Comparison of the efficacy of Hydroquinone cream versus Hydroquinone cream plus Danggui Shaoyao powder in the treatment of melasma.

Introduction: Melasma is an acquired hypermelanosis and occurs in areas exposed to sunlight. Aim: To investigate the effectiveness of Danggui Shaoyao powder (DSP) as a complementary drug in the treatment of melasma. Material and methods: A total of 40 melasma patients over the age of 18 who met the inclusion criteria entered the study randomly in two DSP + Hydroquinone (DSP + H) and Hydroquinone (H) groups. Results: At the beginning of the study, the average MASI score of the two groups of patients had no statistical difference (DSP + H: 15.79 ±1.01 vs. H: 15.37 ±1.17, p = 0.23). But from the eighth week of treatment, the MASI score of the patients decreased significantly and in the DSP + H group it decreased statistically significantly compared to the H group (DSP + H: 5.83 ±0.97 vs. H: 8.29 ±2.23, p < 0.001 for the eighth week and DSP + H: 3.60 ±0.58 vs. H: 5.52 ±1.73, p < 0.001 for the twelfth week of the treatment). It means after 12 weeks of treatment, the average MASI score of patients in the DSP + H group decreased by 77.26 ±2.70%, but in the grroup H, it decreased by 64.31 ±9.68% (p < 0.001). Dynamic PGA showed that excellent treatment occurred in 65% of the + H group H, but only 20% of the H group (p = 0.01). Conclusions: Oral DSP for 12 weeks along with hydroquinone cream can significantly reduce the MASI score of melasma patients and increase the patients' recovery and satisfaction.

Curdione inhibits ferroptosis in isoprenaline-induced myocardial infarction via regulating Keap1/Trx1/GPX4 signaling pathway.

Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae. The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.

Xinbao Pill attenuated chronic heart failure by suppressing the ubiquitination of ß-adrenergic receptors.

BACKGROUD: Xinbao Pill (XBP) is extensively used in the adjuvant treatment of chronic heart failure in China. However, the pharmacological effect and underlying mechanism on CHF remains unclear. PURPOSE: Our research was performed to investigate the cardioprotective effect of XBP against CHF and uncover the potential mechanism. METHODS: Male Sprague-Dawley (SD) rats were subjected to the left anterior descending (LAD) artery ligation for 8 weeks and were treated with different doses of XBP (from the 4th week to the end). Cardiac function and morphology assessment were performed by using M-mode echocardiography, H&E and Masson staining. Western blotting analysis, co-immunoprecipitation (IP) assays, siRNA transfection were used to evaluate the mechanism of XBP. RESULTS: XBP improved cardiac function and alleviated cardiac fibrosis in LAD-induced chronic heart failure rats. Meanwhile, XBP protected cardiomyocytes against oxygen-glucose deprivation (OGD) injury in AC16 cells and H9c2 cells. Additionally, XBP could increase the expression of ß1-AR and ß2-AR and inhibit their ubiquitanation. Further mechanism study showed that XBP upregulated USP18 expression, while silence of USP18 attenuated the cardioprotective effect of XBP and the increase of ß1-AR by XBP. Moreover, XBP increased MDM2 and ß-arrestin2, and disrupted the interaction between Nedd4 and ß2-AR. After using the inhibitor of MDM2, SP141, the cardioprotective effect of XBP and the inhibitory effect on the ubiquitanation of ß2-AR were also blocked. CONCLUSION: Our study firstly revealed that XBP improved cardiac function against CHF through suppressing USP18 and MDM2/ß-arrestin2/Nedd4-mediated the ubiquitination of ß1-AR and ß2-AR.

The Green Walnut Husks Induces Apoptosis of Colorectal Cancer through Regulating NLRC3/PI3K Pathway.

BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal tumor, but the available pharmacological treatment is insufficient. As a traditional Chinese medicine, the green walnut husks (QLY) exhibit anti-inflammatory, analgesic, anti-bacterial and anti-tumor effects. However, the effects and molecular mechanisms of QLY extracts on CRC were not yet made known. OBJECTIVE: This study aims to provide efficient and low toxicity drugs for the treatment of CRC. The purpose of this study is to explore the anti-CRC effect and mechanism of QLY, providing preliminary data support for clinical research of QLY. METHODS: Western blotting, Flow cytometry, immunofluorescence, Transwell, MTT, Cell proliferation assay, and xenograft model were used to perform the research. RESULTS: In this study, the potential of QLY to inhibit the proliferation, migration invasion and induce apoptosis of the mouse colorectal cancer cell line CT26 in vitro was identified. The xenograft tumor model of CRC noted that QLY suppressed tumor growth without sacrificing body weight in mice. In addition, QLY-induced apoptosis in tumor cells through NLRC3/PI3K/AKT signaling pathway was revealed. CONCLUSION: QLY regulates the levels of mTOR, Bcl-2 and Bax by affecting the NLRC3/PI3K/AKT pathway to promote apoptosis of tumor cells, suppressing cell proliferation, invasion and migration, and subsequently preventing the progression of colon cancer.

Exploring the mechanism of anti-chronic heart failure effect of qiweiqiangxin І granules based on metabolomics.

Background: Qiweiqiangxin І granules (QWQX І) is a traditional Chinese medicine preparation based on the basic theory of traditional Chinese medicine, which produces a good curative effect in treating chronic heart failure (CHF). However, its pharmacological effect and potential mechanism for CHF remain unknown. Aim of the study: The purpose of this study is to clarify the efficacy of QWQX І and its possible mechanisms. Materials and methods: A total of 66 patients with CHF were recruited and randomly assigned to the control or QWQX І groups. The primary endpoint was the effect of left ventricular ejection fraction (LVEF) after 4 weeks of treatment. The LAD artery of rats was occluded to establish the model of CHF. Echocardiography, HE and Masson staining were performed to evaluate the pharmacological effect of QWQX І against CHF. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) untargeted metabolomics was to screen endogenous metabolites in rat plasma and heart and elucidate the mechanism of QWQX І against CHF. Results: In the clinical study, a total of 63 heart failure patients completed the 4-week follow-up, including 32 in the control group and 31 in QWQX І group. After 4 weeks of treatment, LVEF was significantly improved in QWQX І group compared with the control group. In addition, the patients in QWQX І group had better quality of life than the control group. In animal studies, QWQX І significantly improved cardiac function, decreased B-type natriuretic peptide (BNP) levels, reduced inflammatory cell infiltration, and inhibited collagen fibril rate. Untargeted metabolomic analysis revealed that 23 and 34 differential metabolites were screened in the plasma and heart of chronic heart failure rats, respectively. 17 and 32 differential metabolites appeared in plasma and heart tissue after QWQX І treatment, which were enriched to taurine and hypotaurine metabolism, glycerophospholipid metabolism and linolenic acid metabolism by KEGG analysis. LysoPC (16:1 (9Z)) is a common differential metabolite in plasma and heart, which is produced by lipoprotein-associated phospholipase A2 (Lp-PLA2), hydrolyzes oxidized linoleic acid to produce pro-inflammatory substances. QWQX І regulates the level of LysoPC (16:1 (9Z)) and Lp-PLA2 to normal. Conclusion: QWQX І combined with western medicine can improve the cardiac function of patients with CHF. QWQX І can effectively improve the cardiac function of LAD-induced CHF rats through regulating glycerophospholipid metabolism and linolenic acid metabolism-mediated inflammatory response. Thus, QWQX I might provide a potential strategy for CHF therapy.

Zn2+ regulates human oxalate metabolism by manipulating oxalate decarboxylase to treat calcium oxalate stones.

A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mostly depends on oxalate-degrading enzymes from the intestinal microbiome. We found that zinc gluconate supplement to patients with CaOx kidney stones could significantly improve the abundance of oxalate metabolizing bacteria in humans through clinical experiments on patients also subjected to antibiotic treatment. The analysis of clinical samples revealed that an imbalance of Lactobacillus and oxalate decarboxylase (OxDC) was involved in the formation of CaOx kidney stones. Then, we identified that Zn2+ could be used as an external factor to improve the activity of OxDC and promote Lactobacillus in the intestinal flora, and this treatment achieved a therapeutic effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and completing in vitro experiments, we propose a model of the Zn2+-induced reduction of CaOx kidney stone symptoms in rats by increasing the metabolism of oxalate through the positive effects of Zn2+ on Lactobacillus and OxDC.

Formononetin improves cardiac function and depressive behaviours in myocardial infarction with depression by targeting GSK-3ß to regulate macrophage/microglial polarization.

BACKGROUND: Depression is a common complication after myocardial infarction (MI) that can seriously affect the prognosis of MI. PURPOSE: To investigate whether formononetin could ameliorate MI injury and depressive behaviours in a mouse model of MI with depression and elucidate its underlying molecular mechanisms. METHODS: Haemodynamic measurements (systolic blood pressure (SYS), the maximum rate of rise of LV pressure (± dp/dtmax)) and behavior tests (tail suspension test, sucrose preference test, forced swimming test) were used to evaluate the effects of formononetin on male C57BL/6N mice after left anterior descending (LAD) coronary artery ligation and chronic unpredictable stress. RT-qPCR, immunohistochemistry, immunofluorescence analysis, western blotting, molecular docking technology, surface plasmon resonance and gene-directed mutagenesis were used to clarify the underlying mechanism. RESULTS: Formononetin significantly suppressed the depressive behaviours and improved cardiac dysfunction in MI with depression mice model. Formononetin inhibited M1 polarization in macrophages/microglia, while promoting M2 polarization. Importantly, elevated serum IL-6 and IL-17A levels were found in patient with MI, and the patient serum induced M1 microglial polarization; however, formononetin reversed the polarization. Further mechanistic studies showed that formononetin inhibited GSK-3ß activity and downstream Notch1 and C/EBPα signaling pathways. Covalent molecular docking showed that formononetin bound to Cys199 of GSK-3ß and it has a high affinity for GSK-3ß. When Cys199 was mutation, the inhibitory effect of formononetin on GSK-3ß activity and M1 polarization in macrophages/microglia were also partly blocked. CONCLUSIONS: Our results firstly uncovered that formononetin improved cardiac function and suppressed depressive behaviours in mice after MI with depression by targeting GSK-3ß to regulate macrophage/microglial polarization. More importantly, IL-6 and IL-17A produced after MI may cause neuroinflammation, which might be the key factors for depression. Formononetin may be a potential drug for treating MI with depression.

Versatile Red Blood Cells for Triple-Negative Breast Cancer Treatment via Stepwise Photoactivations.

Phototherapies have many advantages for triple-negative breast cancer (TNBC) treatment. However, their effects are often limited by short blood circulation time, poor tumor selectivity and weak penetration of phototherapeutic agents, and tumor hypoxia. For overcoming these limitations, a versatile biomimetic system is developed based on red blood cells (RBCs). Photothermal agent new indocyanine green (IR820) is conjugated with the cell/tissue-penetrating TAT peptide and further efficiently encapsulated into the intact RBCs by crossing cell membranes to realize the long blood circulation. Meanwhile, cyclic RGD peptide (cRGD) is linked to the surfaces of RBCs through phospholipid insertion to obtain tumor vessel-targeting ability. Photosensitizer temoporfin (mTHPC) is next loaded into the membranes of RBCs by spontaneous transferring. The acquired biomimetic system (cRGD-RBC@mTHPC/TAT-IR820) exhibits potent photodynamic performance upon 652 nm laser irradiation with the facilitation of oxyhemoglobin, which could not only trigger TAT-IR820 release but also destroy tumor vessels. TAT-IR820 penetrates deeply into tumor tissue via the mediation of TAT peptide, exerting greatly promoted photothermal ablation against TNBC upon 808 nm laser irradiation. In situ generated tumor antigens further induce robust immune responses to suppress TNBC recurrence and metastasis. In summary, this study provides a versatile biomimetic system for comprehensive TNBC treatment via stepwise photodynamic and photothermal activations.

Nuciferine attenuates atherosclerosis by regulating the proliferation and migration of VSMCs through the Calm4/MMP12/AKT pathway in ApoE(-/-) mice fed with High-Fat-Diet.

BACKGROUND: Atherosclerosis (AS) is the pathological basis of multiple cardiovascular diseases. The pathogenesis of AS is closely related to the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Nuciferine, an aporphine alkaloid from lotus leaf, has various pharmacological activities. However, the effect and mechanism of nuciferine on regulating proliferation and migration of VSMCs against AS is still unclear. PURPOSE: To elucidate the pharmacological effect and molecular mechanism of nuciferine on AS in ApoE(-/-) mice fed with High-Fat-Diet (HFD). STUDY DESIGN: HFD-fed ApoE(-/-) mice and 3% fetal bovine serum (FBS) induced mouse aortic vascular smooth muscle cells (MOVAS) were used to investigate the protective effect and mechanism of nuciferine on AS. METHODS: Oil red O staining was used to detect the atherosclerotic lesions. Western blotting and immunofluorescence were used to determine calmodulin 4 (Calm4) expression and localization. CCK-8 assay, transwell and wound-healing assays were used to measure the migration and proliferation of MOVAS cells. RESULTS: Nuciferine at 40 mg/kg significantly ameliorated the aortic lesion and vascular plaque in AS model, which was equal to the effect of the positive control drug (atorvastatin). In addition, nuciferine attenuated the migration and proliferation of VSMCs in vivo and in vitro. Importantly, nuciferine down-regulated the increase of Calm4 induced by HFD-fed in ApoE(-/-) mice or 3% FBS induced MOVAS cells. However, the inhibitory effect of nuciferine on the migration and proliferation of MOVAS cells was blocked when Calm4 was overexpressed. Furthermore, we found that nuciferine suppressed MMP12 and PI3K/Akt signaling pathway via Calm4. CONCLUSION: Our results illustrated that Calm4 promoted the proliferation and motility of MOVAS by activating MMP12/Akt signaling pathway in AS. Nuciferine has a significant anti-atherogenic effect by regulating the proliferation and migration of VSMCs through the Calm4/MMP12/AKT signaling pathway. Thus, Calm4 could potentially be a new target for AS therapy, and nuciferine could be a potential drug against AS.

Steroidal Saponins from the Rhizomes of Smilax china and Their Inhibitory Effects on Lipopolysaccharide-Induced Proinflammatory Cytokines Expression.

Four new furostanol saponins (1:  - 4: ) and a new pregane-type saponin (5: ) along with six known steroidal saponins (6:  - 11: ) were isolated from the rhizomes of Smilax china. The structures of 1:  - 5: were elucidated by extensive analysis of NMR and HR-ESI-MS data in addition to enzymatic hydrolysis and other chemical methods. Compounds 1, 4: , and 11: showed inhibitory activity against the expression of proinflammatory mediators, inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α in lipopolysaccharide-induced RAW264.7 cells. Compound 1: , at a concentration of 20 µM, decreased the production of inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α by 36, 62, 72, and 67%, respectively, which is comparable to that of the positive control dexamethasone.

Efficacy of Xinbao pill on chronic heart failure: Study protocol of a multicenter, randomized, double-blind, placebo-controlled trial.

Introduction: Chronic heart failure (CHF) is a common cardiovascular disease. In China, Xinbao pill (XBP) is widely used as an adjuvant therapy for CHF. However, there is still a lack of high-quality clinical evidence. We designed this multicenter, randomized, double-blind, placebo-controlled trial to critically evaluate the efficacy and safety of XBP as an adjuvant treatment for patients with CHF. Methods and analysis: We will recruit 284 patients with a clinical diagnosis of "heart-kidney yang deficiency syndrome" CHF receiving treatment in six hospitals in China. Patients will be randomly assigned, in a 1:1 ratio, to the treatment or control group using a central randomization system. All patients will receive conventional drug therapy for heart failure combined XBP (Guangdong Xinbao Pharmaceutical Co., Ltd., Guangdong, China) or a placebo. Study physicians, subjects, outcome assessors, and statisticians will be blinded to the group assignment. The primary outcome will be the change in the proportion of patients who show a decrease in serum NT-proBNP of more than 30% after treatment. Secondary outcomes are NYHA class, 6-minute walk distance test, Minnesota Quality of Life Scale score, endpoint events, serum NT-proBNP, echocardiographic parameters, and traditional Chinese medicine (TCM) symptom score. Adverse events will be monitored throughout the trial. Data will be analyzed according to a predetermined statistical analysis plan. Discussion: The results of this study will provide solid evidence of the safety and efficacy of XBP as an alternative and complementary treatment measure for patients with CHF. Clinical Trial Registration: Chinese Clinical Trial Registration Center (ChiCTR2000038492).

Cathepsin B/HSP70 complex induced by Ilexsaponin I suppresses NLRP3 inflammasome activation in myocardial ischemia/reperfusion injury.

BACKGROUND: Myocardial ischemia/reperfusion injury (MI/RI) is a clinical issue in MI therapy that requires effective intervention. Cathepsin B (CTSB) plays an essential role in regulating cell death, inflammatory response and angiogenesis. Ilexsaponin I (ISI), a triterpenoid saponin obtained from Ilex pubescens Hook. et Arn, has anti-inflammatory and cardioprotective effects. However, the effect of ISI on MI/RI is unclear. PURPOSE: The study aims to disclose the mechanism of ISI as a potent therapeutic agent for MI/RI. METHODS: Left anterior descending (LAD) coronary artery ligation and oxygen-glucose deprivation and reperfusion (OGD/R) were used to establish MI/RI model in vivo and in vitro. ELISA, western blot and immunofluorescence were carried out to detect CTSB activity and NLRP3 inflammasome activation. Coimmunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis were used to detect the interaction of CTSB/HSP70 complex. Infarct area determination, echocardiography and hematoxylin and eosin (HE) staining were performed to assess the cardioprotection of ISI in vivo. RESULTS: Plasma CTSB was elevated in patients after percutaneous coronary intervention (PCI), and was positively correlated with the level of cTnI in plasma, which was also found in MI/RI rat model. ISI significantly suppressed the overexpression and activity of CTSB after MI/RI or OGD/R. ISI remarkably suppressed CTSB triggered-NLRP3 inflammasome activation and reduced the maturation of IL-1ß and IL-18. Importantly, we firstly found that ISI promoted CTSB/HSP70 complex formation to disrupt CTSB/NLRP3 complex, leading to NLRP3 inflammasome inactivation. ISI could also limit infarct size, improve cardiac function and reduce inflammatory infiltrates in vivo and protected H9c2 cells against OGD/R insult in vitro. Interrupting the HSP70 and CTSB interaction with HSP70 siRNA blocked the effect of ISI on CTSB, NLRP3 inflammasome activation and the cardioprotective effect. CONCLUSION: ISI probably exerts cardioprotective effect against MI/RI by modulating HSP70 competitively bind to CTSB to suppress the activation of the NLRP3 inflammasome.

Cobaloxime Photocatalysis for the Synthesis of Phosphorylated Heteroaromatics.

Herein, cobaloxime is used for the first time as a catalyst for the synthesis of phosphorylated heteroaromatics, which is an intriguing and versatile functional motif. With visible-light irradiation, cobaloxime not only oxidizes phosphine oxides to form phosphorus radicals (P-radicals) for a subsequent reaction with radical acceptor isocyanides or heteroaromatics, but also combines the radical intermediate with ß-H elimination, thereby producing phosphorylated heteroaromatics with only H2 or CH4 as byproduct. Phosphine oxides with dialkyl, alkylaryl, and diaryl substituents could be directly transformed into phosphorylated phenanthridines, benzothiazoles, isoquinolines, and common heteroaromatics. This catalytic system features extremely mild conditions, broad substrate scope and good to excellent yields. Scale-up reaction and sunlight reaction show the great application potential in the green synthesis of important organophosphorus chemicals.

A Systematic Review and Meta-Analysis of the Efficacy and Safety of Xinbao Pill in Chronic Heart Failure.

Objective: This study aimed to clarify the efficacy and safety of Xinbao pill (XBP) as an adjunctive treatment for chronic heart failure (CHF). Methods: Randomized controlled trials (RCTs) on the efficacy and safety of XBP in the treatment of CHF were searched from the six databases. The risk of bias assessment tool recommended by Cochrane Handbook 5.1 were used to assess the methodological quality of the included studies. RevMan 5.3 software was used for meta-analysis. The subgroup and sensitivity analyses were also performed. The grading recommendations assessment, development, and evaluation (GRADE) technique were used to assess the evidence's certainty. Results: Nine RCTs with a total of 882 patients were identified in this study. The meta-analysis demonstrated that XBP as adjunctive therapy was superior to conventional medicine alone for the treatment of CHF in improving the left ventricular ejection fraction (LVEF; MD = 5.34; 95% CI 4.68 to 5.99; p < 0.001), the total effective rate (RR = 1.21; 95% CI, 1.14 to 1.29; p < 0.001), the cardiac output (MD = 0.56; 95% CI 0.42 to 0.70; p < 0.001), the stroke volume (MD = 3.42; 95% CI 2.03 to 4.81; p < 0.001) and the 6-min walking distance (6-MWD; MD = 31.95; 95% CI 21.83 to 42.06; p < 0.001), meanwhile reducing the left ventricular end-diastolic diameter (LVEDD; MD = -3.22; 95% CI -4.03 to -2.42; p < 0.001) and left ventricular end-systolic dimension (LVESD; MD = -2.93; 95% CI -3.80 to -2.06; p < 0.001). Regarding safety, a total of 2.4% (11/456) adverse reactions occurred in the XBP groups while 3.9% (18/456) in the control group. The outcomes' evidentiary quality ranged from "very low" to "moderate". Conclusion: This study indicated that XBP as adjunctive therapy combined with conventional medicine seemed to be safe and more effective than conventional medicine alone in treating CHF. However, due to the poor methodological quality of the included RCTs, further well-designed RCTs are required to confirm the efficacy and safety of XBP.

Integrated chemical profiling, network pharmacology and pharmacological evaluation to explore the potential mechanism of Xinbao pill against myocardial ischaemia-reperfusion injury.

CONTEXT: Xinbao pill (XBW), a traditional Chinese herbal formula, is widely used in clinical treatment for cardiovascular diseases; however, the therapeutic effect of XBW on myocardial ischaemia-reperfusion injury (MI/RI) is unclear. OBJECTIVE: This study evaluates the cardioprotective effect and molecular mechanism of XBW against MI/RI. MATERIALS AND METHODS: A phytochemistry-based network pharmacology analysis was used to uncover the mechanism of XBW against MI/RI. Ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry method was used to identify chemicals. MI/RI-related targets of XBW were predicted using TargetNet database, OMIC database, etc. Sprague-Dawley (SD) rats under anterior descending artery ligation model were divided into Sham, MI/RI and XBW (180 mg/kg, intragastric administration). After 30 min ischaemia and 24 h reperfusion, heart tissues were collected for measurement of myocardial infarct size. After oxygen glucose deprivation for 6 h, H9c2 cells were treated with XBW (60, 240 and 720 µg/mL) and diazoxide (100 µM) for 18 h of reperfusion. RESULTS: Thirty-seven chemicals were identified in XBW; 50 MI/RI-related targets of XBW were predicted using indicated databases. XBW significantly reduced infarct size and creatine kinase MB (CK-MB) level after MI/RI; XBW protected H9c2 cells against OGD/R injury. Gene ontology (GO) and KEGG pathway enrichment analyses by String database showed that the cardioprotective effect of XBW was associated with autophagy and apoptosis signalling pathways. Experimental investigation also verified that XBW suppressed apoptosis, autophagy and endoplasmic reticulum (ER) stress. CONCLUSIONS: XBW showed therapeutic effects against MI/RI mainly via attenuating apoptosis though suppressing excessive autophagy and ER stress.

Uncovering the molecular mechanisms of Ilex pubescens against myocardial ischemia-reperfusion injury using network pharmacology analysis and experimental pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Ilex pubescens (I. pubescens), has been widely used to treat cardiovascular disease (CVD) in South China. Several studies have revealed aspect of its phytochemistry and pharmacological activities in cardiovascular diseases, but its active compounds and mechanisms of action are still unclear. The aim of this study was to search for the active compounds and the pharmacological mechanisms of I. pubescens for myocardial ischemia-reperfusion injury (MI/RI) by an integrative pharmacology-based investigation. MATERIALS AND METHODS: The main targets of compounds in I. pubescens were predicted using the TargetNet webserver (http://targetnet.scbdd.com). The network between compounds and predicted targets related to MI/RI and compounds was constructed. Functional enrichment analysis was performed to investigate the specific functions and pathways involved in the candidate I. pubescens targets acting on MI/RI, which were further validated by in vitro and in vivo experiments. RESULTS: A total of 191 targets were predicted for 64 chemical compounds in I. pubescens. Following Venn's analysis, we found that 38 candidate targets of I. pubescens were associated with protective effects against MI/RI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that these targets were related to estrogen signaling pathway. Importantly, the cardioprotective effects of I. pubescens and its active compounds were evaluated and the regulatory effects on key targets of heat shock protein 90 alpha family class A member 1 (HSP90AA1) and Estrogen receptor 1 (ESRα) in estrogen signaling pathway were validated in vitro and in vivo. CONCLUSION: Our discoveries revealed that I. pubescens ameliorated MI/RI by regulating HSP90AA1 and ESRα in estrogen signaling pathway.

Plumula Nelumbinis: A review of traditional uses, phytochemistry, pharmacology, pharmacokinetics and safety.

ETHNOPHARMACOLOGICAL RELEVANCE: Plumula Nelumbinis, the green embryo of the mature seeds of Nelumbo nucifera Gaertn, has a medical history of over 400 years. It is widely used for clearing the heart and heat, calming the mind, and promoting astringent essence and hemostasis in traditional Chinese medicine. Moreover, it usually dual use as food and medicine. This review aimed to evaluate the therapeutic potential of Plumula Nelumbinis by summarizing its botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics and safety. METHODS: This review summarized published studies on Plumula Nelumbinis in the Chinese Pharmacopoeia and literature databases including PubMed, Web of Science, Baidu Scholar, Wiley and China Knowledge Resource Integrated Database (CNKI), and limits the different research articles in botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics and safety about Plumula Nelumbinis. RESULTS: Plumula Nelumbinis is used to treat hypertension, arrhythmia, severe aplastic anemia, insomnia, encephalopathy and gynecological disease in traditional Chinese medicine and clinical studies. More than 130 chemicals have been isolated and identified from Plumula Nelumbinis, including alkaloids, flavonoids, polysaccharides and volatile oil. In addition, pharmacological effects, such as protective effects against cardiovascular diseases, neurological diseases, lung and kidney injury, anti-inflammatory and anticancer activities, were also evaluated by in vitro and in vivo studies. Moreover, the potential signaling pathways regulated by Plumula Nelumbinis in cardiovascular and neurological diseases and perspectives on Plumula Nelumbinis research were discussed. CONCLUSION: Plumula Nelumbinis, a commonly used Chinese medicine, has a variety of traditional and modern therapeutic uses. Some traditional uses, especially the treatment of cardiovascular and neurological diseases, have been verified by pharmacological investigation. However, the pharmacological molecular mechanisms, pharmacokinetics and toxicology of Plumula Nelumbinis are still incomplete. In the future, a series of systematic studies on active compounds identification, pharmacological mechanism clarification, quality and safety evaluation are necessary.

An Intelligent Biomimetic Nanoplatform for Holistic Treatment of Metastatic Triple-Negative Breast Cancer via Photothermal Ablation and Immune Remodeling.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were in situ deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC in vitro and in vivo. The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.

Modification-bioremediation of copper, lead, and cadmium-contaminated soil by combined ryegrass (Lolium multiflorum Lam.) and Pseudomonas aeruginosa treatment.

The principal objective of this study was to investigate the strengthened remediation effect and relevant mechanism of P. aeruginosa on ryegrass (Lolium multiflorum Lam.) for soil contaminated by Cu-Pb-Cd compound heavy metals. The results showed that the complex heavy metals' contamination had remarkable inhibiting effect on the growth of plants (P < 0.01), and the biomass of ryegrass's stem and leaves declined by 28.2%, while that of roots decreased by 34.7% after 45 days. The inoculation of P. aeruginosa promoted the growth of ryegrass in polluted soil, in which the biomass recovered to the same level of that in normal plant; the activity of both catalase and urease in the soil also increased strikingly (by 29.3% and 75.7%, respectively); the ratio of residual heavy metals in the soil decreased, while the acid extractable heavy metals increased notably. Therefore, the absorption and accumulation of ryegrass to the heavy metals in soil were improved to some extent; the bioconcentration factor of Cu, Pb, and Cd in ryegrass increased by 35.9%, 55.6%, and 283.5%, respectively. The exterior microorganism allowed the accumulation of Cu, Pb, and Cd in shoots of ryegrass increasing remarkably, while in roots, only the accumulation of Pb increased by 16.3%, and that of both Cu and Cd decreased. Besides, in the P. aeruginosa-inoculated system, the transfer factor of Cu and Cd in plants increased strikingly, while that of Pb decreased.

Natural alkaloids from lotus plumule ameliorate lipopolysaccharide-induced depression-like behavior: integrating network pharmacology and molecular mechanism evaluation.

Depression is a mental disorder that brings severe burdens to patients and their families. Neuroinflammation and neurotrophins are involved in depression. Lotus plumule is a nutritional food with medicinal values. In the present study, we tried to clarify the anti-depressive effect and molecular mechanism of lotus plumule. Network pharmacological analysis, behavior tests, qRT-PCR and western blotting were used. We found 7 potential active components and 91 targets from the TCMSP database. KEGG analysis suggested that lotus plumule significantly affected nitrogen metabolism, calcium signaling, and inflammatory mediator regulation signaling pathways. Consistent with those effects, total alkaloids of lotus plumule (TLA) and active alkaloids differently suppressed the nitric oxide (NO) production and pro-inflammatory mediators. TLA and higenamine significantly ameliorated LPS-induced depression-like behavior, increased BDNF levels, suppressed microglia activation, and inhibited the expression of ER stress-related proteins. Meanwhile, TLA and higenamine activated microglia autophagy by increasing the beclin-1 and LC3B-II expression. Additionally, in the presence of autophagy inhibitor 3-MA, TLA and higenamine did not reduce the LPS-induced NO production or pro-inflammatory mediators. Collectively, TLA and higenamine attenuated LPS-induced depression-like behavior by regulating BDNF-mediated ER stress and autophagy. Therefore, drinking tea of lotus plumule may provide a potential strategy for preventing depression.