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.

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.

Antioxidative and Anti-inflammatory Effects of Plant-derived Hypoglycemic Medicines: An In vivo/In vitro Systematic Review.

BACKGROUND: The activation of oxidative stress and inflammatory conditions has been associated with acceleration in diabetes (DM) onset and complications. Despite various anti-DM medications, there is a growing trend to discover inexpensive and effective treatments with low adverse effects from plants as one of the promising sources for drug development. OBJECTIVE: This study aimed to systematically investigate the simultaneous anti-inflammatory and antioxidant effects of plant-derived hypoglycemic medicines in diabetic experimental models. METHODS: The search terms consisted of "diabetes", "herbal medicine", "antioxidant", "Inflammatory biomarker", and their equivalents among PubMed, Scopus, Web of Science, and Cochrane Library databases up to 17 August 2021. RESULTS: Throughout the search of databases, 201 eligible experimental studies were recorded. The results showed that the most commonly assessed inflammatory and oxidative stress biomarkers were tumor necrosis factor (TNF)-α, interleukin (IL) 6, IL-1ß, IL-10, malondialdehyde (MDA), and nitric oxide (NO). The activity of antioxidant enzymes, including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were assessed in the present review. Among herbal treatments, Trigonella foenum-graecum L., Centella asiatica (L.) Urb., Vitis vinifera L., and Moringa oleifera Lam. were most commonly used for diabetic complications. Due to the dispersion of the treatments, meta-analysis was not applicable. CONCLUSION: Our findings showed that the application of different plant-derived hypoglycemic treatments in animal models improved diabetes and its complications, as well as modulated concomitant inflammatory and oxidative stress biomarkers. These findings suggest that plant-based antidiabetic medicines and food supplements have the potential to manage diabetes and its complications.

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.

Bacillus coagulans T4 and Lactobacillus paracasei TD3 Ameliorate Skeletal Muscle Oxidative Stress and Inflammation in High-Fat Diet-Fed C57BL/6J Mice.

Background: This study aims to investigate the effects of Bacillus coagulans T4 and Lactobacillus paracasei TD3 probiotics on skeletal muscle inflammation and oxidative stress in C57BL/6J mice fed a high-fat diet (HFD). Methods: Probiotics B. coagulans T4, and L. paracasei TD3 were administered to male C57BL/6J mice fed with HFD. The gene expression of macrophage infiltration markers, inflammatory cytokines, and oxidative stress indicators in the muscle tissue was investigated. Results: Treatment with B. coagulans T4 and L. paracasei TD3 reduced macrophage infiltration, accompanied by a decrease in the expression of monocyte chemoattractant protein-1 (MCP-1) and an increase in the expression of interleukin (IL)-10. On the other hand, L. paracasei TD3 decreased malondialdehyde (MDA) while B. coagulans T4 decreased carbonyl and increased catalase activity. Conclusions: Treatment with probiotics B. coagulans T4 and L. paracasei TD3 partially ameliorated obesity-induced skeletal muscle inflammation in HFD-fed mice.

Meta-analysis of the anti-oxidative and anti-inflammatory effects of hypoglycaemic plant-derived medicines.

BACKGROUND: The pivotal role of oxidative stress and inflammation in the pathophysiology of type 2 diabetes mellitus (T2DM) has been firmly established. However, the evidence concerning hypoglycaemic medicinal plants' antioxidant and anti-inflammatory effects remains inconclusive due to inconsistencies in prior studies. To address this gap, our study aims to perform a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) to consolidate previous research findings in this field. METHODS: We conducted a comprehensive search in the PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases to identify relevant English randomized controlled trials (RCTs). Our study adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. All eligible studies that evaluated concurrently the antioxidative and anti-inflammatory effects of hypoglycaemic plant-derived supplements on type 2 diabetes mellitus (T2DM) were included in the meta-analysis. The meta-analysis itself was carried out using both fixed and random effects models to synthesize the findings from the selected studies. RESULTS: Our study included 47 trials with a total of 2636 participants, both male and female, aged between 20 and 79 years, diagnosed with prediabetes, type 2 diabetes mellitus (T2DM), or metabolic syndrome. The meta-analysis revealed that plant-derived treatments, compared to placebos or other medicines, significantly improved oxidative stress (SMD = - 0.36, 95% CI - 0.64 to - 0.09), inflammation (SMD = - 0.47, 95% CI - 0.63 to - 0.31), total antioxidant capacity (SMD = 0.46, 95% CI 0.16-0.75), and antioxidant enzyme activity (SMD = 1.80, 95% CI 1.26-2.33). The meta-regression analysis showed that treatment duration exceeding 8 weeks significantly impacted the heterogeneity of the oxidative stress data. CONCLUSIONS: Several hypoglycaemic plant-based treatments appear to positively affect T2DM patients by concurrently lowering oxidative stress and inflammatory indicators and boosting antioxidant enzyme activity. CLINICAL TRAIL REGISTRY: PROSPERO ID: CRD42021226147.

The critical role of circular RNAs in drug resistance in gastrointestinal cancers.

Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.

The high-intensity interval training (HIIT) and curcumin supplementation can positively regulate the autophagy pathway in myocardial cells of STZ-induced diabetic rats.

OBJECTIVE: Targeting autophagy is a new therapeutic strategy for the complications of diabetes,such as diabetic cardiomyopathy (DCM). During diabetes, increased or insufficient autophagic activity causes aberrations in cellular homeostasis. Regarding the conflicting and unclear results regarding the effect of HIIT and curcumin supplementation on the expression of genes associated to autophagy, this study aimed to assess whether 4-week high-intensity interval training (HIIT) and curcumin supplementation are able to influence the expression of autophagy-related genes in myocardial cells of diabetic rats. METHODS: In an experimental design, 24 male Wistar rats were randomly divided into 4 groups: non-diabetic control (NC), diabetic control (DC), diabetes + HIIT (D + HIIT), and diabetes + curcumin (D + CU). After HIIT program and curcumin treatment, the genes expression of autophagy pathway were assessed in the myocardium by real-time PCR Tanique. RESULTS: The results indicated that the expression levels of ATG1, Beclin1, ATG5, and LAMP-2 genes were significantly reduced in the DC group compared to the NC group (p < 0.001). Following 4-week HIIT, the expression of Beclin1, ATG-5, and LAMP-2 improved considerably compared to the DC group (p < 0.001, p < 0.001, and p < 0.05, respectively). In addition, after 4 weeks of curcumin supplementation, the expression levels of ATG-5 and Beclin-1 were significantly improved compared to the DC group (p < 0.001, p < 0.05, respectively). It seems HIIT and curcumin supplementation can be an effective approach for inducing autophagy and improving cardiac function in DCM rats.However, HIIT seems more effective than curcumin in this regard.

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.

Antioxidative hypoglycemic herbal medicines with in vivo and in vitro activity against C-reactive protein; a systematic review.

BACKGROUND: Inflammation is a double-edged sword in the pathophysiology of chronic diseases, such as type 2 diabetes mellitus (T2DM). The global rise in the prevalence of T2DM in one hand, and poor disease control with currently-available treatments on the other hand, along with an increased tendency towards the use of natural products make scientists seek herbal medicines for the management of diabetes and its complications by reducing C-reactive protein (CRP) as an inflammatory marker. PURPOSE: To systematically review the literature to identify the efficacy of various medicinal plants with antioxidative and anti-inflammatory properties considering their effect on CRP in animal models of T2DM. STUDY DESIGN: systematic review. METHODS: Electronic databases including PubMed, Scopus, Web of Science and Cochran Library were searched using the search terms "herbal medicine", "diabetes", "c-reactive protein", "antioxidants" till August 2021. The quality of evidence was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE's) tool. The study protocol was registered in PROSPERO with an ID number CRD42020207190. A manual search to detect any articles not found in the databases was also made. The identified studies were then critically reviewed and relevant data were extracted and summarized. RESULTS: Among total of 9904 primarily-retrieved articles, twenty-three experimental studies were finally included. Our data indicated that numerous herbal medicines, compared to placebo or hypoglycemic medications, are effective in treatment of diabetes and its complications through decreasing CRP concentrations and oxidative stresses levels. Medicinal plants including Psidium guajava L., Punica granatum L., Ginkgo biloba L., Punica granatum L., Dianthus superbusn L.. Moreover, Eichhornia crassipes (Mart.) Solms, Curcuma longa L., Azadirachta indica A. Juss., Morus alba L., and Ficus racemosa L. demonstrated potential neuroprotective effects in animal models of diabetes. CONCLUSION: Hypoglycemic medicinal plants discussed in this review seem to be promising regulators of CRP, and oxidative stress. Thus, these plants are suitable candidates for management of diabetes' complications. Nevertheless, further high-quality in vivo studies and clinical trials are required to confirm these effects.

Association of Serum Level and DNA Methylation Status of Brain-Derived Neurotrophic Factor with the Severity of Coronary Artery Disease.

New investigations suggest a pivotal role of brain-derived neurotrophic factor (BDNF) in cardiovascular homeostasis. However, no data could indicate the association between BDNF methylation status and the risk of coronary artery disease (CAD). The aim of the present study was to assess the association of BDNF methylation status and its serum level with the severity of CAD. According to the angiography report, a total of 84 non-diabetic CAD patients with at least 50% stenosis in one of the major coronary arteries were selected as the CAD group. For comparison, 62 angiographically proven non-CAD participants were selected as control. Additionally, subjects were categorized according to the Gensini Scoring system. Blood sample was used for genomic DNA isolation. Methylation status of the BDNF gene in exonic region was determined using the MS-PCR method and serum BDNF levels were measured with ELISA. BDNF gene methylation was significantly higher in the CAD group than in the non-CAD group. After adjustment for confounding factors, BDNF gene hypermethylation increases the risk of CAD in the total population (OR = 2.769; 95% CI, 1.033-7.423; P = 0.043). BDNF gene hypermethylation was higher in patients with severe CAD than patients with mild CAD. Additionally, the serum BDNF level was not different from non-diabetic CAD and control groups. Our findings indicate that BDNF hypermethylation was associated with an increased risk of CAD, which may help identify subjects being at the risk of developing CAD. In addition, BDNF hypermethylation shows a significant correlation with the severity of CAD.

Knowledge discovery in genetics of diabetes in Iran, a roadmap for future researches.

PURPOSE: The pathogenesis of diabetes is considered polygenic as a result of complex interactions between genetic/epigenetic and environmental factors. This review intended to evaluate the scientometric and knowledge gap of diabetes genetics researches conducted in Iran as a case of developing countries, and drawn up a roadmap for future studies. METHODS: We searched Scopus and PubMed databases from January 2015 until December 2019 using the keywords: (diabetes OR diabetic) AND (Iran). All publications were reviewed by two experts and after choosing relevant articles, they were categorized based on the subject, level of evidence, study design, publication year, and type of genetic studies. RESULTS: Of 10,540 records, 428 articles were met the inclusion criteria. Generally, the number of researches about diabetes genetics rose since 2015. Case-control/cross-sectional and animal studies were the common types of study design and based on the subject, the most frequent researches were about genetic factors involved in diabetes development (38%). Briefly, the top seven genes that were evaluated for T2DM were TCF7L2, APOAII, FTO, PON1, ADIPOQ, MTHFR, and PPARG respectively, and also, CTL4 for T1DM. miR-21, miR-155, and miR-375 respectively were the most micro-RNAs that were evaluated. Furthermore, there were six studies about lncRNAs. DISCUSSION AND CONCLUSION: Investigation about the genetic of diabetes is progressed although there are some limitations like non-homogenous data from Iran, heterogeneity of ethnicity, and rationale of studies. Compared to the previous analysis in Iran, still, GWAS and large-scale studies are required to achieve better policies for manage and control of diabetes disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00838-8.