Notes

Hereditary ataxias: bring up to date on category along with analysis techniques.
01). Importantly, no signs of pathological complication as a result of treatment were found. In addition, Titanocref and Titanofin treatment reduced angiogenesis by 38% and 54%, respectively. Microarray and qRT-PCR analysis of ccRCC Caki-1 cells treated with Titanocref revealed that the compound alters apoptosis, JNK MAP kinase, and ROS pathways within 3 h of treatment. We further show activation of apoptosis by Titanocref and Titanofin in vivo by caspase 3 assay. Titanocref is active against additional kidney cancer cells. Titanocref and Titanofin are therefore promising candidates for further evaluation toward clinical application in the treatment of ccRCC.Prostaglandin E2 (PGE2) is elevated in the brain by excitotoxic insults and, in turn, aggravates the neurotoxicity mainly through acting on its Gαs-coupled receptor EP2, inspiring a therapeutic strategy of targeting this key proinflammatory pathway. Herein, we investigated the effects of several highly potent and selective small-molecule antagonists of the EP2 receptor on neuronal excitotoxicity both in vitro and in vivo. EP2 inhibition by these novel compounds largely decreased the neuronal injury in rat primary hippocampal cultures containing both neurons and glia that were treated with N-methyl-d-aspartate and glycine. Using a bioavailable and brain-permeant analogue TG6-10-1 that we recently developed to target the central EP2 receptor, we found that the poststroke EP2 inhibition in mice decreased the neurological deficits and infarct volumes as well as downregulated the prototypic inflammatory cytokines in the brain after a transient ischemia. see more Our preclinical findings together reinforced the notion that targeting the EP2 receptor represents an emerging therapeutic strategy to prevent the neuronal injury and inflammation following ischemic stroke.Pulmonary arterial hypertension is a rare and devastating disease characterized by an abnormal chronic increase in pulmonary arterial pressure above 20 mmHg at rest, with a poor prognosis if not treated. Currently, there is not a single fully effective therapy, even though a dozen of drugs have been developed in the last decades. Pulmonary arterial hypertension is a multifactorial disease, meaning that several molecular mechanisms are implicated in its pathology. The main molecular pathways regulating the pulmonary vasomotor tone-endothelin, nitric oxide, and prostacyclin-are the most biologically and therapeutically explored to date. However, drugs targeting these pathways have already found their limitations. In the last years, translational research and clinical trials have made a strong effort in suggesting and testing novel therapeutic strategies for this disease. These approaches involve targeting the main molecular pathways with novel drugs, drug repurposing for novel targets, and also using combinatorial therapies. In this review, we summarize current strategies and drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, as well as, the emerging new drugs proposed to cope with vascular remodelling, metabolic switch, perivascular inflammation, epigenetic modifications, estrogen deregulation, serotonin, and other neurohumoral mechanisms characteristic of this disease. Nowadays, pulmonary arterial hypertension remains an incurable disease; however, the incoming new knowledge makes us believe that new promising therapies are coming to the clinical arena soon.Trefoil factor family peptides (TFF1, TFF2, and TFF3) are key players in protecting, maintaining, and repairing the gastrointestinal tract. Accordingly, they have the therapeutic potential to treat and prevent a variety of gastrointestinal disorders associated with mucosal damage. TFF peptides share a conserved motif, including three disulfide bonds that stabilize a well-defined three-loop-structure reminiscent of a trefoil. Although multiple functions have been described for TFF peptides, their mechanisms at the molecular level remain poorly understood. This review presents the status quo of TFF research relating to gastrointestinal disorders. Putative TFF receptors and protein partners are described and critically evaluated. The therapeutic potential of these peptides in gastrointestinal disorders where altered mucosal biology plays a crucial role in the underlying etiology is discussed. Finally, areas of investigation that require further research are addressed. Thus, this review provides a comprehensive update on TFF literature as well as guidance toward future research to better understand this peptide family and its therapeutic potential for the treatment of gastrointestinal disorders.Heart failure (HF) is a global pandemic with significant mortality and morbidity. Despite current medications, 50% of individuals die within 5 years of diagnosis. Of these deaths, 30-50% will be a result of sudden cardiac death from ventricular arrhythmias. This review discusses two stress-induced mechanisms, phosphorylation from chronic β-adrenoceptor (β-AR) stimulation and thiol modifications from oxidative stress, and how they modulate the cardiac ryanodine receptor type 2 (RyR2) and foster an arrhythmogenic phenotype. Calcium (Ca2+) is the ubiquitous secondary messenger of excitation-contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca2+ is released from the sarcoplasmic reticulum (SR) by RyR2. The open probability of RyR2 is under the dynamic influence of co-proteins, ions, and kinases that are in strict balance to ensure normal physiological functioning. In HF, chronic β-AR activity and production of reactive oxygen species and reactive nitrogen species provide two stress-induced mechanisms uncoupling RyR2 control, resulting in pathological diastolic SR Ca2+ leak. This increased cytosolic [Ca2+] promotes Ca2+ extrusion via the local Na+/Ca2+ exchanger, resulting in net sarcolemmal depolarization, delayed after depolarization and ventricular arrhythmia. Experimental models researching oxidative stress and phosphorylation have aimed to identify how post-translational modifications to the RyR2 macromolecular complex, and the associated Na+/Ca2+ cycling proteins, result in pathological Ca2+ handling and diastolic leak. However, the causative molecular changes remain controversial and undefined. Through understanding the molecular mechanisms that produce an arrhythmic phenotype, novel therapeutic targets to treat HF and prevent its malignant course can be identified.
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