Biomarker For Metabolic Diseases Research Articles

Beyond the 9-to-5 grind: workaholism and its potential influence on human health and disease

Workaholism is often considered a conventional word in the general population to portray those individuals who continuously work and find it challenging not to work. It is usually described as a work addiction and operationalized as a compulsive need to work excessively hard. However, the concept of workaholism remains poorly understood. The first objective of this review is to define workaholism, followed by its related concepts, and how it is assessed. Notably, we distinguish workaholism from work addiction and work engagement. Next, we review the current research literature, largely from the last two decades, to suggest that workaholism contributes toward a wide range of health outcomes, ranging from sleep to stress. In particular, we focus on evidence suggesting that workaholism may be associated with differing risk factors for cardiovascular diseases and potentially other related metabolic abnormalities. Finally, we discuss potential limitations of the existing literature on workaholism, and we provide future directions for this emerging field. Specifically, we underscore the need to link workaholism with more biomarkers of metabolic diseases, such as those related to inflammation, the gut microbiome, and glucose homeostasis. In addition, we highlight the importance of establishing causality between workaholism and poor health outcomes, such as cardiovascular diseases and type 2 diabetes.

Sex Hormone-Binding Globulin as more than a Biomarker of Metabolic Diseases and Reproductive Disorders: What Physicians Should Know?

Sex Hormone-Binding Globulin as more than a Biomarker of Metabolic Diseases and Reproductive Disorders: What Physicians Should Know?

Transglutaminase2: An Enduring Enzyme in Diabetes and Age-Related Metabolic Diseases

Tissue transglutaminase2 (TG2) has emerged as a key enigmatic protein in the development of various metabolic and age-related diseases. It catalyzes covalent cross-linking of countless proteins and provides strength to the extracellular matrix and resistance to proteolytic degradation via different pathways, including NF-kβ, TGF-β and PI3K/Akt as the major signaling pathways. The etiology of diabetes and associated diseases has been found to be linked to unbalanced TG2 activity that may not only result in impaired or delayed wound healing in diabetics but also worsen degenerative and metabolic disease conditions. TG2 is usually overexpressed in diabetes, fibrosis, cancer, and neurodegenerative disorders. These TG2-linked diseases are usually associated with prolonged activation of inflammatory pathways. Therefore, reducing the inflammatory mechanisms and improving tissue remodeling appear to be the main treatment strategies to exterminate TG2-linked diseases. The present review aims to deliver a detailed overview of the existing understanding of TG2 in diabetes and associated diseases’ progression, as well as treatment strategies to regulate TG2 tightly and its potential clinical applications. Our research endorses the notion that TG2 can serve as an effective early-stage diagnostic biomarker for metabolic diseases and a therapeutic target for the development of potential drug.

Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

Pharmacogenetic Variants Can Influence Optical Medication Use.

Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs. Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization. It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy. Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

Potential benefits of microalgae intake against metabolic diseases: beyond spirulina-a systematic review of animal studies.

Microalgae are a diverse source of bioactive molecules, such as polyphenols, carotenoids, and omega-3 fatty acids, with beneficial properties in biomarkers of metabolic diseases. Unlike the rest of the microalgae genera, Arthrospira sp., commonly called spirulina, has been widely studied. This review aims to describe the current knowledge about microalgae, besides spirulina, focusing on their beneficial properties against metabolic diseases. A systematic research of MEDLINE (via PubMed), Cochrane, and Scopus databases was conducted to identify relevant studies published after January 2012. In vivo animal studies including microalgae consumption, except for spirulina, that significantly improved altered biomarkers related to metabolic diseases were included. These biomarkers included body weight/composition, glucose metabolism, lipid metabolism, oxidative damage, inflammation markers, and gut microbiota. After the literature search and the implementation of inclusion and exclusion criteria, 37 studies were included in the revision out of the 132 results originally obtained after the application of the equation on the different databases. Data containing 15 microalgae genera were included reporting on a wide range of beneficial results at different levels, including a decrease in body weight and changes in plasma levels of glucose and lipoproteins due to molecular alterations such as those related to gene expression regulation. The most reported beneficial effects were related to gut microbiota and inflammation followed by lipid and glucose metabolism and body weight/composition. Microalgae intake improved different altered biomarkers due to metabolic diseases and seem to have potential in the design of enriched foodstuffs or novel nutraceuticals. Nevertheless, to advance to clinical trials, more thorough/detailed studies should be performed on some of the microalgae genera included in this review to collect more information on their molecular mechanisms of action.

Principles of metabolome conservation in animals

Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.

Quantification of the renal sinus fat and exploration of its relationship with ectopic fat deposition in normal subjects using MRI fat fraction mapping.

To determine the renal sinus fat (RSF) volume and fat fraction (FF) in normal Chinese subjects using MRI fat fraction mapping and to explore their associations with age, gender, body mass index (BMI) and ectopic fat deposition. A total of 126 subjects were included in the analysis. RSF volume and FF, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area, and hepatic and pancreatic FFs were measured for each subject. The comparisons in gender were determined using two-tailed t-tests or the nonparametric Mann-Whitney U-test for normally or non-normally distributed data for continuous variables and the chi-square test for categorical variables. Comparisons of RFS volume and FF between right and left kidneys were determined using paired sample t-tests. Multivariable logistic models were performed to confirm whether RSF differences between men and women are independent of VAT or SAT area. When parameters were normally distributed, the Pearson correlation coefficient was used; otherwise, the Spearman correlation coefficient was applied. The RSF volumes (cm3) of both kidneys in men (26.86 ± 8.81 for right and 31.62 ± 10.32 for left kidneys) were significantly bigger than those of women (21.47 ± 6.90 for right and 26.03 ± 8.55 for left kidneys) (P < 0.05). The RSF FFs (%) of both kidneys in men (28.33 ± 6.73 for right and 31.21 ± 6.29 for left kidneys) were significantly higher than those of the women (23.82 ± 7.74 for right and 27.92 ± 8.15 for left kidneys) (P < 0.05). The RSF differences between men and women are independent of SAT area and dependent of VAT area (except for right RSF volume). In addition, the RSF volumes and FFs in both kidneys in the overall subjects show significant correlations with age, BMI, VAT area, hepatic fat fraction and pancreatic fat fraction (P < 0.05). However, the patterns of these correlations varied by gender. The RSF volume and FF of left kidney were significantly larger than those of the right kidney (P < 0.05). The association between renal sinus fat and ectopic fat deposition explored in this study may help establish a consensus on the normal values of RSF volume and FF for the Chinese population. This will facilitate the identification of clinicopathological changes and aid in the investigation of whether RSF volume and FF can serve as early biomarkers for metabolic diseases and renal dysfunction in future studies.

The association of soluble cluster of differentiation 36 with metabolic diseases: A potential biomarker and therapeutic target

AbstractA cluster of differentiation 36 (CD36), also known as fatty acid translocase, plays an important role in developing and progressing metabolic diseases. Soluble CD36 (sCD36), a circulating form of CD36, is identified in human plasma. Current studies have demonstrated that sCD36 is an early biomarker of type 2 diabetes (T2DM) and atherosclerosis risk and may act as a key molecule in organ cross‐talks directly or indirectly. This review summarizes the cell sources, molecular structure, potential production mechanism, functions, and regulators of sCD36. We highlight the association of sCD36 with hyperlipidemia, metabolic inflammation, T2DM, cardiovascular disease, non‐alcoholic fatty liver disease, diabetic kidney disease, and obesity. These studies suggest that sCD36 could be a useful biomarker for metabolic diseases in children and a potential therapeutic target in preventing metabolic diseases.

Circulating progranulin in human infants: relation to prenatal growth and early postnatal nutrition.

Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. We longitudinally assessed PGRN concentrations in infants born appropriate (AGA) or small for gestational age (SGA), the latter being at risk for obesity and type 2 diabetes, especially if they experience an excessive postnatal catch-up in weight and are formula-fed (FF). The study population consisted of 183 infants who were exclusively breast-fed [(BF), AGA, n = 66; SGA, n = 40], or FF (AGA, n = 31; SGA, n = 46) over the first 4 months. Assessments included auxology, fasting glucose, insulin, IGF-1, high-molecular-weight adiponectin, PGRN and body composition (by DXA), at birth, and at age 4 and 12 months. PGRN levels were low at birth and unaffected by prenatal growth. PGRN increased at 4 and 12 months, although to a lesser extent in SGA infants, and was unrelated to the mode of feeding. PGRN correlated with markers of adiposity, inflammation and insulin resistance in both AGA and SGA infants, especially in those FF. The attenuated increase of PGRN levels in SGA infants over the first year of life, along with the association to markers of unhealthy metabolic profile, might point to a role of PGRN in future disease risks. Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. In healthy infants, PGRN concentrations are low at birth and experience a significant and progressive increase up to age 12 months, which is less marked in infants born small for gestational age (SGA) and is unrelated to the mode of feeding. Circulating PGRN is related to markers of adiposity, inflammation, and insulin sensitivity, especially in formula-fed SGA infants. PGRN may play a role in the metabolic adaptations of SGA infants during early life, potentially contributing to the risk for obesity and type 2 diabetes in this population.

Characterization and quantification of representative bile acids in ileal contents and feces of diet-induced obese mice by UPLC-MS/MS

• A novel quantification method for bile acids in feces was established. • This method was green and time-saving with high extraction efficiency. • CA, TCA, TCDCA and T-α-MCA were the dominant bile acids in ileal contents. • CA, DCA, α-MCA and β-MCA were the dominant bile acids in feces. • The hydrophobicity index of bile acids was increased in the obese mice. With more requirements for noninvasive diagnosis methods, metabolites in fecal samples are attracting increasing attention to be potential biomarkers of metabolic diseases. Different structured bile acids reveal variable signaling activities related to obesity. A green extraction method coupled with ultra-high performance liquid chromatography-mass spectrometry was developed to simultaneously determine bile acids (BAs) in ileal contents and fecal samples. The separations of all analytes were efficiently performed using ammonium acetate-methanol as the mobile phases with a low limit of detection (LOD at a range of 0.02-0.25 ng/mL). The precision and repeatability of the established method were well-validated. Intra/inter-day precision (relative standard deviation) were lower than 5% and 10%, respectively. And recoveries in spiked samples ranged from 80.80% to 117.83%. In the application among ileal contents and feces of high-fat and high-cholesterol diet-induced obese mice, the results showed that cholic acid was the dominant BA in both samples. Higher concentrations of hydrophobic BAs were observed in obese mice, indicating that hydrophobic BAs were closely connected with the occurrence of metabolic disorders. In summary, the proposed method evaluated the BAs profiling in ileal contents and feces of obese mice and could be used for similar samples of bile acids analysis in patients with obesity.

Fibroblast growth factor 21 is an independent predictor of prevalent and incident obstructive sleep apnea

Fibroblast growth factor 21 (FGF21) is a metabolic regulator and a potential biomarker of metabolic diseases. Limited data are available on the association between FGF21 and obstructive sleep apnea (OSA), which is considered as a manifestation of metabolic syndrome. In the present cross-sectional and longitudinal analyses, the FGF21 level was associated with OSA. This analysis of two clinical cohorts is the first to show that the FGF21 level increased significantly with OSA severity and was an independent predictor of incident OSA in Chinese adults. The circulating FGF21 level could serve as a potential serum biomarker of OSA and its comorbidities and thus aid risk evaluation and early intervention.

Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 μg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.

PMON31 IL-4 Serum Levels Correlate with Triglycerides and VLDL in African American males

Abstract Background Cytokines can play dual roles in diseases, while they signal the activation of the immune system, their mechanism of action results in inflammation. Low grade inflammation is often associated with metabolic diseases and a network of serum cytokines. IL-4 has been found to play a pro-inflammatory role in many conditions surrounding inflammation such as: atopic dermatitis and asthma. As it pertains to lipid metabolism IL4 has been shown to play a protective role in mice. A previous study has shown that IL4 regulates glucose and lipid metabolism by increasing sensitivity to insulin, inhibiting adipogenesis, and increasing glucose tolerance. Dysfunction in lipid metabolism can lead to other metabolic diseases such as cardiovascular disease, diabetes, and obesity. The molecular characterization of IL4's effect in metabolic diseases has yet to be completed. IL4 has been shown to correlate with serum triglyceride and cholesterol, VLDL levels. However, further studies must be carried out to illuminate the molecular cause of these relationships as well as other relationships among metabolic diseases. Methods A total of 68 serum samples were collected from 34 obese, normal HbA1c and 34 obese, elevated HbA1c African American men. Clinical metabolic parameters were determined using standard commercial kits administered by Laboratory Corporation of America. Thirty chemokines/cytokines were measured using a multiplexing assay Luminex X-MAP® technology. Descriptive statistics were computed for each variable for participants with normal and elevated HbA1c. Data are expressed as mean ± SEM. A series of unpaired t-test were computed to determine if there were significant differences between participants with and without elevated HbA1c. Pairwise Pearson Correlation (r) test was computed for each variable. Results In participants with normal HbA1c levels, IL-4 is positively correlated with VLDL (R= 0.6175, P=0.0014). There was no significant correlation in participants with elevated HbA1c in this study (R=0.08168, P=0.1758). Total cholesterol did not have any significant correlation with IL4 in this study; however, there was a positive correlation with IL-4 (R=0.6269, P=0.0013) and triglycerides in participants with normal HbA1c, no correlation seen in this study in participants with high HbA1c. Conclusion This data suggests that IL4-JAK-STAT pathway may play a role in the regulation of IL4, triglycerides, and VLDL in males. The correlations between IL-4 and both serum triglyceride and serum cholesterol, VLDL levels prompt the need to further study possible molecular relationships with other inflammatory biomarkers for metabolic diseases. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease.

Diet influences onset, progression, and severity of several chronic diseases, including heart failure, diabetes, steatohepatitis, and a subset of cancers. The prevalence and clinical burden of these obesity-linked diseases has risen over the past two decades. These metabolic disorders are driven by ectopic lipid deposition in tissues not suited for fat storage, leading to lipotoxic disruption of cell function and survival. Sphingolipids such as ceramides are among the most deleterious and bioactive metabolites that accrue, as they participate in selective insulin resistance, dyslipidemia, oxidative stress and apoptosis. This review discusses our current understanding of biochemical pathways controlling ceramide synthesis, production and action; influences of diet on ceramide levels; application of circulating ceramides as clinical biomarkers of metabolic disease; and molecular mechanisms linking ceramides to altered metabolism and survival of cells. Development of nutritional or pharmacological strategies to lower ceramides could have therapeutic value in a wide range of prevalent diseases.

Extensive Sheep and Goat Production: The Role of Novel Technologies towards Sustainability and Animal Welfare.

Simple SummaryNew technologies have been recognized as valuable in controlling, monitoring, and managing farm animal activities. It makes it possible to deepen the knowledge of animal behavior and improve animal welfare and health, which has positive implications for the sustainability of animal production. In recent years, successful technological developments have been applied in intensive farming systems; however, due to challenging conditions that extensive pasture-based systems show, technology has been more limited. Nevertheless, awareness of the available technological solutions for extensive conditions can increase the implementation of their adoption among farmers and researchers. In this context, this review addresses the role of different technologies applied to sheep and goat production in extensive systems. Examples related to precision livestock farming, omics, thermal stress, colostrum intake, passive immunity, and newborn survival are presented; biomarkers of metabolic diseases and parasite resistance breeding are discussed.Sheep and goat extensive production systems are very important in the context of global food security and the use of rangelands that have no alternative agricultural use. In such systems, there are enormous challenges to address. These include, for instance, classical production issues, such as nutrition or reproduction, as well as carbon-efficient systems within the climate-change context. An adequate response to these issues is determinant to economic and environmental sustainability. The answers to such problems need to combine efficiently not only the classical production aspects, but also the increasingly important health, welfare, and environmental aspects in an integrated fashion. The purpose of the study was to review the application of technological developments, in addition to remote-sensing in tandem with other state-of-the-art techniques that could be used within the framework of extensive production systems of sheep and goats and their impact on nutrition, production, and ultimately, the welfare of these species. In addition to precision livestock farming (PLF), these include other relevant technologies, namely omics and other areas of relevance in small-ruminant extensive production: heat stress, colostrum intake, passive immunity, newborn survival, biomarkers of metabolic disease diagnosis, and parasite resistance breeding. This work shows the substantial, dynamic nature of the scientific community to contribute to solutions that make extensive production systems of sheep and goats more sustainable, efficient, and aligned with current concerns with the environment and welfare.

The effect of vitamin D supplementation on tobacco-related disorders in individuals with a tobacco use disorder: a randomized clinical trial

Vitamin D deficiency in cigarette smokers (CS) might associate with several complications, including metabolic deficits, depression and anxiety. This study evaluated the effects of vitamin D on mental health symptoms, nicotine misuse, and biomarkers of metabolic diseases in individuals with a tobacco use disorder. A randomized, double-blind, placebo-controlled trial was conducted with 60 CS subjects receiving either 50,000 IU vitamin D supplements (n = 30) or placebo (n = 30) every 2 weeks for 24-weeks. Nicotine misuse, mental health scale, and metabolic parameters were measured before and after the intervention in the CS subjects. Compared with the placebo-group, after the 24-weeks intervention, serum 25 (OH) vitamin D levels increased in the intervention group (β 2.96; 95% CI, 0.91, 5.01; P = 0.006). In addition, vitamin D supplementation significantly improved Beck Depression Inventory (BDI) (β −2.06; 95% CI, −3.84, −0.28; P = 0.02). In addition, vitamin D administration significantly decreased fasting plasma glucose (FPG) (β −4.56; 95% CI, −8.94, −0.19; P = 0.04), insulin (β −0.50; 95% CI, −0.88, −0.13; P = 0.009), and homeostasis model of assessment-estimated insulin resistance (HOMA-IR) levels (β −0.21; 95% CI, −0.33, −0.08; P = 0.001). Furthermore, vitamin D resulted in a significant elevation in total antioxidant capacity (TAC) (β 81.20; 95% CI, 18.30, 144.11; P = 0.01), and plasma glutathione (GSH) levels (β 73.05; 95% CI, 18.56, 127.54; P = 0.01), compared with the placebo-group. Administration of vitamin D for 24-weeks to CS subjects had beneficial effects on symptoms of depression and several metabolic biomarkers. While this preliminary study suggests that vitamin D might have beneficial effects, its clinical efficacy in individuals with a tobacco use disorder should be further validated in future clinical trials.

TGR5 Expression Is Associated with Changes in the Heart and Urinary Bladder of Rats with Metabolic Syndrome

Adipose-derived cytokines may contribute to the inflammation that occurs in metabolic syndrome (MetS). The Takeda G protein-coupled receptor (TGR5) regulates energy expenditure and affects the production of pro-inflammatory biomarkers in metabolic diseases. Etanercept, which acts as a tumor necrosis factor (TNF)-α antagonist, can also block the inflammatory response. Therefore, the interaction between TNF-α and TGR5 expression was investigated in rats with high-fat diet (HFD)-induced obesity. Heart tissues isolated from the HFD-induced MetS rats were analyzed. Changes in TGR5 expression were investigated with lithocholic acid (LCA) as the agonist. Betulinic acid (BA) was used to activate TGR5 in urinary bladders. LCA was more effective in the heart tissues of HFD-fed rats, although etanercept alleviated the function of LCA. STAT3 activation and higher TGR5 expression were observed in the heart tissues collected from HFD-fed rats. Thus, cardiac TGR5 expression is promoted by HFD through STAT3 activation in rats. Moreover, the urinary bladders of female rats fed a HFD showed a low response, which was reversed by etanercept. Relaxation by BA in the bladders was more marked in HFD-fed rats. The high TGR5 expression in HFD-fed rats was characterized using a mRNA assay, and the increased cAMP levels were found to be stimulated by BA in the isolated bladders. Therefore, TGR5 expression increases with a HFD in both the hearts and urinary bladders. Collectively, cytokine-medicated TGR5 activation was observed in the hearts and urinary bladders of rats.

Dysregulated Metabolites Serve as Novel Biomarkers for Metabolic Diseases Caused by E-Cigarette Vaping and Cigarette Smoking.

Metabolites are essential intermediate products in metabolism, and metabolism dysregulation indicates different types of diseases. Previous studies have shown that cigarette smoke dysregulated metabolites; however, limited information is available with electronic cigarette (e-cig) vaping. We hypothesized that e-cig vaping and cigarette smoking alters systemic metabolites, and we propose to understand the specific metabolic signature between e-cig users and cigarette smokers. Plasma from non-smoker controls, cigarette smokers, and e-cig users was collected, and metabolites were identified by UPLC-MS (ultra-performance liquid chromatography mass spectrometer). Nicotine degradation was activated by e-cig vaping and cigarette smoking with increased concentrations of cotinine, cotinine N-oxide, (S)-nicotine, and (R)-6-hydroxynicotine. Additionally, we found significantly decreased concentrations in metabolites associated with tricarboxylic acid (TCA) cycle pathways in e-cig users versus cigarette smokers, such as d-glucose, (2R,3S)-2,3-dimethylmalate, (R)-2-hydroxyglutarate, O-phosphoethanolamine, malathion, d-threo-isocitrate, malic acid, and 4-acetamidobutanoic acid. Cigarette smoking significant upregulated sphingolipid metabolites, such as d-sphingosine, ceramide, N-(octadecanoyl)-sphing-4-enine, N-(9Z-octadecenoyl)-sphing-4-enine, and N-[(13Z)-docosenoyl]-sphingosine, versus e-cig vaping. Overall, e-cig vaping dysregulated TCA cycle-related metabolites while cigarette smoking altered sphingolipid metabolites. Both e-cig and cigarette smoke increased nicotinic metabolites. Therefore, specific metabolic signatures altered by e-cig vaping and cigarette smoking could serve as potential systemic biomarkers for early pathogenesis of cardiopulmonary diseases.

Hyocholic acid and glycemic regulation: comments on ‘Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism’

Hyocholic acid species (HCA, hyodeoxycholic acid, and their glycine and taurine conjugated forms) comprise 80% of the composition of pig bile (Haslewood, 1956). An interesting fact about pigs is that they do not get diabetes even though they eat almost anything and in abundant amounts, a diabetes-promoting diet. The first use of pig bile for treatment of 'xiao-ke', a condition known today as diabetes, was recorded ∼400 years ago by the Chinese medical practitioners in the Compendium of Materia Medica (Li, 1573‒1593). Recently, we found HCA species as novel biomarkers for metabolic diseases (Zheng et al., 2021b) and also identified the role of HCA species in the prevention of diabetes as well as their mechanism of action (Zheng et al., 2021a). Although bile acids (BAs) are mostly associated with their aid in food digestion, they have also been shown to act as signaling molecules by binding to two particular receptors, farnesoid X receptor (FXR) and the G-protein-coupled receptor, TGR5. Experiments were thus directed to the effect of HCA binding to these two BA receptors on glycemic regulation in both in vivo and in vitro models.