Acetyl-L-Carnitine protects against LPS induced depression via PPAR-γ induced inhibition of NF-κB/NLRP3 pathway

IntroductionMajor depressive disorder (MDD) is a debilitating human health status characterized by mood swings and high suicidal attempts. Several studies have reported the role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression needs to be further investigated. The present study demonstrated the neuroprotective effects of Acetyl-L- carnitine (ALC) alone or in combination with caffeic acid phenethyl ester (CAPE) on lipopolysaccharide (LPS) induced neuro-inflammation, depression, and anxiety-like behavior.Material and methodsMale Sprague Dawley (SD) rats were used to explore the relative effects of ALC and the mechanistic interplay of the peroxisome proliferator-activated receptors (PPARγ) in depression. Lipopolysaccharide (LPS) was administered to induce depression and anxiety-like symptoms such as a decreased grooming tendency, diminished locomotive activity, and increased immobility period.ResultsWe found marked neuronal alterations in the cortex and hippocampus of LPS intoxicated animals associated with higher inflammatory cytokines expression cyclooxygenase (COX2), tumor necrotic factor-alpha (TNF-α). These detrimental effects exacerbate oxidative stress as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). ALC significantly reverted these changes by positively modulating the PPARγ dependent downstream antioxidant and anti-inflammatory pathways such as NOD and pyrin domain-containing protein 3 (NLRP3) linked nuclear factor kappa B (NF-κB) phosphorylation. Moreover, co-administering NF-κB inhibitor caffeic acid phenethyl ester (CAPE) with ALC also increased PPARγ expression significantly and decreased NF-ᴋB and NLRP3 inflammasome.ConclusionsThese findings indicate that ALC could be a possible depression supplement. The effects are partly mediated by inhibiting neuroinflammation and NLRP3 inflammasome coupled to PPARγ upregulations.

Parsing the Role of PPARs in Macrophage Processes

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

Plant-Based Diet as a Strategy for Weight Control

According to the World Health Organization, obesity has nearly tripled since the 1970s. Obesity and overweight are major risk factors for cardiovascular diseases, diabetes, inflammatory-mediated diseases, and other serious medical conditions. Moreover, recent data suggest that obesity, overweight, diabetes, and cardiovascular diseases are risk factors for COVID-19-related mortality. Different strategies for weight control have been introduced over the last two decades. Unfortunately, these strategies have shown little effect. At the same time, many studies show that plants might be the key to a successful strategy for weight control. Following the PRISMA guidelines for conducting systematic reviews, a search was conducted in PubMed, Web of Science, Scopus, and Embase using the following keywords: obesity, globesity, vegan, plant-based diet, etc. Our results show that vegan diets are associated with improved gut microbiota symbiosis, increased insulin sensitivity, activation of peroxisome proliferator-activated receptors, and over-expression of mitochondrial uncoupling proteins. The key features of this diet are reduced calorie density and reduced cholesterol intake. The combination of these two factors is the essence of the efficiency of this approach to weight control. Our data suggest that plant-based/vegan diets might play a significant role in future strategies for reducing body weight.

Pharmacological properties of selenium and its preparations: from antioxidant to neuroprotector

Selenium is an essential component of more than two dozen enzymes and other selenoproteins that play critical roles in reproduction, DNA synthesis, thyroid hormone metabolism, and protection from oxidative damage and infection. Selenium has a protective action against some forms of cancer and cardiovascular diseases, modulates levels of inflammatory mediators, promotes to maintain bone homeostasis and protects against bone loss. Selenium significance as a cardioprotective agent may be associated not only with its antioxidant properties, but also with its ability to prevent inflammation, autophagy, as well as the intrinsic and extrinsic apoptosis pathways. Signaling pathways, such as p-AMPK, PARP, Nrf2, STAT, are involved in the protective effects of selenium. Selenium protects against cardiovascular damage by increasing the survival rate of cardiomyocytes, including a mitochondria-dependent pathway and autophagy through peroxisome proliferator-activated receptors. Research demonstrating neuroprotective and cardioprotective effects of selenium preparations – selenoline, selenocysteine and selenomethionine – is growing at a rapid rate. It has been established that these compounds are able to normalize the levels of heat shock proteins (HSP70), which limit the cytotoxic effects of free radicals, produce energotropic action, prevent a decrease in the membrane mitochondria charge, and the opening of the mitochondrial pore. Also regulate the expression of transmembrane factors NF-kB, c-fos, which is associated with their main biological function of chaperone proteins, providing protection of neurons from damage. In this review, we want to emphasize pharmacological role of Selenium and its derivatives on human health is very complex and has yet to be fully understood.

GLP-1-mediated delivery of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPAR𝛼/𝛾 dual-agonist Tesaglitazar to GLP-1 to allow for the GLP-1 receptor-dependent delivery of Tesaglitazar. GLP-1/Tesaglitazar does not differ from matched GLP-1 in GLP-1R signaling, but shows GLP-1R-dependent PPAR𝛾-RXR heterodimerization with enhanced efficacy to improve body weight, food intake, and glucose metabolism relative to GLP-1 or Tesaglitazar in mice with diet- and genetically-induced obesity. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout (ko) mice and shows preserved effects in DIO mice at doses subthreshold for GLP-1 and Tesaglitazar to improve metabolism. Consistent with the GLP-1R expression pattern, LC/MS-based proteomics identified a series of novel PPAR protein targets in the hypothalamus that are acutely upregulated by Tesaglitazar and by GLP-1/Tesaglitazar, but not by treatment with GLP-1. Collectively, our data show that GLP-1/Tesaglitazar improves energy and glucose metabolism with superior efficacy to GLP-1 or Tesaglitazar alone and suggest that this conjugate holds therapeutic value to treat hyperglycemia and insulin resistance.

Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Energy Homeostasis of Dairy Animals: Exploiting Their Modulation through Nutrigenomic Interventions

Peroxisome proliferator-activated receptors (PPARs) are the nuclear receptors that could mediate the nutrient-dependent transcriptional activation and regulate metabolic networks through energy homeostasis. However, these receptors cannot work properly under metabolic stress. PPARs and their subtypes can be modulated by nutrigenomic interventions, particularly under stress conditions to restore cellular homeostasis. Many nutrients such as polyunsaturated fatty acids, vitamins, dietary amino acids and phytochemicals have shown their ability for potential activation or inhibition of PPARs. Thus, through different mechanisms, all these nutrients can modulate PPARs and are ultimately helpful to prevent various metabolic disorders, particularly in transition dairy cows. This review aims to provide insights into the crucial role of PPARs in energy metabolism and their potential modulation through nutrigenomic interventions to improve energy homeostasis in dairy animals.

Nuclear Receptors in Myocardial and Cerebral Ischemia—Mechanisms of Action and Therapeutic Strategies

Nearly 18 million people died from cardiovascular diseases in 2019, of these 85% were due to heart attack and stroke. The available therapies although efficacious, have narrow therapeutic window and long list of contraindications. Therefore, there is still an urgent need to find novel molecular targets that could protect the brain and heart against ischemia without evoking major side effects. Nuclear receptors are one of the promising targets for anti-ischemic drugs. Modulation of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) by their ligands is known to exert neuro-, and cardioprotective effects through anti-apoptotic, anti-inflammatory or anti-oxidant action. Recently, it has been shown that the expression of aryl hydrocarbon receptor (AhR) is strongly increased after brain or heart ischemia and evokes an activation of apoptosis or inflammation in injury site. We hypothesize that activation of ERs and PPARs and inhibition of AhR signaling pathways could be a promising strategy to protect the heart and the brain against ischemia. In this Review, we will discuss currently available knowledge on the mechanisms of action of ERs, PPARs and AhR in experimental models of stroke and myocardial infarction and future perspectives to use them as novel targets in cardiovascular diseases.

PPARα Modulation-Based Therapy in Central Nervous System Diseases

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

Protocol for a preclinical systematic review and meta-analysis of pharmacological targeting of peroxisome proliferator-activated receptors in experimental renal injury

IntroductionImpaired lipid metabolism in the renal tubule plays a prominent role in the progression of renal fibrosis following acute kidney injury (AKI) and in chronic kidney disease (CKD). Peroxisome proliferator-activated receptors (PPARs) are promising druggable targets to mitigate renal fibrosis by redirecting metabolism, including restoration of fatty acid oxidation (FAO) capacity. We aim to synthesise evidence from preclinical studies of pharmacological PPAR targeting in experimental renal injury, and inform the design of future studies evaluating PPAR-mediated restoration of FAO in AKI and CKD.Methods and analysisStudies reporting on the impact of pharmacological PPAR modulation in animal models of renal injury will be collected from MEDLINE (Ovid), Embase and Web of Science databases. Predefined eligibility criteria will exclude studies testing medications which are not specific ligands of one or more PPARs and studies involving multimodal pharmacological treatment. The Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool and Collaborative Approach to Meta-Analysis and Review of Animal Experimental Studies checklist will be used to assess quality of the included studies. Data extraction will be followed by a narrative synthesis of the data and meta-analysis where feasible. Analysis will be performed separately for AKI, CKD and renal transplant models. Subgroup analyses will be performed based on study design characteristics, PPAR isotype(s) targeted, and classes of PPAR-targeting medications used. Risk of publication bias will be assessed using funnel plotting, Egger’s regression and trim-and-fill analysis.Ethics and disseminationEthical approval is not required. Findings will be published in a peer-reviewed journal and presented at scientific meetings.PROSPERO registration numberCRD42021265550.