Combination of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist and PPAR Gamma Co-Activator 1α (PGC-1α) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson's Disease

Background: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson’s disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.

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.

Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration

: Peroxisome proliferator activated receptors (PPARs) activity exhibit significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptors expression are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved inside the cells contributing to on- and -off target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons to Aβ toxicity in Alzheimer’s disease (AD) patients. Therefore, the current review delineated the ligands interaction with 3D- PPARs to modulate neuroprotection and also deciphered the efficacy of numerous drugs viz., Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α), and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement; development of novel PPARs agonists may benefit patients with neurodegeneration mainly in AD patients to mitigate the pathophysiology & dementia subsequently to improve overall patient’s quality of life.

Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.

Expressions of Nuclear Factor-kappa B and Peroxisome Proliferator-activated Receptor-Gamma Proportional with Clinical Staging of Nasopharyngeal Carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy induced by the mutation of the transcription factors nuclear factor-kappa B (NF-kB) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). There was no known of the study about the association and targeted therapy of NF-kB and PPAR-gamma-induced NPC. AIM: This study analyzed and compared the proportion of NF-kB and PPAR-gamma and its association with the clinical characteristic of various NPC patients. METHODS: This was a cross-sectional study and conducted in Adam Malik General Hospital. The samples were paraffin block tissue obtained from 58 NPC patients and underwent immunohistochemistry staining for NF-kB or PPAR-gamma overexpression in March–November 2018. Determination of overexpression was based on the immunoreactive score. The association of NF-kB or PPAR-gamma overexpression with the clinical characteristics of the patients was analyzed using Fisher’s exact test. RESULTS: This study showed a significant increase of NF-kB and PPAR-gamma (p < 0.05). Male was found common than women (3.46:1) with non-keratinizing squamous cell carcinoma as the most common form of NPC (75.9%) and the 41–60 years old is the most common age (56.9%). Overexpression of NF-kB and PPAR-gamma was found mostly in T3-T4 (66.0%; 69.6%), N+ (92.5%; 91.3%), and clinical Stage IV (67.9%; 73.9%), respectively. CONCLUSION: The number of samples overexpressed was proportional to the clinical stage of NPC. This study provides an insight into the relationship of NF-kB and PPAR-gamma to NPC, suggesting their role in the development of malignancy.

PPAR-Gamma Activation May Inhibit the In Vivo Degeneration of Bioprosthetic Aortic and Aortic Valve Grafts under Diabetic Conditions

Background: We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). Methods: DM was induced in male Wistar rats by high-fat diet with an intraperitoneal streptozotocin (STZ) injection. The experimental group received additional pioglitazone, and controls received normal chow without STZ (n = 20 each group). Cryopreserved aortic donor grafts including the aortic valve were analyzed after 4 weeks and 12 weeks in vivo for analysis of calcific bioprosthetic degeneration. Results: DM led to a significant media proliferation at 4 weeks. The additional administration of pioglitazone significantly increased circulating adiponectin levels and significantly reduced media thickness at 4 and 12 weeks, respectively (p = 0.0002 and p = 0.0107, respectively). Graft media calcification was highly significantly inhibited by pioglitazone after 12 weeks (p = 0.0079). Gene-expression analysis revealed a significant reduction in relevant chondro-osteogenic markers osteopontin and RUNX-2 by pioglitazone at 4 weeks. Conclusions: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM.

Multi-Targeted Molecular Docking, Pharmacokinetics, and Drug-Likeness Evaluation of Okra-Derived Ligand Abscisic Acid Targeting Signaling Proteins Involved in the Development of Diabetes

Diabetes mellitus is a global threat affecting millions of people of different age groups. In recent years, the development of naturally derived anti-diabetic agents has gained popularity. Okra is a common vegetable containing important bioactive components such as abscisic acid (ABA). ABA, a phytohormone, has been shown to elicit potent anti-diabetic effects in mouse models. Keeping its anti-diabetic potential in mind, in silico study was performed to explore its role in inhibiting proteins relevant to diabetes mellitus- 11β-hydroxysteroid dehydrogenase (11β-HSD1), aldose reductase, glucokinase, glutamine-fructose-6-phosphate amidotransferase (GFAT), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and Sirtuin family of NAD(+)-dependent protein deacetylases 6 (SIRT6). A comparative study of the ABA-protein docked complex with already known inhibitors of these proteins relevant to diabetes was compared to explore the inhibitory potential. Calculation of molecular binding energy (ΔG), inhibition constant (pKi), and prediction of pharmacokinetics and pharmacodynamics properties were performed. The molecular docking investigation of ABA with 11-HSD1, GFAT, PPAR-gamma, and SIRT6 revealed considerably low binding energy (ΔG from −8.1 to −7.3 Kcal/mol) and predicted inhibition constant (pKi from 6.01 to 5.21 µM). The ADMET study revealed that ABA is a promising drug candidate without any hazardous effect following all current drug-likeness guidelines such as Lipinski, Ghose, Veber, Egan, and Muegge.