Exploring the mediating role of calcium homeostasis in the association between diabetes mellitus, glycemic traits, and vascular and valvular calcifications: a comprehensive Mendelian randomization analysis.

BACKGROUND: The interplay between diabetes mellitus (DM), glycemic traits, and vascular and valvular calcifications is intricate and multifactorial. Exploring potential mediators may illuminate underlying pathways and identify novel therapeutic targets. METHODS: We utilized univariable and multivariable Mendelian randomization (MR) analyses to investigate associations and mediation effects. Additionally, the multivariable MR analyses incorporated cardiometabolic risk factors, allowing us to account for potential confounders. RESULTS: Type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) were positively associated with both coronary artery calcification (CAC) and calcific aortic valvular stenosis (CAVS). However, fasting glucose (FG) was only linked to CAVS and showed no association with CAC. Additionally, CAVS demonstrated a causal effect on FG. Calcium levels partially mediated the impact of T2DM on both types of calcifications. Specifically, serum calcium was positively associated with both CAC and CAVS. The mediation effects of calcium levels on the impact of T2DM on CAC and CAVS were 6.063% and 3.939%, respectively. The associations between T2DM and HbA1c with calcifications were influenced by body mass index (BMI) and smoking status. However, these associations were generally reduced after adjusting for hypertension. CONCLUSION: Our findings suggest a genetically supported causal relationship between DM, glycemic traits, and vascular and valvular calcifications, with serum calcium playing a critical mediating role.

Deoxynivalenol and zearalenone: Different mycotoxins with different toxic effects in donkey (Equus asinus) endometrial epithelial cells.

Deoxynivalenol (DON) and zearalenone (ZEA), which are commonly found in feed products, exhibit serious negative effects on the reproductive systems of domestic animals. However, the toxicity of mycotoxins on the uterine function of donkey (Equus asinus) remains unclear. This study investigated the biological effects of DON and ZEA exposure on donkey endometrial epithelial cells (EECs). It was administered 10 µM and 30 µM DON and ZEA to cells cultured in vitro. The results showed that 10 µM DON exposure markedly changed the expression levels of pyroptosis-associated genes and that 30 µM ZEA exposure changed the expression levels of inflammation-associated genes in EECs. The mRNA expression of cancer-promoting genes was markedly upregulated in cells exposed to DON and 30 µM ZEA; in particular, 10 µM and 30 µM DON and ZEA markedly disturbed the expression of androgen and estrogen secretion-related genes. Furthermore, Q-PCR, Western blot, and immunofluorescence analyses verified the different expression patterns of related genes in DON- and ZEA-exposed EECs. Collectively, these results illustrated the impact of exposure to different toxins and concrete toxicity on the mRNA expression of EECs from donkey in vitro.

Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in Rats After Exposure to Simulated High Altitude Hypoxia.

The pharmacokinetic characteristics of drugs were altered under high altitude hypoxia, thereby affecting the absorption, distribution, metabolism, and excretion of drug. However, there are few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs at high altitude. This study aimed to evaluate the pharmacokinetics of acetaminophen and metformin hydrochloride in rats under simulated high altitude hypoxia condition. Mechanically, the protein and mRNA expression of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) were investigated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Compared with the normoxia group, the t1/2 and AUC of acetaminophen were significantly increased, and the CL/F was significantly decreased in rats after exposure to simulated high altitude hypoxia. The t1/2 of metformin hydrochloride was significantly increased by simulated high altitude hypoxia. No significant differences in AUC and CL/F of metformin hydrochloride were observed when comparing the hypoxia group with the normoxia group. The protein and mRNA expression of UGT1A1 and OCT2 were decreased significantly under hypoxia in rats. This study found obvious changes in the pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia, and they might be due to significant decreases in the expressions of UGT1A1 and OCT2. To sum up, our data suggested that the pharmacokinetics of acetaminophen and metformin hydrochloride should be reexamined, and the optimal dose should be reassessed under hypoxia exposure.

Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR.

Little is known about what roles the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play in drug metabolism in high-altitude hypoxia. Likewise, the potential interaction of nuclear receptors and drug metabolism enzymes during drug metabolism of high-altitude hypoxia is not fully understood. In this work, we investigated the effects of high-altitude hypoxia on transcriptional regulation of cytochrome P450 (CYP450) and UDP-glucuronosyltransferase 1A1 (UGT1A1) genes mediated by PXR and CAR proteins. The protein and mRNA expressions of CYP450, UGT1A1, PXR, and CAR were determined by enzyme-linked immunosorbent assay and qPCR in rats and HepG2 cell lines under hypoxia. Hypoxia potently inhibited the CYP450 isoforms, UGT1A1, PXR, and CAR protein and mRNA expression. To clarify whether PXR and CAR regulate various genes involved in drug metabolism of high-altitude hypoxia, we investigated the expression of CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 using a dual-luciferase reporter assay after treatment with Ketoconazole (KCZ) and Retinoic acid (RA), or silenced PXR and CAR gene expression. In HepG2 cells, hypoxia, KCZ, and RA inhibited CYP450 isoforms and UGT1A1 expression. Activation of PXR and CAR in cells treated with 6-(4-chlorophenyl)-imidazo (2,1-b) thiazole-5-carbaldehyde (CITCO) and rifampicin (Rif) resulted in the enhancement of CYP450 isoforms, UGT1A1, PXR, and CAR. In contrast, this effect was not observed under hypoxia. Taken together, our results suggest that hypoxia inhibits CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 expression via the PXR and CAR regulatory pathway.

The role of liver stiffness measurement in the evaluation of liver function and esophageal varices in cirrhotic patients.

OBJECTIVE: We aimed to evaluate the efficacy of liver stiffness measurement (LSM) in predicting the presence and severity of esophageal varices (EV) and investigating its association with liver function (LF) in patients with liver cirrhosis. METHODS: Medical records of 90 cirrhotic patients who underwent LSM by transient elastography were retrospectively reviewed. The relationship between LSM and the presence and severity of EV was evaluated by esophagogastroduodenoscopy (EGD) and multislice spiral computed tomography (MSCT). Another 25 healthy individuals were included as controls. RESULTS: LSM was significantly associated with the Child-Pugh score in cirrhotic patients, with the highest LSM in those with Child-Pugh C. Patients with clinically decompensated cirrhosis had a higher LSM than those with compensated cirrhosis (36.75 ± 16.54 kPa vs 17.65 ± 10.87 kPa, P < 0.01). However, there was no significant difference in LSM value between patients with severe EV and those with no or non-severe EV determined by endoscopy (28.18 ± 17.44 kPa vs 31.00 ± 18.44 kPa) or MSCT (29.71 ± 18.39 kPa vs 24.90 ± 14.80 kPa). The diagnostic value of LSM for predicting severe EV was low in unselected cirrhotic patients. The presence of EV examined by EGD and MSCT was similar to each other. CONCLUSIONS: LSM could be used to evaluate the progression of liver cirrhosis continuously. However, its role in assessing EV grades in advanced cirrhosis needs further confirmation. MSCT can assess EV accurately and may serve as an alternative to endoscopy in the assessment of portal hypertension.

[Mutation analysis of the GLUD1 gene in patients with glutamate dehydrogenase congenital hyperinsulinism].

OBJECTIVE: To investigate the glutamate dehydrogenase 1 (GLUD1) gene mutation of three patients diagnosed as glutamate dehydrogenase congenital hyperinsulinism (GDH-HI). METHODS: Three patients diagnosed as GDH-HI and their parents were involved in the study. PCR-DNA direct sequencing was used to analyze the exons 6,7,10,11 and 12 of the GLUD1 gene. RESULTS: In the first case, an R269H heterozygous mutation was found in the GLUD1 gene, with autosomal dominant inheritance. In the second case, there was a de novo S445L heterozygous mutation of the GLUD1 gene. No mutation was detected in the third case. CONCLUSION: In Chinese, R269H, S445L heterozygous mutation of the GLUD1 gene can lead to GDH-HI. Genetic analysis is necessary in making genetic diagnosis of congenital hyperinsulinsm.

Beneficial effects of oligopeptides from marine salmon skin in a rat model of type 2 diabetes.

OBJECTIVE: This study aimed at investigating whether treatment with oligopeptides from marine salmon skin (OMSS) could modulate type 2 diabetes mellitus (T2DM)-related hyperglycemia and ß-cell apoptosis in rats induced by high fat diet and low doses of streptozotocin and its therapeutic mechanisms. METHODS: Groups of T2DM rats were treated with OMSS or bovine serum albumin (3.0 g/kg/d) for 4 wk and their blood samples, together with those of normal control rats, were collected before and 4 wk after treatment. The levels of fasting blood glucose (FBG) and insulin, serum superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH), tumor necrosis factor-alpha (TNFα), and interferon-gamma (IFNγ) in rats were determined. The islet cell apoptosis and Fas/FasL expression were detected by TUNEL and immunohistochemistry. RESULTS: In comparison with control rats, higher levels of FBG and frequency of apoptotic islet cells were detected in the bovine serum albumin group of diabetic rats, accompanied by higher levels of Fas expression in the pancreatic islets, serum TNFα, IFNγ, and MDA, but lower levels of SOD and GSH. However, the levels of FBG and frequency of apoptotic islet cells were significantly reduced in OMSS-treated rats. Lower levels of Fas expression were observed in the pancreatic islets of OMSS-treated rats. Significantly reduced levels of serum TNFα, IFNγ, and MDA, but increased levels of SOD and GSH, were detected in OMSS-treated rats. CONCLUSIONS: Treatment with OMSS significantly reduced FBG in diabetic rats. This antidiabetic activity may be mediated by down-regulating T2DM-related oxidative stress and inflammation, protecting the pancreatic ß-cells from apoptosis.

[Study on the fluorescence spectra of 7-hydroxyquinoline in dimethyl sulfoxide solution].

7-hydroxyquinoline (7-HQ) is a kind of organic molecule with excited-state proton transfer (ESPT) effect. 7-HQ in ethanol solution causes ESPT reaction under the excitation of ultraviolet light. The fluorescence spectrum of the sample exhibits two bands. In contrast, 7-HQ in dimethyl sulfoxide (DMS) solution does not cause ESPT reaction. The fluorescence spectrum of the sample exhibits a single band. But after the sample was irradiated with a strong UV light, its fluorescence spectrum also exhibits two bands. This phenomenon is reported for the first time in the present paper, and its cause is investigated through the study on the absorption spectra and fluorescence spectra of 7-HQ in ethanol, dimethyl sulfoxide and N, N-dimethyl formamide solution. The conclusion is that the change in the fluorescence spectrum of 7-HQ in DMS solution is due to the fact that 7-HQ causes ESPT reaction which results from the photodecomposition of DMS and the product of water after the solution was irradiated with strong UV light.

[Clinical analysis of tumors of the iris and ciliary body].

OBJECTIVE: To evaluate the clinical features, different diagnosis, pathological features, management, and prognosis of tumors of the iris and ciliary body. METHODS: Medical records, photographs, pathological findings and the results of follow-up of 37 cases with tumors of the iris and ciliary body were reviewed as a retrospective study. RESULTS: Of the 37 cases with tumors of the iris and ciliary body, 26 were male and 11 were female. The mean age at diagnosis was 38 years, ranged from 5 - 64 years. According to the histopathological examination, melanoma was the most common tumor in the iris and ciliary body (15 cases, 40.5%), followed by metastatic tumors (8 cases, 21.6%), teratoid medulloepitheliomas (3 cases, 8.1%) and iris nevus (2 cases, 5.4%). MANAGEMENT: The tumors were excised in 14 cases. Enucleation was performed in 21 cases. Two cases were observed without any surgical treatment. Thirty-four cases were followed-up for 2 months to 15 years, averaged 31 months. Most melanomas of the iris and ciliary body are round or semi-spherical dark brown vascularized mass, with engorged episcleral sentinel vessels in some cases. The tumor showed a shadow during transillumination. Ultrasound biomicroscopy revealed a low to medium echoic solid lesion, with echoic changes in adjacent infiltrated tissues. Melanoma showed positive immunoreactivity for melanoma-specific antigen, and had a good prognosis. Metastatic tumors of the iris and ciliary body were flat or near round, dirty, single or multiple neoplasms, growth rapidly, with abundant neovascularization, and had a poor prognosis. Primary carcinomas could be found in other parts of the body. CONCLUSIONS: Melanoma of the iris and ciliary body has typical features that may help to distinguish them from other tumors. Metastatic tumor has characteristic features, but the diagnosis can be made only with supplementary examination and immunocytochemical studies. Medulloepitheliomas should be differentiated from retinoblastoma.

[The inhibition effect of interleukin-1 receptor antagonist on interleukin-1 alpha-induced intercellular adhesion molecule-1 expression on orbital fibroblasts and adhesion of peripheral blood mononuclear cells].

OBJECTIVE: The aim was to identify whether interleukin-1 receptor antagonist (IL-1ra) inhibits interleukin-1 alpha (IL-1 alpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression on cultured orbital fibroblasts, and adhesion of peripheral blood mononuclear cells (PBMC) to orbital fibroblasts, and to investigate the clinical application potential of IL-1ra in the treatment of Graves' ophthalmopathy (GO). METHODS: Cultured orbital fibroblasts from patients with GO and controls were challenged with IL-1 alpha or/and IL-1ra. Immunocytochemical staining was used to examine the changes of ICAM-1 in response to IL-1ra treatment; fluorescent photomicroscope was used to measure the adhesion between the labeled PBMC and orbital fibroblasts. Neutralizing antibody against ICAM-1 was used to demonstrate the role of ICAM-1 in the IL-1 alpha-induced adhesion. RESULTS: IL-1ra inhibits IL-1 alpha-induced ICAM-1 expression in cultured orbital fibroblasts both from GO patients and controls; IL-1ra inhibits IL-1 alpha-induced adhesion of PBMC to orbital fibroblasts in a concentration and time dependent manner. Moreover, a monoclonal anti-human ICAM-1 antibody produced a concentration dependent inhibition of the IL-1 alpha-induced adhesion of PBMC to the fibroblasts. CONCLUSIONS: IL-1ra inhibits IL-1 alpha-induced ICAM-1 expression in cultured orbital fibroblasts and the adhesion of PBMC to fibroblasts. IL-1 alpha-induced ICAM-1 expression may play an important role in the adhesion process. IL-1ra may be useful in the prevention or treatment of GO.