scholarly journals PFAS and potential adverse impacts on bone and adipose tissue through interactions with PPAR-gamma

Endocrinology ◽  
2021 ◽  
Author(s):  
Andrea B Kirk ◽  
Stephani Michelsen-Correa ◽  
Cliff Rosen ◽  
Clyde F Martin ◽  
Bruce Blumberg
Keyword(s):  
Bone Development ◽  
Broad Class ◽  
Biological Effects ◽  
Ppar Gamma ◽  
Adverse Outcomes ◽  
Risk Assessments ◽  
Peroxisome Proliferator ◽  
Public Health Perspective ◽  
Chemical Risk ◽  
Peroxisome Proliferator Activated Receptors

Abstract Per- and polyfluoroalkyl substances (PFAS) are a widely dispersed, broad class of synthetic chemicals with diverse biological effects, including effects on adipose and bone differentiation. PFAS most commonly occur as mixtures and only rarely, if ever, as single environmental contaminants. This poses significant regulatory questions and a pronounced need for chemical risk assessments, analytical methods, and technological solutions to reduce the risk to public and environmental health. The impacts of PFAS on biological systems may be complex. Each may have several molecular targets initiating multiple biochemical events leading to a number of different adverse outcomes. An exposure to mixtures or co-exposures of PFAS complicates the picture further. This review illustrates how PFAS target peroxisome proliferator activated receptors. Additionally, we describe how such activation leads to changes in cell differentiation and bone development that contributes to metabolic disorder and bone weakness. This discussion sheds light on the importance of seemingly modest outcomes observed in test animals and highlights why the most sensitive endpoints identified in some chemical risk assessments are significant from a public health perspective.

Peroxisome proliferator-activated receptor-γ as a novel and promising target for treating cancer via regulation of inflammation: A brief review

2021 ◽  
Vol 21 ◽  
Author(s):  
Yuvaraj S ◽  
B R Prashantha Kumar
Keyword(s):  
Transcription Factors ◽  
Cancer Cells ◽  
Animal Studies ◽  
Cell Metabolism ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Physiological Processes ◽  
Promising Target ◽  
Peroxisome Proliferator Activated Receptors

: Peroxisome proliferator activated receptors (PPARs) are group of nuclear receptors and the ligand-activated intracellular transcription factors that are known to play a key role in physiological processes such as cell metabolism, proliferation, differentiation, tissue remodeling, inflammation, and atherosclerosis. However, in the past two decades, many reports claim that PPARs also play an imperious role as a tumor suppressor. PPAR- gamma (PPARγ), one of the best-known from the family of PPARs, is known to express in colon, breast, bladder, lung, and prostate cancer cells. Its function in tumour cells includes the modulation of several pathways involved in multiplication and apoptosis. The ligands of PPARγ act by PPARγ dependent as well as independent pathways and are also found to regulate different inflammatory mediators and transcription factors in systemic inflammation and in tumor microenvironment. Both synthetic and natural ligands that are known to activate PPARγ, suppress the tumor cell growth and multiplication through the regulation of inflammatory pathways, as found out from different functional assays and animal studies. Cancer and inflammation are interconnected process that are now being targeted to achieve tumor suppression by decreasing the risks and burden posed by cancer cells. Therefore, PPARγ can serve as a promising target for development of clinical drug molecule attenuating the proliferation of cancer cells. In this perspective, this mini review highlights the PPARγ as a potential target for drug development aiming for anti-inflammatory and thereby suppressing tumors.

scholarly journals Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Angela M Halstead ◽  
Chiraag D Kapadia ◽  
Jennifer Bolzenius ◽  
Clarence E Chu ◽  
Andrew Schriefer ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Growth Factor ◽  
Hot Spot ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Human Bladder ◽  
Bladder Cancer Cells ◽  
Ppar Signaling ◽  
Peroxisome Proliferator Activated Receptors ◽  
Human Bladder Cancer Cells

RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20–25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer.

scholarly journals Modulation of PPAR-γby Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
D. Ortuño Sahagún ◽  
A. L. Márquez-Aguirre ◽  
S. Quintero-Fabián ◽  
R. I. López-Roa ◽  
A. E. Rojas-Mayorquín
Keyword(s):  
Natural Products ◽  
Functional Foods ◽  
Inflammatory Diseases ◽  
Saturated Fat ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Dietary Components ◽  
Peroxisome Proliferator Activated Receptors ◽  
Promising Source

A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γagonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.

scholarly journals PPAR agonists as effective adjuvants for COVID-19 vaccines, by modifying immunogenetics: a review of literature

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Antoine Fakhry AbdelMassih ◽  
Rahma Menshawey ◽  
Jumana H. Ismail ◽  
Reem J. Husseiny ◽  
Yousef M. Husseiny ◽  
...  
Keyword(s):  
T Regulatory Cells ◽  
Plasma Cells ◽  
Ppar Gamma ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Main Body ◽  
Vaccine Response ◽  
Remarkable Effect ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors

Abstract Background Several coronavirus vaccine have been fast-tracked to halt the pandemic, the usage of immune adjuvants that can boost immunological memory has come up to the surface. This is particularly of importance in view of the rates of failure of seroconversion and re-infection after COVID-19 infection, which could make the vaccine role and response debatable. Peroxisome proliferator-activated receptors (PPARs) have an established immune-modulatory role, but their effects as adjuvants to vaccination have not been explored to date. Main body of the abstract It is increasingly recognized that PPAR agonists can upregulate the levels of anti-apoptotic factors such as MCL-1. Such effect can improve the results of vaccination by enhancing the longevity of long-lived plasma cells (LLPCs). The interaction between PPAR agonists and the immune system does not halt here, as T cell memory is also stimulated through enhanced T regulatory cells, antagonizing PD-L1 and switching the metabolism of T cells to fatty acid oxidation, which has a remarkable effect on the persistence of T memory cells. What is even of a more significant value is the effect of PPAR gamma on ensuring a profound secretion of antibodies upon re-exposure to the offending antigen through upregulating lipoxin B4, therefore potentially assisting the vaccine response and deterring re-infection. Short conclusion In view of the above, we suggest the use of PPAR as adjuvants to vaccines in general especially the emerging COVID-19 vaccine due to their role in enhancing immunologic memory through DNA-dependent mechanisms.

scholarly journals Peroxisome proliferator-activated receptors and hepatitis C virus

2011 ◽  
Vol 4 (6) ◽  
pp. 419-431 ◽  
Author(s):  
M. Eslam ◽  
M. A. Khattab ◽  
S. A. Harrison
Keyword(s):  
Insulin Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatic Steatosis ◽  
Adverse Outcomes ◽  
Peroxisome Proliferator ◽  
Nuclear Factors ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Relationship

The prevalence of type 2 diabetes mellitus and insulin resistance are higher among people chronically infected with hepatitis C (CHC) when compared with the general population and people with other causes of chronic liver disease. Both insulin resistance and diabetes are associated with adverse outcomes across all stages of CHC, including the liver transplant population. CHC is also associated with the development of hepatic steatosis, a common histological feature present in approximately 55% (32–81%) of cases. There is a complex interrelationship between insulin resistance and hepatic steatosis and both are postulated to aggravate each other. The peroxisome proliferator-activated receptors (PPARs) are nuclear factors involved in the regulation of glucose, lipid homeostasis, inflammatory response, cell differentiation, and cell cycle. The relationship between hepatitis C virus replication and PPARs has been the focus of recent study. Given the availability of potent agonists, PPARs may represent a novel pharmacological target in the treatment of CHC.

scholarly journals Medicinal Potential of Isoflavonoids: Polyphenols That May Cure Diabetes

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5491
Author(s):  
Qamar Uddin Ahmed ◽  
Abdul Hasib Mohd Ali ◽  
Sayeed Mukhtar ◽  
Meshari A. Alsharif ◽  
Humaira Parveen ◽  
...  
Keyword(s):  
Biological Effects ◽  
Biochanin A ◽  
In Vivo Studies ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Inflammatory Mechanism ◽  
Peroxisome Proliferator Activated Receptors

In recent years, there is emerging evidence that isoflavonoids, either dietary or obtained from traditional medicinal plants, could play an important role as a supplementary drug in the management of type 2 diabetes mellitus (T2DM) due to their reported pronounced biological effects in relation to multiple metabolic factors associated with diabetes. Hence, in this regard, we have comprehensively reviewed the potential biological effects of isoflavonoids, particularly biochanin A, genistein, daidzein, glycitein, and formononetin on metabolic disorders and long-term complications induced by T2DM in order to understand whether they can be future candidates as a safe antidiabetic agent. Based on in-depth in vitro and in vivo studies evaluations, isoflavonoids have been found to activate gene expression through the stimulation of peroxisome proliferator-activated receptors (PPARs) (α, γ), modulate carbohydrate metabolism, regulate hyperglycemia, induce dyslipidemia, lessen insulin resistance, and modify adipocyte differentiation and tissue metabolism. Moreover, these natural compounds have also been found to attenuate oxidative stress through the oxidative signaling process and inflammatory mechanism. Hence, isoflavonoids have been envisioned to be able to prevent and slow down the progression of long-term diabetes complications including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Further thoroughgoing investigations in human clinical studies are strongly recommended to obtain the optimum and specific dose and regimen required for supplementation with isoflavonoids and derivatives in diabetic patients.

scholarly journals Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis

2001 ◽  
Vol 27 (1) ◽  
pp. 1-9 ◽  
Author(s):  
L Fajas ◽  
MB Debril ◽  
J Auwerx
Keyword(s):  
Cell Proliferation ◽  
Hormone Receptors ◽  
Adipocyte Differentiation ◽  
Molecular Targets ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Synthetic Compounds ◽  
Peroxisome Proliferator Activated Receptors ◽  
Differentiation Pathways

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds inducing peroxisome proliferation. PPAR-gamma, the best characterized of the PPARs, plays a crucial role in adipogenesis and insulin sensitization. Furthermore, PPAR-gamma has been reported to affect cell proliferation/differentiation pathways in various malignancies. We discuss in the present review recent advances in the understanding of the function of PPAR-gamma in both cell proliferation and adipocyte differentiation.

scholarly journals Effects of peroxisome proliferator activated receptors-alpha and -gamma agonists on estradiol-induced proliferation and hyperplasia formation in the mouse uterus

2004 ◽  
Vol 182 (2) ◽  
pp. 229-239 ◽  
Author(s):  
AG Gunin ◽  
AD Bitter ◽  
AB Demakov ◽  
EN Vasilieva ◽  
NV Suslonova
Keyword(s):  
Estrogen Receptors ◽  
Ppar Gamma ◽  
Estrogen Signaling ◽  
Peroxisome Proliferator ◽  
Beta Catenin ◽  
Ppar Alpha ◽  
Ovariectomized Mice ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Uterine Glands

It is suggested that the action of peroxisome proliferator-activated receptors (PPARs) cross-talks with estrogen signaling in the uterus. However, it is not known how PPAR agonists affect estrogen-dependent processes in the uterus, especially proliferation and morphogenetic changes. The effects of agonists of PPAR-alpha and -gamma on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments were therefore examined. Ovariectomized mice were treated with estradiol dipropionate (4 micro g/100 g, s.c., once a week) or vehicle and rosiglitazone (PPAR-gamma agonist) or fenofibrate (PPAR-alpha agonist) or with no additional treatment for 2 days or for 30 days. Treatment with estradiol and PPAR agonists for 2 days did not affect uterine mass. In mice treated with estradiol and rosiglitazone for 2 days, proliferation was enhanced and levels of estrogen receptors-alpha and beta-catenin were decreased in all uterine tissues. Treatment with estradiol and fenofibrate for 2 days had the opposite effects on the parameters tested. In animals treated with estradiol and rosiglitazone for 30 days, uterine mass was increased, abnormal uterine glands and atypical endometrial hyperplasia were found more often and levels of estrogen receptors-alpha and beta-catenin were decreased. In animals treated with estradiol and fenofibrate for 30 days, uterine mass was decreased, most of the uterine glands had a normal structure, no cases of atypical hyperplasia were diagnosed, proliferative activity was declined and the levels of estrogen receptors-alpha and beta-catenin were markedly higher. Treatment with rosiglitazone or fenofibrate did not affect the serum estradiol level in the mice which received estradiol together with PPAR agonists for 30 days. Thus, rosiglitazone exerted the proliferative and morphogenetic effects of estradiol, but fenofibrate had the opposite effect. The actions of rosiglitazone and fenofibrate are associated with changes in the expression of estrogen receptors-alpha and beta-catenin in the uterus.

scholarly journals Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma

2018 ◽  
Vol 19 (7) ◽  
pp. 2063 ◽  
Author(s):  
Patricia Corrales ◽  
Adriana Izquierdo-Lahuerta ◽  
Gema Medina-Gómez
Keyword(s):  
Dna Sequences ◽  
Hormone Receptors ◽  
Systemic Blood Pressure ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Renal Metabolism ◽  
Regulatory Dna Sequences ◽  
Key Factor ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARγ in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARγ is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARγ have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARγ in renal metabolism as a likely key factor in the maintenance of systemic homeostasis.

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