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.

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.

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.

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.

Neuroprotective effects of Arctium lappa L. roots against glutamate-induced oxidative stress by inhibiting phosphorylation of p38, JNK and ERK 1/2 MAPKs in PC12 cells.

Many studies have shown that glutamate-induced oxidative stress can lead to neuronal cell death involved in the development of neurodegenerative diseases. In this work, protective effects of ethyl acetate extract (EAE) of Arctium lappa L. roots against glutamate-induced oxidative stress in PC12 cells were evaluated. Also, the effects of EAE on antioxidant system, mitochondrial pathway, and signal transduction pathway were explored. Pretreatment with EAE significantly increased cell viability, activities of GSH-Px and SOD, mitochondrial membrane potential and reduced LDH leakage, ROS formation, and nuclear condensation in a dose-dependent manner. Furthermore, western blot results revealed that EAE increased the Bcl-2/Bax ratio, and inhibited the up-regulation of caspase-3, release of cytochrome c, phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). Therefore, our results indicate that EAE may be a promising neuroprotective agent for the prevention and treatment of neurodegenerative diseases implicated with oxidative stress.

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition.

AIM: 2-(4,6-Dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c) is one of isoindolone derivatives with antiproliferative activity against human umbilical vein endothelial cells (HUVECs). The aim of this study was to investigate its antitumor activity in vitro and anti-angiogenic effects in vitro and in vivo. METHODS: K562 leukemic cells and HUVECs were used for in vitro studies. Cell viability was examined using MTT assay. Cell apoptosis and mitochondrial transmembrane potential (Δψm) were detected with flow cytometry. Tube formation and migration of HUVECs were studied using two-dimensional Matrigel assay and wound-healing migration assay, respectively. VEGF levels were analyzed with RT-PCR and Western blotting. A zebrafish embryo model was used for in vivo anti-angiogenic studies. The molecular mechanisms for apoptosis in K562 cells and antiangiogenesis were measured with Western blotting. RESULTS: In antitumor activity studies, QSN-10c suppressed the viability of K562 cells and induced apoptosis in dose- and time-dependent manners. Furthermore, QSN-10c dose-dependently decreased the Δψm in K562 cells, increased the release of cytochrome c and the level of Bax, and decreased the level of Bcl-2, suggesting that QSN-10c-induced apoptosis of K562 cells was mediated via the mitochondrial apoptotic pathway. In anti-angiogenic activity studies, QSN-10c suppressed the viability of HUVECs and induced apoptosis in dose dependent manners. QSN-10c treatment did not alter the Δψm in HUVECs, but dose-dependently inhibited the expression of VEGF, inhibited the tube formation and cell migration in vitro, and significantly suppressed the number of ISVs in zebrafish embryos in vivo. Furthermore, QSN-10c dose-dependently suppressed the phosphorylation of AKT and GSK3ß in both HUVECs and K562 cells. CONCLUSION: QSN-10c is a novel antitumor compound that exerts both antitumor and anti-angiogenic effects via inhibiting the PI3K/AKT/GSK3ß signaling pathway.