Frailty and risk of systemic atherosclerosis: A bidirectional Mendelian randomization study.

BACKGROUND: Numerous observational studies have reported an association between frailty and atherosclerosis. However, the causal relationship between frailty and the occurrence of atherosclerosis in different anatomical sites remains unclear. we conducted a bidirectional Mendelian randomization (MR) study to evaluate the causal relationship between the frailty index (FI), and both systemic atherosclerosis and lipids. METHODS: We obtained summary statistics from large-scale genome-wide association studies (GWAS) of various phenotypes, including frailty (n = 175,226), coronary atherosclerosis (n = 56,685), cerebral atherosclerosis (n = 150,765), peripheral arterial disease (PAD) (n = 361,194), atherosclerosis at other sites (n = 17,832), LDL-C (n = 201,678), HDL-C (n = 77,409), and triglycerides (n = 78,700). The primary MR analysis employed the inverse variance weighted (IVW) method. Furthermore, to assess reverse causality, we employed inverse MR and multivariate MR analysis. RESULTS: Genetically predicted FI showed positive associations with the risk of coronary atherosclerosis (OR = 1.47, 95% CI 1.12-1.93) and cerebral atherosclerosis (OR = 1.99, 95% CI 1.05-3.78), with no significant association (p >0.05) applied to peripheral arterial disease and atherosclerosis at other sites. Genetically predicted FI was positively associated with the risk of triglycerides (OR = 1.31, 95% CI 1.08-1.59), negatively associated with the risk of LDL-C (OR = 0.87, 95% CI 0.78-0.97), and showed no significant association with the risk of HDL-C (p >0.05). Furthermore, both reverse MR and multivariate MR analyses demonstrated a correlation between systemic atherosclerosis, lipids, and increased FI. CONCLUSION: Our study elucidated that genetically predicted FI is associated with the risk of coronary atherosclerosis and cerebral atherosclerosis by the MR analysis method, and they have a bidirectional causal relationship. Moreover, genetically predicted FI was causally associated with triglyceride and LDL-C levels. Further understanding of this association is crucial for optimizing medical practice and care models specifically tailored to frail populations.

Garcinone C attenuates RANKL-induced osteoclast differentiation and oxidative stress by activating Nrf2/HO-1 and inhibiting the NF-kB signaling pathway.

Osteoporosis is the result of osteoclast formation exceeding osteoblast production, and current osteoporosis treatments targeting excessive osteoclast bone resorption have serious adverse effects. There is a need to fully understand the mechanisms of osteoclast-mediated bone resorption, identify new drug targets, and find better drugs to treat osteoporosis. Gar C (Gar C) is a major naturally occurring phytochemical isolated from mangosteen, and is a derivative of the naturally occurring phenolic antioxidant lutein. We used an OP mouse model established by ovariectomy (OVX). We found that treatment with Gar C significantly increased bone mineral density and significantly decreased the expression of TRAP, NFATC1 and CTSK relative to untreated OP mice. We found that Garcinone C could disrupt osteoclast activation and resorption functions by inhibiting RANKL-induced osteoclast differentiation as well as inhibiting the formation of multinucleated osteoclasts. Immunoblotting showed that Gar C downregulated the expression of osteoclast-related proteins. In addition, Gar C significantly inhibited RANKL-induced ROS production and affected NF-κB activity by inhibiting phosphorylation Formylation of P65 and phosphorylation and degradation of ikba. These data suggest that Gar C significantly reduced OVX-induced osteoporosis by inhibiting osteoclastogenesis and oxidative stress in bone tissue. Mechanistically, this effect was associated with inhibition of the ROS-mediated NF-κB pathway.

Assessment of safety during hospitalization for patients undergoing Surgery after neoadjuvant therapy for moderately advanced Esophageal cancer.

PURPOSE: To study the safety of patients with moderately advanced esophageal cancer during their hospital stay after undergoing surgery. METHODS: The clinical and pathological data of 66 patients with locally advanced esophageal cancer discharged from the Department of Thoracic Surgery of Jiangsu University Hospital from January 2017 to October 2022 were selected, of whom 32 underwent direct surgery (control group) and 34 underwent neoadjuvant therapy followed by surgery (experimental group), to retrospectively analyze whether there were differences in surgical outcomes, complication rates, biochemical and infection indicators between the two groups. RESULTS: The number of lymph node dissections, lymph node dissection rate, and hemoglobin value on the first day after the operation in the experimental group were smaller than those in the control group, and the difference was statistically significant (P < 0.05). The thoracic drainage volume of the experimental group was more than that of the control group, and the difference was statistically significant (P < 0.05). The incidence of pulmonary complications in the experimental group was higher than that in the control group, especially pulmonary infection, and the difference was statistically significant (P < 0.05). Compared with the control group, the experimental group was more prone to anastomotic leakage, and the difference was statistically significant (P < 0.05). CONCLUSION: Neoadjuvant therapy combined with surgery for patients with advanced esophageal cancer is generally safe during hospitalization.

Transcriptome Evidence Reveals Mitochondrial Unfolded Protein Response Participate in SH-SY5Y Cells Exposed to Manganese.

BACKGROUND: Overexposure to manganese (Mn) can lead to neurodegenerative damage, resulting in manganism with similar syndromes to Parkinson's disease (PD). However, little is known about changes in transcriptomics induced by the toxicological level of Mn. In this study, we conducted RNA-seq to explore the candidate genes and signaling pathways included by Mn in human SH-SY5Y neuroblastoma cells. METHODS: The differentially expressed genes (DEGs) between the Mn-treated group and the control group were screened, and weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes. Then, pathway enrichment analyses for those candidate genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We further validated the concentration- and time-response effects of Mn exposure (0-500 µM, 3-12 h) on mitochondrial unfolded protein response (UPRMT) by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results showed 179 up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs were related to neurotoxicity. The comprehensive pathway analysis showed Mn had widespread effects on the mitogen-activated protein kinase (MAPK) signaling pathway, unfolded protein response, longevity regulating pathway, inflammatory bowel disease, and mitophagy signaling pathway. After Mn exposure, the expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein (CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a concentration- and time-dependent manner. CONCLUSIONS: Overall, our study suggests that UPRMT is a new sight in understanding the mechanism of Mn-induced neurotoxicity.

Pyrroloquinoline Quinine and LY294002 Changed Cell Cycle and Apoptosis by Regulating PI3K-AKT-GSK3ß Pathway in SH-SY5Y Cells.

To verify the role of PI3K-AKT-GSK3ß pathway during manganese (Mn)-induced cell death, apoptosis, related indicators were investigated. SH-SY5Y cells were directly exposed to different concentrations of MnCl2. Then, cell viability, apoptosis, necrosis rate, and cell cycle were detected by MTT, FITC Annexin V Apoptosis Detection Kit with PI and PI staining. Then, in two intervention groups, cells were preconditioned with agonist (PQQ) and suppressant (LY294002). The cell viability decreased with a dose-response relationship (p < 0.05), while apoptosis and necrosis increased (p < 0.05). The ratio of G0/G1 and G2/M also decreased, but the percentage of S phase increased (p < 0.05). During above process, PI3K-AKT-GSK3ß pathway was involved by regulating the expression of PI3K, AKT, p-AKT, and GSK3ß (p < 0.05). For further research, cell cycle and apoptosis were detected pretreatment with PQQ and LY294002 before Mn exposure. The result showed cell ability, apoptosis, and necrosis rate changed obviously compared with non-pretreated group (p < 0.05). The variance of G0/G1 and G2/M ratio and percentage of S phase were also different, especially in 2.0 mM (p < 0.05). Mn can cause apoptosis and necrosis, varying cell cycle of SH-SY5Y cells, which could be changed by PQQ and LY294002 by regulating PI3K-AKT-GSK3ß pathway.

Overexpression of miR-138-5p suppresses MnCl2 -induced autophagy by targeting SIRT1 in SH-SY5Y cells.

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.

Functional reduced graphene oxide-based membranes with selective ion transport channels for zwitterionic ions separation based on the pH gradient.

In this work, we report a method for the fabrication of a functional free-standing graphene membrane (FFGM) with high mechanical strength, enlarged interlayer spacing and ion channels for zwitterionic ions separation. To obtain the FFGM, the anionic dye Eosin Y (EY) was introduced into a graphene oxide (GO) and hydroquinone (HQ) mixture to prepare functional graphene-based membranes on Cu foil using simply a drop-casting method. In comparison with a GO membrane, the molar flux and the mechanical strength of the FFGM were dramatically increased. The FFGM was then equipped on custom-built glass reservoirs for zwitterionic amino acids (AAs) separation based on the inner pH gradient, which was formed by controlling H+ and OH- (in the feed and receiver solution) migration in rGO/GO sheets via an external electric field. With the help of the inner pH gradient and external electric field, AAs could change their charge behaviors. The ionized AAs transport through the FFGM and finally separation was realized.

Ozone treatment of graphitic carbon nitride with enhanced photocatalytic activity under visible light irradiation.

An efficient and stable catalyst with fragment-exfoliating structure was prepared by directly ozone treatment of bulk graphitic carbon nitride (g-C3N4). The photocatalytic performances of the as-prepared catalysts were evaluated by degradation of methylene blue (MB) and photocatalytic hydrogen evolution reaction under visible light irradiation. Compared with untreated g-C3N4, the ozone-treated g-C3N4 (OCN) exhibited almost 5 times higher photodegradation activity and 2 times H2 evolution rate. The enhanced photocatalysis capability could be assigned to a narrowed band gap (2.62eV), the increased defects and active sites, and the reduced recombination efficiency of photoinduced carriers in OCN. Furthermore, the photocatalytic mechanism in degradation process of MB was discussed and the hydroxyl radical and superoxide radical have proven to be the predominant active species. It is reasonable to believe that chemical modifying of catalysts through ozone treatment could efficiently regulate its catalytic activity.

Sensitive determination of sulfonamides in environmental water by capillary electrophoresis coupled with both silvering detection window and in-capillary optical fiber light-emitting diode-induced fluorescence detector.

A new detector, silvering detection window and in-capillary optical fiber light-emitting diode-induced fluorescence detector (SDW-ICOF-LED-IFD), is introduced for capillary electrophoresis (CE). The strategy of the work was that half surface of the detection window was coated with silver mirror, which could reflect the undetected fluorescence to the photomultiplier tube to be detected, consequently enhancing the detection sensitivity. Sulfonamides (SAs) are important antibiotics that achieved great applications in many fields. However, they pose a serious threat on the environment and human health when they enter into the environment. The SDW-ICOF-LED-IFD-CE system was used to determine fluorescein isothiocyanate (FITC)-labeled sulfadoxine (SDM), sulfaguanidine (SGD) and sulfamonomethoxine sodium (SMM-Na) in environmental water. The detection results obtained by the SDW-ICOF-LED-IFD-CE system were compared to those acquired by the CE with in-capillary optical fiber light-emitting diode-induced fluorescence detection (ICOF-LED-IFD-CE). The limits of detection (LODs) of SDW-ICOF-LED-IFD-CE and ICOF-LED-IFD-CE were 1.0-2.0 nM and 2.5-7.7 nM (S/N = 3), respectively. The intraday (n = 6) and interday (n = 6) precision of migration time and corresponding peak area for both types of CE were all less than 0.86% and 3.68%, respectively. The accuracy of the proposed method was judged by employing standard addition method, and recoveries obtained were in the range of 92.5-102.9%. The results indicated that the sensitivity of the SDW-ICOF-LED-IFD-CE system was improved, and that its reproducibility and accuracy were satisfactory. It was successfully applied to analyze SAs in environmental water.

A high-sensitivity LIF detector with silver mirror coating detection window and small-angle optical deflection from collinear system for CE.

An LIF detector was integrated into a CE system based on silver mirror coating detection window and small-angle optical deflection from collinear configuration. For this detection scheme, the incident light beam was focused on capillary through the edge of a lens, resulting in a small deflection angle that deviated 18° from the collinear configuration. Meanwhile, the excitation light and emitted fluorescence were effectively reflected by silver mirror coating at the detection window. The fluorescence was collected through the center of the same lens and delivered to a PMT in the vertical direction. In contrast to conventional collinear LIF detection systems, the fluorescence intensity was greatly enhanced and the background level was significantly eliminated. FITC and FITC-labeled amino acids were used as model analytes to evaluate the performance with respect to design factors of this system. The limit LOD was estimated to be 0.5 pM for FITC (S/N = 3), which is comparable to that of optimized confocal LIF systems. All the results indicate that the proposed detection scheme will be promising for development of sensitive and low-cost CE system.

Design and evaluation of capillary coupled with optical fiber light-emitting diode induced fluorescence detection for capillary electrophoresis.

A new detector, capillary coupled with optical fiber LED-induced fluorescence detector (CCOF-LED-IFD, using CCOF for short), is introduced for CE. The strategy of the present work was that the optical fiber and separation capillary were, in the parallel direction, fastened in a fixation capillary with larger inner diameter. By employing larger inner diameter, the fixation capillary allowed the large diameter of the optical fiber to be inserted into it. By transmitting an enhanced excitation light through the optical fiber, the detection sensitivity was improved. The advantages of the CCOF-CE system were validated by the detection of riboflavin, and the results were compared to those obtained by the in-capillary common optical fiber LED-induced fluorescence detector (IC-COF-LED-IFD, using COF for short). The LODs of CCOF-CE and COF-CE were 0.29 nM and 11.0 nM (S/N = 3), respectively. The intraday (n = 6) repeatability and interday (n = 6) reproducibility of migration time and corresponding peak area for both types of CE were all less than 1.10 and 3.30%, respectively. The accuracy of the proposed method was judged by employing standard addition method, and recoveries obtained were in the range of 98.0-102.4%. The results indicated that the sensitivity of the proposed system was largely improved, and that its reproducibility and accuracy were satisfactory. The proposed system was successfully applied to separate and determine riboflavin in real sample.

A novel insertional mutation in the connexin 46 (gap junction alpha 3) gene associated with autosomal dominant congenital cataract in a Chinese family.

PURPOSE: To identify the genetic defect associated with autosomal dominant congenital cataract (ADCC) in a Chinese family, in which 11 individuals across four generations are affected with coralliform cataract. METHODS: Exome sequencing was performed in two of the ADCC-affected family members to scan for potential genetic defects. Sanger sequencing was used to verify these defects in the whole family. RESULTS: By combining whole exome sequencing and Sanger sequencing, the genetic defect was revealed to be a insertion of a cytosine after coding nucleotide 1,361 (1361insC) in the gap junction alpha 3 (GJA3) gene, causing a frameshift at codon 397 (p.Ala397Glyfs×71). This frameshift mutation cosegregates with the ADCC-affected pedigree members, but is absent in unaffected relatives and 100 normal individuals. CONCLUSIONS: A 1361 insC mutation in the C-terminus of GJA3 is found to be associated with autosomal dominant congenital coralliform cataract. This finding is similar to that of a previous publication, thus providing further evidence that the GJA3 C-terminal domain is also its mutation area, and further expanding the mutation spectrum of GJA3 in association with congenital cataract.

A gene locus responsible for dyschromatosis symmetrica hereditaria (DSH) maps to chromosome 6q24.2-q25.2.

Dyschromatosis symmetrica hereditaria (DSH) is a hereditary skin disease characterized by the presence of hyperpigmented and hypopigmented macules on extremities and face. The gene, or even its chromosomal location, for DSH has not yet been identified. In this study, two Chinese families with DSH were identified and subjected to a genomewide screen for linkage analysis. Two-point linkage analysis for pedigree A (maximum LOD score [Z(max)] = 7.28 at recombination fraction [theta] = 0.00) and pedigree B (Z(max) = 2.41 at theta = 0.00) mapped the locus for DSH in the two families to chromosome 6q. Subsequent multipoint analysis of the two families also provided additional support for the DSH gene being located within the region 6q24.2-q25.2, with Z(max) = 10.64. Haplotype analysis confined the locus within an interval of 10.2 Mbp, flanked by markers D6S1703 and D6S1708. The two families had no identical haplotype within the defined region, which suggests that the two families were different in origin. Further work on identification of the gene for DSH will open new avenues to exploration of the genetics of pigmentation.