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Background: Uric acid (UA), a metabolite of purine and fructose metabolism, is linked to inflammation and metabolic disorders, including gout and cardiovascular disease. Its pro-inflammatory effects are largely driven by the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased cytokine production. Beta-hydroxybutyrate (BHB), a ketone produced during fasting or carbohydrate restriction, has been shown to reduce inflammation. This study explores the role of BHB in mitigating the inflammatory and metabolic effects of elevated uric acid levels. Methods: We utilized a murine muscle cell culture treated with UA and BHB. Results: Muscle cells treated with UA had increased production of pro-inflammatory cytokines and reduced cell viability. Co-treatment with BHB reversed these effects, improving cell survival and reducing cytokine levels. Additionally, uric acid impaired mitochondrial function and increased oxidative stress, which were mitigated by BHB. Furthermore, uric acid disrupted insulin signaling, but BHB co-treatment restored insulin sensitivity. Conclusions: These findings suggest that BHB holds therapeutic potential by counteracting the inflammatory and metabolic disruptions caused by elevated uric acid, making it a promising target for conditions such as hyperuricemia and metabolic syndrome. [ABSTRACT FROM AUTHOR]

A genetic variant in the SAND domain of autoimmune regulator (AIRE), R247C, was identified in a patient with type I diabetes mellitus (T1DM) and his mother with rheumatoid arthritis. In vitro, the variant dominantly inhibited AIRE; however, typical features of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECED) were not seen in the subjects. Rather, early manifestation of autoimmunity appeared to be dependent on additional genetic factors. On a population level, diverse variants were identified in this region. Surprisingly, many likely pathogenic variants were seen disproportionately in Africans when compared to Europeans, reinforcing the importance of these variants in altering the immune repertoire. In light of these findings, we propose that R247C and other variants within the SAND-domain alter protein function in a dominant fashion and hold potential as drivers of autoimmunity.

The global rise in type 2 diabetes (T2D) and obesity necessitates innovative dietary interventions. This study investigates the effects of allulose, a rare sugar shown to reduce blood glucose, in a rat model of diet-induced obesity and T2D. Over 12 weeks, we hypothesized that allulose supplementation would improve body weight, insulin sensitivity, and glycemic control. Our results showed that allulose mitigated the adverse effects of high-fat, high-sugar diets, including reduced body weight gain and improved insulin resistance. The allulose group exhibited lower food consumption and increased levels of glucagon-like peptide-1 (GLP-1), enhancing glucose regulation and appetite control. Additionally, allulose prevented liver triglyceride accumulation and promoted mitochondrial uncoupling in adipose tissue. These findings suggest that allulose supplementation can improve metabolic health markers, making it a promising dietary component for managing obesity and T2D. Further research is needed to explore the long-term benefits and mechanisms of allulose in metabolic disease prevention and management. This study supports the potential of allulose as a safe and effective intervention for improving metabolic health in the context of dietary excess. [ABSTRACT FROM AUTHOR]

Previous studies involving workers at brick kilns in the Kathmandu Valley of Nepal have investigated chronic exposure to hazardous levels of fine particulate matter (PM2.5) common in ambient and occupational environments. Such exposures are known to cause and/or exacerbate chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. However, there is a paucity of data regarding the status of systemic inflammation observed in exposed workers at brick manufacturing facilities within the country. In the current study, we sought to elucidate systemic inflammatory responses by quantifying the molecular cytokine/chemokine profiles in serum from the study participants. A sample of participants were screened from a kiln in Bhaktapur, Nepal (n = 32; 53% female; mean ± standard deviation: 28.42 ± 11.47 years old) and grouped according to job category. Blood was procured from participants on-site, allowed to clot at room temperature, and centrifuged to obtain total serum. A human cytokine antibody array was used to screen the inflammatory mediators in serum samples from each of the participants. For the current study, four job categories were evaluated with n = 8 for each. Comparisons were generated between a control group of administration workers vs. fire master workers, administration workers vs. green brick hand molders, and administration workers vs. top loaders. We discovered significantly increased concentrations of eotaxin-1, eotaxin-2, GCSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-6, IL-8, TGF-β1, TNF-α, and TIMP-2 in serum samples from fire master workers vs. administration workers (p < 0.05). Each of these molecules was also significantly elevated in serum from green brick hand molders compared to administration workers (p < 0.05). Further, each molecule in the inflammatory screening with the exception of TIMP-2 was significantly elevated in serum from top loaders compared to administration workers (p < 0.05). With few exceptions, the fire master workers expressed significantly more systemic inflammatory molecular abundance when compared to all other job categories. These results reveal an association between pulmonary exposure to PM2.5 and systemic inflammatory responses likely mediated by cytokine/chemokine elaboration. The additional characterization of a broader array of inflammatory molecules may provide valuable insight into the susceptibility to lung diseases among this population. [ABSTRACT FROM AUTHOR]

Exposure to secondhand smoke (SHS) during fetal development results in negative postnatal effects, including altered organ development, changes in metabolism, and increased risk of respiratory illness. Previously, we found the induction of intrauterine growth restriction (IUGR) dependent on the expression of the receptor for advanced glycation end-products (RAGE) in mice treated with SHS. Furthermore, antenatal SHS exposure increases RAGE expression in the fetal lung. Our objective was to determine the postnatal effects of antenatal SHS treatment in 4- and 12-week-old offspring. Pregnant animals were treated with SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada) for 4 days (embryonic day 14.5 through 18.5), and offspring were evaluated at 4 or 12 weeks of age. Animal and organ weights were measured, and lungs were histologically characterized. Blood pressure and heart rates were obtained, and RAGE protein expression was determined in the lungs of control and treated animals. We observed the following: (1) significant decreases in animal, liver, and heart weights at 4 weeks of age; (2) increased blood pressure in 4-week-old animals; and (3) increased RAGE expression in the lungs of the 4-week-old animals. Our results suggest an improvement in these metrics by 12 weeks postnatally such that measures were not different regardless of RA or SHS exposure. Increased RAGE expression in lungs from 4-week-old mice antenatally treated with SHS suggests a possible role for this important smoke-mediated receptor in establishing adult disease following IUGR pregnancies. [ABSTRACT FROM AUTHOR]

IntroductionThe DNA ligase family is an evolutionarily conserved group of proteins found in both prokaryotic and eukaryotic cells that have previously been implicated in rare immune defects. Substrate dependence divides [...], We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating [gamma][delta]T cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.

Prior studies suggest brick workers in Nepal may be chronically exposed to hazardous levels of fine particulate matter (PM2.5) from ambient, occupational, and household sources. However, findings from these studies were based on stationary monitoring data, and thus may not reflect a worker's individual exposures. In this study, we used RTI International's MicroPEMs to collect 24 h PM2.5 personal breathing zone (PBZ) samples among brick workers (n = 48) to estimate daily exposures from ambient, occupational, and household air pollution sources. Participants were sampled from five job categories at one kiln. The geometric mean (GM) PM2.5 exposure across all participants was 116 µg/m3 (95% confidence interval [CI]: 94.03, 143.42). Job category was significantly (p < 0.001) associated with PBZ PM2.5 concentrations. There were significant pairwise differences in geometric mean (GM) PBZ PM2.5 concentrations among workers in administration (GM: 47.92, 95% CI: 29.81, 77.03 µg/m3) vs. firemen (GM: 163.46, 95 CI: 108.36, 246.58 µg/m3, p = 0.003), administration vs. green brick hand molder (GM: 163.35, 95% CI: 122.15, 218.46 µg/m3, p < 0.001), administration vs. top loader (GM: 158.94, 95% CI: 102.42, 246.66 µg/m3, p = 0.005), firemen vs. green brick machine molder (GM: 73.18, 95% CI: 51.54, 103.90 µg/m3, p = 0.03), and green brick hand molder vs. green brick machine molder (p = 0.008). Temporal exposure trends suggested workers had chronic exposure to hazardous levels of PM2.5 with little to no recovery period during non-working hours. Multi-faceted interventions should focus on the control of ambient and household air pollution and tailored job-specific exposure controls. [ABSTRACT FROM AUTHOR]

Introduction Diabetes occurs when pancreatic β cells fail to meet insulin demand, due to loss of β cell mass and function (1, 2). In the end-stage spiral that leads to [...], Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell- independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

BACKGROUND: Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by alveolar type I (ATI) epithelial cells and are implicated in mechanisms of alveolar development and sustained pulmonary inflammation. [...]