Role of PPARs in Progression of Anxiety: Literature Analysis and Signaling Pathways Reconstruction

Peroxisome proliferator-activated receptor (PPAR) group includes three isoforms encoded by PPARG, PPARA, and PPARD genes. High concentrations of PPARs are found in parts of the brain linked to anxiety development, including hippocampus and amygdala. Among three PPAR isoforms, PPARG demonstrates the highest expression in CNS, where it can be found in neurons, astrocytes, and glial cells. Herein, the highest PPARG expression occurs in amygdala. However, little is known considering possible connections between PPARs and anxiety behavior. We reviewed possible connections between PPARs and anxiety. We used the Pathway Studio software (Elsevier). Signal pathways were created according to previously developed algorithms. SNEA was performed in Pathway Studio. Current study revealed 14 PPAR-regulated proteins linked to anxiety. Possible mechanism of PPAR involvement in neuroinflammation protection is proposed. Signal pathway reconstruction and reviewing aimed to reveal possible connection between PPARG and CCK-ergic system was conducted. Said analysis revealed that PPARG-dependent regulation of MME and ACE peptidase expression may affect levels of nonhydrolysed, i.e., active CCK-4. Impairments in PPARG regulation and following MME and ACE peptidase expression impairments in amygdala may be the possible mechanism leading to pathological anxiety development, with brain CCK-4 accumulation being a key link. Literature data analysis and signal pathway reconstruction and reviewing revealed two possible mechanisms of peroxisome proliferator-activated receptors involvement in pathological anxiety: (1) cytokine expression and neuroinflammation mechanism and (2) regulation of peptidases targeted to anxiety-associated neuropeptides, primarily CCK-4, mechanism.

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Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis

Anais Brasileiros de Dermatologia ◽

10.1590/abd1806-4841.20132653 ◽

2013 ◽

Vol 88 (6) ◽

pp. 1029-1035 ◽

Cited By ~ 11

Author(s):

Emerson de Andrade Lima ◽

Mariana Modesto Dantas de Andrade Lima ◽

Cláudia Diniz Lopes Marques ◽

Angela Luzia Branco Pinto Duarte ◽

Ivan da Rocha Pita ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Metabolic Diseases ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obesity And Diabetes ◽

Interactive Network ◽

Increased Risk ◽

Peroxisome Proliferator Activated Receptors ◽

Skin Conditions

Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis.

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The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210521165532 ◽

2021 ◽

Vol 21 ◽

Author(s):

Carla Quiroga ◽

Juan José Barberena ◽

Jocelyne Alcaraz-Silva ◽

Sérgio Machado ◽

Claudio Imperatori ◽

...

Keyword(s):

Nuclear Receptors ◽

Acid Oxidation ◽

Critical Element ◽

Peroxisome Proliferator ◽

Addictive Behaviors ◽

Health Issues ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors ◽

Novel Drug

: The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARβ/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, and adipogenesis among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest in studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. Similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

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Enhanced Hepatocarcinogenicity Due to Agonists of Peroxisome Proliferator-Activated Receptors in Senescent Rats: Role of Peroxisome Proliferation, Cell Proliferation, and Apoptosis

The Scientific World JOURNAL ◽

10.1100/tsw.2002.352 ◽

2002 ◽

Vol 2 ◽

pp. 1491-1500 ◽

Cited By ~ 9

Author(s):

Jihan Youssef ◽

Mostafa Badr

Keyword(s):

Cell Proliferation ◽

Peroxisome Proliferator ◽

Carcinogenic Effect ◽

Peroxisome Proliferator Activated Receptor ◽

New Findings ◽

Proliferation And Apoptosis ◽

Ppar Agonists ◽

Old Rats ◽

Peroxisome Proliferator Activated Receptors

Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARα) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five- to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARa results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre-existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl-2 than livers of young, adult, and middle-aged animals. Interestingly, the PPARa agonist Wy-14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.

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The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease

Acta Pharmaceutica ◽

10.1515/acph-2017-0007 ◽

2017 ◽

Vol 67 (1) ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Xin Sun ◽

Yan Zhang ◽

Meilin Xie

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Peroxisome Proliferator Activated Receptors ◽

Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD. Many drugs developed so far are targeted at PPARs. Thus, the aim of this paper is to summarize the roles of PPARs in the treatment of NAFLD.

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The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

Current Medicinal Chemistry ◽

10.2174/0929867327999200820173853 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Rana A. Alaaeddine ◽

Perihan A. Elzahhar ◽

Ibrahim AlZaim ◽

Wassim Abou-Kheir ◽

Ahmed S.F. Belal ◽

...

Keyword(s):

Metabolic Diseases ◽

Biological Effects ◽

Arachidonic Acid Metabolism ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Cellular Targets ◽

Design And Synthesis ◽

Early Results ◽

Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

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New trends in the pharmacological intervention of PPARs in obesity: Role of natural and synthetic compounds_

Current Medicinal Chemistry ◽

10.2174/1570162x18666201123114934 ◽

2020 ◽

Vol 28 ◽

Author(s):

Seyed Mohammad Nabavi ◽

Kasi Pandima Devi ◽

Sethuraman Sathya ◽

Ana Sanches-Silva ◽

Listos Joanna ◽

...

Keyword(s):

Tissue Expression ◽

Health Concern ◽

Pharmacological Intervention ◽

Peroxisome Proliferator ◽

Expression Of Genes ◽

Ppar Agonists ◽

Prevalence Of Obesity ◽

Peroxisome Proliferator Activated Receptors ◽

Natural And Synthetic

: Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

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Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽

10.3390/cells10030629 ◽

2021 ◽

Vol 10 (3) ◽

pp. 629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Hugo Christian Monroy-Ramírez ◽

Marina Galicia-Moreno ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Peroxisome Proliferator ◽

White Adipocyte ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽

10.3390/nu13030734 ◽

2021 ◽

Vol 13 (3) ◽

pp. 734

Author(s):

Pietro Antonuccio ◽

Herbert Ryan Marini ◽

Antonio Micali ◽

Carmelo Romeo ◽

Roberta Granese ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Targets ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Age Related ◽

Extracellular Signal ◽

Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

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From Exercise to Cognitive Performance: Role of Irisin

Applied Sciences ◽

10.3390/app11157120 ◽

2021 ◽

Vol 11 (15) ◽

pp. 7120

Author(s):

Mirko Pesce ◽

Irene La Fratta ◽

Teresa Paolucci ◽

Alfredo Grilli ◽

Antonia Patruno ◽

...

Keyword(s):

The Elderly ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

General Exercise ◽

Fibronectin Type Iii ◽

Exercise Induced ◽

Fibronectin Type Iii Domain ◽

The Brain

The beneficial effects of exercise on the brain are well known. In general, exercise offers an effective way to improve cognitive function in all ages, particularly in the elderly, who are considered the most vulnerable to neurodegenerative disorders. In this regard, myokines, hormones secreted by muscle in response to exercise, have recently gained attention as beneficial mediators. Irisin is a novel exercise-induced myokine, that modulates several bodily processes, such as glucose homeostasis, and reduces systemic inflammation. Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5), a transmembrane precursor protein expressed in muscle under the control of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). The FNDC5/irisin system is also expressed in the hippocampus, where it stimulates the expression of the neurotrophin brain-derived neurotrophic factor in this area that is associated with learning and memory. In this review, we aimed to discuss the role of irisin as a key mediator of the beneficial effects of exercise on synaptic plasticity and memory in the elderly, suggesting its roles within the main promoters of the beneficial effects of exercise on the brain.

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The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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