Hematological Indices and Genetic Variants of Premature Ovarian Insufficiency: Machine Learning Approaches.

BACKGROUND: Premature Ovarian Insufficiency (POI) is associated with infertility. Little is known about the potential circulating biomarkers that could be used to predict POI. We have investigated the possible association between white and red blood cells, platelet indices, and eight established single nucleotide polymorphisms (SNPs) associated with POI risk. METHOD: 117 women with premature menopause (PM) and 183 healthy women without a history of menopause before age 40 were recruited for this study. The tetra-primer amplification refractory mutation system-polymerase chain reaction (Tetra ARMS PCR) and allele-specific oligonucleotides-polymerase chain reaction (ASO-PCR) were carried out for genotyping for eight SNPs reported to be associated with POI. Decision tree analysis was applied to test the diagnostic value of hematological parameters to identify the risk of POI. RESULTS: Women with POI had lower neutrophil (NEUT) and white blood cell (WBC), whereas red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and mean cell hemoglobin (MCH) were higher. Platelet (PLT) count was also lower in affected women. Our data also indicated that HGB and HCT count were significantly associated with rs16991615 and rs244715. Mean Platelet volume (MPV) and platelet distribution width (PDW) were associated with rs244715, rs1046089, rs4806660, and rs2303369. The rs16991615 was also associated with RBC count, and rs451417 was associated with NEUTs. The decision tree (DT) model reveals that women with the NEUT count at a cut-off value of less than 2.8 and HCT equal to or more than 38.7% could be identified as high-risk cases for POI. Overall, we found the DT approach had a sensitivity = 85%, specificity = 72%, and accuracy = 74%. CONCLUSION: The genetic variants involved in POI are associated with changes in reproductive hormone levels and with changes in hematological indices.

Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload-induced cardiac hypertrophy model.

Tropisetron exerts a protective effect against cardiac complications, particularly cardiac hypertrophy. Oxidative stress and apoptosis are the main contributors to the pathogenesis of cardiac hypertrophy. Sirtuins, a family of histone deacetylases, are connected to cellular oxidative stress signaling and antioxidant defense. Sirtuins are also linked to apoptosis which is an important mechanism in the progression of cardiac hypertrophy to heart failure. Literature also suggests that tropisetron impedes apoptosis, partly mediated through an antioxidant mechanism. Therefore, we examined if tropisetron fights cardiac hypertrophy by adjusting sirtuin family proteins (Sirts) and components of mitochondrial death pathway, Bcl-associated X (BAX), Bcl-2-associated death promoter (BAD). Male Sprague-Dawley rats got divided into four groups, including control (Ctl), tropisetron (Trop), cardiac hypertrophy (Hyp), and hypertrophic rats under tropisetron treatment (Hyp + Trop). Pathological cardiac hypertrophy was induced by surgical abdominal aortic constriction (AAC). The increased expression of brain natriuretic peptide (BNP) in the Hyp group confirms the cardiac hypertrophy establishment. The mRNA levels of SIRT1, SIRT3, SIRT7, and BAD also upregulated in the hypertrophic group (p < 0.001). Postoperational administration of tropisetron for 3 weeks lowered the increased expression of BNP (p < 0.05) and BAD (p < 0.001), though the reduction of BAX expression was statistically insignificant (p > 0.05). Tropisetron treatment also restored the normal level of SIRT1/3/7 genes expression in the Hyp + Trop group (p < 0.05). Present findings suggest that tropisetron can suppress cardiomyocyte hypertrophy progression to heart failure by counteracting BNP, SIRT1, SIRT3, Sirt7, and BAD overexpression-mediated apoptosis in a rat model of cardiac hypertrophy.

Effects of Vitamin D3 Fortified Low-fat Dairy Products on Bone Density Measures in Adults with Abdominal Obesity: A Randomized Clinical Trial.

Background: Bone disease-related fractures constitute a heavy burden on the healthcare systems and economy. Vitamin D is an important regulator of bone health and its deficiency is a global problem. This study aimed to evaluate the effect of the 1,500 IU nano-encapsulated vitamin D used for fortifying low-fat dairy products (milk and yogurt) on bone health parameters. Methods: This parallel totally blinded, randomized controlled trial was part of the Ultraviolet Intake by Nutritional Approach study and conducted on 306 individuals with abdominal obesity. Individuals were randomly assigned to four groups, including fortified low-fat milk (1,500 IU nano-encapsulated vitamin D3 per 200 g/d), non-fortified low-fat milk, fortified low-fat yogurt (1,500 IU nano-encapsulated vitamin D3 per 150 g/d), and non-fortified low-fat yogurt, for 10 weeks between January and March 2019. Bone mineral density (BMD) and trabecular bone score (TBS) were measured at the baseline and end of the trial. Trabecular bone score and BMD were defined as primary and secondary outcomes. Results: There were no significant differences in TBS and BMD between the intervention and control groups at the end of the trial (P>0.05). Conclusion: This trial demonstrated no significant effect of nano-encapsulated vitamin D fortified milk and yogurt on BMD and TBS. There remains a need for longer-term trials regarding bone health outcomes to establish optimal doses of fortification.

Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3.

There are accumulating reports regarding poor response to common antidepressant therapy. Antidepressant resistance is often linked to inflammatory system activation and patients displaying inflammation prior to the treatment are less responsive to antidepressants. We hypothesized that the inefficacy of antidepressant therapy in some patients may be attributable to the drugs' inflammatory mode of action, which has been overlooked because of their substantial therapeutic benefit. Bupropion is a commonly prescribed antidepressant that is often used to treat seasonal affective disorders as well. Nevertheless, research suggests that bupropion causes inflammation and worsens depressive symptoms. Therefore, we investigated the impact of bupropion on cytokines of innate and adaptive immunity, as well as immune signaling pathways. We treated lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) with different doses of bupropion. Pro-/anti-inflammatory cytokines [tumor necrosis factor alpha (TNFα), interleukin-1ß (IL-1ß), IL-17, and IL-10] were assessed at both transcriptional and translational levels as well as the involvement of JAK2 /STAT3, TLR2, and TLR4 signaling in this process. Bupropion reduced IL-17A, TNFα, and IL-1ß protein levels in the cultures. Nonetheless, bupropion increased IL-1ß (P < 0.0001), TNFα (P < 0.0001), and IL-17A (P < 0.05) mRNA levels. Treatment enhanced both IL-10 concentration (P < 0.0001) and gene expression (P < 0.0001). TLR2 (P < 0.0001), TLR4 (P < 0.0001), JAK2 (P < 0.0001), and STAT3 (P < 0.0001) gene expression also rose in response to bupropion. The findings imply that bupropion, particularly 50 µM and 100 µM, has pro-inflammatory effects and should be co-administered with anti-inflammatory medications, at least in patients with inflammatory conditions.

Tropisetron balances immune responses via TLR2, TLR4 and JAK2/STAT3 signalling pathway in LPS-stimulated PBMCs.

Numerous documents have been stated that tropisetron, an antagonist of the 5-HT3 receptor and α7nAChR agonist, modulates immune responses. However, the mechanistic basis for this aspect of tropisetron action is largely unknown. Here, the immuno-modulatory effects of tropisetron are investigated, focusing on the possible molecular targets and the mechanisms. Aside from the well-characterized role in immune signalling, JAK2/STAT3, TLR2 and TLR4 are signal transducers linked to both immuno-modulatory actions of acetylcholine and serotonin. Therefore, we evaluated their involvement in the immunoregulatory effects of tropisetron. To test the hypothesis, we assessed the expression of pro-/anti-inflammatory cytokines including TNF-α, IL-1ß, IL-17 and IL-10 following tropisetron treatment in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) derived from healthy subjects. Tropisetron up-regulates the transcription of TLR2, TLR4, JAK2 and STAT3 genes. Tropisetron also increases the expression of target pro-inflammatory cytokines, although considerably suppresses the pro-inflammatory cytokines (IL-1ß, IL-17 and TNF-α) levels in media. Tropisetron notably promotes both IL-10 gene expression and secretion. These findings confirm the antiphlogistic properties of tropisetron. The present data also shed light on a new aspect of tropisetron immune-modulatory action that engaged TLR2, TLR4 and JAK2/STAT3 signalling cascades.