Nutritional Agonists of PPAR-γ: An Immunomodulatory Approach to Control Cytokine Storm in Covid19 Patients

Recent examinations express that multi organ failure is seen in Corona virus infected patients with different pathway. It has been shown in contemplates that increased levels of cytokines like IL-1B and INF gamma were observed. It is called as cytokine storm with higher convergences of CCL2 and CXCL10. The cytokine storm is trailed by our immune system attacking own body which thus may cause numerous organ abnormalities and conclusive outcome being death. There is currently no specific treatment for viral illness, and this methodology is an optional path for focusing on specific qualities that may diminish cytokine storm. In such manner Peroxisome Proliferators Activated Receptors (PPARs) have a place with group of transcription factors which are known to manage the inflammatory mechanisms in body. This immunomodulatory approach is intended to focus PPAR-gamma ligands and their molecular docking studies. The activation or increased expression levels of PPAR gamma because of chosen agonists may reduce the cytokine storm in the covid patients. Thus, this is one such fascinating way to deal with neutralization of the cytokines exorbitantly elevated by use of substances like pomegranate, lemon grass and so on to activate PPARs reliably.

Regulation of chicken vanin1 gene expression by peroxisome proliferators activated receptor α and miRNA-181a-5p

Objective: Vanin1 (VNN1) is a pantetheinase that can catalyze the hydrolysis of pantetheine to produce pantothenic acid and cysteamine. Our previous studies showed that <i>VNN1</i> is specifically expressed in chicken liver. In this study, we aimed to investigate the roles of peroxisome proliferators activated receptor α (PPARα) and miRNA-181a-5p in regulating <i>VNN1</i> gene expression in chicken liver.Methods: 5′-RACE was performed to identify the transcription start site of chicken <i>VNN1</i>. JASPAR and TFSEARCH were used to analyze the potential transcription factor binding sites in the promoter region of chicken <i>VNN1</i> and miRanda was used to search miRNA binding sites in 3′ untranslated region (3′UTR) of chicken <i>VNN1</i>. We used a knock-down strategy to manipulate PPARα (or miRNA-181a-5p) expression levels <i>in vitro</i> to further investigate its effect on <i>VNN1</i> gene transcription. Luciferase reporter assays were used to explore the specific regions of VNN1 targeted by PPARα and miRNA-181a-5p.Results: Sequence analysis of the VNN1 promoter region revealed several transcription factor-binding sites, including hepatocyte nuclear factor 1α (HNF1α), PPARα, and CCAAT/enhancer binding protein α. GW7647 (a specific agonist of PPARα) increased the expression level of <i>VNN1</i> mRNA in chicken primary hepatocytes, whereas knockdown of PPARα with siRNA increased VNN1 mRNA expression. Moreover, the predicted PPARα-binding site was confirmed to be necessary for PPARα regulation of <i>VNN1</i> gene expression. In addition, the <i>VNN1</i> 3′UTR contains a sequence that is completely complementary to nucleotides 1 to 7 of miRNA-181a-5p. Overexpression of miR-181a-5p significantly decreased the expression level of <i>VNN1</i> mRNA.Conclusion: This study demonstrates that PPARα is an important transcriptional activator of <i>VNN1</i> gene expression and that miRNA-181a-5p acts as a negative regulator of <i>VNN1</i> expression in chicken hepatocytes.

Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries

Background Voltage-gated K+ (Kv) channels in coronary artery smooth muscle cells (CSMCs), especially the major specific Kv1 subfamily, contribute to coronary artery vasodilation. Advanced glycation end products (AGEs) have been strongly implicated in diabetes-related cardiovascular complications. Our previous study showed AGEs can impair Kv channel-mediated coronary vasodilation by reducing Kv channel activity. However, its underlying mechanism remains unclear. Purpose Here, we used isolated rat small coronary arteries (RSCAs) and primary CSMCs to investigate the effect of AGEs on Kv channel-mediated coronary vasodilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR)-γ pathway. Methods RSCAs and primary CSMCs were isolated, cultured and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO) and/or GW9662, and then divided into the following groups: DMEM, BSA, AGE, AGE+ALA, AGE+PIO, and AGE+PIO+GW9662. Kv channel-mediated coronary vasodilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, the major Kv1 channel subunits expressed in CSMCs (Kv1.2/1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). Results AGEs markedly reduced forskolin-induced Kv channel-mediated vasodilation of RSCAs by interacting with the receptor for AGEs (RAGE), and ALA or PIO significantly reversed this effect. In both RSCAs and primary CSMCs, AGEs decreased Kv1.2 and Kv1.5 channel protein expression, inhibited PPAR-γ expression, increased RAGE and NOX-2 expression. Treatment with ALA or PIO partially reversed the effects of AGEs on Kv1.2/Kv1.5 expression, accompanied by elevation of PPAR-γ level and diminished oxidative stress. Conclusion AGE/RAGE axis-induced inhibition of PPAR-γ pathway and enhancement of oxidative stress may contribute to AGEs-mediated Kv channel dysfunction and coronary vasodilation in RSCAs. Our results may provide new insights into developing therapeutic strategies to manage diabetic vasculature. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China; Natural Science Foundation of Beijing (7172059)

OR-005 Effects of HIITand MICT for 10 weeks on myocardial AMPK and PGC-1α in rats

Objective: The improvement of cardiorespiratory fitness (CRF) is known as an effective strategy for prevention cardiovascular risk. Myocardial aerobic oxidation which control by the signal way of adenosine monophosphate -activated protein kinase (AMPK)- peroxisome proliferators γ activated receptor coativator-1-α (PGC-1α) is the key for CRF. Previous studies only discuss the effect of the Moderate-Intensity Continuous Training (MICT) and High Intensive Interval Training (HIIT) on the signal way of AMPK- PGC-1α in skeletal muscle but not in the myocardium. The aim of this study was to compare the effects of 10 weeks HIIT and MICT on the expression of AMPK and PGC-1α in the myocardium of wistar male rats. Methods: Wistar male rats (n=30) aged 6 weeks were randomly divided into HIIT or MICT or control (CON) group. The training groups ran on a treadmill 5 days/week for 10 weeks. HIIT group ran six times 3 minutes (0° slope) 90% of Vmax separated by 3 minutes 50% of Vmax and MICT group ran for 50min (0° slope) at 60–70% of maximal speed (Vmax). The expression of AMPK and PGC-1α were assessed by Western Blotting. Results: After 10 weeks training, HIIT and MICT both increased the AMPK and PGC-1α expression compared with the CON group. Compared with the MICT group, the expression of AMPK and PGC-1α were significantly higher than the HIIT group (p<0.05). AMPK in MICT group were significant increased 1.16 times, and in HIIT group were significant increased 1.28 times to CON (P<0.05). PGC-1α level of HIIT was significant increased to 1.32 times to CON and also significant increased to 1.15 times to Group M (P<0.05); PGC-1α level of MICT was significant increased to 1.15 times to CON. Conclusion：HIIT seems to improve myocardial AMPK and PGC-1α more efficiently than MICT in rats after 10 weeks training.

DESIGN OF NEW PEROXISOME PROLIFERATORS GAMMA ACTIVATED RECEPTOR AGONISTS (PPARγ) VIA QSAR BASED MODELING

The Peroxisome proliferators-activated receptors (PPARs) are one of the nuclear fatty acid receptors, which contain a type II zincfinger DNA binding pattern and a hydrophobic ligand binding pocket. These receptors are thought to play an essential role in metabolic diseasessuch as obesity, insulin resistance, and coronary artery disease. Therefore Peroxisome Proliferators-Activated Receptor (PPARγ) activators havedrawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize newPPARγ activators. Objective: The aim of the study was to finding new selective human PPARγ (PPARγ) modulators that are able to improveglucose homeostasis with reduced side effects compared with TZDs and identify the specific molecular descriptor and structural constraint toimprove the agonist activity of PPARγ analogs. Material and Method: Software’s that was used for this study include S.P. Gupta QSARsoftware (QSAR analysis), Valstat (Comparative QSAR analysis and calculation of L-O-O, Q2, r2, Spress), BILIN (Comparative QSAR analysisand calculation of Q2, r, S, Spress, and F), etc., allowing directly performing statistical analysis. Then multiple linear regression based QSARsoftware (received from BITS-Pilani, India) generates QSAR equations. Result and Discussion: In this study, we explored the quantitativestructure–activity relationship (QSAR) study of a series of meta-substituted Phenyl-propanoic acids as Peroxisome Proliferators Gamma activatedreceptor agonists (PPARγ).The activities of meta-substituted Phenyl-propanoic acids derivatives correlated with various physicochemical, electronic and steric parameters.Conclusion: The identified QSAR models highlighted the significance of molar refractivity and hydrophobicity to the biological activity.