Search results for "INHIBITORS"
showing 10 items of 2336 documents
Anti-PCSK9 treatment: is ultra-low low-density lipoprotein cholesterol always good?
2018
Anti-PCSK9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-PCSK9 Mab inhibit the targeted low-density lipoprotein (LDL)-receptor degradation induced by PCSK9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy. Though these drugs proved to be very safe in the short-term, little is known about the possible long-term effects, due to the short period of their marketing. The genetic low cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a…
Gut microbiota and cancer: How gut microbiota modulates activity, efficacy and toxicity of antitumoral therapy
2019
Gut microbiota is involved in gastrointestinal carcinogenesis. Also, it modulates the activity, efficacy and toxicity of several chemotherapy agents, such as gemcitabine, cyclophosphamide, irinotecan, cisplatin and 5-Fluorouracil, and target therapy, such as tyrosine kinase inhibitors. More recently, accumulating data suggest that the composition of gut microbiota may also affect efficacy and toxicity of cancer immunotherapy. Therefore, the manipulation of gut microbiota through antibiotics, probiotics, prebiotics or fecal transplantation has been investigating with the aim to improve efficacy and mitigate toxicity of anticancer drugs.
Characterization of a mutant form of human apolipoprotein B (Thr26_Tyr27del) associated with familial hypobetalipoproteinemia
2016
We have previously identified a deletion mutant of human apoB [apoB (Thr26_Tyr27del)] in a subject with primary hypobetalipoproteinemia. The present study determined the effect of Thr26_Tyr27del mutation on apoB secretion using transfected McA-RH7777 cells. Transient or stable transfection of apoB-48 containing the Thr26_Tyr27del mutation showed drastically reduced secretion of the mutant as compared to wild-type apoB-48. No lipoproteins containing the mutant apoB-48 were secreted into the medium. Incubation of transfected cells in a lipid-rich medium in the presence of cycloheximide showed rapid turnover of cell-associated mutant apoB-48 as compared to that of wild-type apoB-48. Immunofluo…
PACAP38 and PAC1 receptor blockade: a new target for headache?
2018
Abstract Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated. Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacol…
GSK-3 in liver diseases: Friend or foe?
2020
Liver diseases, including hepatitis due to hepatitis B or C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma pose major challenges for overall health due to limited curative treatment options. Thus, there is an urgent need to develop new therapeutic strategies for the treatment of these diseases. A better understanding of the signaling pathways involved in the pathogenesis of liver diseases can help to improve the efficacy of emerging therapies, mainly based on pharmacological approaches, which influence one or more specific molecules involved in key signal transduction pathways. These emerging therapies are very promising for the prevention and treatment of …
PCSK9-D374Y mediated LDL-R degradation can be functionally inhibited by EGF-A and truncated EGF-A peptides: An in vitro study.
2019
Abstract Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) through the LDLR epidermal growth factor-like repeat A (EGF-A) domain and induces receptor internalization and degradation. PCSK9 has emerged as a novel therapeutic target for hypercholesterolemia. Clinical studies with PCSK9 inhibiting antibodies have demonstrated strong LDL-c lowering effects, but other therapeutic approaches using small molecule inhibitors for targeting PCSK9 functions may offer supplementary therapeutic options. The aim of our study was to evaluate the effect of synthetic EGF-A analogs on mutated (D374Y) PCSK9-D374Y mediated LDLR degradatio…
Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placeb…
2018
Summary Background Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotec…
Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference
2020
Proper trial design is critical for the success of clinical investigations. Hepatocellular carcinoma (HCC) is a complex disease that has several unique properties. In 2008, after the approval of sorafenib, a panel of experts proposed guidelines for trial design and endpoints in HCC that have been instrumental during the last decade and provided a framework to allow an homogeneous analysis of reported investigations. Since then, several phase III studies have been reported and novel challenges have emerged. A panel of experts conveyed by AASLD organized a Special Topic Conference on trial design and endpoints to address those emerging challenges. This review summarizes the analysis and concl…
Reverse screening on indicaxanthin from Opuntia ficus-indica as natural chemoactive and chemopreventive agent
2018
Indicaxanthin is a bioactive and bioavailable betalain pigment extracted from Opuntia ficus indica fruits. Indicaxanthin has pharmacokinetic proprieties, rarely found in other phytochemicals, and it has been demonstrated that it provides a broad-spectrum of pharmaceutical activity, exerting anti-proliferative, anti-inflammatory, and neuromodulator effects. The discovery of the Indicaxanthin physiological targets plays an important role in understanding the biochemical mechanism. In this study, combined reverse pharmacophore mapping, reverse docking, and text-based database search identified Inositol Trisphosphate 3-Kinase (ITP3K-A), Glutamate carboxypeptidase II (GCPII), Leukotriene-A4 hydr…
Screening of potent phytochemical inhibitors against SARS-CoV-2 protease and its two Asian mutants
2021
Abstract Background COVID-19, declared a pandemic in March 2020 by the World Health Organization is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The virus has already killed more than 2.3 million people worldwide. Object The principal intent of this work was to investigate lead compounds by screening natural product library (NPASS) for possible treatment of COVID-19. Methods Pharmacophore features were used to screen a large database to get a small dataset for structure-based virtual screening of natural product compounds. In the structure-based screening, molecular docking was performed to find a potent inhibitor molecule against the main protease (Mpro) of SARS-…