Cell lines

human umbilical mesenchymal stem cells(HUMSCs)

Preparation Method

MTT assay was used to test the toxicity of VX-765. Oxygen-glucose deprivation (OGD) was applied to mimic ischemic environment in vitro experiments, and The apoptosis of HUMSCs incubated with VX-765 was assessed 12 or 24 hours after OGD exposure.

Reaction Conditions

10μM VX-765 for 12, 24h.

Applications

Compared to OGD groups, TUNEL-positive cells, IL-1β, and IL-6 decreased while IL-10 increased in VX-765+OGD group. The result demonstrate the anti-apoptosis and anti- inflammatory role of VX-765 in HUMSCs.

Animal models

CD1 (ICR) mice

Preparation Method

CD1 (ICR) mice were injected intraperitoneally with 55 mg/kg streptozotocin(STZ). Mice with blood glucose level over 300 mg/dL were considered diabetic.Diabetic mice were administered with VX-765 for 8 weeks.The treatment with VX-765 was initiated 2 weeks after STZ injection

Dosage form

100mg/kg VX-765, intraperitoneal(i.p.) injection

Applications

Administration of VX-765 in diabetic mice effectively ameliorated renal function, compared with that of untreated diabetic mice.VX-765 treatment did not affect blood glucose level or body weight, illustrating that VX-765 ameliorated diabetic nephropathy independent of its metabolic effects.

• Oxid Med Cell Longev (2022).

VX-765 is a newly developed, selective, small molecule caspase-1 inhibitor that can pass the blood-brain barrier and reduce inflammation in vitro and in vivo^[1].

VX-765 potently and specifically inhibited human Casp1 (IC50 3.68 nM)^[2]. Increases of autophagy-related proteins were detected in VX-765-pretreated human umbilical mesenchymal stem cells(HUMSCs), indicating the potential of VX-765 for up-regulating autophagy. Meanwhile, increased p-AMPK and decreased p-mTOR were detected in VX-765-pretreated HUMSCs. Furthermore, the anti-inflammatory and anti-apoptosis effect of VX-765 could be abolished by an autophagy inhibitor or AMPK inhibitor^[3]

In vivo，VX-765 ameliorated renal dysfunction, tubular injury, and renal inflammation in mice with DN, but had no effect on blood glucose level or body weight, illustrating that VX-765 represents a novel and efficacious therapeutic treatment for DN without increasing the risk of hypoglycemia in diabetic patients^[4]

References:
[1]. Boxer MB, Quinn AM, et al. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. ChemMedChem. 2010 May 3;5(5):730-8.
[2]. Flores J, Noel A, et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun. 2018 Sep 25;9(1):3916.
[3]. Sun Z, Gu L, et al. VX-765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke-induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway. CNS Neurosci Ther. 2020 Sep;26(9):952-961.
[4]. Wen S, Deng F, et al. VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation. J Diabetes Investig. 2022 Jan;13(1):22-33.