The downregulation of SCGN induced by lipotoxicity promotes NLRP3-mediated ß-cell pyroptosis.

Lipotoxicity is a well-established phenomenon that could exacerbate damage to islet ß-cells and play a significant role in the development of type 2 diabetes, the underlying mechanisms of which, however, remain unclear. In lipotoxic conditions, secretagogin (SCGN), an EF-hand calcium-binding protein abundantly expressed in islets, is found to undergo downregulation. In light of this, we aim to explore the role of SCGN in lipotoxicity-induced ß-cell injury. Our findings show that exposure to ox-LDL in vitro or long-term high-fat diets (HFD) in vivo decreases SCGN expression and induces pyroptosis in ß-cells. Moreover, restoring SCGN partially reverses the pyroptotic cell death under ox-LDL or HFD treatments. We have observed that the downregulation of SCGN facilitates the translocation of ChREBP from the cytosol to the nucleus, thereby promoting TXNIP transcription. The upregulation of TXNIP activates the NLRP3/Caspase-1 pathway, leading to pyroptotic cell death. In summary, our study demonstrates that lipotoxicity leads to the downregulation of SCGN expression in islet ß-cells, resulting in ChREBP accumulation in the nucleus and subsequent activation of the NLRP3/Caspase-1 pyroptotic pathway. Thus, administering SCGN could be a potential therapeutic strategy to alleviate ß-cell damage induced by lipotoxicity in type 2 diabetes.

The Spectrum of Tigecycline-Induced Pancreatitis in Clinical Characteristics, Diagnosis, and Management.

Introduction: Tigecycline-induced acute pancreatitis (AP) has been frequently increasingly reported in solid organ transplant patients. This review aimed to summarize the characteristics, possible mechanisms, and management of tigecycline-induced AP. Methods: Case reports of tigecycline-induced AP published in Chinese or English were collected until February 2023 for retrospective analysis. Results: Thirty-four patients from 29 articles were included. Fifteen patients (46.9%) had solid organ transplantation, and 4 patients (12.5%) had malignant tumors. Twenty-five patients (89.3%) received a recommended maintenance dose of tigecycline (50 mg q12 h). The median age was 50 years (range 9-87). Compared to the nontransplant patients, the median age of the transplant patients was significantly younger, 44 years (range 12.5-61) versus 57.5 years (range 9-87) (P=0.03). The median time of symptom onset was 7 days (range 2-29), and 91.2% (31/34) were less than 14 days. Typical initial symptoms included abdominal pain (90.6%), nausea (46.9%), vomiting (43.8%), and abdominal distention (21.9%). Most cases were accompanied by elevated levels of pancreatic enzymes. The main radiological features included edematous infiltrate and acute pancreatitis on computed tomography (CT) scan and abdominal ultrasound. Except for one patient who continued tigecycline treatment, all patients discontinued treatment and received symptomatic support such as fasting, acid suppression, and enzyme suppression. The median time to recover pancreatic enzymes to the normal range was 5 days (range 1-43), and the median time to relieve symptoms was 4 days (range 1-12). Four patients died, of whom two died of severe pancreatitis complications and two of cardiogenic shock and septicemia. Conclusion: Tigecycline-induced AP was a rare and serious complication that occurred mainly within two weeks of the medication. This serious side effect should be kept in mind while treating severe infections especially in transplant recipients.

Sinigrin Impedes the Breast Cancer Cell Growth through the Inhibition of PI3K/AKT/mTOR Phosphorylation-Mediated Cell Cycle Arrest.

Breast carcinoma, one of the most lethal variants of carcinogenesis, significantly diagnosed type of cancer amongst the female population. Sinigrin, also known as glucosinolate, is found in the seeds of Brassica nigra and shown to enhance various cancer cells potentially. Nevertheless, the mechanistic explanation of sinigrin (SGN)-mediated breast cancer growth and augmentation is still to be investigated. Therefore, we contended in this study that SGN impedes PI3K/AKT/mTOR phosphorylation-mediated cell cycle arrest in MCF-7 cells. SGN (20 M) was implemented to treat MCF-7 cells for 24 and 48 hours of incubation. A significant increase in cytotoxicity, reactive oxygen species (ROS) generation, cell cycle arrest, mitochondrion membrane alteration, lipid peroxidation, and antioxidant depletion was found in MCF-7 cells. The PI3K/AKT/mTOR events are crucial pathways that participate in survival, proliferation, and cell cycle regulation. Inhibition of PI3K/AKT/mTOR expression thought to be novel approach for alleviating breast cancer growth. We noticed that SGN inhibits PI3K, AKT, and mTOR phosphorylation, resulting in the downregulation of proliferative and cell cycle regulatory proteins, such as cyclin-Dl, PCNA, CDK4, and CDK6. SGN also causes apoptosis in MCF-7 cells by increasing nuclear fragmentation and by inducing pro-apoptotic gene expression. As a result, SGN inhibits breast cancer growth by impeding PI3K/AKT/mTOR phosphorylation-mediated cell cycle arrest in MCF-7 cells.

EphA2 as a new target for breast cancer and its potential clinical application.

PURPOSE: The aim of this research was to study the expression of EphA2 to assess its suitability as a new breast cancer target. METHODS: Immunohistochemistry (IHC) was used to detect EphA2 protein expression in pathology tissue samples from 250 cases of breast cancer, and the expression of EphA2 mRNA was detected by in situ hybridization (ISH). Breast cancer cells were isolated and cultured. The expression of EphA2 in the cells was detected by the indirect immunofluorescence assay (IFA), and the expression of EphA2 in breast cancer was analysed. RESULTS: EphA2 protein and mRNA were mainly expressed in tumor cells and vascular endothelial cells. EphA2 protein was expressed in 187 cases, with a positive rate of 74.80%, whereas EphA2 mRNA was expressed in 209 cases, with a positive rate of 83.60%. EphA2 protein and mRNA expression were correlated with lymph node metastasis, clinical stage, and breast cancer histologic grade (P<0.05). In addition, the positive expression rates of EphA2 protein and EphA2 mRNA were correlated (P<0.05). EphA2 was barely expressed in normal breast cells but highly expressed in breast cancer cells. CONCLUSION: EphA2 is highly expressed in breast cancer tissues and has the potential to be a new breast cancer target, providing a preliminary basis for the development of new targeted drugs for breast cancer and the construction of fluorescent-targeted tracers for fluorescence-guided mastoscopic breast-conserving surgery.

Expression of serum miR-27b and miR-451 in patients with congenital heart disease associated pulmonary artery hypertension and risk factor analysis.

This study investigated expression of serum miR-27b and miR-451 in patients with congenital heart disease associated pulmonary arterial hypertension (CHD-PAH), and analyzed the risk factors of CHD-PAH. A total of 114 patients with CHD admitted to the First Affiliated Hospital of the University of South China were recruited and allocated into a study group (61 patients with PAH) and a control group (53 patients without PAH). Reverse transcription-polymerase chain reaction (RT-PCR) was employed for the qualification of serum miR-27b and miR-451, and an automatic biochemical analyzer was used for the measurement of biochemical indexes in peripheral blood, and enzyme-linked immunosorbent assay (ELISA) for the detection of serum brain natriuretic peptide (BNP) and asymmetric dimethylarginine (ADMA). The patients with CHD-PAH showed higher serum miR-27b, BNP and ADMA but lower miR-451 than the controls. Serum miR-27b was positively correlated with mean pulmonary artery pressure (mPAP), BNP and ADMA, whereas serum miR-451 was negatively correlated with them. The combined detection of miR-27b and miR-451 was more valuable than a single detection in the diagnosis of CHD-PAH. Logistic regression analysis showed that ADMA, miR-27b, miR-451 and ventricular septal defect (VSD) were independent risk factors for CHD-PAH. In conclusion, miR-27b is highly expressed and miR-451 and the expression is low in patients with CHD-PAH. miR-27b and miR-451 are significantly correlated with BNP, ADMA, and the severity of the disease. The combination of miR-27b and miR-451 has high diagnostic value and can be used as a biomarker for the diagnosis and assessment of CHD-PAH. CHD-PAH is common in children with CHD, which poses a serious threat to the life and safety. At present, there are no effective methods for its early diagnosis and treatment. MicroRNAs (miRNAs, miRs) have been found to be closely related to the pathogenesis of CHD-PAH. In this study, miR-27b and miR-451 with differential expression in CHD-PAH were evaluated, and it was found that they were of great significance in the diagnosis and assessment of CHD-PAH.

A microRNA­24­to­secretagogin regulatory pathway mediates cholesterol­induced inhibition of insulin secretion.

Hypercholesterolemia is a key factor leading to ß­cell dysfunction, but its underlying mechanisms remain unclear. Secretagogin (Scgn), a Ca2+ sensor protein that is expressed at high levels in the islets, has been shown to play a key role in regulating insulin secretion through effects on the soluble N­ethylmaleimide­sensitive factor attachment receptor protein complexes. However, further studies are required to determine whether Scgn plays a role in hypercholesterolemia­associated ß­cell dysfunction. The present study investigated the involvement of a microRNA­24 (miR­24)­to­Scgn regulatory pathway in cholesterol­induced ß­cell dysfunction. In the present study, MIN6 cells were treated with increasing concentrations of cholesterol and then, the cellular functions and changes in the miR­24­to­Scgn signal pathway were observed. Excessive uptake of cholesterol in MIN6 cells increased the expression of miR­24, resulting in a reduction in Sp1 expression by directly targeting its 3' untranslated region. As a transcriptional activator of Scgn, downregulation of Sp1 decreased Scgn levels and subsequently decreased the phosphorylation of focal adhesion kinase and paxillin, which is regulated by Scgn. Therefore, the focal adhesions in insulin granules were impaired and insulin exocytosis was reduced. The present study concluded that a miR­24­to­Scgn pathway participates in the mechanism regulating cholesterol accumulation­induced ß­cell dysfunction.

The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis.

This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II.

Sudden onset agranulocytosis and hepatotoxicity after taking methimazole.

Agranulocytosis is a rare adverse effect of methimazole. The usual duration of treatment prior to the onset of agranulocytosis is approximately 1 to 4 months, and can be as long as 1 year. Agranulocytosis together with hepatotoxicity is an extremely rare idiosyncratic side effect of methimazole treatment. We present an unprecedented case of a Grave's disease patient who showed a strong reaction to methimazole with obvious agranulocytosis and hepatotoxicity which developed only six days after administration. This case, along with a literature review, is offered with the aim to increase the awareness of physicians of sudden onset agranulocytosis and hepatotoxicity from methimazole.

[Effects of different feeding patterns on body weight of perinatal women in rural area].

OBJECTIVE: To study the relations between different feeding patterns and the body weight retention of the perinatal women living in rural areas of China. METHODS: A cluster sampling method was used to investigate 409 women, who are currently living in rural areas of Tianjin, at pregnant and perinatal status. While, their body weights and heights before pregnancy, antepartum and postpartum were measured, respectively. Body weight retention was the difference of the measured data after postpartum minus pre-pregnant weight. Variance analysis was used for statistic comparison. RESULTS: The rate of exclusive breastfeeding was 70.9% (290/409) within four months. The net body weight retention of women (5.8 kg) using the exclusive breastfeeding was lower than that of the women (7.0 kg) using artificial feeding within 4 - 6 months, but there was no significantly statistic difference (F = 1.45, P = 0.236). However, there was the opposite result within 7 - 9 months, the data showed that the body weight retention in the women using the exclusive breastfeeding was 4.9 kg, which was significantly higher than that the women (2.9 kg) with artificial feeding (F = 3.17, P = 0.043). The food consumption of the women (901 g) using exclusive breastfeeding was the highest, followed by those (877 g) using mixed feeding and the women (750 g) using artificial feeding. CONCLUSION: The body weight retention after postpartum should be related to infant feeding patterns. After postpartum, the weight loss of women using the exclusive breastfeeding is relatively low. While, for the women using the exclusive breastfeeding, the net weight retention during pregnancy and after postpartum were lower than those with artificial feeding. Therefore, it is necessary to enhance health education and guidance on promoting exclusive breast-feeding as well as increasing awareness on pre-pregnant health.