Advancements in research on the effects of panax notoginseng saponin constituents in ameliorating learning and memory disorders.

Learning and memory disorder is a cluster of symptoms caused by neuronal aging and other diseases of the central nervous system (CNS). Panax notoginseng saponins (PNS) are a series of saponins derived from the natural active ingredients of traditional Chinese medicine (TCM) that have neuroprotective effects on the central nervous system. In this paper, we review the ameliorative effects and mechanisms of Panax notoginseng saponin-like components on learning and memory disorders to provide valuable references and insights for the development of new drugs for the treatment of learning and memory disorders. Our summary results suggest that Panax ginseng saponins have significant effects on improving learning and memory disorders, and these effects and potential mechanisms are mediated by their anti-inflammatory, anti-apoptotic, antioxidant, ß-amyloid lowering, mitochondrial homeostasis in vivo, neuronal structure and function improving, neurogenesis promoting, neurotransmitter release regulating, and probiotic homeostasis in vivo activities. These findings suggest the potential of Panax notoginseng saponin-like constituents as drug candidates for improving learning and memory disorders.

Qilong capsule prevents myocardial ischemia/reperfusion injury by inhibiting platelet activation via the platelet CD36 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qilong capsule (QC) is developed from the traditional Chinese medicine formula Buyang Huanwu Decoction, which has been clinically used to invigorate Qi and promote blood circulation to eliminate blood stasis. Myocardial ischemia‒reperfusion injury (MIRI) can be attributed to Qi deficiency and blood stasis. However, the effects of QC on MIRI remain unclear. AIM OF THE STUDY: This study aimed to investigate the protective effect and possible mechanism of QC on platelet function in MIRI rats. MATERIALS AND METHODS: The left anterior descending artery of adult Sprague‒Dawley rats was ligated for 30 min and then reperfused for 120 min with or without QC treatment. Then, the whole blood viscosity, plasma viscosity, coagulation, platelet adhesion rate, platelet aggregation, and platelet release factors were evaluated. Platelet CD36 and its downstream signaling pathway-related proteins were detected by western blotting. Furthermore, the active components of QC and the molecular mechanism by which QC regulates platelet function were assessed via molecular docking, platelet aggregation tests in vitro and BLI analysis. RESULTS: We found that QC significantly reduced the whole blood viscosity, plasma viscosity, platelet adhesion rate, and platelet aggregation induced by ADP or AA in rats with MIRI. The inhibition of platelet activation by QC was associated with reduced levels of ß-TG, PF-4, P-selectin and PAF. Mechanistically, QC effectively attenuated the expression of platelet CD36 and thus inhibited the activation of Src, ERK5, and p38. The active components of QC apparently suppressed platelet aggregation in vitro and regulated the CD36 signaling pathway. CONCLUSIONS: QC improves MIRI-induced hemorheological disorders, which might be partly attributed to the inhibition of platelet activation via CD36-mediated platelet signaling pathways.

Self-adjuvant Astragalus polysaccharide-based nanovaccines for enhanced tumor immunotherapy: a novel delivery system candidate for tumor vaccines.

The study of tumor nanovaccines (NVs) has gained interest because they specifically recognize and eliminate tumor cells. However, the poor recognition and internalization by dendritic cells (DCs) and insufficient immunogenicity restricted the vaccine efficacy. Herein, we extracted two molecular-weight Astragalus polysaccharides (APS, 12.19 kD; APSHMw, 135.67 kD) from Radix Astragali and made them self-assemble with OVA257-264 directly forming OVA/APS integrated nanocomplexes through the microfluidic method. The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability. APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy. The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution. The FITC-OVA in APS-NVs could be effectively taken up by DCs, and APS-NVs could stimulate the maturation of DCs, improving the antigen cross-presentation efficiency in vitro. The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4. Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.c. injection. Smaller APS-NVs could easily access the lymph nodes. Furthermore, APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells. In addition, APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group. The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region. Subsequently, the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs. Therefore, this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.

Cardiovascular disease and depression: a narrative review.

In clinical practice, it is frequently observed that cardiac and psychological disorders frequently co-occur, leading to the emergence of a field known as cardiovascular disease with depression. Depression, in particular, poses a remarkable risk for the evolution of cardiovascular disease and intimately relates to adverse cardiovascular outcomes and mortality. Moreover, individuals who are depressed exhibit a higher susceptibility to developing cardiovascular disease compared to those in good health. Patients diagnosed with cardiovascular disease with depression disease face a heightened risk of mortality within a 5-year timeframe, and their prognosis remains unsatisfactory even after receiving treatment targeting a single disorder, with a notable recurrence rate. Psychological interventions in conjunction with medications are commonly employed in clinical settings for treating patients with cardiovascular disease and depression diseases, albeit with limited effectiveness and unfavorable prognosis. Traditional Chinese medicine (TCM), such as Shuangxinfang, Chaihujialonggumuli, and Yixin Ningshen Tablet, etc., have been reported and have Therapeutic effects in patients with cardiovascular disease combined with depression. Despite numerous articles documenting a notable association between heart disease and depression, there exists a dearth of studies elucidating the precise pathogenesis and target of action for cardiovascular disease with depression diseases. This article endeavors to consolidate the epidemiological data, potential pathogenic mechanisms, and available treatment modalities for cardiovascular disease with depression diseases. Its primary objective is to unveil plausible co-morbid mechanisms and suitable treatment approaches, thereby offering novel insights for the prevention, diagnosis, and management of cardiovascular disease with depression diseases.

Jiedu Quyu Decoction mitigates monocrotaline-induced right-sided heart failure associated with pulmonary artery hypertension by inhibiting NLRP3 inflammasome in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Right-side heart failure could accelerate mortality in patients of pulmonary hypertension, Jiedu Quyu Decoction (JDQYF) was used to manage pulmonary hypertension, but its right-sided heart protective effect associated with pulmonary artery hypertension is still unclear. AIM OF THE STUDY: Here, we evaluated the therapeutic effect of JDQYF on monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension in Sprague-Dawley (SD) rats and investigated the potential mechanism of action. MATERIALS AND METHODS: The main chemical components of JDQYF were detected and analyzed using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. The effects of JDQYF were investigated using a rat model of monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension. We assessed the morphology of cardiac tissue using histopathology and the structure and function of the right heart using echocardiography. The biomarkers of heart failure, atrial natriuretic peptide and B-type natriuretic peptide, as well as serum pro-inflammatory markers, interleukin (IL)-1ß, and IL-18, were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, the mRNA and protein expression levels of NLRP3 (NOD-, LRR-, and pyrin domain-containing 3), capase-1, IL-1ß, and IL-18 in the right heart tissue were examined by real-time quantitative reverse transcription PCR and western blotting. RESULTS: JDQYF improved ventricular function, alleviated pathological lesions in the right cardiac tissue, reduced the expression levels of biomarkers of heart failure and serum pro-inflammatory factors (IL-1ß and IL-18), and downregulated the mRNA and protein expression levels of NLRP3, caspase-1, IL-1ß, and IL-18 in the right cardiac tissue. CONCLUSIONS: JDQYF possesses cardioprotective effect against right heart failure induced by pulmonary arterial hypertension, possibly owing to reduction of cardiac inflammation through the inhibition of NLRP3 inflammasome activation.

[Research progress on pharmacology of butylphthalide and its derivatives].

The butylphthalide(NBP), a colorless or light yellow viscous oily component isolated from celery seeds, has the effects of anti-inflammation, anti-oxidative stress, protecting blood-brain barrier, improving cerebral microcirculation, and promoting angiogenesis. It can protect the neurological function of patients with ischemic stroke through a variety of mechanisms, improve the symptoms of patients, and contribute to the long-term recovery of them. Therefore, independently developed in China, NBP was approved by State Food and Drug Administration for the clinical treatment of stroke patients in 2002. At the same time, owing to the complex multi-target pharmacological mechanism, NBP has been frequently used in clinical practice. As frequently verified, it has obvious effects in the treatment of other neurological diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, autoimmune diseases, depression, traumatic central nervous system injury. Moreover, it demonstrates significant pharmacological effects on non-neurological diseases such as diabetes mellitus and myocardial infarction. Therefore, this study summarizes the research progress on roles of NBP in nervous system diseases and non-nervous system diseases, and the pharmacological characteristics and mechanisms of NBP, which is expected to lay a basis for research on related targets.

Protective effect and mechanism of Shenkang injection on adenine-induced chronic renal failure in rats.

PURPOSE: To investigate the protective effects of Shenkang injection (SKI) on adenine-induced chronic renal failure (CRF) in rat. METHODS: Sprague Dawley rats were randomly divided into five groups: control, model, and SKI groups (5, 10, 20 mL/kg). Rats in model and SKI groups were treated with adenine i.g. at a dose of 150 mg/kg every day for 12 weeks to induce CRF. Twelve weeks later, SKI was administered to the rat i.p. for four weeks. The effects of SKI on kidney injury and fibrosis were detected. RESULTS: SKI inhibited the elevation of the urine level of N-acetyl-b-D-glucosaminidase, kidney injury molecule-1, beta-2-microglobulin, urea protein in CRF rats. The serum levels of uric acid and serum creatinine increased and albumin decreased in the model group, which was prevented by SKI. SKI inhibited the release of inflammatory cytokines and increasing the activities of antioxidant enzymes in serum. SKI inhibited the expression of transforming growth factor-ß1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, collagen I, collagen III, endothelin-1, laminin in kidney of CRF rats. CONCLUSIONS: SKI protected against adenine-induced kidney injury and fibrosis and exerted anti-inflammatory, and antioxidant effects in CRF rats.

Folium Ginkgo extract and tetramethylpyrazine sodium chloride injection (Xingxiong injection) protects against focal cerebral ischaemia/reperfusion injury via activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

CONTEXT: Folium Ginkgo extract and tetramethylpyrazine sodium chloride injection (Xingxiong injection) is a compound preparation commonly used for treating cerebral ischaemia/reperfusion injury in ischaemic stroke in China. However, its potential mechanisms on ischaemic stroke remain unknown. OBJECTIVE: This study explores the potential mechanisms of Xingxiong injection in vivo or in vitro. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomly assigned to five groups: the sham (normal saline), the model (normal saline) and the Xingxiong injection groups (12.5, 25 or 50 mL/kg). The rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by reperfusion for 14 d. Xingxiong injection was administered via intraperitoneal (i.p.) injection immediately after ischaemia induction for 14 d. Afterwards, rats were sacrificed at 14 d induced by administration of Xingxiong injection. RESULTS: Xingxiong injection significantly reduces infarct volume (23%) and neurological deficit scores (93%) compared with the MCAO/R group. Additionally, Xingxiong injection inhibits the loss in mitochondrial membrane potential (43%) and reduces caspase-3 level (44%), decreases NOX (41%), protein carbonyl (29%), 4-HNE (40%) and 8-OhdG (41%) levels, inhibits the expression of inflammatory factors, such as TNF-α (26%), IL-1ß (34%), IL-6 (39%), MCP-1 (36%), CD11a (41%) and ICAM-1 (43%). Moreover, Xingxiong injection can increase p-Akt/Akt (35%) and Nrf2 (47%) protein expression and inhibit NLRP3 (42%) protein expression. CONCLUSIONS: Xingxiong injection prevents cerebral ischaemia/reperfusion injury via activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome. These findings provide experimental evidence for clinical use of drugs in the treatment of ischaemic stroke.

Paclobutrazol exposure induces apoptosis and impairs autophagy in hepatocytes via the AMPK/mTOR signaling pathway.

Paclobutrazol (PBZ), one of the most widely used plant growth retardants in vegetables, fruits, and traditional Chinese medicine ingredients, exposes people to adverse events. In this study, HepaRG hepatocytes were cultured and exposed to PBZ (360 µM) in vitro to determine its mechanism. Results showed that PBZ exposure inhibited cell viability in a time- and dose-dependent manner and increased the oxidative stress and apoptosis ratio in HepaRG cells. These data revealed that the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) has an important role in PBZ-induced cell apoptosis, which is mediated by impaired autophagy and blocked by the AMPK activator. In conclusion, PBZ exposure induces apoptosis and impairs autophagy in hepatocytes via the AMPK/mTOR signaling pathway.

Hydroxysafflor Yellow A Ameliorates Myocardial Ischemia/Reperfusion Injury by Suppressing Calcium Overload and Apoptosis.

Myocardial ischemia/reperfusion injury (MI/RI) is an urgent problem with a great impact on health globally. However, its pathological mechanisms have not been fully elucidated. Hydroxysafflor yellow A (HSYA) has a protective effect against MI/RI. This study is aimed at further clarifying the relationship between HSYA cardioprotection and calcium overload as well as the underlying mechanisms. We verified the protective effect of HSYA on neonatal rat primary cardiomyocytes (NPCMs) and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from hypoxia-reoxygenation (HR) injury. To explore the cardioprotective mechanism of HSYA, we employed calcium fluorescence, TUNEL assay, JC-1 staining, and western blotting. Finally, cardio-ECR and patch-clamp experiments were used to explain the regulation of L-type calcium channels (LTCC) in cardioprotection mediated by HSYA. The results showed that HSYA reduced the levels of myocardial enzymes and protected NPCMs from HR injury. HSYA also restored the contractile function of hiPSC-CMs and field potential signal abnormalities caused by HR and exerted a protective effect on cardiac function. Further, we demonstrated that HSYA protects cardiomyocytes from HR injury by decreasing mitochondrial membrane potential and inhibiting apoptosis and calcium overload. Patch-clamp results revealed that MI/RI caused a sharp increase in calcium currents, which was inhibited by pretreatment with HSYA. Furthermore, we found that HSYA restored contraction amplitude, beat rate, and field potential duration of hiPSC-CMs, which were disrupted by the LTCC agonist Bay-K8644. Patch-clamp experiments also showed that HSYA inhibits Bay-K8644-induced calcium current, with an effect similar to that of the LTCC inhibitor nisoldipine. Therefore, our data suggest that HSYA targets LTCC to inhibit calcium overload and apoptosis of cardiomyocytes, thereby exerting a cardioprotective effect and reducing MI/RI injury.

Guan Xin Dan Shen formulation protects db/db mice against diabetic cardiomyopathy via activation of Nrf2 signaling.

Guan Xin Dan Shen formulation (GXDSF) is a widely used treatment for the management of coronary heart disease in China and is composed of three primary components: Dalbergiae odoriferae Lignum, Salviae miltiorrhizae Radix et Rhizoma and Panax notoginseng Radix et Rhizoma. However, the potential use of GXDSF for the management of diabetic cardiomyopathy (DCM) has not been previously assessed. The present study aimed to assess the effects of GXDSF on DCM, as well as the underlying mechanism. In the present study, db/db mice were used. Following treatment with GXDSF for 10 weeks, fasting blood glucose, insulin sensitivity, serum lipid levels and cardiac enzyme levels were detected. Cardiac pathological alterations and cardiac function were assessed by performing hematoxylin and eosin staining and echocardiograms, respectively. TUNEL assays were conducted to assess cardiomyocyte apoptosis. Additionally, reverse transcription­quantitative PCR and western blotting were performed to evaluate the expression of apoptosis­associated genes and proteins, respectively. In the model group, the db/db mice displayed obesity, hyperlipidemia and hyperglycemia, accompanied by noticeable myocardial hypertrophy and diastolic dysfunction. Following treatment with GXDSF for 10 weeks, serum triglyceride levels were lower and insulin sensitivity was enhanced in db/db mice compared with the model group, which indicated improvement in condition. Cardiac hypertrophy and dysfunction were also improved in db/db mice following treatment with GXDSF, resulting in significantly increased left ventricular ejection fraction and fractional shortening compared with the model group. Following treatment with metformin or GXDSF, model­induced increases in levels of myocardial enzymes were decreased in the moderate and high dose groups. Moreover, the results indicated that, compared with the model group, GXDSF significantly inhibited cardiomyocyte apoptosis in diabetic heart tissues by increasing Bcl­2 expression and decreasing the expression levels of Bax, cleaved caspase­3 and cleaved caspase­9. Mechanistically, GXDSF enhanced Akt phosphorylation, which upregulated antioxidant enzymes mediated by nuclear factor erythroid 2­related factor 2 (Nrf2) signaling. Collectively, the results of the present study indicated that GXDSF attenuated cardiac dysfunction and inhibited cardiomyocyte apoptosis in diabetic mice via activation of Akt/Nrf2 signaling. Therefore, GXDSF may serve as a potential therapeutic agent for the management of DCM.

Classical Active Ingredients and Extracts of Chinese Herbal Medicines: Pharmacokinetics, Pharmacodynamics, and Molecular Mechanisms for Ischemic Stroke.

Stroke is a leading cause of death and disability worldwide, and approximately 87% of cases are attributed to ischemia. The main factors that cause ischemic stroke include excitotoxicity, energy metabolism disorder, Ca+ overload, oxidative damage, apoptosis, autophagy, and inflammation. However, no effective drug is currently available for the comprehensive treatment of ischemic stroke in clinical applications; thus, there is an urgent need to find and develop comprehensive and effective drugs to treat postischemic stroke. Traditional Chinese medicine (TCM) has unique advantages in treating ischemic stroke, with overall regulatory effects at multiple levels and on multiple targets. Many researchers have studied the effective components of TCMs and have achieved undeniable results. This paper reviews studies on the anticerebral ischemia effects of TCM monomers such as tetramethylpyrazine (TMP), dl-3-n-butylphthalide (NBP), ginsenoside Rg1 (Rg1), tanshinone IIA (TSA), gastrodin (Gas), and baicalin (BA) as well as effective extracts such as Ginkgo biloba extract (EGB). Research on the anticerebral ischemia effects of TCMs has focused mostly on their antioxidative stress, antiapoptotic, anti-inflammatory, proangiogenic, and proneurogenic effects. However, the research on the use of TCM to treat ischemic stroke remains incompletely characterized. Thus, we summarized and considered this topic from the perspective of pharmacokinetics, pharmacological effects, and mechanistic research, and we have provided a reference basis for future research and development on anticerebral ischemia TCM drugs.

Ginsenoside Rb1 ameliorates cardiotoxicity triggered by aconitine via inhibiting calcium overload and pyroptosis.

BACKGROUND: Aconitine-induced cardiotoxicity limits the clinical treatment of cardiotonic, cancers and immune-related diseases. Ginsenoside Rb1 (Rb1) is an active ingredient of traditional Chinese medicine with cardioprotective effect. PURPOSE: This study aims to study the mechanism of aconitine cardiotoxicity and the detoxification mechanism of Rb1. STUDY DESIGN: METHODS: The regulatory effect of Rb1 on aconitine was evaluated in vitro and in vivo by myocardial enzyme indicators, pathological analysis, CardioECR detection, calcium transient analysis, western blotting and immunohistochemistry. RESULTS: Rb1 (10, 20, 40 mg/kg) alleviated apoptotic myocardial damage caused by aconitine in rats. Furthermore, Rb1 (25, 50, 100 µM) restored the contractile function and field potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by regulating calcium channels and reduced myocardial cell damage by inhibiting the calcium transients of adult rat ventricular myocytes (ARVMs). Rb1 significantly reduced calcium levels in hiPSC-CMs, directly indicating that aconitine-induced calcium overload was alleviated by Rb1. Further, aconitine caused calcium overload by changing the expression of calcium pathway proteins, while Rb1 effectively restored calcium homeostasis. In addition, Rb1 also had a cardioprotective role by inhibiting cell pyroptosis. These results suggested that the maintenance of calcium homeostasis helped to suppress the inflammatory response related to pyroptosis of the heart. CONCLUSION: Aconitine-induced cardiotoxicity can be alleviated by Rb1 via restoring calcium homeostasis and inhibiting apoptosis and pyroptosis.

Calenduloside E suppresses calcium overload by promoting the interaction between L-type calcium channels and Bcl2-associated athanogene 3 to alleviate myocardial ischemia/reperfusion injury.

Introduction: Intracellular calcium overload is an important contributor to myocardial ischemia/reperfusion (MI/R) injury. Total saponins of the traditional Chinese medicinal plant Aralia elata (Miq.) Seem. (AS) are beneficial for treating MI/R injury, and Calenduloside E (CE) is the main active ingredient of AS. Objectives: This study aimed to investigate the effects of CE on MI/R injury and determine its specific regulatory mechanisms. Methods: To verify whether CE mediated cardiac protection in vivo and in vitro, we performed MI/R surgery in SD rats and subjected neonatal rat ventricular myocytes (NRVMs) to hypoxia-reoxygenation (HR). CE's cardioprotective against MI/R injury was detected by Evans blue/TTC staining, echocardiography, HE staining, myocardial enzyme levels. Impedance and field potential recording, and patch-clamp techniques of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to detect the function of L-type calcium channels (LTCC). The mechanisms underlying between CE and LTCC was studied through western blot, immunofluorescence, and immunohistochemistry. Drug affinity responsive target stability (DARTS) and co-immunoprecipitation (co-IP) used to further clarify the effect of CE on LTCC and BAG3. Results: We found that CE protected against MI/R injury by inhibiting calcium overload. Furthermore, CE improved contraction and field potential signals of hiPSC-CMs and restored sarcomere contraction and calcium transient of adult rat ventricular myocytes (ARVMs). Moreover, patch-clamp data showed that CE suppressed increased L-type calcium current (ICa,L) caused by LTCC agonist, proving that CE could regulate calcium homeostasis through LTCC. Importantly, we found that CE promoted the interaction between LTCC and Bcl2-associated athanogene 3 (BAG3) by co-IP and DARTS. Conclusion: Our results demonstrate that CE enhanced LTCC-BAG3 interaction to reduce MI/R induced-calcium overload, exerting a cardioprotective effect.

Xuesaitong injection (lyophilized) combined with aspirin and clopidogrel protect against focal cerebral ischemic/reperfusion injury in rats by suppressing oxidative stress and inflammation and regulating the NOX2/IL-6/STAT3 pathway.

BACKGROUND: Combination of aspirin (ASA) and clopidogrel (CLP) [dual antiplatelet therapy (DAPT)] has been limited in reducing early recurrent stroke events. Xuesaitong injection (lyophilized) (XST) made of total saponins from P. notoginseng, which significantly improves cerebral circulation and has been widely used in clinical applications for decades to treat and prevent ischemic stroke. Here, we confirmed the protective effect and mechanism of XST combined with DAPT (XST+ASA+CLP) on cerebral ischemia/reperfusion injury, exploring their better pharmacological action for clinical patients. METHODS: Sprague-Dawley rats (SD rats) (n=9 in each group) were randomly assigned to three groups and pretreated with XST, ASA+CLP, or XST+ASA+CLP for 7 days. Then rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by reperfusion for 24 h. Therapeutic effect of XST+ASA+CLP was measured by infarct volume, neurological behavior and regional cerebral blood flow (rCBF). Inhibition of neuronal apoptosis and glial cells was determined by immunofluorescent staining. We studied the protein levels of neurotrophic factors, neuroplasticity-related factors, oxidative stress indicators and inflammatory factors by ELISA assay. RESULTS: XST+ASA+CLP group showed significant reduction in infarct volumes and neurological deficit scores. XST+ASA+CLP group also had higher levels in rCBF and synaptic growth, and showed remarkable inhibition of microglia and astrocytes activation and the neuronal apoptosis. In addition, XST+ASA+CLP group had lower levels of NADPH, protein carbonyl, 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHdG) and several inflammatory cytokines. Moreover, XST+ASA+CLP group also had lower levels of NOX2, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, and p-STAT3/STAT3. CONCLUSIONS: These results demonstrate that a combination of XST, ASA, and CLP effectively protected rats against middle cerebral artery occlusion/reperfusion (MCAO/R) injury by suppressing the NOX2/IL-6/ STAT3 pathway. These novel findings provide theoretical basis and experimental evidence for the rationality of clinical combined use of drugs in the treatment of ischemic stroke.

Calenduloside E Ameliorates Myocardial Ischemia-Reperfusion Injury through Regulation of AMPK and Mitochondrial OPA1.

Calenduloside E (CE) is a natural triterpenoid saponin isolated from Aralia elata (Miq.) Seem., a well-known traditional Chinese medicine. Our previous studies have shown that CE exerts cardiovascular protective effects both in vivo and in vitro. However, its role in myocardial ischemia/reperfusion injury (MIRI) and the mechanism involved are currently unknown. Mitochondrial dynamics play a key role in MIRI. This study investigated the effects of CE on mitochondrial dynamics and the signaling pathways involved in myocardial ischemia/reperfusion (MI/R). The MI/R rat model and the hypoxia/reoxygenation (H/R) cardiomyocyte model were established in this study. CE exerted significant cardioprotective effects in vivo and in vitro by improving cardiac function, decreasing myocardial infarct size, increasing cardiomyocyte viability, and inhibiting cardiomyocyte apoptosis associated with MI/R. Mechanistically, CE restored mitochondrial homeostasis against MI/R injury through improved mitochondrial ultrastructure, enhanced ATP content and mitochondrial membrane potential, and reduced mitochondrial permeability transition pore (MPTP) opening, while promoting mitochondrial fusion and preventing mitochondrial fission. However, genetic silencing of OPA1 by siRNA abolished the beneficial effects of CE on cardiomyocyte survival and mitochondrial dynamics. Moreover, we demonstrated that CE activated AMP-activated protein kinase (AMPK) and treatment with the AMPK inhibitor, compound C, abolished the protective effects of CE on OPA1 expression and mitochondrial function. Overall, this study demonstrates that CE is effective in mitigating MIRI by modulating AMPK activation-mediated OPA1-related mitochondrial fusion.

Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway.

Non-alcoholic fatty liver disease (NAFLD) is a progressive and chronic liver disease. No effective drug is currently approved for the treatment of NAFLD. Traditionally it is thought that pathogenesis of NAFLD develops from some imbalance in lipid control, thereby leading to hepatotoxicity and disease development. Squalene synthase (SQS), encoded by FDFT1, is a key regulator in cholesterol synthesis and thus a potential target for the treatment of NAFLD. Here we could identify bavachinin, a component from traditional Chinese medicine Fructus Psoraleae (FP), which apparently protects HepaRG cells from palmitic acid induced death, suppressing lipid accumulation and cholesterol synthesis through inhibition of FDFT1 through the AKT/mTOR/SREBP-2 pathway. Over-expression of FDFT1 abolished bavachinin (BVC) -induced inhibition of cholesterol synthesis. The data presented here suggest that bavachinin acts as a cholesterol synthesis enzyme inhibitor, and might serve as a drug for treating NAFLD in the future.

[Effect of Guanxin Danshen Formulation on diabetic kidney disease in db/db mice through regulation of Nrf2 pathway].

Diabetic kidney disease(DKD) has become a primary cause of end-stage kidney disease, without any effective treatment available. In this study, we assessed the protective effect of Guanxin Danshen Formulation(GXDSF) on diabetic nephropathy in db/db mice. The db/m and db/db mice were randomly divided into 4 groups: control group, model group, metformin group, and GXDSF group. After 8 weeks' treatment with GXDSF, metformin or normal saline, the mice were sacrificed, and the blood and kidney tissues were collected for the further analysis. Compared with the model group, TG, TCH and LDL levels significantly decreased in the GXDSF group. The results from HE and PAS staining showed that db/db mice exhibited abnormal kidney tissues with increased glomerular volume, basement-membrane thickening and mesangial cell proliferation, which could be significantly alleviated by GXDSF treatment. GXDSF treatment also reduced serum creatinine and BUN. Meanwhile, GXDSF treatment markedly elevated GSH-PX levels, while reduced LDH and MDA levels in the kidney tissues. Western blot assay showed that GXDSF evidently up-regulated protein levels of ERα and p-Akt, and subsequently promoted HO-1 expression mediated by Nrf2. These data collectively indicated that GXDSF protects db/db mice against DN by regulating ERα and Nrf2-mediated HO-1 expression.

Protective Effects of Biscoclaurine Alkaloids on Leukopenia Induced by 60Co-γ Radiation.

OBJECTIVE: Leukopenia, a common complication of tumor chemoradiotherapy, contributes serious damage to the hematopoietic, gastrointestinal, and immune systems of the body and can cause delay, discontinuation, or even failure to tumor treatment, thereby greatly threatening human health. The present study aims to investigate the protective effects of biscoclaurine alkaloids (BA) on leukopenia. METHODS: This study was conducted on 60 Kunming mice, which were randomly divided into six groups containing 10 animals each. A hematology analyzer was used to count white blood cells (WBC) in the peripheral blood cell. Mice serum was collected, and the granulocyte-macrophage colony-stimulating factor, vascular cell adhesion molecule 1 (VCAM-1), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assays. Pathological changes were detected through hematoxylin and eosin staining in the liver and spleen of mice. The spleen and liver ultrastructures were observed via electron microscopy. RESULTS: Results showed that BA ameliorated WBC, PLT reduction in the peripheral blood and significantly increased the levels of IFN-γ and VCAM-1 in mice serum. BA reduced ionizing radiation-induced injuries to spleen, mitigated the reduction of superoxide dismutase (SOD), and significantly decreased the malonaldehyde (MDA) and xanthine oxidase (XOD) levels in the liver. CONCLUSION: BA enhanced the immune and hematopoietic functions and ameliorated the oxidative stress induced by 60Co-γ radiation, revealing its therapeutic potential both as a radioprotector and as a radiation mitigator for leukopenia induced by 60Co-γ radiation.

Gastrodiae Rhizoma Water Extract Ameliorates Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Inflammation Induced by Chronic Unpredictable Mild Stress in Rats.

Gastrodiae Rhizoma is a highly valuable traditional herbal medicine commonly used to treat neurological disorders. The present study is designed to determine the antidepressant-like effect of the Gastrodiae Rhizoma water extract (GRWE) on a depression model and the potential mechanisms. The chronic unpredictable mild stress (CUMS) rat model was used to induce depression. The sucrose preference test, open field test, forced swimming test, and tail suspension test were performed to assess the depressive-like behaviors, respectively. Hypothalamic-pituitary-adrenal (HPA) function was measured via plasma corticosterone (CORT), adrenocorticotrophic hormone (ACTH), hypothalamic corticotropin-releasing factor (CRF), and glucocorticoid receptor (GR) concentrations. Plasma concentrations of proinflammatory cytokines including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were also evaluated. The results showed that GRWE significantly attenuates the behavioral abnormalities in CUMS rats, as shown by elevated sucrose consumption, raised locomotor activity, and reduced immobility duration. Moreover, GRWE treatment reduced CORT, ACTH, CRF, and GR levels and decreased the plasma IL-1ß, IL-6, and TNF-α concentrations. These findings indicate that GRWE improves depressive behaviors in a chronic stress model of rats; its effect may be ascribed to the modulation of the HPA axis activity and inflammatory response.