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BACKGROUND: Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although nuclear factor erythroid 2-related factor 2 (NRF2) and its Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family member nuclear factor erythroid 2-related factor 1 (NRF1) coordinate various stress responses by regulating the transcription of a variety of antioxidant and cytoprotective genes, they play distinct roles in bone metabolism and remodeling. However, the precise roles of both transcription factors in bone loss induced by prolonged Cd exposure remain unclear. OBJECTIVES: We aimed to understand the molecular mechanisms underlying Cd-induced bone loss, focusing mainly on the roles of NRF2 and NRF1 in osteoclastogenesis provoked by Cd. METHODS: Male wild-type (WT), global Nrf2-knockout (Nrf[2.sup.-/-]) and myeloid-specific Nrf2 knockout [Nrf2(M)-KO] mice were administered Cd (50 or 100 ppm) via drinking water for 8 or 16 wk, followed by micro-computed tomography, histological analyses, and plasma biochemical testing. Osteoclastogenesis was evaluated using bone marrow-derived osteoclast progenitor cells (BM-OPCs) and RAW 264.7 cells in the presence of Cd (10 or 20 nM) with a combination of genetic and chemical modulations targeting NRF2 and NRF1. RESULTS: Compared with relevant control mice, global Nrf[2.sup.-/-] or Nrf2(M)-KO mice showed exacerbated bone loss and augmented osteoclast activity following exposure to 100ppm Cd in drinking water for up to 16 wk. In vitro osteoclastogenic analyses suggested that Nrf2-deficient BM-OPCs and RAW 264.7 cells responded more robustly to low levels of Cd (up to 20 nM) with regard to osteoclast differentiation compared with WT cells. Further mechanistic studies supported a compensatory up-regulation of long isoform of NRF1 (L-NRF1) and subsequent induction of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 (NFATc1) as the key molecular events in the Nrf2 deficiency-worsened and Cd-provoked osteoclastogenesis. L-Nrf1 silenced (via lentiviral means) Nrf2-knockdown (KD) RAW cells exposed to Cd showed dramatically different NFATc1 and subsequent osteoclastogenesis outcomes compared with the cells of Nrf2-KD alone exposed to Cd, suggesting a mitigating effect of the Nrf1 silencing. In addition, suppression of reactive oxygen species by exogenous antioxidants N-acetyl-L-cysteine (2mM) and mitoquinone mesylate (MitoQ; 0.2 [micro]M) mitigated the L-NRF1-associated effects on NFATc1-driven osteoclastogenesis outcomes in Cd-exposed Nrf2-KD cells. CONCLUSIONS: This in vivo and in vitro study supported the authors' hypothesis that Cd exposure caused bone loss, in which NRF2 and L-NRF1 responded to Cd and osteoclastogenic stimuli in a cooperative, but contradictive, manner to coordinate Nfatc1 expression, osteoclastogenesis and thus bone homeostasis. Our study suggests a novel strategy targeting NRF2 and L-NRF1 to prevent and treat the bone toxicity of Cd. https://doi.org/10.1289/EHP13849, Introduction Cadmium (Cd), a nonessential heavy metal, is considered as one of the most toxic environmental and occupational hazards. (1) Human long-term exposure to Cd, which occurs mainly from consumption [...]

Background Early diagnosis of acute kidney injury (AKI) in neonates is difficult with a high mortality rate. However, there is currently a lack of research on severe neonatal asphyxia complicated with AKI. Objective To investigate the risk factors and short-term prognosis of neonatal asphyxia complicated with AKI, and analyze the predictive value of related factors, so as to take measures to reduce the occurrence of AKI and improve the success rate of resuscitation of the neonates. Methods A total of 172 neonates with severe asphyxia who were hospitalized in the Neonatal Intensive Care Unit of the First Affiliated Hospital of Bengbu Medical College from January 2016 to January 2023 were included as the study subjects and divided into AKI group (n=43) and non-AKI group (n=129) according to whether the neonates were complicated with AKI. Clinical data and laboratory results were collected, and the short-term prognosis (survival or death during hospitalization) of the children with AKI was recorded. Multivariate Logistic regression analysis was used to explore the influencing factors of severe neonatal asphyxia complicated with AKI, and receiver operating characteristics (ROC) curve was used to explore the predictive value of related indicators for severe neonatal asphyxia complicated with AKI. Results Gestational age, birth weight, 5-min Apgar score and platelet count in AKI group were lower than those in non-AKI group, and the proportions of coma, invasive mechanical ventilation and combined respiratory failure, cystatin C (Cys C) were higher than those in non-AKI group, with statistically significant difference (P

Background The occurrence of postoperative complications in lumbar degenerative disease (LDD) is closely related to malnutrition, and currently there is a lack of nutritional evaluation methods that can effectively, objectively, and comprehensively assess the nutritional status of LDD patients and predict the occurrence of postoperative complications. Objective To compare the predictive value of four nutritional evaluation methods of Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT), Naples Prognostic Score (NPS) and High-sensitivity Modified Glasgow Prognostic Score (HS-mGPS) for postoperative complications in patients with LDD, so as to formulate a precise nutritional intervention plan and effectively prevent complications. Methods A total of 201 patients diagnosed with LDD and underwent open surgery in Spine Surgery Department of Xiangya Hospital of Central South University from December 2021 to July 2022 were selected as the study subjects, four nutritional evaluation methods of PNI, CONUT, NPS and HS-mGPS were applied to assess the preoperative nutritional status of the patients, respectively, and occurrence of postoperative complications from postoperative period to hospital discharge were observed. The patients were divided into the complication group and non-complication group according to the occurrence of postoperative complications to analyze and compare the difference in clinical characteristics between the two groups; the optimal cut-off values of different nutritional evaluation methods were calculated by plotting the receiver operating characteristic (ROC) curve, and the prediction efficiency of different evaluation methods was compared, the area under curve (AUC) was compared by using MedCalc software. Multivariate Logistic regression model was used to analyze the correlation between different nutritional evaluation methods and postoperative complications. Results Postoperative complications occurred in 60 patients with an incidence rate of 29.8%. The comparison of clinical characteristics data showed statistically significant differences in age, gender, intraoperative bleeding, surgical segment, PNI, CONUT, and NPS scores between the complication group and non-complication group (P

Objective To explore the pathogenic genes in a Chinese family affected by nonsyndromic tooth agenesis so as to study the pathogenesis of oligodontia. Methods Hospital ethical approval and informed consent of the patients and family members were obtained. Clinical data of the proband and close family members were collected, peripheral venous blood was collected, and DNA was extracted. Gene sequencing was performed through whole-exome sequencing, and then the screened pathogenic genes were verified by Sanger sequencing. The three-dimensional structure of the mutant proteins was analyzed and compared with the wild-type using bioinformatics tools. Results The two patients with congenital majority tooth loss in this family were cousins, and there were no other patients with congenital majority tooth loss in the family. Besides congenital multiple tooth loss, the two patients had no obvious hair abnormalities, finger/toe abnormalities, sweating abnormalities or other abnormal manifestations of ectodermal tissue. We found a mutant gene that in this family by carrying out gene sequencing of the patients and their close family members. A novel EDA (ectodysplasin A) missense mutation c.983C>T (p. Pro328Leu) was identified, which changed the encoded amino acid from proline (Pro) to leucine (Leu). Analysis of the mutation site showed that the site was highly conserved, and three-dimensional structure modeling also found that it changed the structure of EDA. Conclusion A novel EDA missense variant (c.983C>T, p.Pro328Leu) was first identified in a Chinese family with nonsyndromic tooth agenesis, extending the mutation spectrum of the EDA gene.