The ADAM17 inhibitor ZLDI-8 sensitized hepatocellular carcinoma cells to sorafenib through Notch1-integrin ß-talk.

ZLDI-8 is an A disintegrin and metalloproteinase domain 17 (ADAM17) inhibitor that suppresses the shedding of Notch1 to the Notch1 intracellular domain (NICD). In previous studies, we found that ZLDI-8 was able to sensitize HCC to sorafenib, but the mechanism of action remains unclear. The sensitizing effects of ZLDI-8 were tested both in vitro and in vivo. EMT-related factors, sorafenib sensitivity-related proteins and ECM-related gene expression were assessed using immunohistochemistry, RTPCR and Western blotting. Knockdown assays were conducted to determine the relationship between the Notch and Integrin pathways. CoIP assays, nuclear and cytoplasmic fractionation and immunofluorescence colocalization were applied to explore the interaction between the Notch and Integrin pathways. Appropriate statistical analysis methods were used to assess the significance of the experimental results and to ensure the scientific validity and reliability of the experimental design. We found that ECM- and EMT-related proteins were downregulated after ZLDI-8 treatment (P<0.05). ZLDI-8 significantly downregulated Integrinß1 and Integrinß3 in HCC in vitro and in vivo (P<0.05), possibly through Foxc2-dependent regulation. Mechanistically, interfering with the expression of both Integrin-linked kinase (ILK) and the NICD may downregulate the expression of proteins targeted by sorafenib, thereby sensitizing cells to sorafenib. The retroregulation of Integrinß by ILK may occur through the interaction between the NICD and ILK and may be the result of the translocation of the complexus. Our study indicates that blocking the Notch pathway may affect Integrinß through crosstalk between the Notch1 and Integrinß/ILK signaling pathways, thus providing a potential therapeutic strategy for HCC.

Gonadotropin-Releasing Hormone Agonists during Gonadal Chemotherapy for the Effect on Pregnancy Outcome and Ovarian Function in Premenopausal Patients with Breast Cancer: A Systematic Review and Meta-Analysis.

Objectives: The aim of this study was to evaluate the effects of gonadotropin-releasing hormone agonists (GnRHas) on pregnancy outcomes, premature ovarian failure (POF), menstrual recovery, disease-free survival (DFS), and adverse events in premenopausal breast cancer patients during gonadal chemotherapy. Methods: We systematically searched PubMed, Cochrane Library, and Embase databases. The trials were eligible if they included premenopausal breast cancer patients treated with chemotherapy alone or with concurrent GnRHa and reported ovarian function recovery data. Heterogeneity for the eligible data was assessed, and a pooled risk ratio (RR) with 95% confidence interval (CI) was calculated. A meta-analysis was conducted using a fixed-effect model. Results: Fifteen randomized controlled trials were included in this analysis. The results indicated that GnRHa combined with chemotherapy significantly increased pregnancy rates compared with chemotherapy alone (RR = 1.76; 95% CI: 1.16-2.67) and decreased rates of POF (RR = 0.42; 95% CI: 0.35-0.51). For secondary endpoints, the GnRHa group improved menstrual recovery rates (RR = 1.20; 95% CI: 1.11-1.30) and decreased the rate of amenorrhea 1-2 years after chemotherapy (RR = 0.50; 95% CI: 0.40-0.63). Furthermore, the 5-year DFS and overall survival (OS) rates were significantly improved in the GnRHa group. Conclusion: For premenopausal breast cancer patients receiving gonadal toxic chemotherapy, adjuvant chemotherapy with GnRHa can better protect the ovarian function of patients, reduce the rate of POF and amenorrhea, and improve the pregnancy rate, menstrual recovery rate, DFS rate, and OS rate of patients.

Addition of PI3K/AKT/mTOR inhibitors to fulvestrant for advanced HR+/HER2- breast cancer: a systematic review and meta-analysis.

Purpose: To analyze whether adding PI3K/AKT/mTOR inhibitors to fulvestrant could restore endocrine therapy sensitivity for the treatment of postmenopausal patients with HR+, HER2- breast cancer. Methods: This meta-analysis was performed using RevMan 5.4 analysis software. Results: Nine studies that included a total of 3199 patients were analyzed. Compared with fulvestrant alone, the addition of PI3K/AKT/mTOR inhibitors significantly prolonged progression-free survival, overall survival and objective response rate of patients in both the total and PI3K-pathway-activated population. The number of grade 3-5 adverse events was also significantly higher. Conclusion: The addition of PI3K/AKT/mTOR to fulvestrant resulted in potential benefits; however, there may be a higher risk, which needs to be carefully managed.

Comparative efficacy and safety of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes: A network meta-analysis.

INTRODUCTION: This study aimed to evaluate the clinical efficacy and safety of 4 weekly formulations of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on glycemic control, including glycemic control, by using a network meta-analysis (NMA). METHODS: PubMed, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched from inception until June 10, 2022. Randomized clinical trials (RCTs) enrolling participants with diabetes mellitus type 2 and a follow-up of at least 12 weeks were included, for which 4 eligible GLP-1RAs Exenatide, Dulaglutide, Semaglutide, Loxenatide were compared with either each other or placebo. The primary outcome is the change of hemoglobin A1c level. Secondary outcomes including additional glycemic control indicators and adverse events (AE). Frequentist random-effect NMA were conducted for effect comparison. This meta-analysis was registered on PROSPERO, CRD42022342241. RESULTS: The NMA synthesized evidence from 12 studies covering 6213 patients and 10 GLP-1RA regimens. A pairwise comparison of glycosylated hemoglobin type A1C (HbA1c) lowering effects showed that once-weekly GLP-1 receptor agonists were significantly better than placebo, and their glucose-lowering intensity was Semaglutide 2.0mg, Semaglutide 1.0mg, Dulaglutide 4.5mg, and Semaglutide 0.5mg, Dulaglutide 3.0mg, PEX168 200ug, Dulaglutide 1.5mg, PEX168 100ug and Dulaglutide 0.75mg. The GLP-1RA regimen has a comparable safety profile for hypoglycemia. And with the exception of PEX168, all other long-acting GLP-1RA drugs had lower rates of diarrhea, nausea and vomiting than placebo. CONCLUSION: Regimens of GLP-1RAs had differential glycemic control. The efficacy and safety of Semaglutide 2.0mg in comprehensively lowering blood sugar showed the best performance.

Effect of erythropoiesis-stimulating agents on breast cancer patients: a meta-analysis.

Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6 months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.

Inhibition of Angiogenesis and Extracellular Matrix Remodeling: Synergistic Effect of Renin-Angiotensin System Inhibitors and Bevacizumab.

Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-ß1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.

Practice guidance for the use of terlipressin for liver cirrhosis-related complications.

Background: Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis-related complications has been recognized during recent years. This article aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis-related complications. Methods: Hepatobiliary Study Group of the Chinese Society of Gastroenterology of the Chinese Medical Association and Hepatology Committee of the Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts' clinical experiences. Results: Overall, 10 major guidance statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. Conclusion: The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis-related complications.

Adherence to Non-Selective Beta Blockers for Prevention of Variceal Bleeding in Cirrhotic Patients.

BACKGROUND AND AIM: Long-term use of non-selective beta blockers (NSBBs) is essential for the prevention of esophageal variceal bleeding in liver cirrhosis but may impair the patient's adherence. The present study aimed to investigate the adherence to NSBBs to prevent variceal bleeding in cirrhotic patients. METHODS: All patients who had an indication of NSBBs for the prophylaxis of variceal bleeding between February 2018 and June 2019 were screened. Clinical pharmacists gave pre-medication education and recorded the adherence to NSBBs during the patients' hospitalizations. Factors associated with poor adherence were evaluated by univariate logistic regression analysis. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. The relationship between poor adherence during follow-up and variceal bleeding after discharge was also evaluated. RESULTS: Overall, 108 patients were screened, of whom 12 were intolerant to NSBBs. Among the 96 remaining patients who could take NSBBs, the average change of heart rate after NSBBs was -10.49 b.p.m. Twenty-two (22.9%) patients had poor adherence to NSBBs due to their refusal to take NSBBs (n = 2), complete forgetfulness to take NSBBs (n = 10), and refusal or forgetfulness to monitor heart rate (n = 10). Univariate logistic regression analysis demonstrated that only older age was significantly associated with poor adherence (OR: 1.065, 95% CI: 1.019-1.114, P = 0.005). Patients with poor adherence during follow-up were more likely to develop variceal bleeding after discharge. CONCLUSION: A significant proportion of cirrhotic patients had poor adherence to NSBBs during their hospitalizations. Further studies should explore how to improve the patient's adherence to NSBBs.

Efficacy and Safety of Bevacizumab Plus Oxaliplatin- or Irinotecan-Based Doublet Backbone Chemotherapy as the First-Line Treatment of Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis.

INTRODUCTION AND OBJECTIVE: Guidelines recommend combined doublet backbone chemotherapy based on 5-fluorouracil and oxaliplatin (OX) or irinotecan (IR) as the first-line treatment options for metastatic colorectal cancer. However, it is still unknown which is better when combined with bevacizumab (BEV). This systematic review and meta-analysis were performed to compare BEV-IR with BEV-OX regimens in terms of efficacy and safety. METHODS: We searched studies from databases including MEDLINE, EMBASE, CENTRAL, and conference papers. The outcomes were overall response rate, overall survival, progression-free survival, and the incidence of the most common adverse events. The dichotomous data were reported as the risk ratio (RR) and the survival outcomes were extracted as the hazard ratio with 95% confidence interval (CI). RESULTS: Eleven studies including 5632 patients were identified. No difference was found in overall survival or overall response rate between BEV-IR and BEV-OX regimens. The pooled progression-free survival was significantly longer in the BEV-IR group than the BEV-OX group (hazard ratio = 0.92, 95% CI 0.87-0.98, p = 0.08). Compared with the BEV-OX group, the BEV-IR group was related to a higher risk of bleeding events (RR = 0.80, 95% CI 0.64-0.98, p = 0.03), venous thromboembolism (RR = 0.60, 95% CI 0.46-0.79, p = 0.0002), and diarrhea (RR = 0.71, 95% CI 0.62-0.80, p < 0.00001). Conversely, the BEV-OX group was related to a higher risk of thrombocytopenia (RR 2.39, 95% CI 1.67-3.42, p < 0.00001) and neuropathy (RR 3.80, 95% CI 1.90-7.64, p = 0.0002). CONCLUSIONS: The BEV-IR regimen was superior in improving progression-free survival as the first-line treatment for metastatic colorectal cancer. The two different doublet regimens combined with BEV had their specific features of adverse events.

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway.

Breast cancer is one of the most frequent cancers among women worldwide. However, there is still no effective therapeutic strategy for advanced breast cancer that has metastasized. Aberrant activation of the PI3K/AKT/mTOR pathway is an essential step for the growth of human breast cancers. In our previous study, we designed and synthesized DHW-208 (2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide) as a novel pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in breast cancer and investigate its underlying mechanism. We found that DHW-208 inhibited the growth, proliferation, migration, and invasion of breast cancer cells. Moreover, DHW-208 induced breast cancer cell apoptosis via the mitochondrial pathway and induced G0/G1 cell-cycle arrest. In vitro results show that DHW-208 is a dual inhibitor of PI3K and mTOR, and suppress the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in breast cancer. Above all, we report for the first time that DHW-208 suppressed the growth of human breast cancer cells by inhibiting the PI3K/AKT/mTOR-signaling pathway both in vivo and in vitro. Our study may provide evidence for the use of DHW-208 as an effective, novel therapeutic candidate for the treatment of human breast cancers in clinical trials.

DCMQA, a caffeoylquinic acid derivative alleviates NMDA-induced neurotoxicity via modulating GluN2A and GluN2B-containing NMDA receptors in vitro.

Compound DCMQA (4, 5-O-dicaffeoyl-1-O-[4-malic acid methyl ester]-quinic acid) is a natural caffeoylquinic acid derivative isolated from Arctium lappa L. roots. Caffeoylquinic acid derivatives have been reported to possess neuroprotective effects through inhibiting oxidative stress and apoptosis in vitro. However, whether DCMQA exerts protective effects on N-methyl-D-aspartate (NMDA)-induced neurotoxicity and the underlying mechanism has not been elucidated. In this study, the results indicated that pretreatment of DCMQA prevented the loss of cell viability and attenuated the LDH leakage in SH-SY5Y cells exposed to NMDA. Hoechst 33342 staining and Annexin V-PI double staining illustrated that DCMQA suppressed NMDA-induced morphological damage and neuronal apoptosis. Moreover, DCMQA inhibited NMDA-mediated Ca2+ influx, excessive intracellular ROS generation and loss of mitochondrial membrane potential (MMP). Western blot analysis showed that DCMQA attenuated the Bax/Bcl-2 ratio, release of cytochrome c as well as expression of caspase-9 and caspase-3. Besides, DCMQA down-regulated GluN2B-containing NMDA receptors (NMDARs) and up-regulated GluN2A-containing NMDARs, promoted the disruption of nNOS and PSD95 as well as activation of CaMK II-α. Furthermore, computational docking study indicated that DCMQA possessed a good affinity for NMDARs. These results indicated that DCMQA protects SH-SY5Y cells against NMDA-induced neuronal damage. In addition, the underlying mechanisms of DCMQA-mediated neuroprotection are associated with modulating NMDARs and disruption of nNOS-PSD95 as well as the activation of CaMK II-α.

Novel ADAM-17 inhibitor ZLDI-8 inhibits the metastasis of hepatocellular carcinoma by reversing epithelial-mesenchymal transition in vitro and in vivo.

AIMS: Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo. MAIN METHODS: The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model. KEY FINDINGS: In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-ß1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo. SIGNIFICANCE: ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.

Alpinia oxyphylla oil induces apoptosis of hepatocellular carcinoma cells via PI3K/Akt pathway in vitro and in vivo.

BACKGROUND: The anti-tumor properties of Alpinia oxyphylla Miquel (A. oxyphylla) extracts and their petroleum ether (PE) fractions have long attracted scientific attention. These extracts' anti-tumor activity and mechanisms in vivo are still unclear. This study was designed to investigate the anti-tumor activity and the underlying mechanism of PE's effect on hepatocellular carcinoma (HCC) in vitro and in vivo. MATERIALS AND METHOD: The anti-tumor activity of PE was evaluated by MTT assay and xenograft study. Mechanistic studies of PE were analyzed by Hoechst 33342 staining, Annexin V-FITC/PI double-staining assay, immunohistochemical staining and western blot assay. The toxicity of the PE treatment was verified by the levels of liver and kidney function in nude mice and the H&E staining of their liver and kidney tissues. RESULT: PE significantly inhibited the growth of HepG2, BEL-7402, SMMC-7721 and Hep3B cells in a concentration- and time-dependent manner. Specifically, PE inhibited the growth of Hep3B cells by inducing apoptosis. PE treatment at the doses of 0.25, 0.5 and 1 g/kg for 21 days caused a respective 35.7 percent, 49.3 percent and 58.8 percent inhibition of the tumor volume, and a 14.8 percent, 40.2 percent and 55.6 percent decrease in the tumor weight, respectively, as compared with the vehicle group in tumor-loaded mice in vivo. PE promoted the release of cytochrome c from mitochondria to cytosol in a concentration-dependent manner. The expression levels of BAX (p < 0.01), cleaved caspase-9 (p < 0.01) and cleaved caspase-3 (p < 0.05) were increased significantly in the PE-treated group at the dose of 1 g/kg; the expression level of BAX (p < 0.05) was increased significantly in the PE-treated group at the dose of 0.5 g/kg, and the expression level of Bcl-2 (p < 0.01) was decreased significantly in the PE-treated group in a concentration-dependent manner. Apoptosis was induced by PE through up-regulating the expression of PTEN, down-regulating the expression of PI3K and inhibiting the phosphorylation of Akt. The liver and kidney function of the plasma and the morphology of the liver and kidney were normal in each group. CONCLUSION: These findings suggested that PE exhibited anti-cancer efficacy on Hep3B cell in vitro and in vivo. The induction of apoptosis might be one mechanism that underlies PE's ability to combat cancer by inhibiting the PI3K/Akt pathway. PE has no obvious toxicity in vivo when it exerts anti-tumor effects and has the potential to develop into an alternative anti-cancer drug for HCC treatment.

Role of metformin in overweight and obese people without diabetes: a systematic review and network meta-analysis.

PURPOSE: Our aim was to assess the efficacy of metformin for weight loss in overweight and obese people through a systematic review and network meta-analysis and to identify the most suitable dosage and intervention period for using metformin in adolescents and adults. METHODS: We searched databases for studies published by April 2018. A total of 34 trials (44 analyses) involving 8461 participants and 16 intervention arms were eligible. The study was registered with PROSPERO International prospective register of systematic reviews (CRD42017081053). RESULTS: Metformin was found to significantly decrease body mass index percentile (BMI) and had a tendency to decrease BMI (kg/m2) and weight (kg). Significant efficacy was observed in many subgroups. The metaregression may have identified the causes of heterogeneity as metformin dosage, control type, and intervention period. Network meta-analysis revealed that in adolescents, intervention with 2000 mg/day metformin ranked better than other interventions; however, 1000 mg/day metformin for 3 months may be most suitable for adolescents. For adults, metformin at doses of 3000 and 1000 mg/day ranked the highest, other than minimeal and lifestyle interventions; moreover, intervention with 3000 mg/day for 6 months and 1000 mg/day for 0.5 months may be suitable for adults. CONCLUSION: When considering the efficacy of interventions for losing weight, metformin offers clear advantages for overweight and obese populations.

A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo.

OBJECTIVES: Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancerCRC patients remains extremely poor with chemotherapy. A disintegrin and metalloproteinase 17 (ADAM17) induces the activation of Notch pathway and contributes to the chemoresistance. This study aimed to discover a novel ADAM17 inhibitor and investigate the chemosensitization effect. MATERIALS AND METHODS: Pharmacophore model, western blot and enzymatic assay were used to discover ZLDI-8. Cell proliferation was determined by MTT and colony formation assay. Cell migratory and invasive ability were determined by wound healing scratch and transwell assay. Immunofluorescence images and western blot analysed the expression of Notch or epithelial-mesenchymal transition (EMT) pathway markers. Xenografts were employed to evaluate the chemosensitization effect of ZLDI-8 in vivo. RESULTS: We found that ZLDI-8 cell-specifically inhibited the proliferation of CRC, and this effect was due to abrogation of ADAM17 and Notch pathway. Meanwhile, we reported for the first time that ZLDI-8 synergistically improved the anti-tumour and anti-metastasis activity of 5-fluorouracil or irinotecan by reversing Notch and EMT pathways. Interestingly, in vivo studies further demonstrated that ZLDI-8 promoted the anti-tumour effect of 5-fluorouracil through Notch and EMT reversal. CONCLUSIONS: A novel ADAM17 inhibitor ZLDI-8 may be a potential chemosensitizer which sensitized CRC cells to 5-fluorouracil or irinotecan by reversing Notch and EMT pathways.

Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC-bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients.

Does music therapy enhance behavioral and cognitive function in elderly dementia patients? A systematic review and meta-analysis.

Demographic aging is a worldwide phenomenon, cognitive and behavioral impairment is becoming global burden of nerve damage. However, the effect of pharmacological treatment is not satisfying. Therefore, we analyzed the efficacy of music therapy in elderly dementia patients, and if so, whether music therapy can be used as first-line non-pharmacological treatment. A comprehensive literature search was performed on PubMed, EMbase and the Cochrane Library from inception to September 2016. A total of 34 studies (42 analyses, 1757 subjects) were included; all of them had an acceptable quality based on the PEDro and CASP scale scores. Studies based on any type of dementia patient were combined and analyzed by subgroup. The standardized mean difference was -0.42 (-0.74 to -0.11) for disruptive behavior and 0.20 (-0.09 to 0.49) for cognitive function as primary outcomes in random effect models using controls as the comparator; the secondary outcomes were depressive score, anxiety and quality of life. No evidence of publication bias was found based on Begg's and Egger's test. The meta-analysis confirmed that the baseline differences between the two groups were balanced. Subgroup analyses showed that disease sub-type, intervention method, comparator, subject location, trial design, trial period and outcome measure instrument made little difference in outcomes. The meta-regression may have identified the causes of heterogeneity as the intervention method, comparator and trial design. Music therapy was effective when patients received interactive therapy with a compared group. There was positive evidence to support the use of music therapy to treat disruptive behavior and anxiety; there were positive trends supporting the use of music therapy for the treatment of cognitive function, depression and quality of life. This study is registered with PROSPERO, number CRD42016036153.

Improvement in Stroke-induced Motor Dysfunction by Music-supported Therapy: A Systematic Review and Meta-analysis.

To conduct a meta-analysis of clinical trials that examined the effect of music-supported therapy on stroke-induced motor dysfunction, comprehensive literature searches of PubMed, Embase and the Cochrane Library from their inception to April 2016 were performed. A total of 10 studies (13 analyses, 358 subjects) were included; all had acceptable quality according to PEDro scale score. The baseline differences between the two groups were confirmed to be comparable. Compared with the control group, the standardized mean difference of 9-Hole Peg Test was 0.28 (-0.01, 0.57), 0.64 (0.31, 0.97) in Box and Block Test, 0.47 (0.08, 0.87) in Arm Paresis Score and 0.35 (-0.04, 0.75) in Action Research Arm Test for upper-limb motor function, 0.11 (-0.24, 0.46) in Berg Balance Scale score, 0.09 (-0.36, 0.54) in Fugl-Meyer Assessment score, 0.30 (-0.15, 0.74) in Wolf Motor Function Test, 0.30 (-0.15, 0.74) in Wolf Motor Function time, 0.65 (0.14, 1.16) in Stride length and 0.62 (0.01, 1.24) in Gait Velocity for total motor function, and 1.75 (0.94, 2.56) in Frontal Assessment Battery score for executive function. There was evidence of a positive effect of music-supported therapy, supporting its use for the treatment of stroke-induced motor dysfunction. This study was registered at PRESPERO (CRD42016037106).

Compound MQA, a Caffeoylquinic Acid Derivative, Protects Against NMDA-Induced Neurotoxicity and Potential Mechanisms In Vitro.

AIMS: Compound MQA (1,5-O-dicaffeoyl-3-O-[4-malic acid methyl ester]-quinic acid) is a natural derivative of caffeoylquinic acid isolated from Arctium lappa L. roots. However, we know little about the effects of MQA on the central nervous system. This study aims to investigate the neuroprotective effects and underlying mechanisms of MQA against the neurotoxicity of N-methyl-d-aspartate (NMDA). METHODS AND RESULTS: Pretreatment with MQA attenuated the loss of cell viability after SH-SY5Y cells treated with 1 mM NMDA for 30 min by MTT assay. Hoechst 33342 and Annexin V-PI double staining showed that MQA inhibited NMDA-induced apoptosis. In addition to preventing Ca(2+) influx, the potential mechanisms are associated with increases in the Bcl-2/Bax ratio, attenuation of cytochrome c release, caspase-3, caspase-9 activities, and expressions. Also, MQA inhibited NMDA-induced phosphorylation of ERK1/2, p38, and JNK1/2. Furthermore, deactivation of CREB, AKT, and GSK-3ß, upregulation of GluN2B-containing NMDA receptors (NMDARs), and downregulation of GluN2A-containing NMDARs were significantly reversed by MQA treatment. Computational docking simulation indicates that MQA possesses a well affinity for NMDARs. CONCLUSION: The protective effects of MQA against NMDA-induced cell injury may be mediated by blocking NMDARs. The potential mechanisms are related with mitochondrial apoptosis, ERK-CREB, AKT/GSK-3ß, p38, and JNK1/2 pathway.

Protective effects of Arctium lappa L. roots against hydrogen peroxide-induced cell injury and potential mechanisms in SH-SY5Y cells.

Accumulated evidence has shown that excessive reactive oxygen species (ROS) have been implicated in neuronal cell death related with various chronic neurodegenerative disorders. This study was designed to explore neuroprotective effects of ethyl acetate extract of Arctium lappa L. roots (EAL) on hydrogen peroxide (H2O2)-induced cell injury in human SH-SY5Y neuroblastoma cells. The cell viability was significantly decreased after exposure to 200 µM H2O2, whereas pretreatment with different concentrations of EAL attenuated the H2O2-induced cytotoxicity. Hoechst 33342 staining indicated that EAL reversed nuclear condensation in H2O2-treated cells. Meanwhile, TUNEL assay with DAPI staining showed that EAL attenuated apoptosis was induced by H2O2. Pretreatment with EAL also markedly elevated activities of antioxidant enzyme (GSH-Px and SOD), reduced lipid peroxidation (MDA) production, prevented ROS formation, and the decrease of mitochondrial membrane potential. In addition, EAL showed strong radical scavenging ability in 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) assays. Furthermore, EAL inhibited H2O2-induced apoptosis by increases in the Bcl-2/Bax ratio, decreases in cytochrome c release, and attenuation of caspase-3, caspase-9 activities, and expressions. These findings suggest that EAL may be regarded as a potential antioxidant agent and possess potent neuroprotective activity against H2O2-induced injury.