Antagonising Yin Yang 1 ameliorates the symptoms of lupus nephritis via modulating T lymphocyte signaling.

Lupus nephritis (LN) is a chronic complication of systemic lupus erythematosus (SLE). At present, no drugs are capable of delaying the progression of LN without a risk of serious side effects. There is thus a pressing need for further studies of LN pathogenesis to identify novel therapeutic targets and aid in the development of new approaches to treating this debilitating disease.

Oxymatrine Ameliorates Lupus Nephritis by Targeting the YY1-Mediated IL-6/STAT3 Axis.

Lupus nephritis (LN) is a severe form of systemic lupus erythematosus (SLE), characterized by inflammation in the renal glomeruli and tubules. Previous research has demonstrated that dihydroartemisinin (DHA) can reduce inflammatory damage in LN mouse models. Oxymatrine, which has similar biological properties to DHA, may also provide therapeutic benefits.

LATS2 degradation promoted fibrosis damage and rescued by vitamin K3 in lupus nephritis.

Background: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE). The limited treatment options for LN increase the economic burdens on patients. Because fibrotic progression leads to irreversible renal damage in LN patients and further progresses to chronic kidney disease (CKD) and the end stage of renal disease (ESRD), developing new targets to prevent LN fibrotic progression could lead to a feasible treatment strategy for LN patients.

An allosteric modulator of the adenosine A receptor potentiates the antilipolytic effect in rat adipose tissue.

The adenosine A receptor plays important roles in tuning free fatty acid (FFA) levels and represents an attractive target for metabolic disorders. Though remarkable progress has been achieved in the exploitation of effective (orthosteric) A receptor agonists in modulating aberrant FFA levels, the effect of A receptor allosteric modulation on lipid homeostasis is less investigated. Herein we sought to explore the effect of an allosteric modulator on the action of an A receptor orthosteric agonist in regulating the lipolytic process in vitro and in vivo.

Structure-Affinity and Structure-Kinetic Relationship Studies of Benzodiazepine Derivatives for the Development of Efficacious Vasopressin V Receptor Antagonists.

Vasopressin V receptors (VR) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of VR antagonists is critical to their efficacy in both ex vivo and in vivo models of ADPKD, we performed extensive structure-kinetic relationship (SKR) analyses on a series of benzodiazepine derivatives. We found that subtle structural modifications of the benzodiazepine derivatives dramatically changed their binding kinetics but not their affinity.

Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V Receptor in , Ex Vivo, and In Vivo Models of ADPKD.

The pharmacological activity of a small-molecule ligand is linked to its receptor residence time. Therefore, precise control of the duration for which a ligand binds to its receptor is highly desirable. Herein, we designed photoswitchable ligands targeting the vasopressin V receptor (VR), a validated target for autosomal dominant polycystic kidney disease (ADPKD).

Discovery of Novel -(5-(Pyridin-3-yl)-1-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound potently inhibited CDK7 with an IC value of 4 nM and showed high selectivity over CDKs.

PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity.

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over-proliferation of cyst-lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate-activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF-06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD.

Benzodiazepine Derivatives as Potent Vasopressin V Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.

Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V receptor (VR) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the VR. Among these derivatives, compound exhibited potent binding affinity to the VR ( = 9.

Long Residence Time at the Vasopressin V Receptor Translates into Superior Inhibitory Effects in and Models of Autosomal Dominant Polycystic Kidney Disease.

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V receptor (VR) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the VR antagonists, but not their affinity, was correlated with the efficacy in both and models of ADPKD.