Metabolically healthy/unhealthy obesity and breast cancer: A possible role of plasma-derived extracellular vesicles on the cancerous behavior of triple-negative breast cancer.

PURPOSE: Obesity has known detrimental effects on breast cancer (BC) development and progression. However, it's essential to consider the obesity phenotype based on metabolic health. This study aims to evaluate the impact of circulating extracellular vesicles (EVs) from women with metabolically healthy or unhealthy normal weight, overweight, and obesity on MDA-MB-231 cell migration, invasion, and apoptosis. METHODS: Plasma EVs were isolated from different obesity phenotypes in women. EVs were characterized and EVs uptake by MDA-MB-231 cells was assessed. MDA-MB-231 cell lines were treated with EVs obtained from various studied groups, and migration, invasion, MMP-2 and MMP-9 activity, Bax and Bcl-2 mRNA expression, p-53 and Thr55 p-p53 protein expression, and apoptosis were assessed. RESULTS: EVs from obese individuals, regardless of phenotype, increased invasion and MMP-2 activity compared to healthy normal-weight EVs. Normal-weight EVs led to higher invasion under unhealthy conditions. BC cell migration was enhanced by EVs from healthy obese individuals compared to healthy normal-weight EVs. EVs from unhealthy obese women exhibited significantly lower p53/p-p53 levels and reduced apoptosis compared to healthy obese groups. CONCLUSION: It appears that EVs from both normal-weight women with unhealthy conditions and those with obesity or overweight, irrespective of metabolic status, worsened the cancerous behavior of TNBC cells. Therefore, considering metabolic health, in addition to BMI, is crucial for understanding obesity-related disorders.

The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line.

BACKGROUND: The diagnosis and treatment processes of cancer are among the main challenges of medical science in recent decades. The use of different therapeutic agents is one of the most common methods frequently utilized for cancer treatment. Accumulating evidence points to a potential effect of Obeticholic acid (OCA), a specific ligand for farnesoid X receptor, on the regulation of cancer-associated pathways. In spite of tremendous efforts to introduce OCA into the clinical setting, there is a great deal of uncertainty about its impact on breast cancer treatment. This study was performed to evaluate the effects of OCA on breast cancer. METHODS AND RESULTS: In this experiment, the MCF-7 (Michigan Cancer Foundation-7) cell line was treated with 0.1 µM OCA, and cancerous characteristics of the MCF-7 cell line was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide) assay, gelatin zymography, western blot, Real-time PCR, flow cytometry, and ELISA techniques. The results indicated that OCA increased the rate of apoptosis and the expression levels of PPARα (Peroxisome proliferator-activated receptor alpha) and TIMP-1 (tissue inhibitor of metalloproteinase-1) genes in this cell line, while it reduced the mRNA levels of MMP7 (matrix metalloproteinase 7) and Bcl-2 (B-cell lymphoma 2) genes, as well as the protein levels of the active form of AKT (protein kinase B), Erk1/2 (extracellular signal-regulated kinase 1/2) and STAT3 (Signal transducers and activators of transcription-3). Also, OCA decreased the activity of MMP9, while it increased the secretion of VEGF-A (vascular endothelial growth factor-A). CONCLUSIONS: It seems that OCA can exert anti-cancer effects on the MCF-7 cells by reducing growth, proliferation, migration, invasion, and regulation of the expression of genes involved in cancer-associated pathways. However, it should be noted that further studies are warranted to establish this concept, especially the increase of VEGF-A can be considered a challenge for the results of this study.

Alterations of SOCS1 and SOCS3 transcript levels, but not promoter methylation levels in subcutaneous adipose tissues in obese women.

BACKGROUND: Animal model studies suggest that change in the members of the suppressor of the cytokine signaling (SOCS) family (mainly SOCS1 and SOCS3) is linked to the pathogenesis of obesity-related metabolic disorders. Moreover, epigenetic modification is involved in the transcriptional regulation of the SOCS gene family. Here, we aimed to evaluate the mRNA expression as well as gene promoter methylation of SOCS1 and SOCS3 in subcutaneous adipose tissue (SAT) from obese women compared to normal-weight subjects. We also intend to identify the possible association of SOCS1 and SOCS3 transcript levels with metabolic parameters in the context of obesity. METHODS: This study was conducted on women with obesity (n = 24) [body mass index (BMI) ≥ 30 kg/m 2] and women with normal-weight (n = 22) (BMI < 25 kg/m 2). Transcript levels of SOCS1 and SOCS3 were evaluated by real-time PCR in SAT from all participants. After bisulfite treatment of DNA, methylation-specific PCR was used to assess the putative methylation of 10 CpG sites in the promoter of SOCS1 and 13 CpG sites in SOCS3 in SAT from women with obesity and normal weight. RESULTS: It was found that unlike SOCS3, which disclosed an elevating expression pattern, the expression level of SOCS1 was lower in the women with obesity as compared with their non-obese counterparts (P-value = 0.03 for SOCS1 transcript level and P-value = 0.011 for SOCS3 transcript level). As for the analysis of promoter methylation, it was found that SOCS1 and SOCS3 methylation were not significantly different between the individuals with obesity and normal weight (P-value = 0.45 and P-value = 0.89). Correlation analysis indicated that the transcript level of SOCS1 mRNA expression had an inverse correlation with BMI, hs-CRP levels, HOMA-IR, and insulin levels. However, the SOCS3 transcript level showed a positive correlation with BMI, waist-to-height ratio, waist circumference, hip circumference, hs-CRP, HOMA-IR, insulin, fasting blood glucose, and total cholesterol. Interestingly, HOMA-IR is the predictor of the transcript level of SOCS1 (ß = - 0.448, P-value = 0.003) and SOCS3 (ß = 0.465, P-value = 0.002) in SAT of all participants. CONCLUSIONS: Our findings point to alterations of SOCS1 and SOCS3 transcript levels, but not promoter methylation levels in subcutaneous adipose tissues from women with obesity. Moreover, mRNA expression of SOCS1 and SOCS3 in SAT was associated with known obesity indices, insulin resistance, and hs-CRP, suggesting the contribution of SOCS1 and SOCS3 in the pathogenesis of obesity-related metabolic abnormalities. However, further studies are required to establish this concept.

Principal component analysis of adipose tissue gene expression of lipogenic and adipogenic factors in obesity.

OBJECTIVE: A better understanding of mechanisms regulating lipogenesis and adipogenesis is needed to overcome the obesity pandemic. We aimed to study the relationship of the transcript levels of peroxisome proliferator activator receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBP-α), liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from obese and normal-weight women with a variety of anthropometric indices, metabolic and biochemical parameters, and insulin resistance. METHODS: Real-time PCR was done to evaluate the transcript levels of the above-mentioned genes in VAT and SAT from all participants. RESULTS: Using principal component analysis (PCA) results, two significant principal components were identified for adipogenic and lipogenic genes in SAT (SPC1 and SPC2) and VAT (VPC1 and VPC2). SPC1 was characterized by relatively high transcript levels of SREBP1c, PPARγ, FAS, and ACC. However, the second pattern (SPC2) was associated with C/EBPα and LXR α mRNA expression. VPC1 was characterized by transcript levels of SREBP1c, FAS, and ACC. However, the VPC2 was characterized by transcript levels of C/EBPα, LXR α, and PPARγ. Pearson's correlation analysis showed that unlike SPC2, which disclosed an inverse correlation with body mass index, waist and hip circumference, waist to height ratio, visceral adiposity index, HOMA-IR, conicity index, lipid accumulation product, and weight-adjusted waist index, the VPC1 was positively correlated with above-mentioned obesity indices. CONCLUSION: This study provided valuable data on multiple patterns for adipogenic and lipogenic genes in adipose tissues in association with a variety of anthropometric indices in obese subjects predicting adipose tissue dysfunction and lipid accumulation.

Polyphenols: Potential anti-inflammatory agents for treatment of metabolic disorders.

Ample evidence highlights the potential benefits of polyphenols in health status especially in obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and cardiovascular diseases. Mechanistically, due to the key role of "Metainflammation" in the pathomechanism of metabolic disorders, recently much focus has been placed on the properties of polyphenols in obesity-related morbidities. This narrative review summarizes the current knowledge on the role of polyphenols, including genistein, chlorogenic acid, ellagic acid, caffeic acid, and silymarin in inflammatory responses pertinent to metabolic disorders and discusses the implications of this evidence for future directions. This review provides evidence that the aforementioned polyphenols benefit health status in metabolic disorders via direct and indirect regulation of a variety of target proteins involved in inflammatory signaling pathways. However, due to limitations of the in vitro and in vivo studies and also the lack of long-term human clinical trials studies, further high-quality investigations are required to firmly establish the clinical efficacy of the polyphenols for the prevention and management of metabolic disorders.

Combination of metformin and chlorogenic acid attenuates hepatic steatosis and inflammation in high-fat diet fed mice.

Non-alcoholic fatty liver disease (NAFLD) has become an important health problem in the world. Natural products, with anti-inflammatory properties, are potential candidates for alleviating NAFLD. Metformin (MET) and chlorogenic acid (CGA) have been reported to be effective in the improvement of NAFLD. Here, we aimed to evaluate the efficacy of MET and CGA combination in ameliorating NAFLD in high-fat diet (HFD) fed mice. Fifty C57BL/6 male mice were divided into two groups, one fed a standard chow diet (n = 10) and the other was fed an HFD (n = 40) for 10 weeks. Animals in the HFD group were then randomly divided into a four groups (HFD, HFD + MET (0.25%), HFD + CGA (0.02%) and HFD + MET + CGA (0.25 + 0.02%). MET and CGA combination decreases fasting blood glucose and improves glucose intolerance. Decreased hepatic triglyceride level was associated with lower expression levels of fatty acid synthase and sterol regulatory element-binding protein-1c in MET+CGA treated mice. MET and CGA combination treatment resulted in the polarization of macrophages to the M2 phenotype, reduction of the expression of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), and decreasing protein level of NF-kB p65. It was found that the lowering effect of combined MET and CGA on the expression of gluconeogenic genes was accompanied by increasing phosphorylation of glycogen synthase kinase 3ß. Treatment of HFD mice with the combination of MET and CGA was found to be more effective at alleviating inflammation and lipid accumulation by increasing phosphorylation of AMP-activated protein kinase. In conclusion, these findings suggest that the MET + CGA combination might exert therapeutic effects against NAFLD.

The gene expression of long non-coding RNAs (lncRNAs): MEG3 and H19 in adipose tissues from obese women and its association with insulin resistance and obesity indices.

BACKGROUND: There is evidence regarding the role of two lncRNAs: MEG3 and H19 the pathomechanism of obesity and related disorders. Here, we aimed to evaluate the expression of MEG3 and H19 in visceral adipose tissues (VAT) and subcutaneous adipose tissues (SAT) of obese women (n = 18), as compared to normal-weight women (n = 17). Moreover, we sought to identify the association of expression of MEG3 and H19 in SAT and VAT with obesity parameters, insulin resistance, and the mRNA expression of possible target genes involved in adipogenesis and lipogenesis including peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). METHODS: Real-time PCR was performed to investigate the mRNA expression of the above-mentioned genes in VAT and SAT from all participants. RESULTS: The results showed lower mRNA levels of H19 in SAT of obese women, compared to normal-weight women, while MEG3 expression was significantly higher in the SAT of the obese group rather than controls. Correlation analysis indicated that the transcript level of H19 had an inverse correlation with obesity indices and HOMA-IR values. However, MEG3 expression displayed a positive correlation with all the indicated parameters in all participants. Interestingly, a positive correlation was found between transcript level of MEG3 in SAT with FAS and PPARγ. However, there was an inverse correlation between SAT expression of H19 and FAS. CONCLUSIONS: It appears that lncRNAs, MEG3 and H19, are involved in obesity-related conditions. However, more clinical studies are still required to clarify the relationships between lncRNAs with obesity and related abnormalities.

Acetylation and insulin resistance: a focus on metabolic and mitogenic cascades of insulin signaling.

Insulin resistance is associated with an increased risk of several metabolic disorders including type 2 diabetes, hypertension and cardiovascular diseases. Advances over the last decade have expanded our understanding of the molecular mechanisms underlying insulin resistance; however, many details of the mechanisms causing insulin resistance remain unknown. Recently, attention has shifted toward the role of epigenetics in insulin resistance. In this regard, acetylation of the histone tails has been widely investigated for its role in influencing both metabolic and mitogenic cascades of insulin signaling. More specifically, histone acetyltransferases and histone deacetylases, as major modulators of chromatin accessibility and gene expression, have been studied to determine a possible interconnectivity between the special effects of lysine acetylation status and tyrosine phosphorylation networks on the target proteins of downstream pathways involved in both metabolic and mitogenic cascades of insulin signaling. There is accumulating evidence for the post-translational modification effects of IGFR, InsR, IRS1/2, PI3K, Akt, GLUT4, FoxO, PGC-1α, PPAR, AMPK and MAPKs on insulin resistance and glucose homeostasis. In this paper, we review the importance of acetylation of these factors in the regulation of insulin signaling and glucose metabolism, with a primary focus on the target proteins of downstream signaling of insulin. We also provide an update on the interplay between epigenetic modification and the cellular genome in the context of insulin signaling and describe the possible effect of the environment on this epigenetic regulation.

The possible effect of silver nanoparticles on glyceraldehyde-3-phosphate dehydrogenase activity and formation of amyloid-like aggregates in MCF-7 cell line.

Silver nanoparticles (AgNPs) are widely used in medicine, however, the underlying mechanisms of their action on cellular signaling have not been completely determined, and fundamental studies are required to clarify them. We aimed to investigate AgNPs effects on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as both the internal control gene and the redox-sensitive enzyme involved in apoptosis-related pathways and the formation of amyloid aggregates. To achieve this purpose, MCF-7 cells were treated with different concentrations (0, 3, 22, and 200 µg/ml) of AgNPs and then cell viability, generation of reactive oxygen species (ROS), induction of apoptosis, expression of GAPDH gene, the formation of amyloid aggregates, and GAPDH activity were assessed. The results indicated that treatment with AgNPs significantly reduced cell viability and increased apoptosis in a dose-dependent manner. The ROS levels increased at lower concentrations of AgNPs (up to 22 µg/ml) and during short-term exposure (30 min). The level of GAPDH gene expression was significantly upregulated by 1.22, 1.47, and 1.56 fold, in the concentrations of 3, 22, and 200 µg/ml, respectively. The amount of amyloid aggregates was significantly increased in a dose-dependent manner. The results of enzyme activity showed that AgNPs were affected on the activity of GAPDH protein, however, it has fluctuated that could not be interpreted by our limited data. In conclusion, our results suggested that AgNPs could affect the GAPDH gene expression and enzyme activity, therefore the selection of GAPDH as a gene and protein internal control in the (AgNPs)-related studies requires careful consideration. Additionally, AgNPs may cause apoptosis due to the increase in the production of amyloid aggregates.

Influence of plasma circulating exosomes obtained from obese women on tumorigenesis and tamoxifen resistance in MCF-7 cells.

Obesity is associated with breast cancer aggressiveness and drug resistance. Although the underlying mechanisms are unknown, recent studies indicated that exosomes have a principal contributory role in obesity-associated metabolic complications. Hence, we investigated whether obesity can mediate breast cancer progression and resistance to tamoxifen by plasma-derived-exosomes from obese women or not. Plasma exosomes isolated from five normal-weight (N-Exo) and five obese women (O-Exo) were characterized for size, zeta potential, and CD63 expression. After the treatment of MCF-7 cells with N-Exo and O-Exo, cell proliferation, migration, invasion as well as levels of MMP-9 and MMP-2 were evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing, transwell, and zymography methods, respectively. For evaluating resistance to tamoxifen, the cell viability, apoptosis, and the p53 protein were evaluated using the MTT assay, flow cytometry, and western blot methods, respectively. Cell proliferation, migration, and invasion were significantly increased in the cells treated with O-Exo than untreated cells (p = .001, p = .018, p = .034, respectively). Levels of MMP-2 and MMP-9 were remarkably increased in the cells treated with O-Exo in comparison with ones treated with N-Exo (p = .040, p = .043, respectively). As for resistance to tamoxifen, O-Exo had significantly the greater anti-apoptotic effects in comparison with the N-Exo group (p = .013). Besides, p53 levels were significantly decreased in the cells treated with O-Exo than ones treated with N-Exo (p = .045). The cell viability was significantly more in cells treated with O-Exo in comparison with the cells only treated with tamoxifen (p = .040). Our findings demonstrated that circulating exosomes derived from obese women could lead to tumorigenesis and tamoxifen resistance in breast cancer cells. However, more studies are needed to establish this notion.

Adipose tissue mRNA expression of HDAC1, HDAC3 and HDAC9 in obese women in relation to obesity indices and insulin resistance.

It is well-established that an impaired adipose tissue function and morphology caused by a dysregulated gene expression contribute substantially to obesity. Nowadays, animal model studies and in vitro surveys provide evidence for possible roles of HDACs as emerging epigenetic players in the pathogenesis of obesity. However, the clinical pertinence of HDACs in the field of obesity research in humans is not yet obvious. Here, we investigated mRNA expression of HDAC1, 3 and 9 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese female participants (n = 20) and normal-weight women (n = 19). We also evaluated the association of the afore-mentioned HDACs gene expression with obesity indices, insulin resistance parameters, and other obesity-related characteristics. Our data revealed the mRNA level of HDAC1 was significantly decreased in both VAT and SAT of obese women, compared to controls. Moreover, the SAT mRNA expression of HDAC3 and VAT mRNA levels of HDAC9 were significantly lower in obese subjects than those found in controls. We observed that HDAC1 and HDAC3 expression in adipose tissue from the whole population is inversely correlated with obesity indices; BMI, waist, hip and waist-to-height ratio (WHtR). Moreover, we found that HDAC3 expression in adipose tissue had an inverse correlation with HOMA-IR, insulin levels, and serum concentration of hs-CRP. Moreover, VAT HDAC9 mRNA level is inversely correlated with obesity indices; BMI, waist, hip and WHtR and with HOMA-IR, insulin levels, and serum concentration of hs-CRP. Hence, it seems that decreased HDAC1,3 and 9 mRNA expression in adipose tissue might be associated with obesity and related abnormalities. However, more studies are needed to establish this concept.

The role of microRNAs in the regulation of insulin signaling pathway with respect to metabolic and mitogenic cascades: A review.

Insulin resistance (IR) is a shared pathological condition among type 2 diabetes, obesity, cardiovascular disease, and other metabolic disorders. It is growing significantly all over the world and consequently, a substantial effort is needed for developing the potential novel diagnostics and therapeutics. An insulin signaling pathway is tightly modulated by different mechanisms including the epigenetic modifications. Today, a deal of great attention has been shifted towards the regulatory role of noncoding RNAs on target proteins of the insulin signaling pathway. Noncoding RNAs are a major area of the epigenetics which control gene expression at the posttranscriptional levels and include a large class of microRNAs (miRNAs). With this in view, many studies have implicated the mediatory effects of miRNAs on the downstream metabolic and mitogenic proteins of the insulin signaling pathway. Since providing new biomarkers for the early diagnosis of IR and related metabolic traits are very significant, we intended to review the possible role of miRNAs in the regulation of the insulin signaling pathway, with a primary focus on the downstream target proteins of the metabolic and mitogenic cascades.

Circulating Levels of IL-35 and Gene Expression of FoxP3 in Coronary Artery Disease: Is There Any Interplay Between Them and 25-Hydroxyvitamin D3?

BACKGROUND: We aimed to evaluate interleukin-35 (IL-35) serum levels and the forkhead box P3 (FoxP3) expression in peripheral blood mononuclear cells (PBMCs) of coronary artery disease (CAD) patients compared with the non-CAD group. Also, we examined the possible relationship between gene expression of FoxP3 and serum levels of IL-35 with several CAD-related clinical parameters. METHODS: This study was conducted on 40 men with CAD and 40 men with a normal coronary artery. The gene expression of FoxP3 was measured by real-time polymerase chain reaction (real-time PCR). The serum concentrations of IL-35 and 25-hydroxyvitamin D3 (25(OH)D3) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: FoxP3 gene expression was significantly decreased in patients compared to controls (p = 0.01). Serum concentrations of IL-35 and 25(OH)D3 were significantly reduced in patients in comparison with the control group (both, p < 0.001), and reduction of IL-35 showed an independent association with CAD. IL-35 levels had a significant positive correlation with serum 25(OH)D3 (r = 0.266, p = 0.044) in the whole population. Moreover, there was an inverse correlation between the FoxP3 expression and CAD severity in CAD patients (r = -0.372, p = 0.01). CONCLUSIONS: It appears that reduced mRNA expression of FoxP3 and circulating level of IL-35 are of significance in the context of CAD pathogenesis. However, more studies are required to elucidate underlying mechanisms.

The Circulating Levels of Complement-C1q/TNF-Related Protein 13 (CTRP13) in Patients with Type 2 Diabetes and its Association with Insulin Resistance.

BACKGROUND: Complement-C1q/TNF-related protein 13 (CTRP13) is a novel adipokine involved in the regulation of energy metabolism. Here, we sought to evaluate serum levels of CTRP13 and adiponectin in patients with type 2 diabetes (T2D) (n = 40) and healthy subjects (n = 40) and also to study the association of CTRP13 levels with diabetes-related indices. METHODS: Circulating levels of CTRP13 and adiponectin were measured by enzyme-linked immunosorbent assay (ELISA) in T2D patients (n = 40) and in an age and gender-matched control group (n = 40). The anthropometric assessment and biochemical evaluation were done in all subjects. RESULTS: Circulating levels of CTRP13 and adiponectin were significantly lower in T2D patients in comparison with controls ( = 0.025 and p < 0.001, respectively). CTRP13 was inversely correlated with fasting blood sugar (Spearman's  = -0.420, p < 0.001), HbA1C (Spearman's  = -0.554, p < 0.001), and HOMA-IR (Spearman's  = -0.403, p < 0.001). ROC curve analysis showed that CTRP13 might be used as a biomarker for differentiating T2D patients from healthy individuals (area under the curve with 95% confidence intervals = 0.841, 0.752 - 0.929). A CTRP13 level equal to or lower than 0.885 ng/mL was found to be the optimal cutoff (sensitivity = 92.5%, specificity = 70%, Youden Index = 0.625) for differentiating T2D patients from healthy individuals. CONCLUSIONS: It appears that CTRP13 is a novel adipokine associated with T2D in humans as its serum level was significantly lower in T2D patients and also was inversely correlated with insulin resistance and FBS in humans.

Evidence for Alteration in Serum Concentrations of Leptin in Infertile Men Categorized Based on BMI.

BACKGROUND: The aim of this study is to compare serum and seminal level of leptin in the context of infertility in men according to BMI. We also investigated the possible correlation of circulating level of leptin with fertility indices. METHODS: This case-control study was conducted on 193 men who consecutively attended a referral outpatient infertility clinic of Shariati Hospital. The leptin level in serum and seminal plasma were quantified by enzymelinked immunosorbent assay (ELISA) in fertile men (n = 95) and infertile men (n = 98). All participant were ageand BMI-matched. Semen was also analyzed in terms of volume, sperm concentration (106/mL), motility (%), and morphology in all subjects prior to study. Based on body mass index (BMI) value, all participants were divided into three groups; lean, body mass index (BMI) 19 - 24.99kg/m2, overweight, BMI 25 - 29.99 kg/m2, and obese BMI ≥ 30 kg/m2. RESULTS: Fertile and infertile men were significantly compatible regarding sperm concentration; however, we found no significant difference in case of the leptin level in serum and semen between the two studied groups (p-value = 0.5 and p-value = 0.1, respectively). In the infertile group, serum leptin level was significantly correlated with BMI (r = -0.291; p = 0.004 for the fertile group). Moreover, there was an inverse correlation between serum leptin level and sperm motility (r = -0.241; p = 0.014) in infertile men. Interestingly, among the infertile group, we observed an augmented serum level of leptin in obese men in comparison with lean (p = 0.009) and overweight (p = 0.07) individuals. CONCLUSIONS: Our findings along with other studies support this concept that increased BMI is of clinical relevance in the context of infertility in men since our data revealed an inverse correlation between seminal leptin level and BMI in infertile men. Specifically, alteration in serum level of leptin was obviously different in infertile men in terms of overweight and obesity. However, more studies are required to unravel obscure issues in this regard.

Association between serum adropin levels and gestational diabetes mellitus; a case-control study.

Gestational diabetes mellitus (GDM) is increasing worldwide. The aim of this study was to investigate the association between serum adropin concentration and GDM. In a case-control study, conducted in 2013, 40 pregnant women with GDM and 40 healthy pregnant women (controls) were evaluated. Fasting serum adropin and lipid concentration were measured during 24th-28th weeks of gestation for both groups. These factors were compared between the two groups using independent sample t-test. There was a significant difference in adropin levels between the two groups and mean adropin levels were lower in GDM group (p: 0.016). There was no significant correlation between serum adropin levels and body mass index as well as fasting blood glucose (FBS) or serum lipid profile including high-density lipoprotein, low-density lipoprotein, cholesterol and triglyceride concentration (p > 0.05). There was a significant association between adropin concentration and GDM even after using regression model for removing confounding factors (odds ratio = 0.681). Low serum adropin concentration is associated with GDM in Iranian pregnant women.

The effects of prebiotic, probiotic or synbiotic supplementation on overweight/obesity indicators: an umbrella review of the trials' meta-analyses.

Background: There is controversial data on the effects of prebiotic, probiotic, or synbiotic supplementations on overweight/obesity indicators. Thus, we aimed to clarify this role of biotics through an umbrella review of the trials' meta-analyses. Methods: All meta-analyses of the clinical trials conducted on the impact of biotics on overweight/obesity indicators in general populations, pregnant women, and infants published until June 2023 in PubMed, Web of Sciences, Scopus, Embase, and Cochrane Library web databases included. The meta-analysis of observational and systematic review studies without meta-analysis were excluded. We reported the results by implementing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart. The Assessment of Multiple Systematic Reviews-2 (AMSTAR2) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) systems were used to assess the methodological quality and quality of evidence. Results: Overall, 97 meta-analysis studies were included. Most studies were conducted on the effect of probiotics in both genders. Consumption of prebiotic: 8-66 g/day, probiotic: 104 -1.35×1015 colony-forming unit (CFU)/day, and synbiotic: 106-1.5×1011 CFU/day and 0.5-300 g/day for 2 to 104 weeks showed a favorable effect on the overweight/obesity indicators. Moreover, an inverse association was observed between biotics consumption and overweight/obesity risk in adults in most of the studies. Biotics did not show any beneficial effect on weight and body mass index (BMI) in pregnant women by 6.6×105-1010 CFU/day of probiotics during 1-25 weeks and 1×109-112.5×109 CFU/capsule of synbiotics during 4-8 weeks. The effect of biotics on weight and BMI in infants is predominantly non-significant. Prebiotics and probiotics used in infancy were from 0.15 to 0.8 g/dL and 2×106-6×109 CFU/day for 2-24 weeks, respectively. Conclusion: It seems biotics consumption can result in favorable impacts on some anthropometric indices of overweight/obesity (body weight, BMI, waist circumference) in the general population, without any significant effects on birth weight or weight gain during pregnancy and infancy. So, it is recommended to intake the biotics as complementary medications for reducing anthropometric indices of overweight/obese adults. However, more well-designed trials are needed to elucidate the anti-obesity effects of specific strains of probiotics.

The interaction between MALAT1 and TUG1 with dietary fatty acid quality indices on visceral adiposity index and body adiposity index.

We aimed to investigate the interaction between the transcript levels of taurine-upregulated gene 1 (TUG1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the Cholesterol-Saturated Fat Index (CSI) in relation to the visceral adiposity index (VAI) and body adiposity index (BAI). This cross-sectional study involved 346 women classified as obese and overweight, aged between 18 and 48 years. Dietary intake and the quality of dietary fat were assessed using a validated and reliable 147-item semi-quantitative food frequency questionnaire, with the Cholesterol-Saturated Fat Index (CSI) used as an indicator. Transcription levels of MALAT1 and TUG1 were evaluated through real-time polymerase chain reaction following the criteria outlined in the Minimum Information for Publication of Quantitative standards. Serum profiles were measured using standard protocols. We observed a positive association between transcription level of MALAT1 and VAI in both crude (ß = 3.646, 95% CI 1.950-5.341, p < 0.001) and adjusted (ß = 8.338, 95% CI 6.110-10.566, p < 0.001) models. Furthermore, after adjusting for confounders, a significant positive interaction was noted between MALAT1 expression and CSI on BAI (ß: 0.130, 95% CI 0.019, 0.240, p = 0.022), with a marginal positive interaction observed on VAI (ß: 0.718, 95% CI - 0.028, 1.463, p = 0.059). It seems that there may be a positive interaction between MALAT1 transcription level and CSI on VAI and BAI among overweight and obese women. However, no associations were seen between TUG1 mRNA level and the above-mentioned outcomes. Further functional studies are still required to elucidate this concept.

Exploring the impact of naltrexone on the THBS1/eNOS/NO pathway in osteoporotic bile duct-ligated rats.

Hepatic osteodystrophy, a prevalent manifestation of metabolic bone disease, can arise in the context of chronic liver disease. The THBS1-eNOS-NO signaling pathway plays a pivotal role in the maturation of osteoclast precursors. This study aimed to investigate the impact of Naltrexone (NTX) on bone loss by examining the THBS1-eNOS-NO signaling pathways in bile duct ligated (BDL) rats. Male Wistar rats were randomly divided into five groups (n = 10 per group): control, sham-operated + normal saline, BDL + normal saline, sham-operated + NTX (10 mg/kg), and BDL + NTX. Parameters related to liver injury were measured at the study's conclusion, and Masson-trichrome staining was employed to evaluate collagen deposition in liver tissue. Bone THBS-1 and endothelial nitric oxide synthase (eNOS) expression levels were measured using real-time PCR, while the level of bone nitric oxide (NO) was assessed through a colorimetric assay. NTX treatment significantly attenuated the BDL-induced increase in circulating levels of liver enzymes and bilirubin. THBS-1 expression levels, elevated after BDL, were significantly suppressed following NTX administration in the BDL + NTX group. Despite no alterations in eNOS expression between groups, the bone NO level, significantly decreased in the BDL group, was significantly reduced by NTX in the BDL + NTX group. This study partly provides insights into the possible molecular mechanisms in BDL-induced osteoporosis and highlights the modulating effect of NTX on these pathways. Further research is needed to establish the impact of NTX on histomorphometric indexes.

Exosomes isolated from metabolically unhealthy normal weight and overweight phenotypes deteriorate the ER/PR positive breast cancer behavior.

Purpose: Obesity has been linked to a higher risk of postmenopausal breast cancer Yet, research indicates an opposite correlation between obesity and premenopausal breast cancer risk. Various obesity phenotypes based on metabolic health could play a significant part. This study aims to assess how plasma exosomes taken from women with varying obesity phenotypes impact MCF-7 cell migration, matrix metalloproteinase-2 activity, and apoptosis. Methods: The characterization of isolated exosomes and their internalization into MCF-7 cells was evaluated. The treatment of MCF-7 cells with exosomes isolated from different groups was done. Migration, the activity of MMP-2, mRNA expression of Bax and Bcl-2, protein expression of p-53 and Thr55 p-p53, and apoptosis were assessed. Results: Isolated exosomes from unhealthy obese individuals increase MCF-7 cell migration. Regarding MMP activities, unhealthy normal weight and overweight and healthy obese groups isolated exosomes increase the MMP-2 activity than the treated group with exosomes isolated from counterpart groups. Furthermore, unhealthy normal weight and overweight and healthy obese obtained exosomes decrease apoptosis compared to counterpart groups. Conclusion: Altogether, plasma exosomes derived from both unhealthy individuals with normal weight and overweight status, as well as those with unhealthy obesity, negatively impacted the behavior of estrogen/progesterone receptor-positive breast cancer cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01295-1.