Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR–ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.     

PPARgamma-mediated ALDH1A3 suppression exerts anti-proliferative effects in lung cancer by inducing lipid peroxidation

Context: The metabolic function of peroxisome proliferator-activated receptor gamma (PPARγ) in lung cancer remains unclear.

Objectives: To determine the relationship of PPARγ on ALDH1A3-induced lipid peroxidation to inhibit lung cancer cell growth.

Materials and methods: In silico analysis using microarray dataset was performed to screen the positive correlation between PPARγ and all ALDH isoforms. NUBIscan software and ChIP assay were used to identify the binding sites (BSs) of PPARγ on ALDH1A3 promoter. The expression of ALDH1A3 under thiazolidinedione (TZD) treatment was evaluated by QPCR and Western Blot in HBEC and H1993 cell lines. Upon treatment of TZD, colony formation assay was used to check cell growth inhibition and 4-hydroxy-2-nonenal (4HNE) production as lipid peroxidation marker was determined by Western Blot in PPARγ positive cell H1993 and PPARγ negative cell H1299.

Results: Compared to other ALDH isoforms, ALDH1A3 showed the highest positive correlation to PPARγ expression. ALDH1A3 upregulated PPARγ expression while PPARγ activation suppressed ALDH1A3. Among 2 potential screened PPARγ response elements, BS 1 and 2 in the promoter of ALDH1A3 gene, PPARγ bound directly to BS2. Ligand activation of PPARγ suppressed mRNA and protein expression of ALDH1A3. Growth inhibition was observed in H1993 (PPARγ positive cell) treated with PPARγ activator and ALDH inhibitor compared to H1299 (PPARγ negative cell). PPARγ activation increased 4HNE which is known to be suppressed by ALDH1A3.

Conclusions: ALDH1A3 suppression could be one of PPARγ tumor suppressive function. This study provides a better understanding of the role of PPARγ in lung cancer.     

Hepatitis C virus–apolipoprotein interactions: molecular mechanisms and clinical impact

Introduction: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. Moreover, chronic HCV infection is associated with liver steatosis and metabolic disorders. With 130–150 million people chronically infected in the world, HCV infection represents a major public health problem. One hallmark on the virus is its close link with hepatic lipid and lipoprotein metabolism.

Areas covered: HCV is associated with lipoprotein components such as apolipoproteins. These interactions play a key role in the viral life cycle, viral persistence and pathogenesis of liver disease. This review introduces first the role of apolipoproteins in lipoprotein metabolism, then highlights the molecular mechanisms of HCV-lipoprotein interactions and finally discusses their clinical impact.

Expert commentary: While the study of virus-host interactions has resulted in a improvement of the understanding of the viral life cycle and the development of highly efficient therapies, major challenges remain: access to therapy is limited and an urgently needed HCV vaccine remains still elusive. Furthermore, the pathogenesis of disease biology is still only partially understood. The investigation of HCV-lipoproteins interactions offers new perspectives for novel therapeutic approaches, contribute to HCV vaccine design and understand virus-induced liver disease and cancer.     

Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPAR alpha form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPAR alpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. It is likely that these actions of PPAR alpha activators on lipid, glucose and energy metabolism are, at least in part, due to the increase of hepatic fatty acid beta-oxidation resulting in an enhanced fatty acid flux and degradation in the liver. Moreover, PPARs are expressed in different immunological and vascular wall cell types where they exert anti-inflammatory and proapoptotic activities. The observation that these receptors are also expressed in atherosclerotic lesions suggests a role in atherogenesis. Finally, PPAR alpha activators correct age-related dysregulations in redox balance. Taken together, these data indicate a modulatory role for PPAR alpha in the pathogenesis of age-related disorders, such as dyslipidemia, insulin resistance and chronic inflammation, predisposing to atherosclerosis.     

Weight loss effect of sweet orange essential oil microcapsules on obese SD rats induced by high-fat diet

Obesity is one of the most common and major health concerns worldwide. Weight management through dietary supplements with natural plant extracts has become the focus of current research. Sweet orange essential oil (SOEO) is a natural plant extract, with many bioactivities. In order to evaluate the weight loss effect of SOEO microcapsules and investigate the underlying mechanism, we fed high-fat diet-induced obese SD rats with SOEO microcapsules for 15 days and found that SOEO microcapsules reduced body weight gain by 41.4%, decreased total cholesterol level, alleviated liver and adipose tissue pathological alteration. The results of fluorescence quantitative PCR revealed that decreasing the expression of peroxisome proliferators-activated receptor-γ, upregulating of uncoupling protein 2, hormone sensitive lipase and carnitine palmitoyltransferase I, inhibiting the expression of acetyl-CoA carboxylase appear to be the mechanism of SOEO microcapsules to lose weight. This study suggests that SOEO microcapsule is a potential dietary supplement for weight loss.

Abbreviations: SOEO: sweet orange essential oil; TC: total cholesterol; TG: triglyceride; LDL-c: low-density lipoprotein cholesterol; HDL-c: high-density lipoprotein cholesterol; PPARα: peroxisome proliferators-activated receptor-α; PPARγ: peroxisome proliferators-activated receptor-γ; UCP2: uncoupling protein 2; HSL: hormone sensitive lipase; CPT1: carnitine palmitoyltransferase I; ACC: acetyl-CoA carboxylase; NPY: neuropeptide Y; LEP: leptin; INS: insulin; ALT: alanine aminotransferase; AST: aspartate aminotransferase.     

Ellagic acid affects mRNA expression levels of genes that regulate cholesterol metabolism in HepG2 cells

Ellagic acid has been shown to improve cholesterol metabolism in animal studies, but the molecular mechanisms underlying this function have not been fully understood. We performed DNA microarray analysis to elucidate the effects of ellagic acid on cholesterol metabolism in HepG2 hepatocytes. This revealed that the expression levels of several genes related to cholesterol metabolism, including the low-density lipoprotein receptor (LDLR), were changed by ellagic acid treatment. Using a real-time PCR and immunoblot we confirmed that ellagic acid treatment up-regulated mRNA and protein expression level of the LDLR. Moreover, In the presence of 25 μM ellagic acid, extracellular apoB protein and MTP mRNA levels were significantly decreased. These findings indicate that ellagic acid improves cholesterol metabolism through the up-regulation of LDLR, down-regulation of MTP mRNA and reduces extracellular apoB levels. The ellagic acid-induced up-regulation of LDLR occurred via the extracellular signal-regulated kinase (ERK) signaling pathway in HepG2 hepatocytes.

Abbreviations: LDLR: low-density lipoprotein receptor; apoB: apolipoprotein B; PKC: diacylglycerol-protein kinase C; MAPK: mitogen-activated protein kinase; ERK: p42/44 extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; VLDLR: very low density lipoprotein receptor; PPARδ: peroxisome proliferator-activated receptor δ; SREBPs: sterol regulatory element-binding proteins; MTP: microsomal triacylglycerol transfer protein; LPDS: lipoprotein-deficient serum     

Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.     

Mineral Nitrogen in Plant Physiology and Plant Nutrition

Nitrogen (N) nutrition enhances metabolic processes that influences the physicochemical environment at the soil-root interface, modifies rhizosphere conditions, interferes with the uptake of cations and anions, and enhances or represses the activity of several enzyme systems. Also, it affects growth patterns, protein content, and protein quality of seeds.

Ammonium (NH₄)-N nutrition increases anion uptake, free amino-N/protein ratios, and acidity of root free space; it reduces carbohydrate levels in plant tissues. NO₃-N nutrition results in higher cation uptake, higher carbohydrate content in tissues, and alkalinization of root free space. N-Assimilation interferes with the allocation of dry matter and energy, which causes different growth rates of plant parts.

In this article we review the effects of mineral-N nutrition on uptake of cations and anions, activity of enzymes, growth patterns of roots and shoots, and water use efficiency, protein content, and protein quality of seeds.     

The adipokine tartrate-resistant acid phosphatase 5a in serum correlates to adipose tissue expansion in obesity

Purpose: Tartrate-resistant acid phosphatase (TRAP) exists as two isoforms, 5a and 5b. TRAP 5a is elevated in adipose tissue of obese women, interacts with pre-adipocytes and is linked to insulin-sensitive hyperplastic obesity when overexpressed in mice. The aim of this study was to investigate the relation between serum TRAP 5a, adiposity indices and metabolic syndrome risk markers in lean and obese women, using a newly developed TRAP 5a-specific ELISA.

Materials and methods: A TRAP 5a sandwich ELISA was optimized using TRAP 5a-specific monoclonal antibodies and tested in sera of healthy males. TRAP 5a levels were quantitated in sera from healthy males and lean and obese women.

Results: Serum TRAP 5a protein levels were lower in obese women in comparison with lean. In obese, but not in lean women, serum TRAP 5a correlated positively to % fat mass, BMI, waist- and hip circumference, waist-to-hip ratio and PAI, while no correlations to serum leptin, HOMA, glucose, insulin, FFA, HDL, TG, APO-A1 and APO-B were observed.

Conclusions: TRAP 5a serum levels correlated positively to anthropometric obesity parameters but not to metabolic syndrome risk factors, indicating that serum TRAP 5a is associated with pathological adipose tissue expansion.     

Phytochemical treatments target kynurenine pathway induced oxidative stress

Objective: The objective of this paper was to link the phytochemical and metabolic research treating quinolinic acid induced oxidative stress in neurodegenerative disorders.

Methods: Quinolinic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, plays a role in the oxidative stress associated with many neurological disorders and is used to simulate disorders such as Parkinson’s disease.

Results: In these models, phytochemicals have been shown to reduce striatal lesion size, reduce inflammation and prevent lipid peroxidation caused by quinolinic acid.

Conclusion: These results suggest that phenolic compounds, a class of phytochemicals, including flavonoids and diarylheptanoids, should be further studied to develop new treatments for oxidative stress related neurological disorders.     

PPARγ 基因与代谢综合征关系的研究进展

过氧化物酶体增殖物激活受体(PPARs)γ基因已被公认在调控脂肪细胞分化和多种代谢(糖、脂肪、能量代谢等)中起重要作用。它在脂肪、肌肉、肝脏等多种与胰岛素作用有关的组织中表达,并且具备激活后调控涉及葡萄糖的产生、转运、利用及脂肪代谢的调节等基因的表达。PPARγ基因在脂肪细胞分化、糖、脂代谢、动脉粥样硬化形成、炎性反应中起重要作用,从而与T2DM、胰岛素抵抗、肥胖症、心血管疾病和高血压等疾病的发病风险相关。本文综述了PPARγ基因的结构、功能及其多态性与代谢综合征关系的研究进展。     

Circulating microRNAs in human obesity: a systematic review

Context: Differential expression profiles of microRNAs have been reported in human obesity suggesting a miRNAs role in the development of obesity and associated disorders.

Objective: To review circulating microRNAs (c-miRNAs) dysregulated in human obesity and to predict their possible target genes.

Methods: We performed a systematic review on PubMed database (PROSPERO, CRD42017077742) for original works on c-miRNAs and human obesity and recorded c-miRNAs with differential expression profiles. Potential target genes and metabolic pathways for dysregulated miRNAs with at least two independent reports were searched using bioinformatic tools.

Results: Twenty-two c-miRNAs are overexpressed, nine underexpressed and two c-miRNAs dysregulated in both directions in people with obesity compared to lean controls. Bioinformatic analyses suggest these c-miRNAs target on genes associated with fatty acid metabolism and PI3k/Akt pathway.

Conclusion: Literature records 33 c-miRNAs confirmedly dysregulated in human obesity. Their predicted target genes are involved in pathways that could explain the development of obesity and its comorbidities. Further research will clarify the role of these miRNAs on metabolic diseases and their usefulness for the prognosis, prevention and treatment of obesity.     

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages.

We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.

The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of α-ketoglutarate (α-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, α-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.

Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS.     

Evidence of alterations in the expression of orphan receptors GPR26 and GPR39 due to the etiology of the metabolic syndrome

Aims: Metabolic syndrome (MS) is composed of several metabolic abnormalities that increase the risk of cardiovascular diseases and diabetes. Although there are treatments for the components of MS, this pathology maintains a high mortality, suggesting that there are other mechanisms in which orphan receptors such as GPR26 and GPR39 may be involved. For this reason, the aim of this work was to evaluate the expression of GPR26 and GPR39 orphan receptors in two models of MS (diet and genetics).

Materials and methods: We used male Wistar rats, which received 70% fructose in drinking water for 9 weeks, and obese Zucker rats. We measured weight, blood pressure, glucose, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol to determine the MS and the expression of the orphan receptors GPR26 and GPR39 in brain, heart, aorta, liver, and kidney by RT-PCR.

Results: The analysis of the expression of the orphan receptors GPR26 and GPR39 showed that the receptors are expressed in some tissues, but the expression of the GPR26 tends to decrease in the heart and aorta, whereas in the brain, no changes were observed, this receptor is not expressed in the liver and kidney of both strains. The expression of GPR39 isoforms depends on the tissue and MS model.

Conclusions: We conclude that the orphan receptors GPR26, GPR39v1, and GPR39v2 are expressed in different tissues and their profile expression is dependent on the etiology of the MS.     

Recent advances in the metabolomic study of bladder cancer

Introduction: Metabolomics is a chemical process, involving the characterization of metabolites and cellular metabolism. Recent studies indicate that numerous metabolic pathways are altered in bladder cancer (BLCA), providing potential targets for improved detection and possible therapeutic intervention. We review recent advances in metabolomics related to BLCA and identify various metabolites that may serve as potential biomarkers for BLCA.

Areas covered: In this review, we describe the latest advances in defining the BLCA metabolome and discuss the possible clinical utility of metabolic alterations in BLCA tissues, serum, and urine. In addition, we focus on the metabolic alterations associated with tobacco smoke and racial disparity in BLCA.

Expert commentary: Metabolomics is a powerful tool which can shed new light on BLCA development and behavior. Key metabolites may serve as possible markers of BLCA. However, prospective validation will be needed to incorporate these markers into clinical care.     

Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation

Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation.

Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets.

Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis.

Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation.