Inhibition of alternative complement system and prolyl hydroxylase ameliorates anaemia of inflammation.

Chronic diseases associated with inflammation cause early destruction of RBCs. Complement system, part of innate immunity, is involved in such RBC destruction. Persistent inflammation causes kidney injury, leading to reduced erythropoietin release and functional iron deficiency, causing anaemia.

HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation.

HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia.

Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD.

Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter BAT1 (SLC6A19).

Amino acid restriction by inhibition of neutral amino acid transporter, BAT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of BAT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable BAT1 inhibitors.

In vivo antidiabetic activity of nimesulide due to inhibition of amino acid transport.

Inhibiting the intestinal and renal neutral amino acid transporter B0AT1 by genetic means has improved insulin sensitivity in mice, but there are no antagonists available for preclinical or clinical use. Since the anti-inflammatory agent nimesulide selectively inhibited B0AT1 in vitro, we hypothesized that nimesulide exhibits in vivo potential to restrict neutral amino acid absorption and, therefore, may improve insulin sensitivity. The dose-related effect of nimesulide (10 to 100 mg/kg, PO) on intestinal absorption of neutral amino acids was estimated in C57 mice.

Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice.

Background: Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis.

Effect of dual PPAR-α/γ agonist saroglitazar on diabetic retinopathy and oxygen-induced retinopathy.

Diabetic retinopathy is a serious complication of diabetes, marked by retinal vascular damage, inflammation, and angiogenesis. This study's objective was to assess the potential benefits of saroglitazar, a peroxisome proliferator-activated receptor-alpha/gamma (PPAR-α/γ) agonist in diabetic retinopathy. Diabetic retinopathy was induced by streptozotocin in Sprague Dawley rats.

Combination of Lorcaserin and GLP-1/glucagon Coagonist Improves Metabolic Dysfunction in Diet Induced-obese Mice.

Background: Obesity and diabetes are major metabolic disorders that progress to severe morbidity and mortality. Neuroendocrine mechanisms controlling energy balance indicate that combination therapies are needed to sustain weight loss. Lorcaserin was one of the approved therapies for the treatment of obesity, which is recently withdrawn because a safety clinical trial, shows an increased occurrence of cancer.

Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone.

Background: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. Coagonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are under clinical investigation for the treatment of obesity and type 2 diabetes. In this study, we have demonstrated the effect of a balanced coagonist in the treatment of NAFLD using mouse models.

Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease.

Background: Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like- Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity.

Coagonist of GLP-1 and glucagon decreases liver inflammation and atherosclerosis in dyslipidemic condition.

Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects.

Central administration of coagonist of GLP-1 and glucagon receptors improves dyslipidemia.

Coagonists of Glucagon-like peptide-1 (GLP-1) and glucagon receptors are under clinical investigation for treatment of obesity associated with diabetes. In addition to their role in glucose homeostasis, GLP-1 and glucagon modulate lipid metabolism. In this study, we have investigated the role of central GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) activation in regulation of lipid metabolism in cholesterol-fed hamsters.

Balanced Coagonist of GLP-1 and Glucagon Receptors Corrects Dyslipidemia by Improving FGF21 Sensitivity in Hamster Model.

Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters.

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.

Background And Purpose: Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life.

Experimental Approach: We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity.

Central and Peripheral Glucagon Reduces Hyperlipidemia in Rats and Hamsters.

Increased lipid levels in blood contribute to increasing the risk of diabetic complications. Glucagon exerts lipid lowering effects in diabetic state. However, the mechanism behind the lipid reduction by glucagon independent of glucose homeostasis is not well understood.

Is the Inhibition of Dipeptidyl Peptidase-4 (DDP-4) Enzyme Route Dependent and/or Driven by High Peak Concentration?- Seeking Answers with ZYDPLA1, a Novel Long Acting DPP-4 Inhibitor, in a Rodent Model.

ZYDPLA1 is a long acting enzyme dipeptidyl peptidase-4 (DPP-4) inhibitor. The comparative effect of DPP-4 inhibition after intravenous (IV) and oral administration of ZYDPLA1 in a rat model was evaluated to answer the question of route dependency and/or the need of high plasma levels of ZYDPLA1. The study was conducted using parallel design in male Wistar rats for IV/oral route (n=9 and 6, for IV and oral respectively).

Central GLP-1 receptor activation improves cholesterol metabolism partially independent of its effect on food intake.

Glucagon-like peptide-1 (GLP-1) receptor agonists modulate lipid metabolism, apart from controlling glucose homeostasis. We investigated the role of central GLP-1 receptor (GLP-1R) agonism in regulation of hepatic lipid metabolism in cholesterol-fed hamsters. Cholesterol-fed hamsters were treated by intracerebroventricular (i.