Effects of sodium arsenite exposure on behavior, ultrastructure and gene expression of brain in adult zebrafish (Danio rerio).

Arsenic, a common metal-like substance, has been demonstrated to pose potential health hazards and induce behavioral changes in humans and rodents. However, the chronic neurotoxic effects of arsenic on aquatic animals are still not fully understood. This study aimed to investigate the effects of arsenic exposure on adult zebrafish by subjecting 3-month-old zebrafish to three different sodium arsenite water concentrations: 0 µg/L (control group), 50 µg/L, and 500 µg/L, over a period of 30 days. To assess the risk associated with arsenic exposure in the aquatic environment, behavior analysis, transmission electron microscopy techniques, and quantitative real-time PCR were employed. The behavior of adult zebrafish was evaluated using six distinct tests: the mirror biting test, shoaling test, novel tank test, social preference test, social recognition test, and T maze. Following the behavioral tests, the brains of zebrafish were dissected and collected for ultrastructural examination and gene expression analysis. The results revealed that sodium arsenite exposure led to a significant reduction in aggression, cohesion, social ability, social cognition ability, learning, and memory capacity of zebrafish. Furthermore, ultrastructure and genes regulating behavior in the zebrafish brain were adversely affected by sodium arsenite exposure.

Spatial-Temporal Analysis of Drinking Water Type of Endemic Fluorosis - China, 2009-2022.

What is already known about this topic?: Endemic fluorosis, caused by high fluoride levels in drinking water, has been a significant health issue in rural areas of China for many decades. What is added by this report?: There has been a notable decline in the detection rate of dental fluorosis in children aged 8-12 years in drinking water fluorosis areas across the country from 2009 to 2022. While 14 provincial-level administrative divisions are classified as low-probability clusters, Tianjin remains classified as a high-probability cluster. What are the implications for public health practice?: The current policy for preventing and controlling endemic fluorosis in China needs adjustment. Rather than focusing solely on regions with high incidence, there should be a shift towards monitoring and early warning of fluoride exposure. Additionally, local containment measures should be intensified.

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing.

Arsenic is a natural toxin which is widely distributed in the environment, incurring diverse toxicities and health problems. Previous studies have shown that long non-coding RNAs (LncRNAs) are also reported to contribute to As-induced adverse effects. LncRNAs are involved in the development of nerve injury, generally acting as sponges for microRNAs (miRNAs). This study aimed to investigate the competitive endogenous RNA (ceRNA) regulatory networks associated with arsenic-induced nerve damage. A total of 40 male Wistar rats were exposed to different doses of arsenic for 12 weeks, and samples were collected for pathological observation and high-throughput sequencing. The ceRNA network was constructed using Cytoscape, and key genes were identified through the PPI network and CytoHubba methods. A real-time quantitative PCR assay was performed to validate gene expression levels. The results showed that subchronic exposure to arsenic in drinking water resulted in pathological and ultrastructural damage to the hippocampal tissue, including changes in neuron morphology, mitochondria, and synapses. Exposure to arsenic results in the dysregulation of LncRNA and mRNA expression in the hippocampal tissues of rats. These molecules participated in multiple ceRNA axes and formed a network of ceRNAs associated with nerve injury. This study also verified key molecules within the ceRNA network and provided preliminary evidence implicating the ENRNOT-00000022622-miR-206-3p-Bdnf axis in the mechanism of neural damage induced by arsenic in rats. These findings provide novel insights into the underlying mechanism of nervous system damage induced by arsenic exposure.

Subchronic Arsenic Exposure Induces Behavioral Impairments and Hippocampal Damage in Rats.

This study investigated the effects of subchronic arsenic exposure on behavior, neurological function, and hippocampal damage in rats. Thirty-two male Wistar rats were divided into four groups and exposed to different concentrations of arsenic in their drinking water for 12 weeks, while weekly water intake and body weight were recorded. Various neurobehavioral tests were conducted, evaluating overall activity levels, exploratory behavior, short-term memory, spatial learning and memory, anxiety-like behavior, and depressive-like states. Arsenic levels in urine, serum, and brain tissue were measured, and histopathological analysis assessed hippocampal damage using hematoxylin and eosin staining. The results demonstrated that arsenic exposure did not significantly affect overall activity or exploratory behavior. However, it impaired short-term memory and spatial learning and memory functions. Arsenic-exposed rats exhibited increased anxiety-like behavior and a depressive-like state. Arsenic levels increased dose-dependently in urine, serum, and brain tissue. The histopathological examinations revealed significant hippocampal damage, including neuronal shrinkage, cell proliferation, irregular structure, disordered arrangement, and vacuolation. These findings emphasize the importance of understanding the impact of arsenic exposure on behavior and brain health, highlighting its potential neurological consequences.

Environment and chronic disease in rural areas of Heilongjiang, China (ECDRAHC).

PURPOSE: Environmental factors such as long-term exposure to cold can increase the risk of chronic diseases. However, few studies have focused on the impact of environmental factors and lifestyle changes on chronic diseases. To fully explore the association between exposure to environmental factors and the prevalent risk of various chronic diseases, we conducted a large cohort study (Environment and Chronic Disease in Rural Areas of Heilongjiang, China (ECDRAHC)). The ECDRAHC collected detailed questionnaire data covering 10 sections, physical measurements and blood and urine samples. In this study, we describe the design and implementation of the cohort study and present the findings for the first 10 000 participants. PARTICIPANTS: The ECDRAHC study was carried out in rural areas where the annual average temperature is 2.9°C, and aimed to recruit 40 000 participants who are long-term residents aged 35-74 years. The participants will be followed up every 5 years. Currently, ECDRAHC has reached 26.7% (n=10 694) of the targeted population. FINDINGS TO DATE: A total of 10 694 adults aged 35-74 years were recruited, including 61.7% women. The prevalence of current smokers was 46.8% in men and 35.4% in women. The mean blood pressure was 140.2/89.9 mm Hg and 135.7/85.0 mm Hg in men and women, respectively. The mean body mass index was 24.74 kg/m2 in men and 24.65 kg/m2 in women, with >7.3% being obese (>30 kg/m2). The main non-communicable diseases found in phase 1 were hypertension, diabetes, hypertriglyceridaemia and metabolic syndrome, with a higher prevalence of 51.0%, 21.6%, 46.8% and 42.6%, respectively. FUTURE PLANS: We plan to complete the follow-up for the first phase of the ECDRAHC in 2024. The second and third phase of the cohort will be carried out steadily, as planned. This cohort will be used to investigate the relationship between environmental factors, lifestyle, and genetic and common chronic diseases.

Breast cancer brain metastasis: Current evidence and future directions.

Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast cancer patients, affecting their survival and quality of life. Compared with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients, brain metastases are more likely to affect patients with triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.

Primary Neuroendocrine Tumor of the Breast: Current Understanding and Future Perspectives.

Primary neuroendocrine carcinoma of the breast (NECB) is characterized with heterogeneity, rarity, and poor differentiation, which is probably an underestimated subtype of breast cancer, including small cell NECs and large cell NECs. The diagnostic criteria for NECB have been constantly updated as the disease changes and the understanding increases. According to the latest WHO Classification, primary neuroendocrine neoplasm (NEN) of the breast consists of well-differentiated neuroendocrine tumors (NET), extremely aggressive neuroendocrine carcinomas (NEC) as well as invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation. The accurate diagnosis of NECB remains a challenge for its low incidence, which needs multi-disciplinary methods. For the rarity of the disease, there is a lack of large samples and prospective clinical research. For these invasive tumors, there are no standardized therapeutic guidelines or norms, and the treatment often refers to nonspecific breast cancer. In addition, the prognosis of such patients remains unknown. In 2003, the World Health Organization (WHO) listed NECB as an independent entity for the first time, while few features of NECB were clarified. In this review, it presents the WHO Classification, clinicopathologic characteristics, diagnosis, treatment, and prognosis of these patients. In addition, it summarizes the latest studies on molecular features of NECB, aiming to provide new therapeutic perspectives for the disease.

The role of Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis in vivo and in vitro.

The molecular mechanisms underlying arsenic-induced neurotoxicity have not been completely elucidated. Our study aimed to determine the role of the Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis. Pathological and molecular biological tests were performed on the cerebral cortex of arsenic-exposed rats and SH-SY5Y neuroblastoma cells. Arsenic induced apoptosis in the cortical neurons, which corresponded to abnormal ultrastructural changes. Mechanistically, arsenic activated the Fas-FasL-FADD signaling pathway and the downstream caspases both in vivo and in vitro. ZB4 treatment reversed the apoptotic effects of arsenic on the SHSY5Y cells. Taken together, arsenic induces neurotoxicity by activating the Fas-FasL-FADD signaling pathway.

Survival outcome and prognostic factors for colorectal cancer with synchronous bone metastasis: a population-based study.

Prognostic factors of synchronous bone metastatic colorectal cancer (CRC) are still undetermined. We aimed to investigate survival outcome and prognostic factors of patients with synchronous bone metastatic CRC. Information of patients with synchronous bone metastatic CRC were obtained from the Surveillance, Epidemiology, and End Results (SEER) and West China Hospital (WCH) databases. Cases from SEER database composed construction cohort, while cases from WCH database were used as validation cohort. A novel nomogram was constructed to predict individual survival probability based on Cox regression model. The performance of the nomogram was internally and externally validated using calibration curves and concordance index (C-index). Three hundred and eighty-one patients from SEER database were eligible. The median disease specific OS was 9.0 months (95% confidence interval [CI]: 7.3-10.7 months). Multivariate Cox analysis identified seven independent prognostic factors including histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis. A novel nomogram was established based on these variables. In the internal validation, the C-index (0.72, 95% CI 0.69-0.75) and calibration curve indicated well performance of this nomogram at predicting survival outcome in bone metastatic CRC. In the external validation, the C-index was 0.57 (95% CI 0.46-0.68). The prognosis of synchronous bone metastatic CRC is very poor. Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis are independent prognostic factors. Further study is warranted to confirm the practicality of the prognostic nomogram.

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.

Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements, IDH1 mutations, and NTRK gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, BRAF V600E and HER2. Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene. Targeting the MET signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of MET inhibitors has been demonstrated in several phase II studies, but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC. In this article, we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of MET amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

Third-line sunitinib treatment in a VHL-mutated metastatic intrahepatic cholangiocarcinoma: a case report and literature review.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis. There is no standard treatment beyond first-line chemotherapy and no molecular-targeted drug approved for advanced iCCA. We herein present a case of a 46-y-old Asian iCCA patient with multiple metastases in lung, bone, and liver. The patient progressed rapidly after first- and second-line chemotherapy. According to next-generation sequencing result of somatic Von Hippel-Lindau (VHL) gene mutation, the patient was administered third-line sunitinib and obtained a relatively longer survival of 9 months after taking sunitinib. Additionally, we briefly summarized the current targeted treatment of iCCA. To our knowledge, this is the first report of VHL mutation and sunitinib usage in metastatic iCCA patient. As a highly heterogeneous and aggressive malignancy, we strongly recommend making clinical decisions based on precision medicine concept in advanced iCCA.

Usefulness of Serum Calcium in the Risk Stratification of Midterm Mortality among Patients with Acute Coronary Syndrome.

Serum calcium has been reported to be a predictor of short-term prognosis; however, evidence regarding its association with midterm mortality is scarce. We investigated the association between serum calcium levels at admission and midterm mortality in a retrospective cohort of 2594 consecutive patients with acute coronary syndrome (ACS) who presented to the First Affiliated Hospital of Harbin Medical University from November 2014 to December 2016. Patients were assigned to 4 groups according to the quartiles of serum calcium levels (Ca-Q1-4) and were followed longitudinally for the time to all-cause death. During a median follow-up period of 21.8 months (17.5∼29.5, IQR), 124 patients died (4.8%) of all causes. Kaplan-Meier curves showed that the incidence of midterm mortality differed significantly (log-rank P=0.038) among the quartiles of serum calcium levels at admission. After adjustment for the confounders that were significant in the univariate analysis, the hazard ratios for the lowest quartile of serum calcium was 1.86 (95% CI, 1.05-3.31; P=0.033), compared with the third quartile (reference group). A multiple restricted cubic spline regression model suggested a reverse J-shaped association between serum calcium levels and midterm mortality, and the lowest risk of mortality was associated with approximately 2.32 mmol/l of serum calcium. In conclusion, the serum calcium level is an independent predictor of all-cause midterm mortality among ACS patients. Patients with abnormal serum calcium levels at admission need more targeted treatments.

Nitric oxide is involved in the hypothyroidism with significant morphology changes in female Wistar rats induced by chronic exposure to high water iodine from potassium iodate.

Epidemiological studies indicated that chronic exposure to high water iodine is associated with primary hypothyroidism (PH) and subclinical hypothyroidism (SCH). However, the mechanism is not well understood. In this study, we explored whether chronic exposure to high water iodine from potassium iodate (KIO3) can induce hypothyroidism in addition to determining if nitric oxide (NO) is involved in the pathogenesis. 96 female Wistar rats were divided into six groups: control, I1000µg/L, I3000µg/L, I6000µg/L, N-nitro-L-arginine methylester (L-NAME) and L-NAME+I6000µg/L. After 3 months, urine iodine concentration, thyroid hormone, NO and nitric oxide synthase (NOS) serum levels were determined. Additionally, thyroid expression of inducible nitric oxide synthase (iNOS) was also investigated. Thyroid morphology was observed under light microscopy and transmission electron microscope. SCH as indicated by elevated serum thyrotropin (TSH) was induced among rats exposed to 3000 µg/L I-, while rats treated with 6000 µg/L I- presented PH characterized by elevated TSH and lowered total thyroxine in serum. Moreover, serum NO, NOS and iNOS expression in the thyroid were significantly increased in I3000µg/L and I6000µg/L groups. Changes in thyroid function and morphology in the L-NAME+I6000µg/L group were extenuated compared to I6000µg/L group. These findings suggested that chronic exposure to high water iodine from KIO3 likely induces hypothyroidism with significant morphology changes in female Wistar rats and NO appears to be involved in the pathogenesis.

Sodium Arsenite-Induced Learning and Memory Impairment Is Associated with Endoplasmic Reticulum Stress-Mediated Apoptosis in Rat Hippocampus.

Chronic arsenic exposure has been associated to cognitive deficits. However, mechanisms remain unknown. The present study investigated the neurotoxic effects of sodium arsenite in drinking water over different dosages and time periods. Based on results from the Morris water maze (MWM) and morphological analysis, an exposure to sodium arsenite could induce neuronal damage in the hippocampus, reduce learning ability, and accelerate memory impairment. Sodium arsenite significantly increased homocysteine levels in serum and brain. Moreover, sodium arsenite triggered unfolded protein response (UPR), leading to the phosphorylation of RNA-regulated protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2 subunit α (eIF2α), and the induction of activating transcription factor 4 (ATF4). Arsenite exposure also stimulated the expression of the endoplasmic reticulum (ER) stress markers, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and the cleavage of caspase-12. Furthermore, exposure to arsenite enhanced apoptosis as demonstrated by expression of caspase-3 and TUNEL assay in the hippocampus. The results suggest that exposure to arsenite can significantly decrease learning ability and accelerate memory impairment. Potential mechanisms are related to enhancement of homocysteine and ER stress-induced apoptosis in the hippocampus.

Role of PTEN-Akt-CREB Signaling Pathway in Nervous System impairment of Rats with Chronic Arsenite Exposure.

The nervous system is a target of arsenic toxicity. Phosphatase and tensin homologue deleted on chromosome 10/protein kinase B/cAMP-response element binding protein (PTEN/Akt/CREB) signaling pathway has been reported to be involved in maintaining normal function of the nervous system, modulating growth and proliferation of neurocyte, regulating neuron synaptic plasticity, and long-term memory. And many studies have demonstrated that expressions of PTEN, Akt, and CREB protein were influenced by arsenic, but it is not clear whether this signaling pathway is involved in the nervous system impairment of rats induced by chronic arsenite exposure, and we have addressed this in this study. Eighty male Sprague-Dawley (SD) rats were randomly divided into eight groups (n = 10 each), four groups exposed to NaAsO2 (0, 5, 10, and 50 mg/L NaAsO2 in drinking water) for 3 months, the other four groups exposed to NaAsO2 (0, 5, 10, 50 mg/L NaAsO2 in drinking water) for 6 months. Hematoxylin and eosin (HE) staining showed that chronic arsenite exposure induced varying degrees of damage in cerebral neurons. And arsenite exposure increased arsenic amount in serum and brain samples in a dose- and time-dependent manner. Moreover, the protein levels of PTEN and Akt in brain tissue were not significantly changed compared with the control group, but p-Akt, CREB, and p-CREB were all significantly downregulated in arsenite-exposed groups with a dose-dependent pattern. These results suggested that chronic arsenite exposure negatively regulated the PTEN-Akt-CREB signaling pathway, and dysfunction of the signaling pathway might be one of the mechanisms of nervous system impairment induced by chronic arsenite exposure.

[Technical optimization for extracting hypotensive active peptides from Agrocybe aegerita].

OBJECTIVE: To optimize the techniques for extracting hypotensive active peptides from Agrocybe aegerita. METHODS: The effects of the liquid/solid ratio, extraction time and temperature, pH value of the initial liquid on the extraction percentage (EP) of the hypotensive active peptides were investigated, and inhibition percentage (IP) of the extracts on angiotensin I-converting enzyme was determined. RESULTS: Optimal extraction of the hypotensive active peptides from Agrocybe aegerita was achieved with the liquid/solid ratio of 40:1, extraction time of 3 h, extraction temperature at 30 degrees Celsius;, and pH=8 of the initial liquid. The EP of the hypotensive active peptides from Agrocybe aegerita could reach 87.7% with IP of the extracts on angiotensin I-converting enzyme of 54.0%. CONCLUSION: This method is simple and efficient for extracting hypotensive active peptides from Agrocybe aegerita.