Activation Of Peroxisome Proliferator-activated Receptor Research Articles

Abstract 6318: Effects of per- and polyfluoroalkyl substances on bone marrow adipose environment: Potential implications for bone metastatic cancers

Abstract Bone is a site of metastasis from several tumor types including prostate cancer (PCa). Metastatic PCa is lethal, largely due to the complex nature of bone microenvironment, and the functional cross-talk between bone-resident cells and tumor cells that favors therapy evasion. We have shown previously that age- and obesity-induced changes in the bone microenvironment, specifically increased marrow adiposity, promote tumor adaptation in bone. Numerous studies have also linked the disruption in bone homeostasis with aggressive tumor phenotype. Whether environmental toxicants with propensity to accumulate in bone can modulate bone microenvironment to support tumor growth and progression is, however, not known. Per- and polyfluoroalkyl substances (PFAS) are “forever” chemicals with very long half-lives and ability to accumulate in bone. Limited reports have linked PFAS exposure with adipocyte differentiation and osteoclast activation, but their specific effects on bone are not known. It is also unclear whether the exposure to PFAS can directly impact metastatic tumor cells. Here, we hypothesized that PFAS contribute to metastatic progression by impacting both the tumor and its microenvironment. Specifically, we aimed to establish that exposure to PFAS promotes adipogenesis and osteoclastogenesis, creating microenvironment conducive to tumor growth. We also sought to determine whether direct effects of PFAS exposure on tumor cells lead to activation of growth and survival signaling that drives aggressive phenotype in bone. Our data show that 12-week exposure of mice to a cocktail of 5 PFAS chemicals (PFOS, PFOA, PFNA, PFHxS, and GenX) increases the number of adipocytes in the tibia and augments expression of adipogenesis-associated genes, such as FABP4 and adiponectin. RNAseq analyses of tibia from mice exposed to PFAS chemicals for 3 and 6 weeks indicate changes in bone metabolism and turnover, results supported by in vitro osteoclastogenesis assays. Mass spectrometry analyses of bone extracts from PFAS cocktail exposed mice reveal that the compound with highest concentration in bone is PFHxS. Interestingly, our in vitro assays employing bone marrow derived mesenchymal cells show that PFHxS can activate peroxisome proliferator-activated receptor (PPAR) signaling, leading to an increase in adipogenesis. Studies examining the direct impact of long term PFHxS as well as PFAS cocktail exposure on in vitro PCa cultures and progression of intratibially implanted PCa tumors are currently ongoing. Our findings to date indicate that changes in bone marrow microenvironment induced by PFAS chemicals have a potential to disrupt the balance between osteoblasts and adipocytes, promote marrow adipogenesis and osteoclastogenesis, and activate specific signaling pathways in tumor cells that support growth and survival. Citation Format: Laimar C. Garmo, Mackenzie K. Herroon, Shane Mecca, Alexis Wilson, Michael C. Petriello, Izabela Podgorski. Effects of per- and polyfluoroalkyl substances on bone marrow adipose environment: Potential implications for bone metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6318.

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity.

The consumption of phytochemicals, bioactive compounds in fruits and vegetables, has been demonstrated to ameliorate obesity and related metabolic symptoms by regulating specific metabolic pathways. This review summarizes the progress made in our understanding of the potential of phytochemicals as metabolic signals: we discuss herein selected molecular mechanisms which are involved in the occurrence of obesity that may be regulated by phytochemicals. The focus of our review highlights the regulation of transcription factors toll like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the peroxisome proliferator-activated receptors (PPARs), fat mass and obesity-associated protein (FTO) and regulation of microRNAs (miRNA). In this review, the effect of phytochemicals on signaling pathways involved in obesity were discussed on the basis of their chemical structure, suggesting molecular mechanisms for how phytochemicals may impact these signaling pathways. For example, compounds with an isothiocyanate group or an α, β-unsaturated carbonyl group may interact with the TLR4 signaling pathway. Regarding Nrf2, we examine compounds possessing an α, β-unsaturated carbonyl group which binds covalently with the cysteine thiols of Keap1. Additionally, phytochemical activation of PPARs, FTO and miRNAs were summarized. This information may be of value to better understand how specific phytochemicals interact with specific signaling pathways and help guide the development of new drugs to combat obesity and related metabolic diseases.

Angiopoietin-Like Protein 4 Is Involved in Manganese Superoxide Dismutase-Mediated Suppression of Breast Cancer Cell Growth.

This study aims to understand the molecular basis of manganese superoxide dismutase (MnSOD) impacts on breast cancer cell growth. Modulation of the level of MnSOD by genetic engineering led significant changes in the expression of angiopoietin-like protein 4 (ANGPTL4) and activity of peroxisome proliferator-activated receptor α (PPARα) in MCF7 cells. PPARα agonist increased ANGPTL4 expression inhibited by MnSOD. Proliferation of MCF7 cells was inhibited by MnSOD, however, ANGPTL4 transduction into MCF7 cells with MnSOD overexpression significantly stimulated cell proliferation. MnSOD induced G0/G1 cell cycle arrest, nevertheless, ANGPTL4 transduction significantly reduced the percentage of cells in G0/G1 phase overexpressing MnSOD. In conclusion, MnSOD suppressed the expression of ANGPTL4 in breast cancer cells via the PPARα signaling pathway, and ANGPTL4 was involved in MnSOD-mediated proliferation inhibition and cell cycle arrest.

Randomized, placebo-controlled, double blind, phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors.

11568 Background:A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, and categorized localized (L-TGCT) or diffuse-type (D-TGCT). D-TGCT most commonly develops in the knee or ankle. We revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Therefore, we conducted a randomized trial to evaluate whether zaltoprofen was effective for patients with TGCT. Methods:This study was a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with L-TGCT or D-TGCT. For the treatment group, zaltoprofen 480 mg/day was administered for 48 weeks. The primary outcome was the progression-free rate (PFR) at week 48 after treatment administration. Disease progression was defined as follows requiring surgical interventions: 1) repetitive joint swelling due to hemorrhage; 2) limited range of joint motion; 3) invasion of adjacent cartilage or bone; 4) severe joint space narrowing; or 5) increase in tumor size (target lesion). This study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000025901). Results:We allocated forty-one patients to zaltoprofen (n = 21; Z) or placebo (n = 20; P) groups. The mean age was 44 years (range, 26 to 66) in the group Z and 47 years (range, 24 to 69) in the group P. TGCTs located at a knee in 26 patients and at an ankle in 15 patients. The primary outcome of PFR for the group Z was not higher than that for the group P at week 48 (84.0% vs. 90.0%; p = 0.619). The objective tumor response was graded as partial response (PR) in 1 patient, stable disease (SD) in 19, and progressive disease (PD) in 1 for the group Z, and SD in 17 and PD in 3 for the group P. The mean musculoskeletal tumor society scoring system for group Z was significantly improved from baseline to week 48 (83.8% vs. 93.0%, p = 0.02), whereas that for the group P was not significantly improved (82.2% vs. 86.8%; p = 0.167). During the study period, one severe adverse event was observed (grade 3 hypertension) in the group Z. Conclusions:To our knowledge, this was the first study to evaluate the efficacy of zaltoprofen in patients with TGCT. The TGCT patients in zaltoprofen group did not have higher PER compared with those in the placebo group at week 48. Zaltoprofen appeared to improve the limb-function. Both groups presented with a stable disease course for 48 weeks, therefore, the long-term clinical course of TGCT should be clarified. Further analysis with long-term administration of zaltoprofen is considered for the future study. Clinical trial information: UMIN000025901.

Pinolenic acid exhibits anti-inflammatory and anti-atherogenic effects in peripheral blood-derived monocytes from patients with rheumatoid arthritis

Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. PNLA reduced percentage of monocytes expressing cytokines: TNF-α by 23% (p = 0.048), IL-6 by 25% (p = 0.011), IL-1β by 23% (p = 0.050), IL-8 by 20% (p = 0.066). Pathway analysis identified upstream activation of peroxisome proliferator-activated receptors (PPARs), sirtuin3, and let7 miRNA, and KLF15, which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-α, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p = 9.14E−09) and mitochondrial dysfunction (p = 4.18E−08), while the sirtuin (SIRTs) signalling pathway was activated (p = 8.89E−06) which interfere with the pathophysiological process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and acetyl-CoA acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.

Iloprost requires the Frizzled-9 receptor to prevent lung cancer

SummaryPrevention of premalignant lesion progression is a promising approach to reducing lung cancer burden in high-risk populations. Substantial preclinical and clinical evidence has demonstrated efficacy of the prostacyclin analogue iloprost for lung cancer chemoprevention. Iloprost activates peroxisome proliferator-activated receptor gamma (PPARG) to initiate chemopreventive signaling and in vitro, which requires the transmembrane receptor Frizzled9 (FZD9). We hypothesized a Fzd9−/− mouse would not be protected by iloprost in a lung cancer model. Fzd9−/− mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that Fzd9−/− mice treated with iloprost were not protected from adenoma development compared to wild-type mice nor did they demonstrate increased activation of iloprost signaling pathways. Our results established that iloprost requires FZD9in vivo for lung cancer chemoprevention. This work represents a critical advancement in defining iloprost’s chemopreventive mechanisms and identifies a potential response marker for future clinical trials.

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

Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions 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 in 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 from 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 that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.

Fatty acids derived from apoptotic chondrocytes fuel macrophages FAO through MSR1 for facilitating BMSCs osteogenic differentiation

The nonunion following a fracture is associated with severe patient morbidity and economic consequences. Currently, accumulating studies are focusing on the importance of macrophages during fracture repair. However, details regarding the process by which macrophages facilitate endochondral ossification (EO) are largely unknown. In this study, we present evidence that apoptotic chondrocytes (ACs) are not inert corpses awaiting removal, but positively modulate the osteoinductive ability of macrophages. In vivo experiments revealed that fatty acid (FA) metabolic processes up-regulated following EO. In vitro studies further uncovered that FAs derived from ACs are taken up by macrophages mainly through macrophage scavenger receptor 1 (MSR1). Then, our functional experiments confirmed that these exogenous FAs subsequently activate peroxisome proliferator-activated receptor α (PPARα), which further facilitates lipid droplets generation and fatty acid oxidation (FAO). Mechanistically, elevated FAO is involved in up-regulating the osteoinductive effect by generating BMP7 and NAD+/SIRT1/EZH2 axis epigenetically controls BMP7 expression in macrophages cultured with ACs culture medium. Our findings advanced the concept that ACs could promote bone regeneration by regulating metabolic and function reprogram in macrophages and identified macrophage MSR1 represents a valuable target for fracture treatments.

IRX5 promotes adipogenesis of hMSCs by repressing glycolysis

Iroquois homeobox transcription factor 5 (IRX5) plays a pivotal role in extramedullary adipogenesis, but little is known about the effects of IRX5 on adipogenesis of human bone marrow-derived mesenchymal stem cells (hMSCs). In this study, we aimed to determine the effect of IRX5 on hMSCs adipogenesis. By means of qPCR analysis, we determined that IRX5 expression was elevated during adipogenic commitment of hMSCs. The biologic role of IRX5 was further investigated by employing a gain/loss-of-function strategy using an in vitro lentivirus-based system. IRX5 overexpression promoted adipogenesis whereas IRX5 knockdown reduced the adipogenic phenotype. RNA-seq and metabolomics revealed that IRX5 overexpression repressed glycolysis. Dual-luciferase assay results showed that IRX5 overexpression transcriptionally activates peroxisome proliferator-activated receptor gamma coactivator (PGC-1α). Metformin and PGC-1α inhibitor reversed IRX5-induced adipogenesis and glycolytic inhibition. Collectively, IRX5 facilitates adipogenic differentiation of hMSCs by transcriptionally regulating PGC-1α and inhibiting glycolysis, revealing a potential target to control bone marrow-derived mesenchymal stem cells (BMSCs) fate decision and bone homeostasis.

Maternal Sodium p-Perfluorous Nonenoxybenzene Sulfonate Exposure Disturbed Lipid Metabolism and Induced an Imbalance in Tyrosine Metabolism in the F1 Generation of Mice.

The toxicity of perfluorinated compounds (PFCs) to mammals has recently received increasing attention. However, the effects of maternal sodium p-perfluorous nonenoxybenzene sulfonate (OBS) exposure during pregnancy and lactation on the liver function of dams (F0) and offspring (F1) mice are still unknown. The results demonstrated that maternal OBS treatment could not only induce lipid metabolism dysfunction but also disrupt amino acid metabolism in the liver of F0 and F1 generations. OBS had marked accumulation in the liver, and the serum and liver triglyceride (TG) levels increased in the F0 and F1 generations after maternal OBS exposure. Moreover, maternal OBS exposure changed the transcriptional levels of genes related to lipid metabolism (fatty acid (FA) synthesis, TG synthesis, and transport) and induced changes in the amino acid level in dams and 20-day-old mice offspring (F1-20 d). Additionally, the regulation of lipid metabolism by OBS was mainly dependent on the activation of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36). Interestingly, OBS could also disturb tyrosine (TYR) metabolism by increasing the TYR level and downregulating fumarate acetoacetate hydrolase (FAH). Together, these results indicated that the liver can be perceived as the major target tissue of OBS, which strongly affected metabolic function and ultimately led to an imbalance in the metabolism of lipids and TYR. In summary, maternal OBS exposure during pregnancy and lactation has toxic effects on the hepatic metabolism of dams and offspring, indicating that the toxic effects could obviously cross generations of mice, and we should pay more attention to understanding the health risk to both dams and offspring.

Exploring compounds to be used as cosmetic agents that activate peroxisome proliferator-activated receptor alpha.

ObjectiveThe human epidermis is formed by the proliferation and differentiation of keratinocytes adjacent to the basement membrane. The outermost layer, the stratum corneum, is equipped with a barrier function that prevents water evaporation, and intercellular lipids play an important role in this barrier function. When the barrier is functioning normally, evaporation is prevented; however, when barrier function is impaired, moisture evaporates, resulting in dry and rough skin. Therefore, maintenance of normal barrier function is critical for maintaining normal skin function. Peroxisome proliferator‐activated receptor α (PPARα) is mainly not only involved in lipid metabolism in the liver but is also expressed in the epidermis and is involved in inducing keratinocyte differentiation, promoting lipid production, maintaining barrier function and suppressing skin inflammation. Hence, compounds that activate PPARα are expected to control skin function. Therefore, we identified PPARα activators from among extracts of natural resources that have been approved for use in humans and analysed the effects of these extracts on skin function.MethodsFirst, extracts of 474 natural resources were screened using a PPARα activator screening cell line independently constructed in our laboratory. Next, reporter assays were performed using the Gal4‐chimera system to evaluate whether these extracts act as ligands for PPARα. We then analysed their effect on primary normal human epidermal keratinocyte cells by using real‐time RT‐PCR. Finally, we evaluated PPARα activation effect by the combination of these extracts.ResultsWe identified 36 extracts having the effect of activating PPARα. In particular, #419, a Typha angustifolia spike extract, showed concentration‐dependent transcriptional activation through PPARα‐LBD and was considered to be likely to contain a compound that is a ligand of PPARα. #419 increased the expression of PPARα target genes and genes related to skin function in primary cultured human epidermal keratinocytes. Finally, the use of #419 in combination with nine extracts increased PPAR activity more than twice as much as #419 alone treatment.ConclusionsThese results showed that the reporter cell line could be useful for discovering extracts of natural resources and that the identified Typha angustifolia spike extract could be used in cosmetics that activate PPARα, which expected to improve skin function.

Mitochondrial Respiratory Complexes as Targets of Drugs: The PPAR Agonist Example.

Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.

Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)

Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions of the Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, and gmPparg, and demonstrate that the carboxylic acids PFHxA, PFOA, PFNA, as well as the sulfonic acid PFHxS, activate gmPpara1 in vitro, which was also supported by in silico analyses. Intriguingly, a binary mixture of PFOA and the non-activating PFOS produced a higher activation of gmPpara1 compared to PFOA alone, suggesting that PFOS has a potentiating effect on receptor activation. Supporting the experimental data, docking and molecular dynamics simulations of single and double-ligand complexes led to the identification of a putative allosteric binding site, which upon binding of PFOS stabilizes an active conformation of gmPpara1. Notably, binary exposures of gmPpara1, gmPpara2, and gmPparb to model-agonists and PFAAs produced similar potentiating effects. This study provides novel mechanistic insights into how PFAAs may modulate the Ppar signaling pathway by either binding the canonical ligand-binding pocket or by interacting with an allosteric binding site. Thus, individual PFAAs, or mixtures, could potentially modulate the Ppar-signaling pathway in Atlantic cod by interfering with at least one gmPpar subtype.

Peroxisome proliferator-activator receptor γ and psoriasis, molecular and cellular biochemistry.

The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.

Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury.

Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury. This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.

Tri-2-Hydroxyarachidonein Induces Cytocidal Autophagy in Pancreatic Ductal Adenocarcinoma Cancer Cell Models.

Cell proliferation in pancreatic cancer is determined by a complex network of signaling pathways. Despite the extensive understanding of these protein-mediated signaling processes, there are no significant drug discoveries that could considerably improve a patient’s survival. However, the recent understanding of lipid-mediated signaling gives a new perspective on the control of the physiological state of pancreatic cells. Lipid signaling plays a major role in the induction of cytocidal autophagy and can be exploited using synthetic lipids to induce cell death in pancreatic cancer cells. In this work, we studied the activity of a synthetic lipid, tri-2-hydroxyarachidonein (TGM4), which is a triacylglycerol mimetic that contains three acyl moieties with four double bonds each, on cellular and in vivo models of pancreatic cancer. We demonstrated that TGM4 inhibited proliferation of Mia-PaCa-2 (human pancreatic carcinoma) and PANC-1 (human pancreatic carcinoma of ductal cells) in in vitro models and in an in vivo xenograft model of Mia-PaCa-2 cells. In vitro studies demonstrated that TGM4 induced cell growth inhibition paralleled with an increased expression of PARP and CHOP proteins together with the presence of sub-G0 cell cycle events, indicating cell death. This cytocidal effect was associated with elevated ER stress or autophagy markers such as BIP, LC3B, and DHFR. In addition, TGM4 activated peroxisome proliferator-activated receptor gamma (PPAR-γ), which induced elevated levels of p-AKT and downregulation of p-c-Jun. We conclude that TGM4 induced pancreatic cell death by activation of cytocidal autophagy. This work highlights the importance of lipid signaling in cancer and the use of synthetic lipid structures as novel and potential approaches to treat pancreatic cancer and other neoplasias.

Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury.

Hepatic ischemia reperfusion injury (IRI), a fascinating topic that has drawn a lot of interest in the last few years, is a major complication caused by a variety of clinical situations, such as liver transplantation, severe trauma, vascular surgery, and hemorrhagic shock. The IRI process involves a series of complex events, including mitochondrial deenergization, metabolic acidosis, adenosine-5'-triphosphate depletion, Kupffer cell activation, calcium overload, oxidative stress, and the upregulation of pro-inflammatory cytokine signal transduction. A number of protective strategies have been reported to ameliorate IRI, including pharmacological therapy, ischemic pre-conditioning, ischemic post-conditioning, and machine reperfusion. However, most of these strategies are only at the stage of animal model research at present, and the potential mechanisms and exact therapeutic targets have yet to be clarified. IRI remains a main cause of postoperative liver dysfunction, often leading to postoperative morbidity or even mortality. Very recently, it was reported that the activation of peroxisome proliferator-activated receptor γ (PPARγ), a member of a superfamily of nuclear transcription factors activated by agonists, can attenuate IRI in the liver, and FAM3A has been confirmed to mediate the protective effect of PPARγ in hepatic IRI. In addition, non-coding RNAs, like LncRNAs and miRNAs, have also been reported to play a pivotal role in the liver IRI process. In this review, we presented an overview of the latest advances of treatment strategies and proposed potential mechanisms behind liver IRI. We also highlighted the role of several important molecules (PPARγ, FAM3A, and non-coding RNAs) in protecting against hepatic IRI. Only after achieving a comprehensive understanding of potential mechanisms and targets behind IRI can we effectively ameliorate IRI in the liver and achieve better therapeutic effects.

Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis.

Background & AimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration–approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin–FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet–induced NAFLD and high fat– and choline-deficient diet–induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α–FGF21 axis and is a promising therapeutic target for NAFLD.

Perfluorooctanoic acid (PFOA) as a stimulator of estrogen receptor-negative breast cancer MDA-MB-231 cell aggressiveness: Evidence for involvement of fatty acid 2-hydroxylase (FA2H) in the stimulated cell migration.

Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. However, there is very little information on the PPARα-regulated genes responsible for the effects of PFOA in ERα-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ERα-negative human MDA-MB-231 cells, and PPARα is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPARα-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPARα transcription and FA2H expression in relation to MDA-MB-231 cell migration. We found that simultaneously with stimulated migration, PFOA upregulated FA2H and activated the transcription of PPARα. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPARα and PPARβ/δ (i.e., PPARβ/δ can suppress PPARα-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPARβ/δ expression, PFOA appeared to free PPARα to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPARα-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPARβ/δ suppression of PPARα activity to upregulate FA2H in MDA-MB-231 cells.

Herbal remedies through cactus nutrients

The main constituent of Opuntiaficus-indica cladodes is water (80-95%), followed by small amounts of carbohydrates (3-7%), fiber (1-2%), and protein (0. 5-1%); other compounds are only partly known and have not been quantitatively determined. The sugar moiety includes mucilaginous components containing polymers, such as chains of (1-4)-linked β-D-galacturonic acid and R (1-2)-linked L-rhamnose residues. Beneficial effects of herbal remedies can be obtained from active constituents present in the whole plant, parts of the plant (e. g., flowers, fruits, roots or leaves), or plant materials or combinations thereof, whether in crude or processed state. Cactus (Opuntiaficus-indica) commonly known as prickly pear belongs to the family Cactaceae. Opuntiaficus-indica produces sweet, nutritionally rich edible fruits; its tender cladodes are used as fresh green vegetable and salad. In South Africa, Mediterranean areas and South American this species is also cultivated for its edible fruit (prickly pear), although in some countries different parts of the plant are utilized in the food and cosmetic industry. Opuntiaficus-indica, fruits and stems, have been traditionally used in folk medicine in several countries for several medicinal purposes. Cactus dietary fiber is composed of several chemical components that are resistant to digestive enzymes such as cellulose, hemicelluloses, pectin, lignin, gums, etc. The benefits associated with fiber content are well known, especially for the prevention of illnesses such as diabetes, treatment of gastrointestinal disorders, illnesses associated with low dietary fiber intake, reduction of glucose values in the blood, anti-hyperlipidemic and anti-hypercholesterolemic effects. Throughout history, the benefits of consuming dietary fiber have been recognized. Soluble fibers, including pectins, gums, and mucilages, increase the viscosity of food in the gut, slowing or reducing sugar absorption. The effect of soluble fiber in reducing serum glucose concentrations is a proposed mechanism of action for the herbal hypoglycemic cactus. It has been reported that Opuntiaficus-indica contain phenolic compounds like ferulic acid, feruloyl-sucrose and sinapoyl-diglucoside, fatty acids like palmitic acid, stearic acid, oleic acid, vaccenic acid and linoleic acid (seeds, peel and juicy pulp). It has been observed that Opuntiaficus-indica oil extract with these components’ present antioxidant and anti-free radical activity, having a potential as anticancer, anti-inflammatory, hypoglycemic, hypolipidemic and hypocholesterolemic activities. Cactus fiber tablet contains 500 mg standardized cactus fiber; as well as common tableting excipients were used. Cactus fiber showed an increased fecal fat excretion compared with placebo. No adverse events were reported throughout the study period. The fruit peel contains large amounts of isorhamnetin. Isorhamnetin (3'-methoxy-3,4',5,7-tetrahydroxyflavone) exerts anticancer action by inhibition of epidermal growth factor (EGF)-induced neoplastic cell transformation through a direct lowering of MAP (mitogen-activated protein)/ERK (extracellular signal regulated kinase) kinase1 and phosphoinositol 3-kinase signaling pathways. Isorhamnetin exhibits cardio protective effects by improving viability of neonatal rat ventricular myocytes under invitro ischemia/reperfusion (I/R) via inhibition of lactate dehydrogenase (LDH) activity and prevention of apoptosis. Isorhamnetin improves skin barrier function through activation of Peroxisome Proliferator-Activated Receptor (PPAR)-αand suppression of inflammatory cytokines production. It also inhibits a dipocyte differentiation of murine 3T3 fibroblasts via a decrease of adiponectine expression and secretion, and down regulation of mRNAs of PPAR-γand C/EBP-α, the major adipogenic nuclear receptors. In contrast, isorhamnetin significantly increases the expression of PPAR-γin tumor tissues obtained from xenograft model of gastric cancer cells and, in combination with chemotherapeutic drugs, causes strong antiproliferative effects and cytotoxicity. The linoleic acid content in cactus cladode (34. 87%) is thus close to the percentage (29% to 40. 41%) found in argan oil. It is however lower than in extracts from barely (51. 26%) and soybean (53. 0%), respectively. Cactus pear (O. boldinghii) cladodes having high fiber content and potential health benefits bakery products have been produced and evaluated from composite flours of wheat (WF) and cactus pear stems (SF). Orange-yellow cactus pear fruit pulp has been used to produce a dehydrated cactus pulp sheet and pasteurized cactus pear fruit juices.