Association of Adiponectin 45T/G (rs2241766) and Visfatin 4689G/T (rs2110385) Gene Polymorphisms with Susceptibility to Obesity.

Background: This study aimed to see whether the adiponectin 45T/G (rs2241766) and visfatin 4689G/T (rs2110385) gene polymorphisms in an Iranian population are linked to obesity and/or obesity-related traits in normal and obese individuals. Methods: 230 obese individuals and 169 healthy controls had their genomic DNA taken. The alleles and genotypes of the rs2241766 and rs2110385 polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: Obese individuals had considerably greater frequencies of the G allele and GG genotypes of the rs2241766 polymorphism than healthy controls (35% vs 21%, Probability (P) <0.0001, odds ratios (OR): 1.99, 95% confidence intervals (CI): 1.45-2.75 and 21% vs 7%, P = 0.002, OR: 3.52, 95% CI: 1.81-6.85, respectively). In comparison to healthy controls, obesity patients had substantially lower frequencies of the T allele and TT genotype of the rs2241766 polymorphism (65% vs 79%, P < 0.0001, OR: 0.50, 95% CI: 0.36-0.69 and 51% vs 65%, P = 0.008, OR: 0.58, 95% CI: 0.39-0.87, respectively). Obese individuals had substantially higher frequencies of the G allele and GG genotype in the rs2110385 polymorphism than healthy controls (77% vs 69%, P = 0.01, OR: 1.47, 95% CI: 1.07-2.0 and 61% versus 51%, P = 0.047, OR: 1.5, 95% CI: 1.0-2.2, respectively). When compared to healthy controls, the frequency of the T allele in the rs2110385 polymorphism was considerably lower in obese individuals (23% vs 31%, P = 0.01, OR: 0.68, 95% CI: 0.5-0.93). Furthermore, these single nucleotide polymorphisms (SNPs) were shown to have a strong link to clinical data in obese individuals. In the case of adiponectin, 45T/G (rs2241766) genotypes, serum low-density lipoprotein, waist circumference, and diastolic blood pressure were substantially different among the rs2241766 genotypes (P = 0.007, P = 0.000, and P = 0.011, respectively). In the instance of the visfatin 4689G/T (rs2110385) gene polymorphism, serum triglycerides was substantially different among the rs2110385 genotypes (P = 0.039). Conclusions: In the Iranian population, our findings revealed a strong link between adiponectin and visfatin gene polymorphisms and obesity and several obesity-related clinical characteristics. These SNPs might be used to identify those who are at risk of becoming obese.

Immune and metabolic checkpoints blockade: Dual wielding against tumors.

Recent advances in cancer immunotherapy have raised hopes for treating cancers that are resistant to conventional therapies. Among the various immunotherapy methods, the immune checkpoint (IC) blockers were more promising and have paved their way to the clinic. Tumor cells induce the expression of ICs on the immune cells and derive them to a hyporesponsive exhausted phenotype. IC blockers could hinder immune exhaustion in the tumor microenvironment and reinvigorate immune cells for an efficient antitumor response. Despite the primary success of IC blockers in the clinic, the growing numbers of refractory cases require an in-depth study of the cellular and molecular mechanisms underlying IC expression and function. Immunometabolism is recently found to be a key factor in the regulation of immune responses. Activated or exhausted immune cells exploit different metabolic pathways. Tumor cells can suppress antitumor responses via immunometabolism alteration. Therefore, it is expected that concurrent targeting of ICs and immunometabolism pathways can cause immune cells to restore their antitumor activity. In this review, we dissected the reciprocal interactions of immune cell metabolism with expression and signaling of ICs in the tumor microenvironment. Recent findings on dual targeting of ICs and metabolic checkpoints have also been discussed.

Xanthomicrol Exerts Antiangiogenic and Antitumor Effects in a Mouse Melanoma (B16F10) Allograft Model.

Xanthomicrol, a trimethoxylated hydroxyflavone, is the main active component of Dracocephalum kotschyi Boiss leaf extract. Preliminary in vitro studies identified this compound as a potential antiangiogenic and anticancer agent. This study aimed to evaluate in vivo anticancer effect of xanthomicrol and investigate its molecular mechanism of action in a mouse melanoma (B16F10) model. Effect of xanthomicrol on B16F10 melanoma cell viability was determined using the MTT assay. For in vivo experiments, C57BL/6 mice were inoculated subcutaneously with B16F10 cells. After five days, once daily administration of xanthomicrol, thalidomide, or vehicle was commenced and continued for 21 consecutive days. On the 26th day, blood samples and tumor biopsies were taken for subsequent molecular analysis. Xanthomicrol showed inhibitory effect on viability of B16F10 melanoma cells (IC50 value: 3.433 µg/ml). Initial tumor growth, tumor volume and weight, and angiogenesis were significantly decreased in xanthomicrol-treated animals compared with those in vehicle group. Protein expression of phosphorylated Akt, mRNA expressions of HIF-1α and VEGF in tumor tissues, and serum VEGF were significantly decreased in xanthomicrol-treated animals compared with vehicle-treated animals. Thus, xanthomicrol inhibited cancer cell growth both in vitro and in vivo. This effect, at least in part, was exerted by interfering with PI3K/Akt signaling pathway and inhibiting VEGF secretion by tumor cells. Further studies are required to elucidate the exact molecular mechanisms of antitumor activity of xanthomicrol.

Oridonin Could Inhibit Inflammation and T-cell Immunoglobulin and Mucin-3/Galectin-9 (TIM-3/Gal-9) Autocrine Loop in the Acute Myeloid Leukemia Cell Line (U937) as Compared to Doxorubicin.

The T-cell immunoglobulin and mucin-3 (TIM-3)/galectin-9 (Gal-9) autocrine loop is an indispensable signaling in acute myeloid leukemia (AML) cells, which induces their self-renewal through activation of nuclear factor-kappa b (NF-kB) and ß-catenin pathways. In this study, we evaluated the effects of oridonin and doxorubicin on the TIM-3/Gal-9 autocrine loop. We also evaluated oridonin anti-inflammatory and anti-cancer properties on U937 cells, as an AML cell line in comparison to doxorubicin as a common anthracycline drug for AML treatment. Cell counting kit-8 (CCK-8) was applied to evaluate the cytotoxicity of oridonin and doxorubicin on U937 cells and also to determine the impact of galectin-9 (Gal-9) on their proliferation. The effects of oridonin and doxorubicin on Gal-9, TIM-3, and interleukin-1ß (IL-1ß) gene expression were determined by real-time polymerase chain reaction (RT-PCR). The Gal-9 secretion level was measured by enzyme-linked immunosorbent assay (ELISA) and activation of NF-kB pathway was assessed by western blotting. In a dose-dependent manner, oridonin and doxorubicin were capable to eradicate U937 cells while Gal-9 expanded them. Following the treatment of U937 cells with oridonin, the expression of Gal-9, TIM-3, and IL-1ß genes was down-regulated, and the Gal-9 secretion and NF-kB phosphorylation were diminished, whereas doxorubicin increased all of these factors. Doxorubicin is a common treatment agent in AML, but it may induce inflammation and up-regulate the TIM3/Gal-9 autocrine loop, consequently can enhance the possibility of disease relapse. Meanwhile, oridonin is capable to inhibit the essential signaling pathways in AML cells and reduce the inflammation and expansion of tumor cells and postpone AML recurrence.