Is resistin the master link between inflammation and inflammation-related chronic diseases?

Sudan S.K., Deshmukh S.K., Poosarla T., Holliday N.P., Dyess D.L., Singh A.P., Singh S.

Systemic and organ-confined inflammation has been associated with cancer development and progression. Resistin, initially described as an adipocyte-derived cytokine in mice, is mostly expressed by the macrophages in humans. It has potent pro-inflammatory properties, and its elevated serum levels are detected in cancer patients. Aberrant expression of resistin receptors is also reported in several malignancies and associated with aggressive clinicopathological features. Several lines of evidence demonstrate that resistin, acting through its different receptors, promotes tumor growth, metastasis, and chemoresistance by influencing a variety of cellular phenotypes as well as by modulating the tumor microenvironment. Racially disparate expression of resistin has also attracted much interest, considering prevalent cancer health disparities. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling and impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.

Derosa G., Catena G., Gaudio G., D'Angelo A., Maffioli P.

The aim of this study was to valuate if there are some differences in metabolic parameters among obese which will develop diabetes and those that will not develop diabetes. We enrolled 959 obese, normal glucose tolerant, of either sex, outpatients and evaluated them for 8 years. We evaluated: body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (HOMA) index, blood pressure, lipid profile, lipoprotein(a), adiponectin (ADN), resistin, leptin, high sensitivity reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), retinol binding protein-4 (RBP-4), adipsin, vaspin, visfatin, omentin-1, chemerin. After 8 years of observation, 429 patients maintained euglycemia, while 133 patients developed dysglycemia, and 90 developed diabetes. In dysglycemic patients, ADN was lower, and resistin was higher compared to baseline, while in diabetic patients ADN was lower, and resistin was higher both compared to baseline, and compared to euglycemic and dysglycemic patients. High sensitivity C-reactive protein, TNF-α were higher in both dysglycemic and diabetic patients compared to baseline, but the values recorded in diabetics were higher both compared to euglycemic and dysglycemic. Visfatin was higher and omentin-1 was lower compared to baseline, and compared to euglycemic patients in diabetics. Odds ratio showed that lower levels of adiponectin and higher levels of resistin, but not of other cytokines, increased the risk of developing type 2 diabetes mellitus. Data seem to suggest that lower levels of adiponectin, and higher levels of resistin can be predictive of a future diabetes in obese people, even years before the disease onset.

Singh N., Baby D., Rajguru J., Patil P., Thakkannavar S., Pujari V.

Acquarone E., Monacelli F., Borghi R., Nencioni A., Odetti P.

From a biological point of view, aging can be considered a progressive inability of an organism to react to stress, maintain homeostasis, and survive unfavourable changes during post-maturational life. The expression of several adipokines changes during aging and for some changes, a role in the onset of chronic disease and frailty has been proposed. Among adipokines, resistin was shown in recent studies to play a key role in aging. Resistin is a small secreted protein that regulates glucose metabolism in mammalians. High resistin levels induce insulin resistance and exert proinflammatory effects. Consistently, resistin has been shown to play a pivotal role in various metabolic, inflammatory, and autoimmune diseases. Herein, the role of resistin as a molecular link between aging and age-related conditions was reviewed and the clinical implications of this knowledge discussed.

HU W., QIAO S., HOU Q., YUAN J.

Resistin, a novel adipokine linked to insulin resistance and obesity in rodents, which is derived mainly from macrophages and identified in atheromas in human, has been shown to play a potential role in atherosclerosis. Resistin levels were reported to increase in coronary artery disease (CAD), while data concerning resistin in different stages of CAD in Chinese people are lacking. The aim of this study was to assess whether plasma concentrations of resistin differed between patients with unstable and stable angina pectoris.Plasma resistin levels were determined by means of enzyme-linked immunosorbent assay (ELISA) in 46 patients with unstable angina (UAP), 37 with stable angina (SAP) and 31 control subjects.Plasma concentrations of resistin were significantly increased in UAP group (geometric mean (interquartile range) 12.09 ng/ml (8.40, 18.08)) in comparison with SAP (9.04 ng/ml (7.09, 11.44)) and control groups (8.71 ng/ml (6.58, 11.56)). No differences in resistin levels were found between patients with SAP and controls. We also found that plasma resistin positively correlated with leukocyte counts (r = 0.21, P = 0.027), high sensitive C-reactive protein (hs-CRP) (r = 0.25, P = 0.008), and endothelin-1 (r = 0.21, P = 0.025) after adjustment for age, sex and BMI.Resistin may be involved in the development of CAD by influencing systemic inflammation and endothelial activation.

Zhang M., Yan L., Wang G., Jin R.

Resistin, secreted by macrophages in tumor microenvironment, has never been investigated in pancreatic cancer models, despite a vibrant tumor microenvironment around pancreatic tumors. We evaluated serum resistin levels in healthy individuals versus pancreatic cancer patients representing different tumor grades. In vitro mechanistic analysis involved MiaPaCa-2 and SW1990 cells. Resistin signaling depends on binding of resistin to its cognitive receptors. Therefore, we silenced adenylyl cyclase-associated protein 1 (CAP1) and toll-like receptor 4 (TLR4), its two known receptors, individually as well as in combination, by short hairpin RNA (shRNA). Effect of resistin on cell proliferation, migration, invasion, cell cycle, and sensitivity to gemcitabine was studied without or with silencing of resistin receptors CAP1 and/or TLR4. The results were also confirmed in vivo in mice xenografted with MiaPaCa-2 cells without or with receptor silencing. We report high resistin levels in pancreatic cancer patients which correlate positively with tumor grades. We observed a marked reduction in the resistin-induced proliferation, migration, invasion, and cell cycle of pancreatic cancer cells MiaPaCa-2 and SW1990 when the receptors were silenced. The results were confirmed in vivo wherein resistin effects were significantly attenuated in MiaPaCa-2 xenografts with silenced receptors. The combined silencing of CAP1 and TLR4 was found to be most effective in vitro and in vivo. We found activation of STAT3 by resistin in vivo and in vitro which was dependent on the presence of CAP1 and TLR4. Further, resistin was found to induce resistance to gemcitabine through its receptors. Our results describe novel functional roles of resistin with implications toward a better understanding of pancreatic tumor microenvironment.

Qiu L., Zhang G., Yu L., Wang H., Jia X., Wang T.

Resistin plays a role in the growth, proliferation, angiogenesis, metastasis and therapeutic resistance in different cancers. However, such effects of resistin have never been evaluated in ovarian cancer, a deadly gynecological malignancy. We observed a significant induction of ovarian cancer cells’ growth, invasion and cisplatin resistance, and established a mechanism of resistin action that included induction of EMT and stemness, as evidenced by down-regulated epithelial marker e-cadherin and up-regulated mesenchymal markers vimentin/ ZEB1 and stemness markers sox2, oct4 and nanog. The mechanism also included suppression of tumor suppressor miRNAs, let-7a, miR-200c and miR-186. Over-expression of these miRNAs significantly reversed the resistin-mediated effects on invasion and chemoresistance. We further validated our results in vivo where resistin administration significantly enhanced tumor growth in mice. Our results provide first evidence for such oncogenic effects of resistin in ovarian cancer models and a rationale for future studies to further understand the mechanistic role of resistin in ovarian cancer invasiveness, metastasis and therapy resistance.

Su C., Tang C., Chi M., Lin C., Fong Y., Liu Y., Chen W., Wang S.

Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Accumulating evidence shows that resistin, a cytokine secreted from adipocytes and monocytes, also promotes tumor pathogenesis. Notably, chondrosarcoma can easily metastasize. In this study, we demonstrate that resistin enhances VEGF-C expression and lymphatic endothelial cells (LECs)-associated lymphangiogenesis in human chondrosarcoma cells. We also show that resistin triggers VEGF-C-dependent lymphangiogenesis via the c-Src signaling pathway and down-regulating micro RNA (miR)-186. Overexpression of resistin in chondrosarcoma cells significantly enhanced VEGF-C production and LECs-associated lymphangiogenesis in vitro and tumor-related lymphangiogenesis in vivo. Resistin levels were positively correlated with VEGF-C-dependent lymphangiogenesis via the down-regulation of miR-186 expression in clinical samples from chondrosarcoma tissue. This study is the first to evaluate the mechanism underlying resistin-induced promotion of LECs-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis.

Gong W., Liu J., Yin J., Cui J., Xiao D., Zhuo W., Luo C., Liu R., Li X., Zhang W., Zhou H., Liu Z.

Metastasis is the main cause of lung cancer-related death. The tumor microenvironment greatly contributes to tumor metastasis. Resistin, mainly secreted by tumor-associated macrophages in tumor tissues, is a 12.5-kDa cysteine-rich secretory protein that is found at significantly higher levels in the serum or plasma of cancer patients compared with healthy controls. In this study, we explored the expression and role of resistin in lung adenocarcinoma. Our study showed that resistin was strongly expressed in lung adenocarcinoma tissues and promoted the migration and invasion of lung adenocarcinoma cells in a dose-dependent manner. Toll-like receptor 4 (TLR4) was the functional receptor of resistin for migration and invasion in A549 cells. Src/epidermal growth factor receptor (EGFR) was involved in resistin-induced migration and invasion. Resistin increased the phosphorylation of EGFR through the TLR4/Src pathway. We also found that PI3K/nuclear factor (NF)-κB were the intracellular downstream effectors mediating resistin-induced migration and invasion. Taken together, our results suggested that resistin promoted lung adenocarcinoma metastasis through the TLR4/Src/EGFR/PI3K/NF-κB pathway.

Malvi P., Chaube B., Singh S.V., Mohammad N., Vijayakumar M.V., Singh S., Chouhan S., Bhat M.K.

Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various cancers. Obesity-associated factors or adipokines, especially leptin and resistin, are purported to promote growth, survival, proliferation, and invasiveness of cancer cells. However, the mechanistic link between these adipokines and therapeutic response in malignancies is not clearly understood. ob/ob and db/db mouse models were used in this study to evaluate the role of leptin and resistin towards the outcome of dacarbazine (DTIC) therapy in melanoma. Unique in vitro approaches were employed to complement in vivo findings by culturing melanoma cells in the serum collected from the experimental mice. Here, we have shown the role of important adipokines leptin and resistin in growth and the outcome of DTIC therapy in melanoma. Both leptin and resistin not only enhance proliferation of melanoma cells but also are involved in impairing the therapeutic efficacy of DTIC. Leptin and resistin treatment caused an increase in the protein levels of fatty acid synthase (FASN) and caveolin 1 (Cav-1) respectively, through their stabilization in A375 cells. Further, it was observed that leptin and resistin impaired the response of melanoma cells to DTIC via upregulation of heat shock protein 90 (Hsp90) and P-glycoprotein (P-gp) respectively. These findings unraveled the involvement of adipokines (leptin and resistin) in melanoma progression, and more importantly, in the outcome of DTIC therapy.

Wang C., Wang P., Hsieh Y., Lo S., Lee Y., Chen Y., Tsai C., Chiu W., Chu-Sung Hu S., Lu C., Yang Y., Chiu C., Ou-Yang F., Wang Y., Hou M., et. al.

Growing evidence indicates that resistin—an obesity-related cytokine—is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial–mesenchymal transition and stemness in breast cancer cells—mechanisms critical to tumorigenesis and metastasis—through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.

Gierej P., Gierej B., Kalinowski P., Wróblewski T., Paluszkiewicz R., Kobryń K., Ziarkiewicz-Wróblewska B.

Nagaev I., Andersen M., Olesen M.K., Nagaeva O., Wikberg J., Mincheva-Nilsson L., Andersen G.N.

Rheumatoid arthritis (RA) is caused by complex interactions between immune cells and sustained by Th1 response cytokines. Resistin [resistance to insulin; (RETN)] is an inflammatory cytokine, first discovered in murine adipocytes. In man, RETN is mainly secreted by monocytes. The distinct role of RETN in the immune reaction is uncertain; however, RETN has pro-inflammatory, pro-fibrotic and possibly tolerogenic properties. The aim was to assess the reaction of RETN gene expression to TNF-α inhibition (I) in pathogenetic immune cell subsets in RA, in the context of Th1, inflammatory and regulatory cytokine gene expressions. Accordingly, we measured RETN, IFN-γ, TNF-β, IL-1β, TNF-α, TGF-β and IL-10 gene expressions in CD14(+) monocytes, CD4(+) T helper (Th) lymphocytes (ly), CD8(+) T cytotoxic (Tc) ly and CD19(+) B ly in active RA before and 3 months after start of TNF-αI. Leucocyte subsets were separated by specific monoclonal antibody-covered beads, RNA extracted and levels of RETN, Th1 response, inflammatory and regulatory cytokine mRNAs measured by quantitative reverse transcription-polymerase chain reaction technique. We found that TNF-αI caused a significant downregulation of RETN gene expression in CD14(+) monocytes and CD4(+) Th ly and was unchanged in CD8(+) Tc ly and CD19(+) B ly. Both in active RA and during TNF-αI, RETN mRNA levels were significantly higher in CD14(+) monocytes than in all other examined cell types. In monocytes, fold change in RETN and TGF-β gene expressions upon TNF-αI correlated significantly. Our findings indicate that RETN has pro-inflammatory as well as proresolving roles in active RA.

Gencer B., Auer R., de Rekeneire N., Butler J., Kalogeropoulos A., Bauer D.C., Kritchevsky S.B., Miljkovic I., Vittinghoff E., Harris T., Rodondi N.

Objective Prospective data on the association between resistin levels and cardiovascular disease (CVD) events are sparse with conflicting results. Methods We studied 3044 aged 70–79 years from the Health, Aging, and Body Composition Study. CVD events were defined as coronary heart disease (CHD) or stroke events. «Hard » CHD events were defined as CHD death or myocardial infarction. We estimated hazard ratio (HR) and 95% confidence intervals (CI) according to the quartiles of serum resistin concentrations and adjusted for clinical variables, and then further adjusted for metabolic disease (body mass index, fasting plasma glucose, abdominal visceral and subcutaneous adipose tissue, leptin, adiponectin, insulin) and inflammation (C-reactive protein, interleukin-6, tumor necrosis factors-α). Results During a median follow-up of 10.1 years, 559 patients had « hard » CHD events, 884 CHD events and 1106 CVD Events. Unadjusted incidence rate for CVD events was 36.6 (95% CI 32.1–41.1) per 1000 persons-year in the lowest quartile and 54.0 per 1000 persons-year in the highest quartile (95% CI 48.2–59.8, P for trend  Conclusions In older adults, higher resistin levels are associated with CVD events independently of clinical risk factors and metabolic disease markers, but markedly attenuated by inflammation.

Benomar Y., Amine H., Crépin D., Al Rifai S., Riffault L., Gertler A., Taouis M.

Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

Kim B., Jo Y., Baek J.Y., Park S.J., Jung H., Lee E., Jang I., Sakong H., Ryu D.

Boren C., Barr B., Mubtasim N., Gollahon L.

(1) Background: Overconsumption of processed meats, fats, and carbohydrates drives the obesity epidemic in the USA. Associated with this epidemic are increases in metabolic diseases, such as type 2 diabetes, cardiovascular disease, and cancer. In this study, protein levels of adipocytokines isolated from visceral fat in mice fed high-fat diets with proteins modified through ammonium supplementation were analyzed to determine changes that occur as a result of dietary protein source and its modification based on age or sex. (2) Methods: Male and female C3H/HeJ mice were randomized into six customized diets—Group 1: CCN = Control Chow (CC) + Ammonium Hydroxide Enhancement (AHE); Group 2: CC = Control Chow; Group 3: HFBN = High Fat (HF) AHE Dietary Beef; Group 4: HFB = HF Beef; Group 5: HFCN = HF AHE Dietary Casein; Group 6: HFC = HF Dietary Casein. Mice were censored at six-month intervals, and visceral fat was collected for analysis. This study highlights sex- and age-related changes in cellular adipocytokine protein expression from 12 to 18 months. (3) Results: When compared to dietary casein, dietary-beef-fed mice showed increased expression of adiponectin, leptin, and MCP-1. In dietary casein protein diets, high fat content was correlated with the expression of pro-inflammatory adipocytokines leptin, MCP-1, resistin, VEGF-A, and TIMP-1. Sex-related differences were observed in adiponectin, leptin, and MCP-1 expression levels. AHE of dietary protein decreased the expression of adiponectin, leptin, MCP-1, and TIMP-1. Age-related changes in expression were observed in leptin, MCP-1, and VEGF-A. (4) Conclusions: Our results indicate that the source of dietary protein plays a critical role in determining adipocytokine expression in WAT. Furthermore, this study shows that in addition to dietary protein type (beef or casein), AHE and fat content also impact the relative expression of both pro-inflammatory and anti-inflammatory adipocytokines based on sex over time, with leptin and MCP-1 identified as the most frequently affected.

Akagbosu C.O., McCauley K.E., Namasivayam S., Romero-Soto H.N., O’Brien W., Bacorn M., Bohrnsen E., Schwarz B., Mistry S., Burns A.S., Perez-Chaparro P.J., Chen Q., LaPoint P., Patel A., Krausfeldt L.E., et. al.

Cuachirria-Espinoza R.L., García-Miranda A., Hernández-Barragán R., Nava-Tapia D.A., Olea-Flores M., Navarro-Tito N.

Obesity increases the risk and mortality of breast cancer through dysregulated secretion of proinflammatory cytokines and tumor adipokines that induce an inflammatory breast microenvironment. Resistin is an adipokine secreted by adipocytes, immune cells, and predominantly macrophages, which contributes to cancer progression, but its molecular mechanism in cancer is not completely described. In this study, we analyzed the relationship of resistin on breast cancer prognosis and tumor progression and the effect in vitro of resistin on p38 and ERK1/2 activation in breast cancer cell lines. By bioinformatic analysis, we found that resistin is overexpressed in the basal subtype triple-negative breast cancer and is related to poor prognosis. In addition, we demonstrated a positive correlation between RETN and MAPK3 expression in basal triple-negative breast cancer. Importantly, we found amplifications of the RETN gene in at least 20 % of metastatic samples from patients with breast cancer. Most samples with RETN amplifications metastasized to bone and showed high expression of IL-8 (CXCL8) and IL-6 (IL6). Finally, resistin could be considered a prognostic marker for basal triple-negative breast cancer, and we also proposed the possibility that resistin-induced cell migration involves the activation of MAPK in breast cancer cells.

Kwak M.K., Baek J.Y., Park S.J., Jung H., Lee E., Jang I., Ji E., Hong E., Jo Y., Ryu D., Kim B.

Abstract Context Experimental evidence indicates that resistin, an adipokine, negatively impacts muscle metabolism by hindering myogenesis. Objective To explore resistin's potential as a biomarker of muscle health in humans by examining the relationship between circulating resistin levels and sarcopenia in older adults. Design and Setting A case-control study conducted in a geriatric clinical unit. Participants The study included 247 individuals aged 65 and older who underwent comprehensive geriatric evaluations. Main Outcome Measures Sarcopenia was defined based on Asian-specific thresholds, with serum resistin concentrations measured using an enzyme-linked immunosorbent assay. Results After adjusting for sex, age, fat mass, smoking, osteoarthritis, and diabetes, participants with sarcopenia, low muscle mass, and weak muscle strength exhibited at least 27.0% higher circulating resistin concentrations than controls (P = 0.002 to 0.003). Elevated serum resistin levels were inversely associated with skeletal muscle mass, gait speed, and the short physical performance battery score, and positively associated with the time to complete five chair stands (P = 0.019 to 0.048). Higher serum resistin levels were linked to an increased risk of sarcopenia, low muscle mass, and weak muscle strength (all P = 0.005). Finally, participants in the highest resistin quartile had at least three times higher odds of having adverse muscle outcomes compared to those in the lowest quartile (P = 0.007 to 0.029). Conclusion This study is to establish a link between blood resistin levels and sarcopenia, suggesting that circulating resistin may serve as a potential biomarker reflecting poor muscle health in humans.

Yang J., Chen Y., Zhang S., Gao X.

Akagbosu C.O., McCauley K.E., Namasivayam S., Romero-Soto H.N., O’Brien W., Bacorn M., Bohrnsen E., Schwarz B., Mistry S., Burns A.S., Perez-Chaparro P.J., Chen Q., LaPoint P., Patel A., Krausfeldt L.E., et. al.

ABSTRACTBackgroundBariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown.Objectives1) To comprehensively examine gut microbiome and metabolome changes after laparoscopic vertical sleeve gastrectomy (VSG) in adolescents and 2) to assess whether the microbiome/metabolome changes observed with VSG influence phenotype using germ-free murine models.Design1) A longitudinal observational study in adolescents undergoing VSG with serial stool samples undergoing shotgun metagenomic microbiome sequencing and metabolomics (polar metabolites, bile acids and short chain fatty acids) and 2) a human-to-mouse fecal transplant study.ResultsWe show adolescents exhibit significant gut microbiome and metabolome shifts several months after VSG, with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited an inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG.ConclusionWe show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG.What is already known on this topicBariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown.What this study addsSignificant gut microbiome and metabolome shifts were found several months after vertical sleeve gastrectomy in adolescents, notably with enrichment of oral-associated taxa. Using human to germ-free mice fecal transplant studies, the post-surgery changes in the gut microbiome/metabolome were shown to have inflammatory potential. Furthermore, raised fecal calprotectin and inflammatory systemic pathways were seen in a subset of adolescents post-surgery.How this study might affect research, practice or policyThese findings may be of importance given the growing recognition of an increased incidence of inflammatory bowel disease after bariatric surgery and warrants further investigation.

Vastrad B.M., Vastrad C.M.

AbstractCardiac arrest (CA) is a common cause of death world wide. The disease has lacks effective treatment. Efforts have been made to elucidate the molecular pathogenesis of CA, but the molecular mechanisms remain elusive. To identify key genes and pathways in CA, the next generation sequencing (NGS) GSE200117 dataset was downloaded from the Gene Expression Omnibus (GEO) database. DESeq2 tool was used to recognize differentially expressed genes (DEGs). Gene ontology (GO) and REACTOME pathway enrichment analyses were performed to analyze the DEGs and associated signal pathways in the g:Profiler database. The IID database was used to construct the protein-protein interaction (PPI) network, and modules analysis was performed using Cytoscape. A miRNA-hub gene regulatory network and TF-hub gene regulatory network were then constructed to screen miRNAs, TFs and hub genes by miRNet and NetworkAnalyst database and Cityscape software. Receiver operating characteristic curve (ROC) analysis used to verified the hub genes. In total, 844 DEGs were identified, comprising 414 up regulated genes and 430 down regulated genes. GO and REACTOME pathway enrichment analyses indicated that the DEGs for CA were mainly enriched in organonitrogen compound metabolic process, response to stimulus, translation and immune system. Ten hub genes (up-regulated: HSPA8, HOXA1, INCA1 and TP53; down-regulated: HSPB1, LMNA, SNCA, ADAMTSL4 and PDLIM7) were screened. We also predicted miRNAs (hsa-mir-1914-5p and hsa-mir-598-3p) and TFs (JUN and PRRX2) targeting hub genes. This study uses a series of bioinformatics technologies to obtain hug genes, miRNAs and TFs, and key pathways related to CA. These analysis results provide us with new ideas for finding biomarkers and treatment methods for CA.

Butts B.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. This chapter provides an overview of the biological pathways of CVD risk. Molecular contributions to CVD risk may provide an insight into the mechanisms of CVD and individualized risk. The immune system plays a major role in the promotion of CVD development, progression, and exacerbation. Dysregulation of neurohormonal systems, including the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), contributes to many pathophysiological processes in CVD. Metabolic risk factors, such as insulin resistance and adiposity, are the major contributors to CVD risk. As many of these biological pathways are driven by modifiable risk factors, understanding the role of these pathways in CVD risk reduction can help nurses and clinicians identify individuals who are at a higher risk, provide insights into the underlying mechanisms of the diseases, and develop personalized prevention and treatment strategies.

Magnan C.

Berthelsen L.O., Skydsgaard M., Nedergaard J.

The study of adipose tissue in the field of toxicologic pathology is in its infancy. However, the increasing global burden of obesity, the impact of obesogens, and the development of drugs to treat obesity and associated health issues have led to a need for more information in this field, especially in the area of pathology evaluation and interpretation. The major adipose tissues include white adipose tissue, brown adipose tissue, and bone marrow adipose tissue. Since adipose tissues are heterogenous, responses in one adipose tissue depot cannot be extrapolated to all adipose tissue depots. Knowledge of lesions and changes typical for the different adipose tissue types must be developed with consistent sampling, standardized across species and gender, an important first step. Adipose tissue changes that occur in nonclinical toxicology studies are mostly adaptive changes related to changes in energy storage, and thermogenic and/or endocrine roles. Insights into differences and similarities across the various adipose tissue types, their origins and functions, and their impacts locally and systemically may reveal new therapeutic targets as well as identify new aspects needing to be addressed in risk and safety evaluation during drug development.

Fiorotti A.M., Gomes A.C., Bortoli A.M., Brito B.B., Nunes K.Z., Haraguchi F.K., Bolsoni-Lopes A.

The remission of obesity-related diseases following bariatric surgery appears to result from the reorganization of metabolic and hormonal pathways involving adipokines. This study aimed to investigate the relationship between changes in body adiposity and serum adipokine levels, as well as the association between variations in adiponectin or resistin levels and cardiometabolic risk blood biomarkers before and after Roux-en-Y gastric bypass. A longitudinal and prospective study was conducted with bariatric surgery patients. Anthropometric, body composition and blood biochemical parameters were measured before and at 2 and 6 months post-surgery. The data were analyzed using ANOVA, Pearson or Spearman correlation, and simple linear regression with a significance level of p < 0.05. Among 36 mostly female patients aged 30 to 39 years, significant reductions in body weight (−26.8%), fat mass (−50%), waist circumference (−18%) and waist-to-height ratio (−22%) were observed post-surgery. Serum adiponectin levels increased (+107%), while resistin (−12.2%), TNF-α (−35%), and PAI-1 (−11.1%) decreased. Glucose, insulin, CRP, cholesterol, LDL-c, triglycerides, and vitamin D also decreased. Waist circumference variation showed a positive correlation with PAI-1 and TNF-α and a negative correlation with adiponectin. The total fat mass showed a positive correlation with PAI-1. Adiponectin variation correlated negatively with glucose, resistin, and CRP but positively with HDL-c. Resistin showed a positive correlation with insulin and CRP. In conclusion, 6 months post-bariatric surgery, reducing abdominal adiposity had a more significant impact on serum adipokine levels than total fat mass. Adiponectin increase and resistin decrease acted as endocrine mediators driving the remission of cardiometabolic risk biomarkers in individuals with obesity following Roux-en-Y gastric bypass.

Monserrat-Mesquida M., Bouzas C., García S., Quetglas-Llabrés M.M., Mateos D., Ugarriza L., Gómez C., Sureda A., Tur J.A.

Background: Carbon dioxide (CO2) is a primary greenhouse gas (GHG) causing global temperature to rise. Unsustainable diets induce an increment in the risk of obesity and noncommunicable diseases but also contribute to the global GSG burden. Objective: To assess whether CO2 dietary emissions influence the inflammatory and oxidative status of subjects with metabolic syndrome (MetS). Methods: As part of the PREDIMED-Plus study, 100 adults (55–75 years old) from the Balearic Islands, Spain, were recruited and classified according to their dietary CO2 emissions. Anthropometric parameters were determined, fasting blood samples were collected and plasma, neutrophils, and peripheral blood mononuclear cells (PBMCs) were obtained. Dietary inflammatory index (DII), adherence to a Mediterranean diet (ADM), fatty liver index (FLI), and estimated glomerular filtration (eGFR) were calculated. Clinical biochemical parameters, blood count, and oxidative stress and inflammatory biomarker levels were also determined. Results: DII was higher in participants with high dietary CO2 emissions. Adherence to the MedDiet was inversely associated with CO2 emissions. Malondialdehyde (MDA) levels were higher in urine and plasma samples from subjects with high dietary CO2 emissions. Reactive oxygen species (ROS) production by PBMCs was greater in participants with high CO2 emissions. Interleukin-15, resistin, and leptin plasma levels were increased in participants with high dietary CO2 emissions. Conclusion: Dietary CO2 emissions influence oxidative status and inflammation in relation to the increased prooxidative and proinflammatory status in PBMCs and plasma. These biomarkers were useful for monitoring diet sustainability and health.

Li Z., Sun Y.

Srikanth M., Rasool M.