Klausenturner0201

Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.Cyclic nucleotide phosphodiesterases (PDEs) are superfamily of enzymes that regulate the spatial and temporal relationship of second messenger signaling in the cellular system. Among the 11 different families of PDEs, phosphodiesterase 1 (PDE1) sub-family of enzymes hydrolyze both 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in a mutually competitive manner. The catalytic activity of PDE1 is stimulated by their binding to Ca2+/calmodulin (CaM), resulting in the integration of Ca2+ and cyclic nucleotide-mediated signaling in various diseases. The PDE1 family includes three subtypes, PDE1A, PDE1B and PDE1C, which differ for their relative affinities for cAMP and cGMP. These isoforms are differentially expressed throughout the body, including the cardiovascular, central nervous system and other organs. Thus, PDE1 enzymes play a critical role in the pathophysiology of diseases through the fundamental regulation of cAMP and cGMP signaling. This comprehensive review provides the current research on PDE1 and its potential utility as a therapeutic target in diseases including the cardiovascular, pulmonary, metabolic, neurocognitive, renal, cancers and possibly others.Recent years have seen a renewed interest on the possible therapeutic exploitations of specific cannabinoids derived from the Cannabis sativa plant. Thus far, the most studied non-psychotomimetic cannabinoid is cannabidiol (CBD), which has shown promising therapeutic potential for relieving a variety of neurological diseases. However, also its propyl analogue, cannabidivarin (CBDV), has recently gained much attention as a potential therapeutic agent for the management of disabling neurological conditions. This review aims at providing a comprehensive and updated overview of the available animal and human data, which have investigated the possible therapeutic potential of CBDV for the management of epilepsy and autism spectrum disorder.Heterocyclic scaffolds are widely utilized for drug design by taking into account the molecular structure of therapeutic targets that are related to a broad spectrum of ailments, including tumors. Such compounds display various covalent and non-covalent interactions with the specific residues of the target proteins while causing their inhibition. There is a substantial number of heterocyclic compounds approved for cancer treatment, and these compounds function by interacting with different therapeutic targets involved in tumorogenesis. In this review, we trace and emphasize the privileged heterocyclic pharmacophores that have immense potency against several essential chemotherapeutic tumor targets microtubules, kinases and carbonic anhydrases. Potent compounds currently undergoing pre-clinical and clinical studies have also been assessed for ascertaining the effective class of chemical scaffolds that have significant therapeutic potential against multiple malignancies. In addition, we also describe briefly the role of heterocyclic compounds in various chemotherapy regimens. GSK2656157 The optimized molecular hybridization of delineated motifs may result in the discovery of more active anticancer therapeutics and circumvent the development of resistance by specific targets in the future.Pancreatic cancer is one of the malignant tumors with poor prognosis. The molecular mechanisms of pancreatic oncogenesis and malignant progression are not fully elucidated. Several key signaling pathways, such as Notch, Wnt and hedgehog pathways, are important to drive pancreatic carcinogenesis. Recently, noncoding RNAs, especially circular RNAs (circRNAs), have been characterized to participate into pancreatic cancer development. Therefore, in this review article, we describe the association between circRNAs and pancreatic cancer prognosis. Moreover, we discuss how circRNAs are involved in regulation of cellular processes in pancreatic cancer, including proliferation, apoptosis, cell cycle, migration, invasion, EMT, metastasis, angiogenesis, drug resistance and immune escape. Furthermore, we mention that several compounds could regulate the expression of circRNAs, indicating that targeting circRNAs by compounds might be helpful for treating pancreatic cancer patients.In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was found to cause cardiac valvulopathy. Available evidence indicates that appetite suppression and cardiac valvulopathy are mediated by different serotonergic mechanisms. In particular, appetite suppression can be ascribed mainly to the enantiomers d-fenfluramine and d-norfenfluramine, the primary metabolite of d-fenfluramine, whereas cardiac valvulopathy can be ascribed mainly to d-norfenfluramine. Because of early observations of markedly improved seizure control in some forms of epilepsy, fenfluramine remained available in Belgium through a Royal Decree after 1997 for use in a clinical trial in patients with Dravet syndrome at average dosages lower than those generally information about the comparative activity of the individual enantiomers of fenfluramine and norfenfluramine in experimental models of seizures and epilepsy, and on receptors systems considered to be involved in antiseizure effects. Preliminary data suggest that l-fenfluramine retains prominent antiseizure effects in a genetic zebrafish model of Dravet syndrome. If these findings are confirmed and extended to other seizure/epilepsy models, there would be an incentive for a chiral switch from racemic-fenfluramine to l-fenfluramine, which could minimize the risk of cardiovascular toxicity and reduce the incidence of adverse effects such as loss of appetite and weight loss.Iron is an essential element for the mammalian body however, its homeostasis must be regulated accurately for appropriate physiological functioning. Alterations in physiological iron levels can lead to moderate to severe iron disorders like chronic and acute iron deficiency (anemia) or iron overload. Hepcidin plays an important role in regulating homeostasis between circulating iron and stored iron in the cells as well as the absorption of dietary iron in the intestine. Inflammatory disorders restrict iron absorption from food due to increased circulating levels of hepcidin. Increased production of hepcidin causes ubiquitination of ferroportin (FPN) leading to its degradation, thereby retaining iron in the spleen, duodenal enterocytes, macrophages, and hepatocytes. Hepcidin inhibitors and antagonists play a consequential role to ameliorate inflammation-associated anemia. Many natural and synthesized compounds, able to reduce hepcidin expression during inflammation have been identified in recent years. Few of which are currently at various phases of clinical trial. This article comprises a comprehensive review of therapeutic approaches for the efficient treatment of anemia associated with inflammation. Many strategies have been developed targeting the hepcidin-FPN axis to rectify iron disorders. Hepcidin modulation with siRNAs, antibodies, chemical compounds, and plant extracts provides new insights for developing advanced therapeutics for iron-related disorders. Hepcidin antagonist's treatment has a high potential to improve iron status in patients with iron disorders, but their clinical success needs further recognition along with the identification and application of new therapeutic approaches.Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification "soluble ligands" that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible thaargest protein target class in medicine, with much potential for the drugs targeting them.Cancer immunotherapy is an option to enhance physiological defence mechanism to fight cancer, where natural substances (e.g., antigen/antibody) or small synthetic molecule can be utilized to improve and restore the immune system to stop or slacken the development of malignant cells, stop metastasis and/or help the immune response with synthetic monoclonal antibodies (mAbs) and tumour-agnostic therapy to eliminate cancer cells. Interaction between the programmed cell death ligand 1 (PD-L1) and its receptor (programmed cell death protein 1, PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) linked signalling pathways have been identified as perilous towards the body's immune mechanism in regulating the progression of cancer. It is known that certain cancers use these pathways to evade the body's defence mechanism. The immune system is capable of responding to cancer by stalling these trails with specific synthetic antibodies or immune checkpoint inhibitors, which can ultimately either stop or slow cancer cell development.