The role of family of cation-chloride cotransporters and drug discovery methodologies.

The () of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl loading.

Genomic and phenotypic characterization of finger millet indicates a complex diversification history.

Advances in sequencing technologies mean that insights into crop diversification can now be explored in crops beyond major staples. We use a genome assembly of finger millet, an allotetraploid orphan crop, to analyze DArTseq single nucleotide polymorphisms (SNPs) at the whole and sub-genome level. A set of 8778 SNPs and 13 agronomic traits was used to characterize a diverse panel of 423 landraces from Africa and Asia.

Neuronal K-Cl cotransporter KCC2 as a promising drug target for epilepsy treatment.

Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABA receptor (GABAR) regulates Cl and bicarbonate (HCO) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K-Cl cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl concentration, ensuring GABAR-mediated inhibition.

Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting.

Potassium chloride cotransporters 2 (KCC2) is a member of the solute carrier family 12 (SLC12) of cation-chloride-cotransporters (CCCs), found exclusively in the neuron and is essential for the proper functioning of Cl homeostasis and consequently functional GABAergic inhibition. Failure in proper regulation of KCC2 is deleterious and has been associated with the prevalence of several neurological diseases, including epilepsy. There has been considerable progress with regard to understanding the mechanisms involved in the regulation of KCC2, accredited to the development of techniques that enable researchers to study its functions and activities; either via direct (assessing kinase regulatory sites phosphorylation) or indirect (observing and monitoring GABA activity) investigations.

Polyphenol-rich leaf extract abates cerebral ischemia/reperfusion-induced disturbed glutamate-ammonia metabolism and multiorgan toxicity in rats.

This study investigated the protective properties of leaf extract (SML), in cerebral ischemia/reperfusion (I/R) mediated toxicity in the brain, liver, and kidney of male Wistar rats. Animals were subjected to 30 min of bilateral common carotid artery occlusion followed by 24 h of reperfusion (BCCAO/R). The animals were divided into sham, I/R, and I/R treated with SML (25, 50 and 100 mg/kg) or quercetin (20 mg/kg) groups.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.

Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).

Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.

Dihydroquercetin improves rotenone-induced Parkinsonism by regulating NF-κB-mediated inflammation pathway in rats.

This study examined the effect of dihydroquercetin (DHQ), also knofigurewn as taxifolin, on rotenone-induced Parkinsonism in rats. Male Wistar rats were administered 1.5 mg/kg rotenone for 10 days and subsequently treated with 0.

Role of the cation-chloride-cotransporters in the circadian system.

The circadian system plays an immense role in controlling physiological processes in our body. The suprachiasmatic nucleus (SCN) supervises this system, regulating and harmonising the circadian rhythms in our body. Most neurons present in the SCN are GABAergic neurons.

VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling.

Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.

Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na-K-Cl and K-Cl cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway.

In-silico analysis of the inhibition of the SARS-CoV-2 main protease by some active compounds from selected African plants.

Objectives: Over the years, and have been shown to possess some antiviral characteristics. This study applies molecular docking techniques to assess inhibitory effects of some bioactive compounds from the plants mentioned above against the main protease (Mpro), a key protein involved in SARS-CoV-2 replication. Furthermore, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles for screened compounds were predicted .

Modulatory activities of polyphenols on crude acetylene-induced cardiac and hepatic dysfunctions in a rat model.

Exposure to crude acetylene can occur in occupational settings. This study assessed the modulatory activities of selected polyphenols on the hematotoxic, cardiotoxic, and hepatotoxic effects of crude acetylene. Wistar rats were exposed to 58 000 ppm crude acetylene for 10 min at 12 h intervals for 30 days.

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington's Disease and Its Comorbidities.

Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K-Cl co-transporter-2 (KCC2) and Na-K-Cl co-transporter-1 (NKCC1). These CCCs are differentially expressed throughout the course of development, thereby determining the excitatory-to-inhibitory γ-aminobutyric acid (GABA) switch. GABAergic excitation (depolarisation) is important in controlling the healthy development of the nervous system; as the brain matures, GABAergic inhibition (hyperpolarisation) prevails.

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2.

SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2.

Cognitive impairment by non-insulin-dependent diabetes mellitus was attenuated by dietary supplements of marble vine (Dioclea reflexa) and plantain (Musa paradisiaca) dough meals in albino rats.

This study investigates the protective effect of formulated marble vine/plantain dough meals on cognitive impairment in diabetic rats. Wistar rats were divided into eight groups (n = 6) and fed with HFD for 14 days and a single dose of streptozotocin intraperitoneally on the 14th day (except control rats). Diabetic rats were treated with formulated diets and metformin.

Effects of co-administration of Ganoderma terpenoid extract with chloroquine on inflammatory markers and antioxidant status in Plasmodium berghei-infected mice.

Objective: To understand the protective effects of Ganoderma terpenoid extract (GTE) against Plasmodium berghei-malarial infection in mice, the present study was carried out to evaluate the effects of GTE in combination with chloroquine disulphate (CQ) on erythrocyte-selected inflammatory markers and antioxidant defense status in P. berghei-infected mice.

Methods: P.

Toxicological and pharmacological assessment of a multiherbal phytopharmaceutical on Triton X-1339-induced hyperlipidemia and allied biochemical dysfunctions.

This study investigated the safety and therapeutic effect of a multiherbal tea (MHT) on Triton X-1339-induced hyperlipidemia and associated biochemical and tissue dysfunctions. An infusion of the MHT was assessed for phytoconstituents, proximate and mineral composition, and antioxidant activity. Wistar rats administered 200 mg/kg Triton X-1399 were post-treated with MHT for 14 days followed by biochemical estimations in serum, heart, liver, and kidney of animals.

Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma.

Purpose: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG.

Ameliorative effect of quercetin, catechin, and taxifolin on rotenone-induced testicular and splenic weight gain and oxidative stress in rats.

Background The physiological functions of the testis and spleen can be affected through several cellular and molecular mechanisms such as the generation of reactive oxygen species (ROS) that causes oxidative stress. This study aimed at investigating the protective effect of catechin, quercetin, and taxifolin in rotenone-induced testicular and splenetic toxicity. Methods Male Wistar rats were administered with 1.

Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease in which the dystrophin coding for a membrane stabilizing protein is mutated. Recently, the vasculature has also shown to be perturbed in DMD and DMD model mdx mice. Recent DMD transcriptomics revealed the defects were correlated to a vascular endothelial growth factor (VEGF) signaling pathway.

SRD005825 Acts as a Pharmacologic Chaperone of Opsin and Promotes Survival of Photoreceptors in an Animal Model of Autosomal Dominant Retinitis Pigmentosa.

Purpose: Mutations in , the gene for a rhodopsin, are a leading cause of autosomal dominant retinitis pigmentosa. The objective of this study was to determine if a synthetic retinal analogue (SRD005825) serves as a pharmacologic chaperone to promote appropriate membrane trafficking of a mutant version of human rhodopsin.

Methods: A tetracycline-inducible cell line was used to produce human wild-type and T17M opsin.

Modulation of key enzymes linked to Parkinsonism and neurologic disorders by Antiaris africana in rotenone-toxified rats.

Background The physiopathologies of many neurologic diseases are characterized by related biochemical dysfunctions that could be explored as drug targets. This study evaluated the effect of a methanol leaf extract of Antiaris africana (MEA) on critical bioindices of Parkinsonism and related neurologic dysfunctions in rats with rotenone-induced neurotoxicity. Methods Animals were administered 50 or 100 mg/kg MEA for 14 consecutive days.

Pharmacokinetics and intraocular pressure-lowering activity of TAK-639, a novel C-type natriuretic peptide analog, in rabbit, dog, and monkey.

TAK-639 is a topical, 9-amino acid, synthetic, C-type natriuretic peptide analog in development for the treatment of primary open-angle glaucoma and ocular hypertension. This study investigated the impact of TAK-639 on intraocular pressure (IOP), the levels of TAK-639 in aqueous humor, and the pharmacokinetic/pharmacodynamic relationship of TAK-639 following topical ocular administration to normotensive female Dutch belted rabbits, beagle dogs, and cynomolgus monkeys. In the IOP studies, rabbits (n = 6/group) and dogs (n = 8/group) received a single topical ocular dose of TAK-639 0.

Effects of Catechin, Quercetin and Taxifolin on Redox Parameters and Metabolites Linked with Renal Health in Rotenone-toxified Rats.

Nephrotoxicity, with the attendant risk of progression to kidney failure, is a growing problem in many parts of the world. Current orthodox treatment options for nephrotoxicity and kidney failure are limited and there is need for alternative or complementary approaches. This study aimed at evaluating the effect of three structurally related flavonoids, catechin, quercetin and taxifolin on renal redox and metabolite biochemical disturbances in rotenone intoxicated animals.