Pancreastatin inhibitor, PSTi8 ameliorates metabolic health by modulating AKT/GSK-3β and PKCλ/ζ/SREBP1c pathways in high fat diet induced insulin resistance in peri-/post-menopausal rats

Valicherla, Guru R.; Gupta, Anand P.; Hossain, Zakir; Riyazuddin, Mohammed; Syed, Anees A.; Husain, Athar; Lahiri, Shibani; Dave, Kandarp M.; Gayen, Jiaur R.

doi:10.1016/j.peptides.2019.170147

Cited by 19 publications

(17 citation statements)

References 55 publications

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“…Increased PST levels were detected in diabetic patients ( Funakoshi et al., 1990 ; Kim et al., 2010 ). PSTi8 is a well elucidated potential inhibitor of endogenous peptide PST, as we mentioned in our previous studies ( Gupta et al., 2019 ; Valicherla et al., 2019 ). Above all, we optimized the Met and PSti8 doses in combination for further in-vitro and in-vivo studies and found that Met 50 μM and PSTi8 100 nM is best possible combination in order to use in in-vitro experiments while Met 150 mg/kg with PSTi8 2.5 mg/kg combination worked best among other combination doses during acute treatment ( Figure 2 A–E) in HFD induced diabetic mice.…”

Section: Discussionmentioning

confidence: 74%

“…In this regard, we identified increased expression of Pepck and G6pase, important regulators of gluconeogenesis, and significantly reduced expression of these genes (Figure 7A) in HFD þ Comb group. Furthermore, the expression of proinflammatory markers is intriguingly associated with increased fat accumulation in the liver and the progression of IR (van der Heijden et al, 2015). Results displayed elevated expression of proinflammatory markers TNF-α, IL-6, and IL-1β in the liver of HFD mice.…”

Section: Discussionmentioning

confidence: 99%

“…Hence there is an urgent need for combination therapy with Met at lower doses to preserve glycemic control. PSTi8, an emerging peptide, reported to have antidiabetic effects by inhibiting PST derived IR and inflammation ( Bandyopadhyay et al., 2015 ; Funakoshi et al., 1990 ; Hossain et al., 2018 ; Valicherla et al., 2019 ). Chronic treatment of PSTi8 improved glycemic control, glucose tolerance, and IR, as stated in previous research ( Valicherla et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice

Singh

Garg

Goand

et al. 2020

Heliyon

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In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepatic lipid accumulation, insulin resistance (IR), and culminates in type 2 diabetes (T2D). Metformin (Met) is a widely known first-line drug for the treatment of T2D. We previously unveiled PSTi8, an inhibitor of PST, comprising antidiabetic property. Hence, we hypothesized that combination therapy of Met and PSTi8, at reduced therapeutic doses, would mitigate HFD-induced IR by inhibiting hepatic Fetuin-A in mice model of T2D. C57BL/6 mice were fed HFD for 12 weeks, followed by treatment with Met, PSTi8, and its combination for 10 days. Glucose and insulin tolerance tests were conducted. Circulatory levels of PST, Fetuin-A, and lipid markers were determined. Also, the mRNA and protein expression of Fetuin-A was assessed by qPCR, western blotting, and immunofluorescence. Moreover, the energy expenditure was measured by comprehensive laboratory animal monitoring system (CLAMS). Combination therapy displayed improved PST, Fetuin-A, and lipid profile in plasma. We also found reduced hepatic Fetuin-A, which reduced inhibitory phosphorylation of IRS and increased phosphorylation of AKT. Consequently, ameliorated hepatic lipogenesis, gluconeogenesis, and inflammation. Also, combination treatment attenuated Fetuin-A expression, lipid accumulation, and glucose production in palmitate-induced HepG2 cells. Altogether current study promulgates the beneficial effect of combination therapy of Met and PSTi8 (comparable to alone higher therapeutic doses) to ameliorate Fetuin-A activation, hepatic lipid accumulation, insulin resistance, and associated progressive pathophysiological alterations in T2D.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice

Singh

Garg

Goand

et al. 2020

Heliyon

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“…Pancreastatin inhibitor peptide-8 (PSTi8), which consists of 21 amino acids (PEGKGEQEHSQQKEEEEEMAV-amide), exerts antidiabetic effects. These effects have been demonstrated by cell and animal studies [ 13 , 142 , 143 , 144 ]. PSTi8 decreases pancreastatin-induced insulin resistance in HepG2 cells (human liver cancer cells) and 3T3-L1 cells (mouse adipocyte cells) [ 13 , 142 ].…”

Section: Diabetesmentioning

confidence: 92%

“…These effects have been demonstrated by cell and animal studies [ 13 , 142 , 143 , 144 ]. PSTi8 decreases pancreastatin-induced insulin resistance in HepG2 cells (human liver cancer cells) and 3T3-L1 cells (mouse adipocyte cells) [ 13 , 142 ]. PSTi8 increases glucose uptake via enhanced glucose transporter type 4 in L6 cells (rat skeletal myoblast cells) [ 13 , 143 ] and decreases hepatic glucose release [ 144 ].…”

Section: Diabetesmentioning

confidence: 92%

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease

Watanabe

2021

IJMS

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Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

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The combined effect of Raspberry Ketone with Resveratrol against oxidative stress and steatohepatitis in rats: Pharmacokinetic and pharmacodynamic studies

Verma

Goand

Rathaur

et al. 2023

J Biochem & Molecular Tox

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Raspberry Ketone (RK) and Resveratrol (RSV) are natural phenolic antioxidants and anti-inflammatory agents. However, its combined pharmacokinetic and pharmacodynamics potentials are not reported. The study aims to assess the combined effect of RK with RSV to protect rats from carbon-tetrachloride (CCl4) induced oxidative stress and NASH. The toxicant CCl4 was employed at a concentration of 1 mL/kg as a 1:1 (v/v) mixture with olive oil twice weekly for 6 weeks to induce liver toxicity.Animal treatment was followed for 2 weeks. Silymarin was used as a standard control drug to compare the hepatoprotective effect of RK and RSV. Hepatic histology, oxidative stress, MMP, reduced glutathione (GSH), plasma levels of SGOT, SGPT, and lipid profile (total cholesterol and triglycerides) were measured. Antiinflammation genes (IL-10), and fibrotic genes (TGF-β) were also examined in liver tissue. Oral administration of combined RK with RSV (50 + 50 mg/kg for 2 weeks) showed significantly more hepatoprotection by significantly decreasing elevated plasma markers and lipid profile than alone RK and RSV (100 mg/kg daily for 2 weeks). It also significantly alleviated the hepatic lipid peroxidation, restoring the activities of GSH levels in the liver. RT-PCR and Immunoblotting studies confirmed that significantly upregulation of anti-inflammation genes and protein expression (MMP-9) ameliorated the disease. Pharmacokinetic studies confirmed more synergistic stability in simulated gastric-intestinal fluids (FaSSGF, FaSSIF) and rat liver microsomes (CYP-450, NADPH oxidation & glucuronidation. Moreover, coadministration of drugs augmented the relative bioavailability, V d/ F (L/Kg), and MRT 0-∞( h), which leads to more efficacy. This pharmacokinetic and pharmacodynamic reveals a new adjuvant therapy for the treatment of steatohepatitis.

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Pancreastatin inhibitor, PSTi8 ameliorates metabolic health by modulating AKT/GSK-3β and PKCλ/ζ/SREBP1c pathways in high fat diet induced insulin resistance in peri-/post-menopausal rats

Cited by 19 publications

References 55 publications

Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice

Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease

The combined effect of Raspberry Ketone with Resveratrol against oxidative stress and steatohepatitis in rats: Pharmacokinetic and pharmacodynamic studies

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