Registration study for the prevention and treatment of cerebral hemorrhage using naoxueshu oral liquid: Protocol for a research study.

BACKGROUND: Naoxueshu oral liquid is the only approved drug for acute treatment of cerebral hemorrhage in China. It has been used widely for the treatment of acute ischemic stroke and acute hemorrhagic stroke. However, safety and efficacy data on the early use of Naoxueshu oral liquid are lacking. The main purpose of this study is to observe the benefit and safety of early use of Naoxueshu oral liquid (< 72 h of cerebral hemorrhage) and offer evidence into the potential superiority of Naoxueshu oral liquid in patients with hemorrhagic stroke, and its healthcare costs. METHODS: This registration study for the prevention and treatment of cerebral hemorrhage using Naoxueshu oral liquid will be a quantitative, prospective, multicenter, observational clinical registry study. We aim to register 2000 patients with cerebral hemorrhage within 7 days of disease onset. This study will be an observational study and not interfere with the medication regimen of participants. Hence, we will not allocate patients. The main observation indicators will be the hematoma volume and the proportion of reduction 14 days post-cerebral hemorrhage (or at hospital discharge), onset of new stroke (ischemic stroke, hemorrhagic stroke) within 12 months of disease onset, independence in everyday life activities (modified Rankin Scale score ≤ 2), total cost during hospitalization, and treatment costs. CONCLUSION: This registration study will offer strong evidence for the efficacy and safety of Naoxueshu oral liquid for the prevention and treatment of cerebral hemorrhage, particularly with regard to early use (72 h after onset). It will offer evidence into the potential advantages of Naoxueshu oral liquid in patients with hemorrhagic stroke, including healthcare costs.

[Research progress in mechanism of puerarin in treating vascular dementia].

Vascular dementia(VD) is a condition of cognitive impairment due to acute and chronic cerebral hypoperfusion. The available therapies for VD mainly focus on mitigating cerebral ischemia, improving cognitive function, and controlling mental behavior. Achievements have been made in the basic and clinical research on the treatment of VD with traditional Chinese medicine(TCM) active components, including Ginkgo leaf extract, puerarin, epimedium, tanshinone, and ginsenoside. Most of these components have anti-inflammatory, anti-apoptotic, anti-oxidant, and neuroprotective effects, and puerarin demonstrates excellent performance in mitigating cholinergic nervous system disorders and improving synaptic plasticity. Puerarin, ginkgetin, and epimedium are all flavonoids, while tanshinone is a diterpenoid. Puerariae Lobatae Radix, pungent in nature, can induce clear Yang to reach the cerebral orifices and has the wind medicine functions of ascending, dispersing, moving, and scurrying. Puerariae Lobatae Radix entering collaterals will dredge blood vessels to promote blood flow, and that entering the sweat pore will open the mind, which is in line with the TCM pathogenesis characteristics of VD. This study reviews the progress in the mechanism of puerarin, the main active component of Puerariae Lobatae Radix, in treating VD. Puerarin can ameliorate cholinergic nervous system disorders, reduce excitotoxicity, anti-inflammation, inhibit apoptosis, alleviate oxidative stress injury, enhance synaptic plasticity, up-regulate neuroprotective factor expression, promote cerebral circulation metabolism, and mitigate Aß injury. The pathways of action include activating nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE), vascular endothelial growth factor(VEGF), extracellular regulated protein kinases(ERK), phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt), Janus-activating kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3), AMP-activated protein kinase(AMPK), as well as inhibiting the tumor necrosis factor α(TNF-α), transient receptor potential melastatin 2(TRPM2)/N-methyl-D-aspartate receptor(NMDAR), p38 mitogen-activated protein kinase(p38 MAPK), Toll-like receptor 4(TLR4)/nuclear factor-kappaB(NF-κB), early growth response 1(Egr-1), and matrix metalloproteinase 9(MMP-9). By reviewing the papers about the treatment of VD by puerarin published by CNKI, Wanfang, VIP, PubMed, and Web of Science in the last 10 years, this study aims to support the treatment and drug development for VD.

Inhibiting leukocyte-endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no-reflow after arterial recanalization in ischemic stroke.

AIMS: Despite successful vascular recanalization in stroke, one-fourth of patients have an unfavorable outcome due to no-reflow. The pathogenesis of no-reflow is fully unclear, and therapeutic strategies are lacking. Upon traditional Chinese medicine, Tongxinluo capsule (TXL) is a potential therapeutic agent for no-reflow. Thus, this study is aimed to investigate the pathogenesis of no-reflow in stroke, and whether TXL could alleviate no-reflow as well as its potential mechanisms of action. METHODS: Mice were orally administered with TXL (3.0 g/kg/d) after transient middle cerebral artery occlusion. We examined the following parameters: neurological function, no-reflow, leukocyte-endothelial cell interactions, HE staining, leukocyte subtypes, adhesion molecules, and chemokines. RESULTS: Our results showed stroke caused neurological deficits, neuron death, and no-reflow. Adherent and aggregated leukocytes obstructed microvessels as well as leukocyte infiltration in ischemic brain. Leukocyte subtypes changed after stroke mainly including neutrophils, lymphocytes, regulatory T cells, suppressor T cells, helper T type 1 (Th1) cells, Th2 cells, B cells, macrophages, natural killer cells, and dendritic cells. Stroke resulted in upregulated expression of adhesion molecules (P-selectin, E-selectin, and ICAM-1) and chemokines (CC-chemokine ligand (CCL)-2, CCL-3, CCL-4, CCL-5, and chemokine C-X-C ligand 1 (CXCL-1)). Notably, TXL improved neurological deficits, protected neurons, alleviated no-reflow and leukocyte-endothelial cell interactions, regulated multiple leukocyte subtypes, and inhibited the expression of various inflammatory mediators. CONCLUSION: Leukocyte-endothelial cell interactions mediated by multiple inflammatory factors are an important cause of no-reflow in stroke. Accordingly, TXL could alleviate no-reflow via suppressing the interactions through modulating various leukocyte subtypes and inhibiting the expression of multiple inflammatory mediators.

Thoracic Jia-Ji electro-acupuncture mitigates low skeletal muscle atrophy and improves motor function recovery following thoracic spinal cord injury in rats.

OBJECTIVES: The goal of this study was to determine whether electro-acupuncture (EA) stimulation might protect the motor endplate, minimize muscle atrophy in the hind limbs, and enhance functional recovery of rats with spinal cord injury (SCI). METHODS: Sprague-Dawley adult female rats (n = 30) were randomly assigned into Sham, SCI, and EA + SCI groups (n = 10 each). Rats in the Sham and SCI groups were bound in prone position only for 30 min, and rats in the EA + SCI group were treated with electro-acupuncture. The EA was conducted from the first day after surgery, lasted for 30 mins, once every day for 28 consecutive days. RESULTS: EA significantly prevented motor endplate degeneration, improved electrophysiological function, and ameliorated hindlimb muscle atrophy after SCI. Meanwhile, EA upregulated Tuj-1 expression, downregulated GFAP expression, and reduced glial scar formation. Additionally, after 4 weeks of EA treatment, the serum of SCI rats exhibited a reduced inflammatory response. CONCLUSION: These findings suggest that EA can preserve the motor endplate and reduce muscular atrophy. In addition, EA has been shown to improve the function of upper and lower neurons, reduce glial scar formation, suppress systemic inflammation, and improve axon regeneration.

Efficacy and safety of Songling Xuemaikang capsule for essential hypertension: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertension is one of the most significant public health challenges worldwide. An increasing number of patients prefer to incorporate traditional Chinese medicine into their hypertensive care. The Songling Xuemaikang capsule (SXC), a Chinese herbal formula, is widely used in China for essential hypertension. PURPOSE: To assess the efficacy and safety of SXC for essential hypertension. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We conducted a systematic literature search of seven databases to identify randomized controlled trials of SXC for hypertension. The outcome measures included blood pressure parameters and patient-reported outcomes. Potential heterogeneity between the studies was resolved by subgroup and sensitivity analyses. The quality of the results was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: A total of 34 trials with 4306 patients were included. The results showed that SXC plus antihypertensive drugs produced a greater effect on reducing systolic blood pressure (SBP) (MD: -7.54 mmHg; 95% CI: -8.92, -6.17; p < 0.00001), diastolic blood pressure (DBP) (MD: -6.42 mmHg; 95% CI: -7.54, -5.29; p < 0.00001), 24-hour SBP (MD: -6.88 mmHg; 95% CI: -8.36, -5.39; p < 0.00001), and 24-hour DBP (MD: -4.31 mmHg; 95% CI: -6.55, -2.07; p = 0.0002) and improving hypertensive symptoms (SMD: -1.09; 95% CI: -1.34, -0.84; p < 0.00001) than antihypertensive drugs alone. SXC monotherapy was less effective than antihypertensive drugs for 24-hour SBP reduction (MD: 2.07 mmHg; 95% CI: 0.19, 3.96; p = 0.03). No significant difference was observed in the incidence of adverse events between the SXC and control groups. CONCLUSION: SXC is beneficial for essential hypertension; it can lower BP, improve hypertensive symptoms and is well tolerated.

Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE): Protocol for a mixed-methods research study.

Background: As the only traditional Chinese medicine injection approved by the China Food and Drug Administration for use as stroke first aid in ambulances, Xingnaojing Injection (XNJI) has been widely used in cases of both acute ischemic stroke (IS) and intracerebral hemorrhage (ICH). However, there is no robust clinical evidence regarding the efficacy and safety of the early use of XNJI during stroke first aid. The main purpose of this trial is to observe whether XNJI, intravenously administered within 24 h of onset in the prehospital ambulance setting, protects against early neurological deterioration (END) on the third day of onset in patients with acute stroke. Methods: The Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE) is a Mixed-Methods research (MMR) study that involves a combination of quantitative and qualitative research. The quantitative research part of this project is a prospective, multicenter, observational, clinical registry study, for which we aimed to recruit 1,000 patients with acute stroke (IS and ICH). Based on our observation of whether XNJI was intravenously administered within 24 h of onset in the prehospital ambulance setting, patients with acute stroke will be divided into two groups: the exposure group comprising patients who were intravenously administered XNJI and the nonexposure group comprising patients who were not. The primary outcome is early neurological deterioration (END) on the third day of onset defined as an increase of 2 or more points in the National Institute of Health Stroke Scale score between baseline and day 3. In addition, based on the aforementioned quantitative research, qualitative research will be conducted by interviewing emergency doctors about their knowledge and attitude regarding XNJI used for stroke first aid. Discussion: The results of the TRACE study will provide preliminary evidence for the relationship between XNJI used within 24 h of onset and the presence of END on the third day after stroke onset; it will aid in improving the current knowledge regarding the early use of XNJI for stroke first aid. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04275349.

Tanshinone Ameliorates Glucocorticoid-Induced Bone Loss via Activation of AKT1 Signaling Pathway.

Purpose: Osteoporosis, a common disorder especially prevalent in the postmenopausal women and the elderly, is becoming a worldwide public health problem. Osteoporosis can cause severe joint pain, fragility fractures, and other symptoms, which can seriously impair the daily lives of affected patients. Currently, no gold-standard drug is available that can completely cure osteoporosis. Tanshinone is a traditional Chinese medicine, which can exhibit multiple biological activities. It might also display a protective effect on osteoporosis. However, the molecular mechanism through which tanshinone can improve osteoporosis remain unclear. The objective of our study is to explore the underlying mechanism behind the protective actions of tanshinone. Methods: The common KEGG pathways of tanshinone-targeted genes and osteoporosis were analyzed by using bioinformatics analysis. The bioinformatics analysis results were further validated both by in vitro and in vivo experiments. Results: 21 common KEGG pathways were identified between osteoporosis and tanshinone-targeted genes. It was further found that tanshinone could induce expression of AKT1, promote the proliferation of MSCs, and ultimately suppress their apoptosis. Conclusion: Taken together, our findings indicate that tanshinone can alleviate osteoporosis, its effect was potentially mediated through modulating AKT1 expression. Thus, tanshinone could serve as a promising treatment option for osteoporosis.

Qiguiyin Decoction Improves Multidrug-Resistant Pseudomonas aeruginosa Infection in Rats by Regulating Inflammatory Cytokines and the TLR4/MyD88/NF-κB Signaling Pathway.

Pseudomonas aeruginosa (PA), a Gram-negative bacterium, has a high detection rate in hospital-acquired infections. Recently, the frequent appearance of multidrug-resistant (MDR) PA strain with high morbidity and mortality rates has aggravated the difficulty in treating infectious diseases. Due to its multiple resistance mechanisms, the commonly used antibiotics have gradually become less effective. Qiguiyin decoction (QGYD) is a clinically experienced prescription of Chinese herbal medicine, and its combined application with antibiotics has been confirmed to be effective in the clinical treatment of MDR PA infection, which could be a promising strategy for the treatment of drug-resistant bacterial infections. However, the mechanism of QGYD restoring antibiotics susceptibility to MDR PA remains unclear. In the present study, we investigated the effects of QGYD and levofloxacin (LEV) singly or in combination on MDR PA-induced pneumonia rat models. Further analysis was carried out in the serum differential expression profiles of inflammatory cytokines by cytokine antibody array. Besides, the lung TLR4/MyD88/NF-κB signaling pathway was detected by RT-qPCR. Our results showed that based on the treatment of MDR PA-infected rat model with LEV, the combination of QGYD improved the general state and immune organ index. Furthermore, it moderately increased the expressions of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α in the early stage of infection and decreased their release rapidly in the later stage, while regulated the same phase change of anti-inflammatory cytokine IL-10. In addition, the adhesion molecule ICAM-1 was significantly downregulated after QGYD combined with LEV treatment. Moreover, the mRNA expressions of TLR4, MyD88, NF-κB, and ICAM-1 were significantly downregulated. These results indicated that the mechanism of QGYD restoring LEV susceptibility to MDR PA was related to its regulation of inflammatory cytokines and the TLR4/MyD88/NF-κB signaling pathway, which provides theoretical support for the clinical application of QGYD combined with LEV therapy to MDR PA infection.

China Stroke Registry for Patients With Traditional Chinese Medicine (CASES-TCM): Rationale and Design of a Prospective, Multicenter, Observational Study.

Background: Given the complexity of stroke treatment and the current widespread use of traditional Chinese medicine (TCM) in the absence of robust, large, long-term effectiveness and safety studies, and the lack of nationwide epidemiology and clinical characteristics of patients with stroke receiving TCM treatment, the acquisition of data from longitudinal cohorts is essential. We intend to generate the major clinical characteristics of patients with stroke who receive TCM treatment and to investigate the effectiveness and safety of TCM in the Chinese population. Methods: The China Stroke Registry for Patients with Traditional Chinese Medicine (CASES-TCM) study is a prospective, multicenter, observational disease registry aiming to register 20,000 hospitalized patients. Eligible adult patients with clearly diagnosed acute ischemic stroke or intracerebral hemorrhage within 7 days of symptom onset will be consecutively registered from 126 participating sites across China. Baseline data will be recorded, and all patients will be regularly followed up at 3, 6, 12, and 24 months after stroke onset. Collected data will be entered into a web-based system with high-level data security. The primary outcomes include the distribution of scores on the modified Rankin Scale at the 3-months follow-up, and recurrent stroke events within the 12-months follow-up. Conclusion: To our knowledge, the CASES-TCM study is the first and largest nationwide registry to document comprehensive data on TCM treatment in patients with acute stroke. The findings of this study will be valuable to improve our knowledge about TCM treatment for patients with stroke and its subsequent outcomes in the actual clinical setting, consequently facilitating and standardizing the optimization of individualized interventions with TCM for stroke prevention and treatment in China. Study registration: This study was registered with Clinicaltrials.gov (URL: https://clinicaltrials.gov/, Unique identifier: NCT04921397).

High-Throughput Untargeted Serum Metabolomics Analysis of Hyperuricemia Patients by UPLC-Q-TOF/MS.

Hyperuricemia (HUA) as a metabolic disease is closely associated with metabolic disorders. The etiology and pathogenesis of HUA are not fully understood, so there is no radical cure so far. Metabolomics, a specialized study of endogenous small molecule substances, has become a powerful tool for metabolic pathway analysis of selected differential metabolites, which is helpful for initially revealing possible development mechanisms of various human diseases. Twenty HUA patients and 20 healthy individuals participated in the experiment, and ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was employed to investigate serum samples to find differential metabolites. The statistical techniques used were principal component analysis and orthogonal partial least-squares discriminant analysis. The differences in metabolomics results of samples after pretreatment with different solvents were compared, 38, 20, 26, 28, 33, 50, and 40 potential differential metabolites were found, respectively, in HUA patient samples, and each group involved different metabolic pathways. Repetitive metabolites were removed, 138 differential metabolites in HUA serum were integrated for analysis, and the human body was affected by 7 metabolic pathways of glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and α-linolenic acid metabolism. In this work, the metabolomics approach based on UPLC-Q-TOF/MS was employed to investigate serum metabolic changes in HUA patients, 138 potential differential metabolites related to HUA were identified, which provided associations of lipids, amino acids, fatty acids, organic acids, and nucleosides profiles of HUA individuals. Metabolic pathways involved in glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and a-linolenic acid metabolism shed light on the understanding of the etiology and pathogenesis process of HUA.

Chinese Herbal Medicine Xingnaojing Injection for Acute Ischemic Stroke: An Overview of Systematic Reviews and Meta-Analyses.

Background: Xingnaojing injection (XNJ) is the only Chinese herbal injection approved for both intracerebral hemorrhage and ischemic stroke (IS) first-aid on ambulances in China; many systematic reviews (SRs) and meta-analyses (MAs) of XNJ on stroke have been published. The purpose of this research was to evaluate and summarize the current evidence on XNJ for IS. Methods: A comprehensive search was conducted for SRs and MAs of XNJ on IS in seven databases up to January 1, 2021. Two authors independently identified SRs and MAs, extracted data, assessed the quality of the included SRs and MAs using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and assessed quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Results: A total of 10 SRs met the inclusion criteria. The quality of included SRs using AMSTAR 2 was critically low as the critical items were poorly reported. Only 10% of SRs reported 50% of the 16 items, while the remaining 90% SRs reported just less than half of the items on AMSTAR 2. For GRADE, 7 (35%) of outcomes had low-quality evidence, 10 (50%) with very low, and 3 (15%) with moderate quality evidence. Very low to low quality of evidence indicated XNJ plus conventional therapy (CT) alleviated the neurological deficits of acute IS. Moderate-quality evidence showed XNJ plus CT reduced mortality when compared to Danshen injection plus CT, and very low-quality evidence showed XNJ plus CT could not improve the degree of coma, while low-quality evidence indicated the opposite. Mild adverse events in the CT group were less than those in the XNJ plus CT group, and there were no serious adverse events, but there was no statistical difference between the two groups. The included 10 SRs indicated that XNJ was used for acute IS, but only four SRs (40%) reported the course of disease. Conclusion: XNJ appears to be effective and safe for acute IS in improving the neurological deficits, but the evidence is not robust enough. However, whether administering XNJ immediately after or within 24 h of IS is best remains unknown due to the lack of data. Well-designed large-scale randomized controlled trials with measurable outcomes are required in future studies.

[Screening of key genes and pathways of ischemic stroke and prediction of traditional Chinese medicines based on bioinformatics].

The aim of this paper was to explore the key genes and pathogenesis of ischemic stroke(IS) by bioinformatics, and predict the potential traditional Chinese medicines for IS. Based on the gene-chip raw data set of GSE22255 from National Center of Biotechnology Information(NCBI), the article enrolled in 20 patients with ischemic stroke and 20 sex-and age-matched controls, and differentially expressed genes(DEGs) were screened based on R language software. The DAVID tool and R language software were used to perform gene ontology(GO) biological process enrichment analysis and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analysis. The DEGs were imported into STRING to construct a protein-protein interaction network, and the Molecular Complexity Module(MCODE) plug-in of Cytoscape software was used to visualize and analyze the key functional modules. Moreover, the core genes and the medical ontology information retrieval platform(Coremine Medical) were mapped to each other to screen the traditional Chinese medicines and construct drug-active ingredient-target network. Compared with healthy controls, 14 DEGs were obtained, of which 12 genes were up-regulated and 2 genes were down-regulated. DEGs were mainly involved in immune response, inflammatory process, signal transduction, and cell proliferation regulation. The interleukin-17(IL-17), nuclear factor kappaB(NF-κB), tumor necrosis factor(TNF), nucleotide binding oligomerization domain(NOD)-like receptor and other signaling pathways were involved in KEGG pathway enrichment analysis. The key modules of the DEGs-encoding protein interaction network mainly focused on 7 genes of TNF, JUN, recombinant immediate early response 3(IER3), recombinant early growth response protein 1(EGR1), prostaglandin-endoperoxide synthase 2(PTGS2), C-X-C motif chemokine ligand 8(CXCL8) and C-X-C motif chemokine ligand 2(CXCL2), which were involved in biological processes widely such as neuroinflammation and immunity. TNF and JUN were the key nodes in this module, which might become potential biological markers for diagnosis and prognosis evaluation of IS. The potential traditional Chinese medicines for the treatment of IS includes Salviae Miltiorrhizae Radix et Rhizoma, Croci Stigma, Scutellariae Radix, and Cannabis Fructus. The occurrence of stroke was the result of multiple factors. Dysregulation of genes and pathways related to immune regulation and inflammation may be the key link for the development of IS. This study provided research direction and theoretical basis for further exploring the mechanism of action of traditional Chinese medicine in the treatment of IS and searching for potential drug targets.

Identification and Quantification, Metabolism and Pharmacokinetics, Pharmacological Activities, and Botanical Preparations of Protopine: A Review.

Through pharmacological activity research, an increasing number of natural products and their derivatives are being recognized for their therapeutic value. In recent years, studies have been conducted on Corydalis yanhusuo W.T. Wang, a valuable medicinal herb listed in the Chinese Pharmacopoeia. Protopine, one of its components, has also become a research hotspot. To illustrate the identification, metabolism, and broad pharmacological activity of protopine and the botanical preparations containing it for further scientific studies and clinical applications, an in-depth and detailed review of protopine is required. We collected data on the identification and quantification, metabolism and pharmacokinetics, pharmacological activities, and botanical preparations of protopine from 1986 to 2021 from the PubMed database using "protopine" as a keyword. It has been shown that protopine as an active ingredient of many botanical preparations can be rapidly screened and quantified by a large number of methods (such as the LC-ESI-MS/MS and the TLC/GC-MS), and the possible metabolic pathways of protopine in vivo have been proposed. In addition, protopine possesses a wide range of pharmacological activities such as anti-inflammatory, anti-platelet aggregation, anti-cancer, analgesic, vasodilatory, anticholinesterase, anti-addictive, anticonvulsant, antipathogenic, antioxidant, hepatoprotective, neuroprotective, and cytotoxic and anti-proliferative activities. In this paper, the identification and quantification, metabolism and pharmacokinetics, pharmacological activities, and botanical preparations of protopine are reviewed in detail to lay a foundation for further scientific research and clinical applications of protopine.

Overview of Cellular Mechanisms and Signaling Pathways of Piceatannol.

Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene. However, differences in the nature and position of substituents have made it possible to produce many derivatives. Piceatannol [PT], a hydroxylated derivative from resveratrol, exerts various biological activities ranging from cancer prevention, cardio- protection, neuro-protection, anti-diabetic, depigmentation and so on. Although positive results were obtained in most cell culture and animal studies, the relevant cellular and molecular mechanisms of cytokines and signaling pathway about their biological effects still unclear. Thus, in the current review, we focus on the latest findings of PT on cellular biology in order to better understand the underlying therapeutic mechanisms of PT among various diseases.

M1 and M2 macrophage polarization and potentially therapeutic naturally occurring compounds.

Macrophages, as crucial cellular components of innate immunity, are characterized by possessing high plasticity and an abnormal ability to differentiate in response to numerous stimuli. Given this, macrophages show extreme heterogeneity under both physiological and pathological conditions. Typically, macrophages can be polarized into classically activated macrophages (M1) and alternatively activated macrophages (M2) depending on their environment. The relative functions of these two subtypes are almost exactly opposed to one another. Recent studies have suggested that some naturally occurring compounds can exert regulatory effects on the progression of macrophage polarization, which implies that they could be promising therapeutic tools to treat relevant diseases. Therefore, in our current review, we summarize recent studies on several naturally occurring compounds that may possess the ability to regulate macrophage polarization and explore the associated molecular mechanisms.

Role of nutrition, gene polymorphism, and gut microbiota in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. The nutrients play important roles in the development and progression of NAFLD. High-calorie diet, especially the diet rich in saturated fatty acids and cholesterol, as well as sugary drinks with high fructose content, induces hepatic steatosis and triggers progression of steatohepatitis, fibrosis, and even hepatocellular carcinoma. Disordered micronutrient status and gut microbiota are also involved in the pathogenesis of NAFLD. Nutrients related NAFLD could be aggravated by a genetic predisposition, for instance, genetic mutations in patatinlike phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2). Reduction of caloric intake through lifestyle interventions and use of dietary supplements such as omega-3 fatty acids, vitamins, and probiotics may help alleviate liver injury in NAFLD.

Xingnaojing for Moderate-to-severe Acute ischemic Stroke (XMAS): study protocol for a randomized controlled trial.

BACKGROUND: Xingnaojing injection (XNJ) is widely used for the treatment of stroke in China. However, there is currently a lack of high-quality evidence of its efficacy for acute ischemic stroke. The main objective of this study is to determine whether the addition of XNJ to standard care improves the 3-month functional outcome in patients with acute ischemic stroke (AIS). METHODS/DESIGN: The XMAS study is a multicenter, prospective, randomized controlled, open-label trial with a blinded endpoints design. A total of 720 patients will be randomly allocated to either the intervention or the control group in a 1:1 ratio. The intervention group receives XNJ combined with standard care, and the control group receives standard care alone. XNJ will be administered intravenously every 12 h for 10 days. The primary outcome is the proportion of patients who are independent at 3 months after stroke onset defined as a modified Rankin Scale score of 0 to 2. Secondary outcomes include early neurological deterioration at 48 h, the change in National Institutes of Health Stroke Scale score, patient-reported outcome, symptomatic intracranial hemorrhage at 10 days, the Barthel Index score, deaths from any cause and cardiovascular events at 3 months. DISCUSSION: The results of this trial will provide critical evidence for XNJ in the treatment of AIS as a complementary approach that can be initiated after reperfusion therapy or when the AIS is not eligible for thrombolytic treatment. TRIAL REGISTRATION: Clinical Trials.gov, ID: NCT02728180 . Registered on 28 March 2016.

Picroside II Inhibits RANKL-Mediated Osteoclastogenesis by Attenuating the NF-κB and MAPKs Signaling Pathway In Vitro and Prevents Bone Loss in Lipopolysaccharide Treatment Mice.

Picroside II, one of the major components isolated from the seed of natural plant picrorhiza, is widely used in traditional Chinese medicine. The present study was performed to define effects of picroside II on nuclear factor-kappaB ligand (RANKL)-stimulated osteoclast differentiation in vitro and on lipopolysaccharide (LPS)-induced bone loss in vivo. The bone marrow cells (BMMs) were harvested and induced with RANKL followed by treatment with picroside II at several doses, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit formation assay. The effects of picroside II on osteoclastogenesis were studied by examining RANKL-induced osteoclast F-actin ring formation and osteoclast bone resorption. Moreover, we explored the mechanisms of these downregulation effects by performed Western blotting and quantitative RT-PCR examination. Results demonstrated picroside II strongly inhibited RANKL-induced osteoclast formation when added during the early stage of BMMs cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Moreover, picroside II markedly decreased the phosphorylation of p38, ERK, JNK, p65, and I-κB degradation, and significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), both the key transcription factors during osteoclastogenesis. Furthermore, in vivo studies verified the bone protection effects of picroside II. These results collectively suggested that picroside II acted as an anti-resorption agent by blocking osteoclast activation. J. Cell. Biochem. 118: 4479-4486, 2017. © 2017 Wiley Periodicals, Inc.

TLR4­dependent signaling pathway modulation: A novel mechanism by which pioglitazone protects against nutritional fibrotic steatohepatitis in mice.

Activation of the innate immune system is involved in the development of chronic liver diseases, including nonalcoholic steatohepatitis. Toll­like receptor 4 (TLR4) is one of the sensors of the innate immune system. The aim of the present study was to elucidate the role of the TLR4­dependent signaling pathway, and examine the effect of pioglitazone on hepatic fibrosis, through modulation of the TLR4 pathway in a mouse model of nutritional fibrotic steatohepatitis. Male C57BL/6J mice were fed a methionine­choline deficient (MCD) diet for 8 weeks to induce nonalcoholic fibrotic steatohepatitis. The PPARγ agonist, pioglitazone, and PPARγ inhibitor, GW9662, were administered to the mice, respectively. The effects of the induction of PPARγ on liver biochemistry and histology, the modulation of TLR4 and its downstream pathway, and the expression levels of inflammatory and fibrogenic genes were assessed using reverse transcription­quantitative polymerase chain reaction and Western blot analyses. The MCD­fed mice exhibited progressive hepatic steatosis, necrotic inflammation and fibrosis, along with increase levels of serum alanine aminotransferase and aspartate aminotransferase, accompanied by the upregulation of TLR4, the TLR4­myeloid differentiation primary response gene 88­dependent pathway and downstream genes, and proinflammatory and profibrotic genes; and downregulation of basic membrane protein and activin membrane­bound inhibitor. The administration of pioglitazone was found to reverse hepatic nutritional fibrosis via restoration of the expression levels of proinflammatory and profibrotic genes in the MCD­fed mice. The results of the present study provide novel evidence supporting the protective role of pioglitazone in ameliorating nutritional fibrotic steatohepatitis, through modulation of the TLR4­mediated signaling pathway.

Effect of Qiguiyin Decoction on multidrug-resistant Pseudomonas aeruginosa infection in rats.

OBJECTIVE: To investigate the effect of Qiguiyin Decoction, QGYD) on multidrug-resistant Pseudomonas aeruginosa infection in Sprague-Dawley (SD) rats. METHODS: A pseudomonal infection model in SD rats was established by injecting multidrug-resistant P. aeruginosa intraperitoneally. Infected rats were randomized into four groups treated with Pure water, QGYD, ceftazidime, or combined QGYD and ceftazidime. Blood samples were obtained from the abdominal aorta. Serum was then collected and analyzed by peptide array for immune responsiveness to multidrug-resistant beta-lactamase proteins, including Verona integronen-coded metallo-beta-lactamase 1 (VIM-1), Sao Paulo metallo-beta-lactamase 1 (SPM-1), and Temoniera (TEMs). Blood levels of interleukin-1ß (IL-1ß), interleukin-4 (IL-4), and interferon-γ (IFN-γ) were assessed by enzyme-linked immunosorbent assay. RESULTS: QGYD enhanced antibody reactivity against VIM-1 [epitopes 7-11 and 36-40] and TEM-1 [epitopes 26-27, 52-55, and 66-70]. QGYD treatment restored the compromised antibody reactivity against VIM-1 [epitopes 53-54 and 56-58] and SPM-1 [epitopes 16-19 and 82-85] following pseudomonal infection. Serum levels of IL-1ß and Th1/Th2 in the rats were significantly elevated following pseudomonal infection (P<0.05 orP<0.01). In contrast, QGYD and combination QGYD and ceftazidime treatment restored the elevated serum IL-1ß and Th1/Th2 levels to normal (P>0.05). CONCLUSIONS: QGYD improves the immune response to pseudomonal infection in rats by stimulating the production of protective antibodies against drug-resistant proteins VIM-1, SPM-1, and TEM-1. In addition, it protects the immune system and maintains immune responsiveness by restoring IL-1ß and Th1/Th2 levels.