Epigallocatechin gallate suppresses mitotic clonal expansion and adipogenic differentiation of preadipocytes through impeding JAK2/STAT3-mediated transcriptional cascades.

BACKGROUND: Mitotic clonal expansion (MCE) is a prerequisite for preadipocyte differentiation and adipogenesis. Epigallocatechin gallate (EGCG) has been shown to inhibit preadipocyte differentiation. However, the exact molecular mechanisms are still elusive. PURPOSE: This study investigated whether EGCG could inhibit adipogenesis and lipid accumulation by regulating the cell cycle in the MCE phase of adipogenesis and its underlying molecular mechanisms. METHOD: 3T3-L1 preadipocytes were induced to differentiate by a differentiation cocktail (DMI) and were treated with EGCG (25-100 µM) for 9, 18, and 24 h to examine the effect on MCE, or eight days to examine the effect on terminal differentiation. C57BL/6 mice were fed a high-fat diet (HFD) for three months to induce obesity and were given EGCG (50 or 100 mg/kg) daily by gavage. RESULTS: We showed that EGCG significantly inhibited terminal adipogenesis and lipid accumulation in 3T3-L1 cells and decreased expressions of PPARγ, C/EBPα, and FASN. Notably, at the MCE phase, EGCG regulated the cell cycle in sequential order, induced G0/G1 arrest at 18 h, and inhibited the G2/M phase at 24 h upon DMI treatment. Meanwhile, EGCG regulated the expressions of cell cycle regulators (cyclin D1, cyclin E1, CDK4, CDK6, cyclin B1, cyclin B2, p16, and p27), and decreased C/EBPß, PPARγ, and C/EBPα expressions at MCE. Mechanistic studies using STAT3 agonist Colivelin and antagonist C188-9 revealed that EGCG-induced cell cycle arrest in the MCE phase and terminal adipocyte differentiation was mediated by the inhibition of JAK2/STAT3 signaling cascades and STAT3 (Tyr705) nuclear translocation. Furthermore, EGCG significantly protected mice from HFD-induced obesity, reduced body weight and lipid accumulations in adipose tissues, reduced hyperlipidemia and leptin levels, and improved glucose intolerance and insulin sensitivity. Moreover, RNA sequencing (RNA-seq) analysis showed that the cell cycle changes in epididymal white adipose tissue (eWAT) were significantly enriched upon EGCG treatment. We further verified that EGCG treatment significantly reduced expressions of adipogenic factors, cell cycle regulators, and p-STAT3 in eWAT. CONCLUSION: EGCG inhibits MCE, resulting in the inhibition of early and terminal adipocyte differentiation and lipid accumulation, which were mediated by inhibiting p-STAT3 nucleus translocation and activation.

Clinical study of drug-loaded calcium sulfate in the treatment of hematogenous osteomyelitis in children.

BACKGROUND: At present, good results have been obtained in the treatment of hematogenous osteomyelitis(HO) in children by the use of drug-loaded calcium sulfate, but there are few clinical studies reported. The aim of this study was to investigate the clinical efficacy of radical debridement combined with drug-laden calcium sulphate antibiotics in paediatric haematogenous osteomyelitis. METHODS: In this study, we retrospectively analyzed the clinical data of 15 cases of pediatric hematogenous osteomyelitis admitted to our hospital in recent years. A total of 15 pediatric patients with HO treated in our hospital from January 2018 to February 2022 were included for evaluation. RESULTS: All 15 patients were treated with drug-laden calcium sulfate, and the antibiotic of choice was vancomycin in 14 cases and vancomycin combined with gentamicin in 1 case. The follow-up period ranged from 12 to 36 months, with a mean follow-up time of 24.73 months, and all children were treated with drug-laden calcium sulfate with satisfactory clinical outcomes. The results of serological examination showed that the preoperative white blood cell count level, C-reactive protein and erythrocyte sedimentation rate were higher than the postoperative ones, and the differences were statistically significant (P < 0.05).After the operation, referring to the treatment standard of McKee's osteomyelitis, 15 cases were cured without recurrence; According to the Lower Extremities Functional Scale, 12 cases were excellent, 2 cases were good and 1 case was moderate, with an excellent rate of 93.33%. Children with lower limb involvement could walk with full weight bearing, and gait was basically normal. CONCLUSION: Drug-loaded calcium sulfate is a good therapeutic method for the treatment of hematogenous osteomyelitis in children, with a effect of reducing complications and reducing recurrence.

COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: An increasing number of studies have elucidated a close nexus between COVID-19 phenotypes and neuromyelitis optica spectrum disorder (NMOSD), yet the causality between them remains enigmatic. Methods: In this study, we conducted a Mendelian randomization (MR) analysis employing summary data sourced from genome-wide association studies (GWAS) pertaining to COVID-19 susceptibility, hospitalization, severity, and NMOSD. The primary MR analysis employed the Inverse variance weighted (IVW) approach, which was supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We implemented various sensitivity analyses including Cochran's Q test, MR-PRESSO method, MR-Egger intercept, leave-one-out analysis, and funnel plot. Results: The MR results demonstrated a nominal association between COVID-19 susceptibility and the risk of AQP4+ NMOSD, as evidenced by the IVW method (OR = 4.958; 95% CI: 1.322-18.585; P = 0.018). Conversely, no causal association was observed between COVID-19 susceptibility, hospitalization, or severity and the increased risk of NMOSD, AQP4-NMOSD, or AQP4+ NMOSD. The comprehensive sensitivity analyses further bolstered the robustness and consistency of the MR estimates. Conclusion: Our findings provide compelling evidence for a causal effect of COVID-19 phenotype on AQP4+ NMOSD, shedding new light on the understanding of the comorbidity between COVID-19 and NMOSD.

Isorhamnetin inhibits progression of ovarian cancer by targeting ESR1.

Background: Although reports suggest Chinese herbal medicine treatment of ovarian cancer (OC) has a good effect, the role of isorhamnetin (ISO), a flavonol aglycone with immune, anti-inflammatory, cardiovascular and cerebrovascular protective effects, as well as an anticancer effect, in OC remains unclear. Network pharmacology was used to explore this in vitro and in vivo, and to identify relevant targets. Methods: The common targets of ISO in the treatment of OC were screened by constructing drug targets and disease gene databases for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein-protein interaction network was constructed by STRING. Overlapping targets were further analyzed using the online tool UALCAN to analyze the correlation between gene expression and patient survival and prognosis. The effect of ISO on OC cell proliferation, migration, and invasion was assessed in vivo and in vitro, and the function of the estrogen receptor 1 (ESR1) in the development of OC was examined by overexpressing and knocking down ESR1 expression. Results: Through network pharmacology analysis, 25 target genes related to ISO-OC were screened out. The overall survival rate of OC patients only significantly correlated with high expression of ESR1 among 13 highly expressed overlapping genes. ISO significantly inhibited the proliferation, migration and invasion of OC cells in vitro and inhibited tumor growth in vivo. Overexpression of ESR1 significantly promoted the proliferation, migration and invasion of OC cells, whereas knockdown of ESR1 showed the opposite result. In addition, overexpression of ESR1 significantly reversed the inhibitory effect of ISO on the proliferation, migration and invasion of OC cells. Conclusions: We confirmed that ISO inhibits OC cell proliferation, migration and invasion by targeting ESR1 expression, which provides a theoretical basis for further pharmacological research.

Moxibustion alleviates depression-like behavior in rats with Crohn's disease by inhibiting the kynurenine pathway metabolism in the gut-brain axis.

Background: Moxibustion is a potential therapy for inflammatory bowel disease-related depression, but its specific mechanism of action is unclear. This study aimed to investigate the molecular mechanism by which moxibustion alleviates depressive behavior in rats with Crohn's disease (CD). Methods: The CD rat model was established with 2,4,6-trinitrobenzenesulfonic acid. Treatment with moxibustion was applied to Tianshu (ST25, bilateral), Qihai (CV6), and Baihui (GV20) acupoints, and the effect of moxibustion was compared with that of the combination of moxibustion plus indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, 1-methyltryptophan (1-MT). The effects of moxibustion and moxibustion plus 1-MT combination on colonic inflammation and depressive behavior (assessed by forced swimming test, sucrose preference test, and open field test) were investigated. The changes in IDO1, TNF-α, and IL-1ß in rat colon and hippocampus were assessed by Western blot (WB). Gas chromatography-mass spectrometry, immunofluorescence staining, and WB were applied to detect kynurenine pathway (KP) metabolites, hippocampal neuronal activity, and microglia activation, respectively. Results: Both moxibustion and moxibustion plus 1-MT combination significantly alleviated intestinal inflammation and depressive behavior, downregulated the levels of IDO1 in the colon and hippocampus, and inhibited inflammation-inducing factors IL-1ß and TNF-α, as well as the kynurenine/tryptophan (KYN/TRP) ratio of KP metabolites, and upregulated the kynurenic acid (KYNA)/KYN ratio and the KYNA/quinolinic acid (QUIN) ratio in the hippocampus in rats with CD; Hippocampal ionized calcium-binding adaptor molecule-1 (Iba-1), c-fos protein expression, activated microglia, and neuronal activation was also significantly reduced by moxibustion and moxibustion plus 1-MT. The addition of 1-MT did not significantly increase the therapeutic effect of moxibustion. Conclusion: Moxibustion can improve depressive behavior in rats with CD, which may be related to its regulation of KP metabolism in the gut-brain axis and inhibition of hippocampal microglia activation and neuronal activation.

Effects of Danhong injection on cardiac function and blood lipid in patients with angina pectoris of coronary heart disease: A protocol for randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Angina pectoris of coronary heart disease is the leading cause of death worldwide. Danhong injection is a supplement for angina pectoris of coronary heart disease. A large number of studies have confirmed its efficacy and safety. However, there is no rigorous clinical study to evaluate the effects of Danhong injection on cardiac function and blood lipid in patients with angina pectoris of coronary heart disease. METHODS: This is a prospective, randomized, double-blind, placebo-controlled trial to study the effects of Danhong injection on cardiac function and lipid profile in patients with angina pectoris of coronary heart disease. Participants will be randomly divided into treatment group and control group. The treatment group will be treated with Danhong injection and the control group will be treated with placebo under basic treatment according to recommended guideline, and followed up for 3 months after 14 consecutive days of treatment. Outcomes include: cardiac function (left ventricular end-diastolic diameter); left ventricular end-systolic diameter; left ventricular ejection fraction, blood lipid levels (total cholesterol; triacylglycerol; low density lipoprotein cholesterol; high density lipoprotein cholesterol), the number of angina attacks per week, total amount of nitroglycerin tablets, and adverse reactions. DISCUSSION: This study will evaluate the efficacy of Danhong injection in improving cardiac function and blood lipid in patients with angina pectoris of coronary heart disease. The results of this study will provide reference for clinical use of Danhong injection to improve cardiac function and blood lipid in patients with angina pectoris of coronary heart disease.Trial registration: OSF Registration number: DOI 10.17605/OSF.IO/TPZJ5.

Insights into the role of in-situ and ex-situ hydrogen peroxide for enhanced ferrate(VI) towards oxidation of organic contaminants.

Recently, several studies have been conscious of the promotion effect of hydrogen peroxide (H2O2), a self-decay product of ferrate (Fe(VI)), on Fe(VI) to oxidize contaminations, but the pivotal activation mechanism has not been thoroughly evaluated. This work aims to compare and reveal the promoting mechanism of H2O2 in Fe(VI) and Fe(VI)-H2O2 processes, and to illustrate the practical use potential of Fe(VI)-H2O2 system. Many lines of evidence verified the involvement of •OH and O2•- in pollutant degradation were excluded in Fe(VI) and Fe(VI)-H2O2 systems, meaning that high dosage of H2O2 cannot trigger an activation pathway different from in-situ H2O2. The better oxidation performance of the Fe(VI)-H2O2 system than Fe(VI) alone was ascribed to the catalytic role of in-situ and ex-situ H2O2, which can directly and/ or indirectly facilitate the formation of Fe(IV) and Fe(V). Considering the structural similarity of peroxymonosulfate (PMS) and peroxydisulfate (PDS) with H2O2 as well as their universality in water pollutant remediation, the oxidation properties and reactive oxidants of Fe(VI)-PMS and Fe(VI)-PDS processes were also examined. Besides, the Fe(VI)-H2O2 system suffered from less restriction by inorganic ions and natural organic matter, and exhibited satisfactory pollutant removal effects in real water. Overall, this work provides a further and comprehensive cognition about the role of H2O2 in Fe(VI) and Fe(VI)-H2O2 systems.

Metal-free black-red phosphorus as an efficient heterogeneous reductant to boost Fe3+/Fe2+ cycle for peroxymonosulfate activation.

In this work, a novel metal-free black-red phosphorus (BRP) was prepared from red phosphorus (RP) and applied in Fe2+/peroxymonosulfate (PMS) process. Compared with that of RP, the contaminant degradation performance of BRP was significantly elevated due to the enhanced electron transfer from BRP to Fe3+. This enhancement was mainly induced by size decrease effect, the removal of oxidation layer and the partial phase conversion. Moreoevr, BRP avoided the radical quenching reaction caused by reductant itself, whereas it was inevitable using homogeneous reductant like hydroxylamine. More importantly, the system had a superior recyclability and strong resistance to natural water. Though concurrent side-reaction between PMS and BRP occured, multiple PMS dosage could remarkedly alleviated the side-reaction, thus elevating PMS utilization efficiency. The dominant BRP oxidation products included phosphite and phosphate. Interestingly, moderate increase of Fe3+ concentration could efficiently reduce the by-product formation via the prompt PMS activation by regenerated Fe2+. Our work clarified the acceleration mechanism of Fe3+/Fe2+ cycle by BRP and proposed the control strategy of by-prodoct formation.

Lignans from Schisandra chinensis ameliorate alcohol and CCl4-induced long-term liver injury and reduce hepatocellular degeneration via blocking ETBR.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl4-induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes. AIM OF THE STUDY: This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection. MATERIALS AND METHODS: We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro. RESULTS: The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl4-induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCß, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-ß1 (TGF-ß1) level. CONCLUSION: The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity.

Effect of Scalp Nerve Block with Ropivacaine on Postoperative Pain in Patients Undergoing Craniotomy: A Randomized, Double Blinded Study.

Scalp nerve block with ropivacaine has been shown to provide perioperative analgesia. However, the best concentration of ropivacaine is still unknown for optimal analgesic effects. We performed a prospective study to evaluate the effects of scalp nerve block with varied concentration of ropivacaine on postoperative pain and intraoperative hemodynamic variables in patients undergoing craniotomy under general anesthesia. Eighty-five patients were randomly assigned to receive scalp block with either 0.2% ropivacaine, 0.33% ropivacaine, 0.5% ropivacaine, or normal saline. Intraoperative hemodynamics and post-operative pain scores at 2, 4, 6, 24 hours postoperatively were recorded. We found that scalp blockage with 0.2% and 0.33% ropivacaine provided adequate postoperative pain relief up to 2 h, while administration of 0.5% ropivacaine had a longer duration of action (up to 4 hour after craniotomy). Scalp nerve block with varied concentration of ropivacaine blunted the increase of mean arterial pressure in response to noxious stimuli during incision, drilling, and sawing skull bone. 0.2% and 0.5% ropivacaine decreased heart rate response to incision and drilling. We concluded that scalp block using 0.5% ropivacaine obtain preferable postoperative analgesia compared to lower concentrations. And scalp block with ropivacaine also reduced hemodynamic fluctuations in craniotomy operations.

Efficient removal of cadmium from soil-washing effluents by garlic peel biosorbent.

Paddy field soil contaminated by cadmium may produce cadmium-contained corns causing Itai-itai disease, and in situ washing of soil with the organic acid is a good technical choice due to its convenience and cost-effectiveness. While the bottleneck of this technique is how to recycle the huge volume of washing effluent in an efficient and economical way. Biosorption of cadmium on the garlic peel was attempted in present study and it was found quite satisfactorily effective to remove all cadmium from the real soil leaching effluent after three-time sequential adsorption. The systematical investigation on the effect of various parameters on the adsorption of cadmium on garlic peel in the existence of tartaric ligand was performed and it was found that tartrate could change Cd2+ into Cd(tar)0 species whose electrical charge state would restrain its approach to the adsorbent particles. The porous microstructure in the transversal surface of garlic peel and the abundant groups of -COOH are the main factors affecting the adsorption capability. A demonstrative flowsheet of soil remediation by chemical washing coupled with biosorption was proposed correspondingly, in which the cadmium could be recovered from the soil washing effluent, and the recovered effluent was reused for next soil washing, and recovered garlic peel was reused for cadmium adsorption from the effluents again, showing a great prospect in the remediation of paddy field soil contaminated by cadmium. Garlic peel was used to remove the cadmium from the soil washing effluent.

Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension.

Puerarin, a major isoflavonoid compound from Chinese herb Kudzu roots, has been widely used for the treatment of hypertensive and cardiovascular diseases in China. Here, we investigated puerarin's beneficial effects on the cardiovascular system in angiotensin (Ang) II-induced hypertensive rats. Sprague-Dawley rats were treated with Ang II for 5 days or with puerarin for 10 days followed by Ang II and puerarin for 5 days. Endothelium-dependent relaxation (EDR) to acetylcholine was determined using an organ chamber bath. Ang II increased the systolic blood pressure (SBP: 178 ± 5 mmHg vs. 112 ± 3 mmHg in control, p < 0.05), aortic (30%, p < 0.05), and left ventricular (LV) weight (23%); puerarin reduced SBP (160 ± 2 mmHg, p < 0.05), aortic, and left ventricular weight in Ang II-infused rats. Puerarin also reduced aortic medial thickness and myocardial cell surface area in Ang II-infused rats. Compared with control rats, Ang II infused rats exhibited an impaired EDR with reduction in the protein expression of phosphor-eNOS at Ser 1177 and an increase in the expression of gp91phox (85%), p22phox (113%), transforming growth factor ß1 (145%) and vascular cell adhesion molecule 1 (82%). Puerarin improved EDR and reversed the changes in Ang II-induced protein expression of above molecules. Our results demonstrate that in Ang II-induced hypertensive rats, puerarin protects against endothelial dysfunction and end organ damage with a mild reduction in SBP, and that the cardiovascular beneficial effects of puerarin may be in part attributed to its anti-oxidant and upregulation of phosphor-eNOS.

Pharmacological treatment for memory disorder in multiple sclerosis.

BACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. OBJECTIVES: To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. SELECTION CRITERIA: All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. MAIN RESULTS: We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. AUTHORS' CONCLUSIONS: We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

Curcumin as a potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase 1: improving lipid profiles in high-fat-diet-treated rats.

BACKGROUND: 11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11ß-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11ß-HSD1 have not been reported. METHODOLOGY: Curcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11ß-HSD1 with selectivity against 11ß-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months. RESULTS AND CONCLUSIONS: Curcumin exhibited inhibitory potency against human and rat 11ß-HSD1 in intact cells with IC50 values of 2.29 and 5.79 µM, respectively, with selectivity against 11ß-HSD2 (IC50, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11ß-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11ß-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC50 values of 93 and 184 nM for human and rat 11ß-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11ß-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11ß-HSD1 with selectivity against 11ß-HSD2.

Hitting the golden TORget: curcumin's effects on mTOR signaling.

The polyphenol natural product curcumin possesses a plethora of biological and pharmacological properties. For years, much interest has been placed in the development and use of curcumin and its derivatives for the prevention and treatment of cardiovascular, diabetic, and neurodegenerative diseases, as well as cancer. Increasing evidence suggests that curcumin displays amazing molecular versatility, and the number of its proposed cellular targets grows as the research continues. The mammalian target of rapamycin (mTOR) is a master kinase, regulating cell growth/proliferation, survival, and motility. Dysregulated mTOR signaling occurs frequently in cancer, and targeting mTOR signaling is a promising strategy for cancer therapy. Recent studies have identified mTOR as a novel target of curcumin. Here we focus on reviewing current knowledge regarding the effects of curcumin on mTOR signaling for better understanding the anticancer mechanism of curcumin. The emerging studies of mTOR signaling and clinical studies on curcumin with cancer patients are also discussed here.

Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells.

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.

Imaging manifestation of conventional and contrast-enhanced ultrasonography in percutaneous microwave ablation for the treatment of uterine fibroids.

OBJECTIVES: To evaluate the image changes and the relationship between conventional ultrasonography and contrast-enhanced ultrasound (CEUS) in the perioperative period of microwave (MW) ablation for uterine fibroids; to guide clinical ablation therapy and evaluate the efficacy of MW. METHODS: Twenty-nine patients with 31 uterine fibroids were recruited in this study. All patients received conventional ultrasound as well as CEUS examination before, immediately after and 12-24 h after MW, in order to detect variations of echo and characteristics of blood supply. t-Tests were used to compare the hyperecho area on gray-scale ultrasound to immediately after ablation non-enhanced CEUS measurements, as well as to compare the immediately after ablation non-enhanced CEUS measurements to the 12-24 h after ablation measurements. RESULTS: Immediately after ablation, the average hyperecho area in gray-scale was 82.20±72.32 cm3; the average non-enhancement area was 76.34±70.63 cm3 by CEUS, showing a strong correlation (r=0.997, P<0.01) to the hyperecho area in gray-scale. The average non-enhancement area measured by CEUS immediately after ablation was 90.55±74.41 cm3 and average 12-24h after ablation was 98.29±78.25 cm3; no statistically significant difference was detected between the two time points (P>0.05). CONCLUSIONS: Measurements made by hyperechoic range on gray-scale ultrasonography is strongly correlated to the no enhancement area by CEUS. The hyperechoic range on gray-scale image can represent the ablated area immediately after MW.

Pharmacologic treatment for memory disorder in multiple sclerosis.

BACKGROUND: Memory disorder is one of the most frequent cognitive impairment and has a great negative impact on the quality of life in patients with multiple sclerosis (MS). A few pharmacologic agents appear to be effective to memory disorder in patients with MS in some existing randomised controlled trials. OBJECTIVES: To assess the absolute and comparative efficacy, tolerability and safety of pharmacologic treatments for memory disorder in adult patients with MS. SEARCH STRATEGY: We searched the Cochrane Multiple Sclerosis Group's Trials Register (17 January 2011), PsycINFO (January 1980 - April Week 4 2011) and CBMdisc (January 1978 - 6 April 2011), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. SELECTION CRITERIA: All double-blind, randomized controlled parallel trials on pharmacologic treatment versus placebo treatment or no treatment or one or more pharmacologic treatments, without restrictions regarding dose, route of administration and frequency, administration duration≥12 weeks for memory disorder in adult patients with MS who display at least mild memory impairment at 0.5 standard deviations below age -and-sex-based normative data on a validated memory scale. Adequately randomized or quasi-randomized trials were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation. MAIN RESULTS: Four RCTs involving adult patients with all the types of MS and at least mild memory impairment were included, evaluating donepezil, Ginkgo biloba (GB), memantine and rivastigmine respectively vs placebo in treating memory disorder in MS.There were no serious adverse events in intervention groups.The quality of the included studies was overall low, some of important variables were not matched between groups at baseline, the samples of subjects were relatively small and the follow-up was short. Three RCTs which evaluate GB, memantine, rivastigmine respectively vs placebo are currently ongoing. AUTHORS' CONCLUSIONS: Until the results of ongoing studies are available, there is no convincing evidence to support pharmacologic intervention as an effective treatment for memory disorder in MS patients. However, donepezil, Ginkgo biloba, memantine and rivastigmine resulted to be safe and well tolerated as adverse events such as nausea, diarrhea, somnolence, and constipation were not frequent,  while no serious adverse effects were reported. Future high quality randomised controlled trials are needed.

Cryptotanshinone inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3/ERK and small GTPase pathways.

Cryptotanshinone (CPT), isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism remains to be defined. Here, we show that CPT inhibited lymphangiogenesis in an in vitro model (tube formation). This effect was partly attributed to inhibiting expression of VEGF receptor 3 (VEGFR-3) in murine lymphatic endothelial cells (LEC), as overexpression of VEGFR-3 conferred resistance to CPT inhibition of the tube formation, whereas downregulation of VEGFR-3 mimicked the effect of CPT, blocking the tube formation. Furthermore, CPT inhibited phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2). Overexpression of VEGFR-3 attenuated CPT inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited ERK1/2 phosphorylation in LECs. Expression of constitutively active MKK1 resulted in activation of ERK1/2 and partially prevented CPT inhibition of LEC tube formation. In addition, CPT also inhibited protein expression and activities of Rac1 and Cdc42 but not RhoA. Expression of constitutively active Rac1 and Cdc42 concurrently, but not Rac1 or Cdc42 alone, conferred resistance to CPT inhibition of LEC tube formation. Taken together, the results suggest that CPT inhibits LEC tube formation, in part, by inhibiting VEGFR-3-mediated ERK1/2 phosphorylation and, in part, by inhibiting expression of the small GTPases.

Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer.

Three new dammarane-type triterpene ginsenosides, together with six known ginsenosides, were isolated from the leaves of Panax ginseng C.A. Meyer. The new saponins were named as ginsenoside Rh11, ginsenoside Rh12, and ginsenoside Rh13. Their structures were elucidated as (20S)-3ß,6α,12ß,20-tetrahydroxydammara-25-ene-24-one 20-O-ß-d-glucopyranoside (1), (20S)-3ß,12ß,20,24,25-pentahydroxydammarane 20-O-ß-d-glucopyranoside (2), and (20S,23E)-3ß,12ß,20,25-tetrahydroxydammara-23-ene 20-O-ß-d-glucopyranoside (3) on the basis of 1D and 2D NMR experiments and mass spectra. The known ginsenosides were identified as ginsenoside M(7cd), ginsenoside Rg6, ginsenoside Rb3, gypenoside XVII, gypenoside IX, and 20-(E)-ginsenoside F4.