Dysregulated circulating SOCS3 and haptoglobin expression associated with stable coronary artery disease and acute coronary syndrome: An integrated study based on bioinformatics analysis and case-control validation.

OBJECTIVE: To extensively use blood transcriptome analysis to identify potential diagnostic and therapeutic targets for cardiovascular diseases. METHODS: Two gene expression datasets (GSE59867 and GSE62646) were downloaded from GEO DataSets to identify altered blood transcriptomes in patients with ST-segment elevation myocardial infarction (STEMI) compared to stable coronary artery disease (CAD). Thereafter, several computational approaches were taken to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Finally, the expression of dysregulated two hub genes-suppressor of cytokine signaling 3 (SOCS3) and haptoglobin (HP)-were validated in a case-control study. RESULTS: A total of 119 DEGs were identified in the discovery phase, consisting of 71 downregulated genes and 48 upregulated genes; two hub modules consisting of two hub genes-SOCS3 and HP-were identified. In the validation phase, both SOCS3 and HP were significantly downregulated in the stable CAD and acute coronary syndrome (ACS) patients when compared with healthy controls. Meanwhile, HP was significantly upregulated in STEMI patients when compared with stable CAD patients (p=0.041). Logistic regression analysis indicated that: downregulated expression of HP correlated with increased risk of CAD [odds ratio (OR)=0.52, 95% confidence interval (CI)=0.31~0.87, p=0.013]; and downregulated expression of SOCS3 correlated with increased risk of ACS (OR=0.66, 95% CI=0.46~0.94, p=0.023) when age, gender, history of hyperlipidemia, diabetes and hypertension were included as covariates. CONCLUSION: Future clarification of how SOCS3 and HP influence the pathogenesis of disease may pave the way for the development of novel diagnostic and therapeutic methods.

Association between the methylation of the STAT1 and SOCS3 in peripheral blood and gastric cancer.

BACKGROUND AND AIM: DNA methylation is an important epigenetic modification that can promote the development of various cancers. The STAT1 and SOCS3 have been observed to be hypermethylated in tumor tissues and peripheral blood. This study aimed to explore the relationship between the methylation status of the STAT1 and SOCS3 in peripheral blood and gastric cancer (GC). METHODS: This hospital-based case-control study involved 372 patients with GC and 379 controls. The methylation status of the STAT1 and SOCS3 was semiquantitatively determined using the methylation-sensitive high-resolution melting method. Logistic regression analysis was used to analyze the relationship between the STAT1 and SOCS3 methylation status and GC susceptibility. Moreover, propensity scores were used to control confounding factors. RESULTS: Compared with negative methylation, the positive methylation of SOCS3 significantly increased the risk of GC (ORa  = 1.820, 95% CI: 1.247-2.658, P = 0.002). This trend was also found via stratified analysis, and methylation positivity of the SOCS3 significantly increased the risk of GC in the < 60 years group, in the ≥ 60 years group, and in the positive Helicobacter pylori infection group (ORa  = 1.654, 95% CI: 1.029-2.660, P = 0.038; ORa  = 1.957, 95% CI: 1.136-3.376, P = 0.016; ORa  = 2.084, 95% CI: 1.270-3.422, P = 0.004, respectively). Additionally, no significant association was found between STAT1 methylation and GC risk (ORa  = 0.646, 95% CI: 0.363-1.147, P = 0.135). This study found that the interaction between the methylation status of STAT1 and SOCS3 and environmental factors did not have an impact on GC risk. CONCLUSION: SOCS3 methylation may serve as a new potential biomarker for GC susceptibility.

Suppressor of cytokine signaling-3 in pregnant females with or without hypertension.

Suppression of Cytokine Signalling-3 (SOCS-3) modulates the inflammatory pathways responsible for vascular stability. Therefore, we aimed to estimate SOCS-3 levels in 2nd trimester pregnant females and correlate it with blood pressure. A case control study recruiting (n=111) females was conducted at the Aga Khan University. They were classified as pregnancy induced hypertensives ornormotensive as per American College of Obstetricians and Gynecologists Guidelines. Weight, Body mass index, lipid profile and blood glucose were recorded while SOCS-3 was measured by ELISA. Higher SOCS-3 levels were seen in hypertensive group (30 pg/ml) versus normotensive (16 pg/ml). Both Systolic & diastolic blood pressure (r=0.520; p <0.001) (r=0.490; p <0.001) showed an independent significant positive correlation with SOCS-3 level. It is safe to suggest that SOCS-3 has an association of causing high blood pressure. However, more research needs to be conducted to establish a mechanism and chronological order to these events in a pregnant female.

Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome.

Context: Inflammation and insulin resistance (IR) are often present in polycystic ovary syndrome (PCOS). Objective: We determined the effect of saturated fat ingestion on circulating lipopolysaccharide (LPS) and mononuclear cell (MNC) toll-like receptor-4 (TLR-4) and suppressor of cytokine signaling-3 (SOCS-3) in women with PCOS. Design: Cross-sectional study. Setting: Academic medical center. Patients: Nineteen reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory control subjects (10 lean, 9 obese). Main Outcome Measures: LPS and TNFα levels were measured in plasma. TLR-4 and SOCS-3 mRNA and protein content were quantified in MNC from blood collected after fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood collected after fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results: Regardless of PCOS status, subjects who were obese had lipid-induced increases in circulating LPS and TLR-4 protein content compared with subjects who were lean. Lean and obese women with PCOS had lipid-induced increases in plasma TNFα and SOCS-3 mRNA and protein content compared with lean control subjects. Both PCOS groups had lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The LPS and SOCS-3 responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion: In PCOS, lipid-induced LPS-mediated inflammation through TLR-4 is associated with obesity and worsened by PCOS, whereas lipid-induced increases in SOCS-3 may represent an obesity-independent, TNFα-mediated mechanism of IR.

IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling.

Ulcerative colitis (UC) is a chronic condition in which the overreacting immune system may play an important role. It has been confirmed that the interleukin (IL) 9 (IL-9) participates in the pathogenesis of UC but the molecular mechanism is not fully illustrated. Here, we show that levels of peripheral blood cytokines IL-9, IL-8, IL-10, IL-6, IL-1ß, IL-12, and tumor necrosis factor (TNF) were higher in patients with UC than normal control, and serum and local IL-9 levels were positively correlated with the disease activity grade. Moreover, IL-9 stimulation inhibited suppressor of cytokine signaling 3 (SOCS3) expression and wound healing ability in colonic epithelial cells and promoted the phosphorylation level of signal transducers and activators of transcription 3 (STAT3). And IL-9 stimulation promoted claudin-2 expression while inhibited claudin-3 and occludin expression. Furthermore, SOCS3 overexpression rescued the IL-9-induced effects. Altogether, IL-9 participates in the pathogenesis of UC through STAT3/SOCS3 signaling pathway and has the potential to serve as a possible therapeutic candidate in patients with UC.

Effect of combined exercise training on serum brain-derived neurotrophic factor, suppressors of cytokine signaling 1 and 3 in patients with multiple sclerosis.

BACKGROUND: Suppressors of cytokine signaling (SOCS) and brain-derived neurotrophic factor (BDNF) are important immunologic, and neurotrophic factors for MS pathogenesis. The impact of exercise on these factors is yet to be fully elucidated in patients with MS. OBJECTIVE: The primary aim of this study is to investigate the effect of 8-week combined exercise training on serum concentrations of SOCS1, SOCS3, and BDNF. The secondary aim is to determine the effects of combined exercise training on balance, functional exercise capacity, and fatigue in patients with MS. METHODS: Serum SOCS1, SOCS3, and BDNF levels were assessed in 36 MS patients and 18 healthy individuals. In addition, balance, functional exercise capacity, and fatigue were assessed in the patients with MS. The patients were randomly divided into the combined exercise group (MS-EX, n:18) and the control group (MS-C, n:18). MS-EX received an 8-week combined exercise training. RESULTS: The serum SOCS1, SOCS3, and BDNF levels were similar in the MS patients and healthy control (HC). In MS-EX, the serum BDNF level, balance, functional exercise capacity, and fatigue improved after 8weeks (p<0.05), but the serum SOCS1, and SOCS3 levels did not change significantly (p>0.05). In MS-C, the serum SOCS1 level, and fatigue increased significantly after 8weeks (p<0.05), but serum SOCS3, BDNF, balance and functional exercise capacity did not change (p>0.05). CONCLUSIONS: In summary, the combined exercise training improved BDNF, and physical performance in patients with MS. But, future studies are needed to clarify the role of SOCS proteins in MS pathogenesis and the effect of exercise on SOCS.

Effects of chronic sugar consumption on lipid accumulation and autophagy in the skeletal muscle.

PURPOSE: In recent years, the increasing consumption of soft drinks containing high-fructose corn syrup or sucrose has caused a rise in fructose intake, which has been related to the epidemic of metabolic diseases. As fructose and glucose intake varies in parallel, it is still unclear what the effects of the increased consumption of the two single sugars are. In the present study, the impact of chronic consumption of glucose or fructose on skeletal muscle of healthy mice was investigated. METHODS: C57BL/6J male mice received water (C), 15 % fructose (ChF) or 15 % glucose (ChG) to drink for up to 7 months. Lipid metabolism and markers of inflammation and autophagy were assessed in gastrocnemius muscle. RESULTS: Increased body weight and gastrocnemius muscle mass, as well as circulating glucose, insulin, and lipid plasma levels were observed in sugar-drinking mice. Although triglycerides increased in the gastrocnemius muscle of both ChF and ChG mice (+32 and +26 %, vs C, respectively), intramyocellular lipids accumulated to a significantly greater extent in ChF than in ChG animals (ChF +10 % vs ChG). Such perturbations were associated with increased muscle interleukin-6 levels (threefold of C) and with the activation of autophagy, as demonstrated by the overexpression of LC3B-II (ChF, threefold and ChG, twofold of C) and beclin-1 (ChF, sevenfold and ChG, tenfold of C). CONCLUSIONS: The present results suggest that intramyocellular lipids and the pro-inflammatory signaling could contribute to the onset of insulin resistance and lead to the induction of autophagy, which could be an adaptive response to lipotoxicity.

MicroRNA-19a-3p enhances the proliferation and insulin secretion, while it inhibits the apoptosis of pancreatic ß cells via the inhibition of SOCS3.

MicroRNAs (miRNAs or miRs), a group of small non-coding RNAs, have been demonstrated to play key roles in various physicological processes and diseases, including diabetes, the most common metabolic disorder. However, the underlying mechanisms remains largely unknown. In this study, we aimed to investigate the role of miR­19a­3p in diabetes. The results of RT-qPCR demonstrated that the level of miR­19a­3p was significantly decreased in the diabetic patients, and that the decreased miR­50a-5p level was significantly associated with a high concentration of blood glucose. miR­19a­3p mimic was further used to transfect pancreatic ß cells, and we found that the overexpression of miR-19a-3p promoted cell proliferation and insulin secretion, while it suppressed the apoptosis of pancreatic ß cells. Suppressor of cytokine signaling 3 (SOCS3) was further identified as a direct target gene of miR­19a­3p, and its protein level was significantly decreased following the overexpression of miR­19a­3p. Moreover, the siRNA-induced downregulation of SOCS3 also enhanced cell proliferation and insulin secretion, while it inhibited the apoptosis of pancreatic ß cells. In addition, the overexpression of SOCS3 reversed the effects of miR­19a­3p overexpression on cell proliferation, insulin secretion and on the apoptosis of pancreatic ß cells, which further indicates that SOCS3 acts as a downstream effector in the miR-19a-3p-mediated function of pancreatic ß cells. Finally, the level of SOCS3 was increased in diabetic patients, and inversely correlated with the miR­19a­3p level, suggesting that the downregulation of miR-19a-3p leads to the upregulation of SOCS3, which contributes to the dysfunction of pancreatic ß cells. On the whole, the findings of this study suggest that miR­19a­3p plays an important role in ß cell function, and that the miR-19a-3p/SOCS3 axis may become a potential therapeutic target for diabetes.

Neutrophil and monocyte responses to downhill running: Intracellular contents of MPO, IL-6, IL-10, pstat3, and SOCS3.

High-intensity exercise results in immune activation. This study determined whether (a) there is concordance between serum MPO and neutrophil and/or monocyte intracellular MPO content; (b) peripheral blood mononuclear cells respond to inflammatory interleukins (ILs) by increasing intracellular signaling. Healthy male (n = 12) volunteers participated in high-intensity running (12 × 5 min, 10% decline, 15 km/h). Blood sample (pre, post, 4 h) analyses included serum concentrations of IL-1ß, IL-1ra, IL-4, IL-6, IL-8, IL-10, matrix metalloprotease-9 (MMP-9) and creatine kinase (CK). Intracellular IL-6, IL-10, MPO and STAT3/SOCS3 signaling were assessed in mononuclear cells. CK (1573 ± 756 u/L), MMP-9 (101 ± 27 ng/mL), neutrophil (9.89 ± 0.76 × 10(9) cells/L) and monocyte counts (1 ± 0.08 × 10(9) cells/L) increased at 4 h. At 4 h serum (7.1 ± 1.3 ng/mL) and monocyte MPO (1.7-fold) increased, whereas neutrophil MPO decreased (0.8-fold). Intracellular monocyte IL-10 and IL-6 decreased by 15% and 20-30%, respectively, coinciding with elevations in serum IL-10 of 14.5 ± 4.7 pg/mL and IL-6 of 5.4 ± 2.9 pg/mL, suggesting immune cell cytokine release in response to exercise. Intracellular PBMC p-STAT3 to total STAT3 ratio increased from pre to 4 h. Circulating monocytes are responsive to increased serum IL-6 suggesting a negative feedback loop via STAT3 signaling.