Metabolic syndrome (MS) is a cluster of metabolic disorders that collectively increase the risk of cardiovascular disease. Nitric oxide (NO) plays a crucial role in the pathogeneses of MS components and is involved in different mitochondrial signaling pathways that control respiration and apoptosis. The present review summarizes the recent information regarding the interrelations of mitochondria and NO in MS. Changes in the activities of different NO synthase isoforms lead to the formation of metabolic disorders and therefore are highlighted here. Reduced endothelial NOS activity and NO bioavailability, as the main factors underlying the endothelial dysfunction that occurs in MS, are discussed in this review in relation to mitochondrial dysfunction. We also focus on potential therapeutic strategies involving NO signaling pathways that can be used to treat patients with metabolic disorders associated with mitochondrial dysfunction. The article may help researchers develop new approaches for the diagnosis, prevention and treatment of MS.

It is believed that damage to the membranes of brain cells of schizophrenia (SCZ) patients induces the formation of autoantigens and autoantibodies. Nevertheless, the importance of immunological changes leading to the loss of tolerance to self-antigens in the genesis of SCZ has not been established. The MALDI mass spectra of the IgG light chains of 20 healthy donors were relatively homogeneous and characterized by one peak with only one maximum. In contrast to the healthy donors, the MALDI mass spectra of IgG light chains corresponding to 20 SCZ patients demonstrated, similarly to 20 autoimmune systemic lupus erythematosus (SLE) patients, two maxima of a comparable intensity. In addition, the MALDI spectra of the IgG light chains of five SLE and four SCZ patients contained a small additional brightly pronounced peak with remarkably lower molecular mass compared with the main one. DNase autoantibodies (abzymes) can be found in the blood of patients with several autoimmune diseases, while the blood of healthy donors or patients with diseases without a significant disturbance of the immune status does not contain DNase abzymes. Here, we present the first analysis of anti-DNA antibodies and DNase abzymes in the sera of SCZ patients. Several strict criteria have been applied to show that the DNase activity is an intrinsic property of IgGs from the sera of SCZ patients. The sera of approximately 30% of SCZ patients displayed a higher content of antibodies (compared with 37% of SLE) interacting with single- and double-stranded DNA compared with healthy donors. Antibodies with DNase activity were revealed in 80% of the patients. These data indicate that some SCZ patients may show signs of typical autoimmune processes to a certain extent.

The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. We uncover long-range regulation of this process originating at the telencephalic dorsal midline, where levels of secreted Bmps are maintained by factors in both the neuroepithelium and the overlying mesenchyme. In the mouse, the combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. This alters the spatial and temporal Wnt signaling profile of the dorsal midline cortical hem, which in turn causes gyrification of the distal neocortex. Our study uncovers early mesenchymal-neuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling.

The purpose of this research was to study the gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), vascular endothelial growth factor A (VEGF-A) and adiponectin (AdipoQ) genes in the visceral (omental, mesenteric) and subcutaneous adipose tissue depots in metabolic syndrome (MS). We studied 23 women with MS, with a mean age of 50.7 ± 4.5 years and mean body mass index (BMI) of 45.6 ± 9.8 kg/m2. The control group included 10 women, with a mean age of 40.6 ± 8.7 years and normal BMI (22.3 ± 3.7 kg/m2). The gene expression levels in the omental (OAT), mesenteric (MAT) and subcutaneous (SAT) adipose tissues were assessed by quantitative real-time PCR. Increased gene expression levels of IL-6 and TNF-α were detected in MAT in patients with MS, compared with the control group (p < 0.05 and p < 0.005, respectively). Significant positive correlations were observed between IL-6 mRNA expression levels in OAT and the content of CD14 + cells in the peripheral blood (r = 0.55, p < 0.05), as well as between NF-κB and VEGF-A mRNA levels in OAT (r = 0.43, p < 0.05) in patients with MS. The AdipoQ gene expression levels in OAT were significantly decreased in women with MS compared with the control group (p < 0.05). In addition, there were inverse correlations between AdipoQ gene levels in MAT and serum CRP levels (r = −0.63, p < 0.05), as well as between AdipoQ gene levels in MAT and serum IL-6 levels (r = −0.46, p < 0.05). These data demonstrate that proinflammatory gene expression of MAT in women with MS was increased compared with the control group. The AdipoQ gene expression levels in OAT were significantly decreased in women with MS compared with the control group.

Background/objectives The frequency of metabolic syndrome (MetS) is significantly higher in schizophrenia (SCH) patients, when compared to the general populatiotin. The goal of this study was to evaluate whether genetic variants T-786C (rs2070744), G894T (rs1799983) and C774T (rs1549758) in the endothelial nitric oxide (NOS3) gene and/or their haplotypes could be associated with the risk of MetS in SCH patients or healthy subjects from Russian population. Subjects/methods We performed two case−control comparisons. NOS3 polymorphisms were genotyped in 70 SCH patients with MetS, 190 normal weight SCH patients, 155 MetS patients, and 100 healthy controls. MetS was defined as per the criteria proposed by the International Diabetes Federation (IDF). Anthropometric, clinical, biochemical parameters, and serum nitrite concentrations were measured in all samples. Haplotype frequency estimations and linkage disequilibrium measures were made using Haploview 4.2. Results The higher C allele (P = 0.009) and lower TT genotype (P = 0.008) frequencies of T-786C polymorphism were found in SCH patients with MetS compared to those in normal weight SCH patients. SCH patients with MetS who were carriers of the T-786C TT genotype had lower serum total cholesterol levels in comparison to the CC genotype (P = 0.016). Furthermore, the 774T/894T haplotype was more frequent in non-SCH individuals with MetS compared to healthy controls (P = 0.0004, odds ratio = 2.18, 95% confidence interval 1.4–3.37). Conversely, the most common haplotype 774C/894G was less frequent in MetS patients than in healthy controls (P = 0.013, odds ratio = 0.61, 95% confidence interval 0.41–0.9). Conclusions These results indicate that the NOS3 T-786C promoter polymorphism was closely associated with MetS risk in SCH patients. In addition, the haplotypes composed of G894T and C774T polymorphisms are associated with the MetS susceptibility in Russian population.

Cancers co-opt stress response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these pathways also provide protection from ferroptosis, an iron-dependent oxidative cell death pathway triggered by clinically available drugs, including chemotherapies, rheumatologic agents, and novel ferroptosis inducers under evaluation in clinical trials. In this study, we found that disrupting cap-dependent translation initiation in diffuse large B-cell lymphoma (DLBCL) sensitizes cells to ferroptosis. Specifically, the eIF4A1 inhibitor zotatifin synergized with pharmacologic ferroptosis inducers primarily through suppression of glutathione production, which protects polyunsaturated fatty acids from ferroptotic oxidation. Loss of nuclear factor erythroid 2–related factor 2 (NRF2) translation, a master regulator of antioxidant genes, was a key consequence of rocaglates, including zotatifin, and other disruptors of cap-dependent initiation. Although NRF2 loss alone was insufficient to trigger ferroptosis, it lowered the antioxidant threshold, sensitizing cells to lipid peroxidation and ferroptotic death under additional oxidative stress. In vivo, combining zotatifin with the optimized ferroptosis inducer imidazole ketone erastin significantly reduced tumor burden in DLBCL patient-derived xenografts. Treatment with zotatifin in combination with chimeric antigen receptor (CAR) T cells, a vital treatment modality for patients with DLBCL, revealed that zotatifin preexposure sensitized DLBCL tumors to CD19-directed CAR T cells in vitro and extended survival of CAR T-cell–treated immunocompetent mice bearing syngeneic DLBCL tumors in vivo. Overall, eIF4A1 inhibition–induced translational disruption provides opportunities to leverage the therapeutic impacts of ferroptosis inducers, including cytotoxic immunotherapies. Significance: Translational disruption causes NRF2 loss that sensitizes lymphomas to ferroptosis and enhances CAR T-cell and drug efficacy, highlighting eIF4A1 targeting as a promising therapeutic strategy for treating cancer.