collagen. This disruption in collagen assembly and the von Willebrand factor (VWF)-collagen interaction reduces platelet adhesion, significantly impacting circulation in both DIC and atherosclerosis. This represents a novel mechanism of antithrombotic action, distinct from currently available therapies.

Conclusion: Targeting PHD2 to modulate collagen structure and platelet adhesion presents a promising novel therapeutic strategy for thrombosis-related circulatory disorders.

Background: The incidence of papillary thyroid carcinoma (PTC) is on the rise globally. It is frequently associated with early lymphatic metastasis, and the poor prognosis tends to be poor once metastasis or recurrence occurs, even with current treatment modalities. Kushenol O, a novel extract derived from Sophora flavescens, has shown remarkable anticancer properties. However, its specific role in the treatment of PTC remains to be elucidated.

Purpose: This objective of this study is to examine the effects of kushenol O on the proliferation and invasion capacity of PTC cells, as well as to delve into its potential mechanisms of action.

Methods: Multi-omics was employed to identify the potential therapeutic targets for PTC. Single-cell RNA sequencing (scRNA-seq) investigated how these targets influence the remodeling of the tumor immune microenvironment (TIME). Kushenol O was employed to treat the PTC cell lines, with assessments conducted on its effects regarding cell viability, apoptosis, oxidative stress, and invasiveness. Molecular simulation was used to validate kushenol O's affinity for the therapeutic targets and biological toxicity. The impact of kushenol O was further evaluated using qRT-PCR and EdU assays, while cytotoxicity was measured by the CCK-8.

Results: GALNT7 is a potential new target for the treatment of PTC. It may regulate the macrophage M2 polarization and efferocytosis in the TIME of PTC through regulating the NF-κB axis. Kushenol O inhibits PTC cells proliferation and promotes apoptosis by inhibiting the expression of GALNT7, induces a decrease in SOD levels and an increase in MDA levels by inhibiting mitochondrial function, and promotes the accumulation of ROS, which inhibits G1 phase and promotes early apoptosis.

Conclusions: Kushenol O may inhibit the inflammation-cancer transformation and tumor progression of PTC by inhibiting GALNT7 and thus regulating NF-κB axis. These findings highlight the potential of kushenol O as immunomodulator or therapeutic agent, which may have important clinical implications.

Background: Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy.

Purpose: We investigate the pharmacological characteristics and mechanism of OMT in mitochondrial function and autophagy in cardiac hypertrophy.

Study design and methods: A murine model of cardiac hypertrophy was induced by aldosterone in combination with high-salt drinking water, while primary cardiomyocyte hypertrophy was induced by aldosterone in vitro. Cardiac hypertrophy was assessed using echocardiography and histopathological staining. Autophagosomes and mitochondrial morphology were visualized by transmission electron microscopy. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP) were quantified using commercial kits. The binding affinity of OMT with Nrf2 was assessed through molecular docking. Furthermore, adenovirus, agonists, and inhibitors were employed to modulate Nrf2, followed by quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, immunohistochemistry, and cellular thermal shift assay.

Results: OMT effectively attenuated aldosterone-induced cardiac hypertrophy both in vivo and in vitro. OMT promoted the activation of Nrf2, leading to elevated SIRT3 expression and enhanced autophagolysosome fusion, thereby modulating mitophagy and improving mitochondrial function. Moreover, the cardioprotective effects of OMT were abolished upon silencing or inhibition of Nrf2. OMT binds to Nrf2, facilitating its dissociation and nuclear translocation.

Conclusion: OMT activates Nrf2, consequently enhancing SIRT3 transcription, restoring autophagic flux, and preserving mitochondrial integrity, thereby mitigating aldosterone-induced cardiac hypertrophy. In summary, our study is the first to discover and confirm that OMT can stabilize Nrf2, promoting its activation and subsequently up-regulating SIRT3, which in turn facilitates mitochondrial autophagy. Additionally, PARKIN appears to play a key role in SIRT3-mediated regulation of mitophagy, warranting further investigation.

Background: Depression is a common mental disorder characterized by prolonged loss of interest and low mood, accompanied by symptoms such as sleep disturbances and cognitive impairments. In severe cases, there may be a tendency toward suicide. Depression can be caused by a series of highly complex pathological mechanisms; However, its key pathogenic mechanism remains unclear. As a novel programmed cell death (PCD) pathway and inflammatory cell death mode, pyroptosis involves a series of tightly regulated gene expression events. It may play a significant role in the pathogenesis and management of depression by modulating neuroinflammatory processes. In addition, a large number of studies have shown that various pharmacologically active natural products can regulate pyroptosis through multiple targets and pathways, demonstrating significant potential in the treatment of depression. These natural products offer advantages such as low costs and minimal side effects, making them a viable supplement or alternative to traditional antidepressants. In this review, we summarized recent research on natural products that regulate pyroptosis and neuroinflammation to improve depression. The aim of this review was to contribute to a scientific basis for the discovery and development of more natural antidepressants in the future.

Methods: To review the antidepressant effects of natural products targeting pyroptosis-mediated neuroinflammation, data were collected from the Web of Science, ScienceDirect databases, and PubMed to classify and summarize the relationship between pyroptosis and neuroinflammation in depression, as well as the pharmacological mechanisms of natural products.

Results: Multiple researches have revealed that pyroptosis-mediated neuroinflammation serves as a pivotal contributory factor in the pathological process of depression. Natural products, such as terpenoids, terpenes, phenylethanol glycosides, and alkaloids, have antidepressant effects by regulating pyroptosis to alleviate neuroinflammation.

Conclusion: We comprehensively reviewed the regulatory effects of natural products in depression-related pyroptosis pathways, providing a uniquely insightful perspective for the research, development, and application of natural antidepressants. However, future research should further explore the modulatory mechanisms of natural products in regulating pyroptosis, which is of great importance for the genration of effective antidepressants.

Objective: Sepsis is a life-threatening condition characterized by organ dysfunction resulting from the body's aberrant response to infection. A primary indicator of early sepsis is vascular leakage due to endothelial injury. The immunomodulatory effects of paeoniflorin are well established. However, its effect on vascular endothelial injury in sepsis remains to be verified.

Methods: The sepsis model was established by cecal ligation and puncture (CLP), along with simultaneous administration of paeoniflorin. The therapeutic effectiveness of paeoniflorin was evaluated by assessing the survival rate, the bacterial load in blood and the histopathological lung tissue injury. The pulmonary vascular endothelial barrier integrity was assessed using immunofluorescence, western blot, Evans blue dye, and qPCR. Human umbilical vein endothelial cells (HUVECs) were used for in vitro validation and exploration of the underlying mechanisms.

Results: The CLP mice exhibited significant damage to pulmonary tissue and breakdown of endothelial barrier. Administration of paeoniflorin markedly improved survival rates, mitigated lung injury, and preserved the integrity of the pulmonary vascular endothelial barrier in CLP mice which was confirmed by in vitro experiments. Pharmacological mechanism studies showed that the protective effects of paeoniflorin on the vascular endothelium was achieved through activation of RXRα signaling, which could be reversed by RXRα knockdown.

Conclusion: Our experiments demonstrates the protective effect of paeoniflorin on the vascular endothelial barrier through activation of the RXRα, thereby offering potential therapeutic options for sepsis treatment. We also identified RXRα as a novel transcription factor for VE-cadherin, providing a potential new intervention target for vascular endothelial barrier damage in sepsis.

Background: Ischemic stroke is a predominant cause of neurological disability, characterized by neuroinflammation and neuronal apoptosis. The Wnt signaling pathway plays a critical role in brain repair. Yangyin Yiqi Huoxue Decoction, a traditional Chinese herbal formula, has shown potential in alleviating neuroinflammatory injury, yet, the precise mechanism underlying its effects remains unclear.

Purpose: This study aims to explore the therapeutic efficacy of Yangyin Yiqi Huoxue Decoction on ischemic stroke and its potential mechanism of action, particularly focusing on its modulation of the Wnt signaling pathway and impact on neuroinflammation and neural stem cells activity.

Study design and methods: The middle cerebral artery occlusion (MCAO) rat model and an Oxygen glucose deprivation/re-oxygenation (OGD/R) cell model were employed. In vivo experiments were conducted to investigate the therapeutic effects of the Yangyin Yiqi Huoxue Decoction at high, medium, and low dosages (3.3, 1.65, and 0.83 g/kg). The effects of Yangyin Yiqi Huoxue Decoction on neuroinflammatory cytokine levels, microglial activation, and neural stem cells proliferation and differentiation were assessed in vivo experiments. Wnt signaling components were evaluated through Quantitative Real-Time PCR and Western blot in both vivo and vitro. Additionaly, the Wnt inhibitor Dickkopf-related protein 1(DKK1) was used to confirm the pathway's involvement.

Results: The high-dose group(3.3 g/kg) of the Yangyin Yiqi Huoxue Decoction exhibited the most pronounced therapeutic effects. Yangyin Yiqi Huoxue Decoction significantly reduced pro-inflammatory cytokine levels, inhibited microglial overactivation, and enhanced neural stem cells proliferation and differentiation. It also modulated the Wnt pathway by upregulating Wnt Family Member 3A(Wnt3a) and β-catenin, while downregulating Wnt Family Member 5A(Wnt5a) and glycogen synthase kinase-3β(GSK-3β). The inhibition of Wnt signaling by Dickkopf-related protein 1(DKK1) reversed these beneficial effects, confirming Yangyin Yiqi Huoxue Decoction 's mechanism.

Conclusions: Yangyin Yiqi Huoxue Decoction exerts neuroprotective effects by suppressing neuroinflammation and promoting neural-stem-cell-mediated brain repair through the Wnt signaling pathway, positioning it as a potential candidate for ischemic stroke treatment.

Background: The concept of a Quality marker (Q-marker) has emerged as a crucial tool for ensuring the safety and efficacy of Traditional Chinese Medicine (TCM) formulas. However, significant challenges remained in the identification and practical application of Q-marker, particularly due to the scarcity of reference standards.

Purpose: This study aimed to achieve a multidimensional integration of chemical profiling, target tissue distribution and in vivo high-throughput screening model to effectively identify the Q-marker of Shensong Yangxin Capsule (SSYX) and propose a linear substitution strategy for the quantification of multiple components.

Methods: First, the chemical constituents of SSYX were detected and systematically characterized using UHPLC/Q-TOF MS. Next, through heart distribution study, high-exposure components in vivo were identified after the oral administration of SSYX. Third, a high-throughput arrhythmia zebrafish model was employed to further screen for key constituents. Finally, potential Q-marker were selected by integrating the aforementioned studies, and a quantification method for the Q-marker was developed using UHPLC-TQ-MS.

Results: The results of chemical profiling, heart tissue distribution and anti-arrhythmic activities were integrated into four properties: specificity, traceability from prescription to in vivo, effectiveness and prescription compatibility, which led to the identification of 30 ingredients as potential Q-marker of SSYX. Subsequently, an external standard method (ESM) was developed for these 30 components and applied to the analysis of 10 commercial batches of SSYX. In addition, the feasibility of multi-marker detection via a linear substitution method (LSM) was explored for the first time using SSYX as a case study for method development, based on the stability of linear equations of the compounds in single standard solutions and multi-component mixed standard solutions. The simultaneous quantification of 30 components in SSYX was achieved by employing two linearly stable substances, greatly reducing the amount of standard substances used while maintaining measurability and convenience. A comparison of LSM and ESM revealed no significant difference in the component contents calculated by the two methods, with relative errors within ± 4 %.

Conclusion: Our results suggested that 30 ingredients, including six key elements, could be considered as Q-marker of SSYX. Moreover, the LSM strategy offered a novel approach for developing environmentally friendly and convenient methods for the quality control of multi-index components in TCM formulas.

Background: Cellular histones are DNA-binding nuclear proteins involved in chromatin remodelling and regulation of gene expression. However, extracellular histones act as damage-associated molecular patterns (DAMPs) and contribute to multiorgan damage in conditions with sepsis and diseases with acute critical illnesses. Alongside, histones are associated with thrombocytopenia due to dysfunctional platelets that regulate hemostasis and thrombosis. There is no drug available to prevent histone-induced platelet toxicity. Therefore, we for the first time examined quercetin (QUE) as a novel therapeutic to protect histone-induced platelet toxicity.

Purpose: To delineate how histones induce platelet toxicity and investigate the protective efficacy of quercetin (QUE), a natural dietary phytochemical.

Study design/method: Histone-treated platelets were evaluated for platelet aggregation/activation markers, various autophagy-related signaling proteins, and cytotoxicity in vitro. For the inhibition study, QUE and other standard inhibitors were pre-treated before stimulation with histones. Further, we injected histones into mice in the presence or absence of QUE and evaluated the tail bleeding, lung toxicity, and circulatory platelet stress markers. Additionally, QUE-treated mice were challenged for histone-primed Collagen-epinephrine-induced pulmonary thromboembolism.

Result: Extracellular histones induce platelet activation and aggregation by interacting with sialic acid in TLR1/2 or TLR4. Also, we have demonstrated for the first time that histones induce ER stress-mediated autophagy in platelets. QUE inhibited histone-induced platelet activation, aggregation, and ER-stress-mediated autophagy in response to histone treatment. Ex vivo experiments indicate that oral administration of QUE can safeguard platelets while concurrently mitigating their response to histone stimulation. In addition, quercetin increased the survival rates of histone-primed, collagen-epinephrine-induced acute pulmonary thromboembolism in mice.

Conclusion: In summary, this study demonstrated the beneficial effect of QUE in protecting platelets with possible implications for addressing histone-accelerated pathologies.

Background: Puerarin is a crucial constituent separated from the Chinese herbaceous plant, Pueraria lobata (Willd.) Ohwi, which exhibits multiple biological activities. Previous studies have indicated that puerarin has a function to alleviate renal damage in animal models of diabetic nephropathy (DN). However, there is still a dearth of systematic preclinical studies.

Purpose: This study was designed to assess the effectiveness of puerarin on DN through meta-analysis. Furthermore, it aimed to reveal the underlying mechanisms of puerarin's efficacy in treating DN.

Methods: The animal studies were retrieved from 5 electronic databases. In total, 26 studies were included in our analysis. STATA 18.0 software was employed to evaluate crucial parameters, including fasting blood glucose (FBG), serum creatinine (SCr), blood urea nitrogen (BUN), proteinuria, oxidative stress, inflammatory responses, and lipid metabolism.

Results: The results indicate that puerarin significantly improves FBG, SCr, BUN, proteinuria, and kidney index (KI). Additionally, puerarin enhances indicators of oxidative stress including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), while reduces inflammatory indicators like interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α). Moreover, puerarin lowers triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) levels.

Conclusion: In conclusion, puerarin has the effect of improving renal function in DN animals possibly through antioxidative, anti-inflammatory, and the regulation of renal lipid accumulation, which offers preclinical support for its possible therapeutic use in the management of DN.

Background: Microsatellite stable (MSS) colorectal carcinomas (CRCs) exhibit poor responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). In the realm of clinical cancer treatment, traditional Chinese medicines (TCMs) are extensively utilized for their immunomodulatory properties. Shen Qi Yi Chang (SQYC), a clinical prescription for CRC treatment, improve the life quality of CRC patients and enhance their immune function.

Purpose: This study was to reveal the effect and mechanism of SQYC in improving the effect of PD-1 inhibitors in the treatment of MSS-type CRC.

Methods: CT26-luc in situ CRC tumor model and human CRC organoid model was established to evaluate the anti-tumor efficacy of SQYC combined with PD-1 inhibitor. Flow cytometry analysis was utilized to investigate the effect of SQYC on the infiltration and immune function of TILs and DCs in the immune microenvironment. Following this, RNA sequencing analysis, seahorse, TEM and immunofluorescence were performed to regulation of SQYC on mitophagy in DCs cells. UPLC-Q-TOF/MS and molecular docking were used to reveal the key blood-entering components of SQYC-regulated PINK1-parkin pathway.

Results: The SQYC-containing serum improved the efficacy of sintilimab in MSS CRC organoid model. After combined administration of 11.4 g/kg/day SQYC extract and 5 mg/kg α-PD-1, it was observed that SQYC enhanced the efficacy of PD-1 inhibitor against MSS CRC. Flow cytometry and immunofluorescence analysis revealed an augmented infiltration of tumor-infiltrating lymphocytes (TILs) and an improved antigen presentation function of dendritic cells (DCs). Notably, RNA sequencing analysis demonstrated an evident correlation with mitochondrial function related pathways following SQYC treatment. Mechanistically, SQYC promoted mitophagy in DCs via the PINK1-Parkin pathway, thereby improving mitochondrial quality, energy metabolism, and mitochondrial dynamics. Evaluation of the blood components of SQYC coupled with molecular docking, demonstrated good binding affinity with PINK1/PARKIN/LC3.

Conclusion: Our findings highlight SQYC as a promising candidate for improving immunotherapy in MSS CRC, suggesting that targeting PINK1-Parkin in DCs could represent a novel strategy for improving the efficacy of ICIs. Furthermore, it provides new theoretical and scientific underpinnings to enhance the clinical efficacy of immunosuppressants.