Metformin Attenuates Palmitate-Induced Endoplasmic Reticulum Stress, Serine Phosphorylation of IRS-1 and Apoptosis in Rat Insulinoma Cells

Lipotoxicity refers to cellular dysfunctions caused by elevated free fatty acid levels playing a central role in the development and progression of obesity related diseases. Saturated fatty acids cause insulin resistance and reduce insulin production in the pancreatic islets, thereby generating a vicious cycle, which potentially culminates in type 2 diabetes. The underlying endoplasmic reticulum (ER) stress response can lead to even β-cell death (lipoapoptosis). Since improvement of β-cell viability is a promising anti-diabetic strategy, the protective effect of metformin, a known insulin sensitizer was studied in rat insulinoma cells. Assessment of palmitate-induced lipoapoptosis by fluorescent microscopy and by detection of caspase-3 showed a significant decrease in metformin treated cells. Attenuation of β-cell lipotoxicity was also revealed by lower induction/activation of various ER stress markers, e.g. phosphorylation of eukaryotic initiation factor 2α (eIF2α), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1) and induction of CCAAT/enhancer binding protein homologous protein (CHOP). Our results indicate that the β-cell protective activity of metformin in lipotoxicity can be at least partly attributed to suppression of ER stress

Maternal bonding styles in smokers and non-smokers: a comparative study

BACKGROUND: Parental bonding has been implicated in smoking behavior, and the quality of maternal bonding (MB) has been associated with poor mental health and substance use. However, little is known about the association of MB and the smoking of the offspring. METHODS: In our study, 129 smokers and 610 non-smoker medical students completed the parental bonding instrument, which measures MB along two dimensions: care and overprotection. Four categories can be created by high and low scores on care and overprotection: optimal parenting (OP; high care/low overprotection); affectionless control (ALC; low care/high overprotection); affectionate constraint (AC; high care/high overprotection), and neglectful parenting (NP; low care/low overprotection). Nicotine dependence was assessed by the Fagerstrom Nicotine Dependence Test, exhaled CO level, and daily cigarette consumption (CPD). RESULTS: Higher CPD was significantly associated with lower overprotection (p = 0.016) and higher care (p = 0.023) scores. The odds for being a smoker were significantly higher in the neglectful maternal bonding style compared to the other rearing styles (p = 0.022). Besides, smokers showed significantly higher care and lower overprotection scores with the Mann-Whitney U-test than non-smokers, although these associations did not remain significant in multiple regression models. CONCLUSION: Our results indicate that focusing on early life relationship between patient and mother can be important in psychotherapeutic interventions for smoking. Registration trials retrospectively registered

Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents

mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Constant elasticity of substitution functions for energy modeling in general equilibrium integrated assessment models:a critical review and recommendations

Applying constant elasticity of substitution (CES) functions in general equilibrium integrated assessment models (GE-IAMs) for the substitution of technical factor inputs (e.g., replacing fossil fuels) fails to match historically observed patterns in energy transition dynamics. This method of substitution is also very sensitive to the structure of CES implementation (nesting) and parameter choice. The resulting methodology-related artifacts are (i) the extension of the status quo technology shares for future energy supply relying on fossil fuels with carbon capture, biomass, and nuclear; (ii) monotonically increasing marginal abatement costs of carbon; and (iii) substitution of energy with non-physical inputs (e.g., knowledge and capital) without conclusive evidence that this is possible to the extent modeled. We demonstrate these issues using simple examples and analyze how they are relevant in the case of four major CES-based GE-IAMs. To address this, we propose alternative formulations either by opting for carefully applied perfect substitution for alternative energy options or by introducing dynamically variable elasticity of substitution as a potential intermediate solution. Nevertheless, complementing the economic analysis with physical modeling accounting for storage and resource availability at a high resolution spatially and temporally would be preferable

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Genetic association of human Corticotropin-Releasing Hormone Receptor 1 (CRHR1) with Internet gaming addiction in Korean male adolescents

Background The number of people with Internet gaming addiction (IGA) is increasing around the world. IGA is known to be associated with personal characteristics, psychosocial factors, and physiological factors. However, few studies have examined the genetic factors related to IGA. This study aimed to investigate the association between IGA and stress-related genetic variants. Methods This cross-sectional study was conducted with 230 male high school students in a South Korean city. We selected five stress-related candidate genes: DAT1, DRD4, NET8, CHRNA4, and CRHR1. The DAT1 and DRD4 genes were genotyped by polymerase chain reaction, and the NET8, CHRNA4, and CRHR1 genes were genotyped by pyrosequencing analysis. We performed a Chi-square test to examine the relationship of these five candidate genes to IGA. Results Having the AA genotype and the A allele of the CRHR1 gene (rs28364027) was associated with higher odds of belonging to the IGA participant group (p = .016 and p = .021, respectively) than to the non-IGA group. By contrast, the DAT1, DRD4, NET8, and CHRNA4 gene polymorphisms showed no significant difference between the IGA group and control group. Conclusions These results indicate that polymorphism of the CRHR1 gene may play an important role in IGA susceptibility in the Korean adolescent male population. These findings provide a justification and foundation for further investigation of genetic factors related to IGA

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants

The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype.

OBJECTIVES: Neuronal nicotinic acetylcholinergic receptors (nAChR) and especially alpha4beta2 nAChRs are the major targets for cessation medications and also for some promising antidepressant agents. Furthermore, depressive symptoms pose multifacet difficulties during cessation therapy. However, gene encoding for the beta2 subunit of nAChRs has been poorly investigated in association with depression. Since both nicotine dependence (ND) and depressive phenotype are complex disorders, we investigated the effects of a significant early life experience, maternal bonding style (MB) and CHRNB2 gene SNPs on smoking-related depression. METHODS: We recruited two hundred and thirty-two treatment-seeking smokers in our study. Phenotypic variants were evaluated using the Fagerstrom Test for Nicotine Dependence (FTND), the Zung Self-Rating Depression Scale (ZSDS) and the Parental Bonding Instrument (PBI). Besides the total score (TS) of ZSDS, impulsivity (ZSDS-I) and suicidal ideation (ZSDS-S) were distinguished as phenotypic variable. DNAs were extracted from buccal mucosa samples and one SNP in promoter and two SNPs in 3' UTR of CHRNB2 gene were genotyped. GLM and ANOVA tests were performed for genotype associations and interaction analyses. RESULTS: Maternal bonding had a significant impact on depressive phenotypes. Low care, high protection and affectionless control (ALC) were associated with ZSDS-TS and all subphenotypes of ZSDS. One SNP, the rs2072660 in 3' UTR, had a significant effect on the FTND score (p=0.010). Direct association of CHRNB2 variants and depressive phenotypes were not significant. However, in interaction with ALC, rs2072660 was significantly associated with ZSDS-S (p=0.005). MB had no significant effect on smoking-related phenotype. CONCLUSIONS: Our results highlight the important role of 3' UTR in the CHRNB2 gene in the shared molecular background of ND and depressive phenotype. Parental bonding style can be suggested as a significant environmental factor in further GxE studies of depression. The presented significant GxE interaction on smoking-related suicidal subphenotype may help establish further investigations on development of more effective and safer smoking cessation and antidepressant agents