Spatio-temporal distribution of cadmium levels in Chinese population and its potential risk factors.

Cadmium (Cd), a ubiquitous heavy metal, exists in numerous environmental matrices and has severe adverse effects on various human organs and tissues. This research evaluates blood and urine Cd levels in the Chinese population through data mining using Monte Carlo simulation (MCS). A total of 168 scientific studies (120 on urine and 48 on blood) published between January 1980 and December 2020, reflecting a population of 109,743 individuals in China, were included in the study. The results indicate that the blood and urine Cd levels in the Chinese population exhibited a peak from 1990 to 1995 and remained stable after 1995, averaging 1.21 µg/L of blood Cd (BCd) and 0.61 µg/L of urine Cd (UCd). The spatial trend of Cd levels varied significantly. Shandong, Zhejiang, Heilongjiang, and Guangdong provinces were identified as the top provinces with high Cd levels, which were related to factors such as tobacco sales, E-waste amounts, and contaminated rice. Additionally, the study highlights that BCd concentrations are highest among preschool-aged individuals, whereas school-age and adolescent groups exhibit the lowest levels. However, no significant difference existed among the different age groups. Males showed significantly higher Cd levels than females in the general population. Moreover, exposure to smoking, drinking, and staple food preferences had an impact on Cd levels. Furthermore, this comprehensive study, using biological monitoring and data mining, provides valuable information on Cd pollution levels in the Chinese population. It presents a statistical analysis that can aid decision-makers in implementing effective measures to control potential Cd pollution and improve the health of vulnerable populations.

The insulin-like growth factor binding protein-microfibrillar associated protein-sterol regulatory element binding protein axis regulates fibroblast-myofibroblast transition and cardiac fibrosis.

BACKGROUND AND PURPOSE: Excessive fibrogenesis is associated with adverse cardiac remodelling and heart failure. The myofibroblast, primarily derived from resident fibroblast, is the effector cell type in cardiac fibrosis. Megakaryocytic leukaemia 1 (MKL1) is considered the master regulator of fibroblast-myofibroblast transition (FMyT). The underlying transcriptional mechanism is not completely understood. Our goal was to identify novel transcriptional targets of MKL1 that might regulate FMyT and contribute to cardiac fibrosis. EXPERIMENTAL APPROACH: RNA sequencing (RNA-seq) performed in primary cardiac fibroblasts identified insulin-like growth factor binding protein 5 (IGFBP5) as one of the genes most significantly up-regulated by constitutively active (CA) MKL1 over-expression. IGFBP5 expression was detected in heart failure tissues using RT-qPCR and western blots. KEY RESULTS: Once activated, IGFBP5 translocated to the nucleus to elicit a pro-FMyT transcriptional programme. Consistently, IGFBP5 knockdown blocked FMyT in vitro and dampened cardiac fibrosis in mice. Of interest, IGFBP5 interacted with nuclear factor of activated T-cell 4 (NFAT4) to stimulate the transcription of microfibril-associated protein 5 (MFAP5). MFAP5 contributed to FMyT and cardiac fibrosis by enabling sterol response element binding protein 2 (SREBP2)-dependent cholesterol synthesis. CONCLUSIONS AND IMPLICATIONS: Our data unveil a previously unrecognized transcriptional cascade, initiated by IGFBP5, that promotes FMyT and cardiac fibrosis. Screening for small-molecule compounds that target this axis could yield potential therapeutics against adverse cardiac remodelling.

Effect of salting and dehydration treatments on the physicochemical and gel properties of hen and duck egg yolks, plasma and granules.

BACKGROUND: Salted hen egg yolks are less oily and less flavorful than salted duck egg yolks. However, hen eggs have a more adequate market supply and have a broader application prospect than duck eggs. In the present study, egg yolks, plasma, and granules were dehydrated by adding 1% NaCl to simulate traditional curing process of salted egg yolk. The changes in the pickling process of hen egg yolks (HEY) and duck egg yolks (DEY) plasma and granules were compared to reveal the gelation mechanism and the underlying causes of quality differences in salted HEY and DEY. Salted HEY can be compared with the changes in DEY during the pickling process to provide a theoretical basis for the quality improvement of salted HEY to salted DEY. RESULTS: The results showed that both plasma and granules were involved in gel formation, but exhibited different aggregation behaviors. Based on the intermolecular forces, the HEY proteins achieved aggregation mainly through hydrophobic interactions and DEY proteins mainly through covalent binding. According to spin-spin relaxation time, HEY gels immobilized a large amount of lipid and interacted strongly with lipids. DEY gels showed much free lipid and had weak interaction with lipid. The microstructure showed that HEY proteins were easily unfolded to form a homogeneous three-dimensional gel network structure after salting, whereas heterogeneous aggregates were formed to hinder the gel development in DEY. Changes in protein secondary structure content showed that pickling can promote the transformation of the α-helices to ß-sheets structure in HEY gels, whereas more α-helices structure was formed in DEY gels. CONCLUSION: The present study has demonstrated that different gelation behaviors of hen and duck egg yolk proteins (especially in plasma) through salting treatment led to the difference in the quality of salted HEY and DEY. © 2024 Society of Chemical Industry.

Association between dietary inflammatory index and risk of fatty liver disease: A systematic review and meta-analysis.

AIMS: This meta-analysis aimed to investigate the correlation between dietary inflammatory index (DII) and risks of fatty liver disease. METHODS: A comprehensive systematic literature search was conducted to select studies published from database inception to 6 September 2023 from five databases. Observational studies examining the association between elevated DII levels and the prevalence of fatty liver disease/liver fibrosis were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using either random-effects or fixed-effect models. RESULTS: In total, 10 studies comprising 242,006 participants were included in the meta-analysis. Individuals with higher DII had a significantly increased risk of fatty liver disease (OR 1.63; 95% CI 1.08-2.45) and liver fibrosis (OR 1.15; 95% CI 1.09-1.21) compared to those with lower DII. CONCLUSIONS: This meta-analysis demonstrated an association between higher DII and increased odds of fatty liver disease. However, additional prospective studies are required to further address this question.

Metabolic associated fatty liver disease and sarcopenia additively increase mortality: a real-world study.

BACKGROUND AND AIMS: Sarcopenia is associated with worse prognosis for non-alcoholic fatty liver disease (NAFLD). However, disease progression in the MAFLD-related sarcopenia is largely unknown. We aimed to clarify the relationship between MAFLD and/or sarcopenia with mortality and liver fibrosis in the real world. METHODS: A total of 13,692 individuals were selected from the third National Health and Nutrition Examination Surveys and linked mortality until December 2019. MAFLD is diagnosed based on a radiologically diagnosed hepatic steatosis and the presence of any one of the following three conditions: overweight/obesity, diabetes mellitus (DM), or metabolic dysregulation. Sarcopenia is defined by weight-adjusted skeletal muscle mass. RESULTS: The mean age was 43.7 ± 15.97 years, and 47.3% of the individuals were male. MAFLD was diagnosed in 4207/13,692 (30.73%) participants, and the proportion of sarcopenic was 19.42% amongst subjects with MAFLD. The mean follow-up duration was of 23.7 ± 7.62 years. MAFLD (aHR 1.152, 95% CI 1.070-1.241) and sarcopenia (aHR 1.123, 95% CI 1.042-1.210) were related to increased all-cause mortality in MAFLD after adjustment for age, sex, race, marital status, education, and smoking. Stratified analysis revealed that MAFLD and sarcopenia additively increased the risk of mortality (aHR 1.247, 95% CI 1.132-1.373) and liver fibrosis (aOR 2.296, 95% CI 1.718-3.069 assessed by NFS score >0.676; aOR 2.218, 95% CI 1.788-2.752 assessed by FIB-4 score >1.3) in fully adjusted models (P < 0.001 for all). CONCLUSION: Sarcopenia in individuals with MAFLD portends increased mortality and significant liver fibrosis. Novel therapeutic strategies targeting at increasing skeletal muscle mass should be explored for patients with MAFLD.

Proximity-Induced Interfacial Room-Temperature Ferromagnetism in Semiconducting Fe3GeTe2.

The discoveries of two-dimensional ferromagnetism and magnetic semiconductors highly enrich the magnetic material family for constructing spin-based electronic devices, but with an acknowledged challenge that the Curie temperature (Tc) is usually far below room temperature. Many efforts such as voltage control and magnetic ion doping are currently underway to enhance the functional temperature, in which the involvement of additional electrodes or extra magnetic ions limits their application in practical devices. Here we demonstrate that the magnetic proximity, a robust effect but with elusive mechanisms, can induce room-temperature ferromagnetism at the interface between sputtered Pt and semiconducting Fe3GeTe2, both of which do not show ferromagnetism at 300 K. The independent electrical and magnetization measurements, structure analysis, and control samples with Ta highlighting the role of Pt confirm that the ferromagnetism with the Tc of above 400 K arises from the Fe3GeTe2/Pt interfaces, rather than Fe aggregation or other artificial effects. Moreover, contrary to conventional ferromagnet/Pt structures, the spin current generated by the Pt layer is enhanced more than two times at the Fe3GeTe2/Pt interfaces, indicating the potential applications of the unique proximity effect in building highly efficient spintronic devices. These results may pave a new avenue to create room-temperature functional spin devices based on low-Tc materials and provide clear evidence of magnetic proximity effects by using nonferromagnetic materials.

An adhesion-based method for rapid and low-cost isolation of circulating tumor cells.

BACKGROUND: Noninvasive monitoring of cancer through circulating tumor cells (CTCs) is hampered long by unsatisfactory CTCs testing techniques. Efficient isolation of CTCs in a rapid and price-favorable way from billions of leukocytes is crucial for testing. METHODS: We developed a new method based on the stronger adhesive power of CTCs versus leukocytes to sensitively isolate CTCs. Using a BSA-coated microplate and low-speed centrifuge, this method could easily separate cancer cells within 20 min at a very low cost. RESULT: The capture ratio can reach 70.7-86.6% in various cancer cell lines (breast/lung/liver/cervical/colorectal cancer) covering different epithelial-mesenchymal transformation (EMT) phenotypes and cell sizes, demonstrating the potential for efficient pan-cancer CTCs detection. Moreover, the label-free process can well preserve cell viability (∼99%) to fit downstream DNA/RNA sequencing. CONCLUSIONS: A novel technique for non-destructive and rapid enrichment of CTCs has been devised. It has enabled the successful isolation of rare tumor cells in the patient blood sample and pleural effusion, highlighting a promising future of this method in clinical translation.

An MRTF-A-ZEB1-IRF9 axis contributes to fibroblast-myofibroblast transition and renal fibrosis.

Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-CreERT2 mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast-myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-ß-induced FMyT. In conclusion, our data unveil a novel MRTF-A-Zeb1-IRF9 axis that can potentially contribute to fibroblast-myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis.

The implications and prospect of cuproptosis-related genes and copper transporters in cancer progression.

Currently, cancer has become one of the major public health problems worldwide. Apoptosis is an important anti-cancer defense mechanism, which is used in the development of targeted drugs. Because cancer cells have endogenous resistance to apoptosis,the clinical efficacy of related drugs is not ideal. Therefore, non-apoptotic regulatory cell death may bring new therapeutic strategies for cancer treatment. Cuproptosis is a novel form of regulatory cell death which is copper-dependent, regulated and distinct from other known cell death regulatory mechanisms. FDX1,LIAS,and DLAT named cuproptosis-related genes play an essential role in regulating cuproptosis. Meanwhile, abnormal accumulation of copper can be observed in various malignant tumors. The correlation has been established between elevated copper levels in serum and tissues and the progression of several cancers. Copper transporters, CTR1 and Copper-transporting ATPases(ATP7A and ATP7B), are mainly involved in regulating the dynamic balance of copper concentration to maintain copper homeostasis. Thus,cuproptosis-related genes and copper transporters will be the focus of cancer research in future. This review elaborated the basic functions of cuproptosis-related genes and copper transporters by retrievalling PubMed. And then we analyzed their potential relationship with cancer aiming to provide theoretical support and reference in cancer progression, diagnosis and treatment for future study.

Omics analyses indicate sdhC/D act as hubs of early response of E. coli to antibiotics.

In recent years, the phenomenon of microbial resistance has become increasingly serious. The generation of reactive oxygen species (ROS) during the bactericidal process of antibiotics has attracted great interest, but little research has been done on the generation of ROS in the early stage of antibiotic action. We confirmed the rapid production of ROS by flow cytometry and transmission electron microscopy (TEM). GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis indicated that the oxidative phosphorylation pathway is the key pathway of ROS production. Protein-protein interaction (PPI) network results indicate that sdhC/D are key genes in the oxidative phosphorylation pathway. The overexpression of sdhC/D resulted in a lower survival rate than the control strain after antibiotic treatments, which might be due to excess ROS induced by sdhC/D overexpression. The production of superoxide anion in the overexpress strain was significantly higher than that in the control strain, which further verified the importance of sdhC/D in the ROS release of bacteria. Current results showed that bacteria produce large amounts of ROS in the early stage of gentamicin and ampicillin action, and the regulation patterns of genes in the key pathway were consistent. sdhC/D are key genes in the early ROS release process of bacteria. Our study provides a basis for the search of ROS-related enhancers of antimicrobial action.

Molecular Typing of Gastric Cancer Based on Invasion-Related Genes and Prognosis-Related Features.

Background: This study aimed to construct a prognostic stratification system for gastric cancer (GC) using tumour invasion-related genes to more accurately predict the clinical prognosis of GC. Methodology: Tumour invasion-related genes were downloaded from CancerSEA, and their expression data in the TCGA-STAD dataset were used to cluster samples via non-negative matrix factorisation (NMF). Differentially expressed genes (DEGs) between subtypes were identified using the limma package. KEGG pathway and GO functional enrichment analyses were conducted using the WebGestaltR package (v0.4.2). The immune scores of molecular subtypes were evaluated using the R package ESTIMATE, MCPcounter and the ssGSEA function of the GSVA package. Univariate, multivariate and lasso regression analyses of DEGs were performed using the coxph function of the survival package and the glmnet package to construct a RiskScore model. The robustness of the model was validated using internal and external datasets, and a nomogram was constructed based on the model. Results: Based on 97 tumour invasion-related genes, 353 GC samples from TCGA were categorised into two subtypes, thereby indicating the presence of inter-subtype differences in prognosis. A total of 569 DEGs were identified between the two subtypes; of which, four genes were selected to construct the risk model. This four-gene signature was robust and exhibited stable predictive performance in different platform datasets (GSE26942 and GSE66229), indicating that the established model performed better than other existing models. Conclusion: A prognostic stratification system based on a four-gene signature was developed with a desirable area under the curve in the training and independent validation sets. Therefore, the use of this system as a molecular diagnostic test is recommended to assess the prognostic risk of patients with GC.

SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription.

Oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis, activates the transcription of adhesion molecules (ICAM-1) in endothelial cells. We previously showed that myocardin-related transcription factor A (MRTF-A) mediates oxLDL-induced ICAM-1 transcription. Here we confirm that ICAM-1 transactivation paralleled dynamic alterations in MRTF-A acetylation. Since treatment with the antioxidant NAC dampened MRTF-A acetylation, MRTF-A acetylation appeared to be sensitive to cellular redox status. Of interest, silencing of SIRT6, a lysine deacetylase, restored MRTF-A acetylation despite the addition of NAC. SIRT6 directly interacted with MRTF-A to modulate MRTF-A acetylation. Deacetylation of MRTF-A by SIRT6 led to its nuclear expulsion thus dampening MRTF-A occupancy on the ICAM-1 promoter. Moreover, SIRT6 expression was downregulated with oxLDL stimulation likely owing to promoter hypermethylation in endothelial cells. DNA methyltransferase 1 (DNMT1) was recruited to the SIRT6 promoter and mediated SIRT6 repression. The ability of DNMT1 to repress SIRT6 promoter partly was dependent on ROS-sensitive serine 154 phosphorylation. In conclusion, our data unveil a novel DNMT1-SIRT6 axis that contributes to the regulation of MRTF-A acetylation and ICAM-1 transactivation in endothelial cells.

Myocardin-related transcription factor A regulates integrin beta 2 transcription to promote macrophage infiltration and cardiac hypertrophy in mice.

AIMS: Macrophage-mediated inflammatory response represents a key pathophysiological process in a host of cardiovascular diseases including heart failure. Regardless of aetiology, heart failure is invariably preceded by cardiac hypertrophy. In the present study, we investigated the effect of macrophage-specific deletion of myocardin-related transcription factor A (MRTF-A) on cardiac hypertrophy and the underlying mechanism. METHODS AND RESULTS: We report that when subjected to transverse aortic constriction (TAC), macrophage MRTF-A conditional knockout (CKO) mice developed a less severe phenotype of cardiac hypertrophy compared to wild-type (WT) littermates and were partially protected from the loss of heart function. In addition, there was less extensive cardiac fibrosis in the CKO mice than WT mice following the TAC procedure. Further analysis revealed that cardiac inflammation, as assessed by levels of pro-inflammatory cytokines and chemokines, was dampened in CKO mice paralleling reduced infiltration of macrophages in the heart. Mechanistically, MRTF-A deficiency attenuated the expression of integrin beta 2 (ITGB2/CD18) in macrophage thereby disrupting adhesion of macrophages to vascular endothelial cells. MRTF-A was recruited by Sp1 to the ITGB2 promoter and cooperated with Sp1 to activate ITGB2 transcription in macrophages. Administration of a CD18 blocking antibody attenuated TAC-induced cardiac hypertrophy in mice. Interaction between MRTF-A and the histone demethylase KDM3A likely contributed to IGTB2 transcription and consequently adhesion of macrophages to endothelial cells. CONCLUSIONS: Our data suggest that MRTF-A may regulate macrophage trafficking and contribute to the pathogenesis of cardiac hypertrophy by activating ITGB2 transcription.

Prognostic marker identification based on weighted gene co-expression network analysis and associated in vitro confirmation in gastric cancer.

The aim of this study was to explore the potential molecular mechanisms of Gastric cancer (GC) and identify new prognostic markers for GC. RNA sequencing data were downloaded from the Gene Expression Omnibus database, and 418 differentially expressed genes (DEGs) were screened. Weighted correlation network analysis (WGCNA) was performed to identify six hub modules related to the clinical features of GC. Cytoscape software was used to identify five hub genes in the co-expression network, including CST1, CEMIP, COL8A1, PMEPA1, and MSLN. The TCGA database was used to verify hub gene expression in GC. The overall survival in the high CEMIP expression group was significantly lower than that of patients in the low CEMIP expression group. CEMIP expression was also found to be negatively correlated with B cell and CD4 + T cell infiltration. Further, associated in vitro experiments confirmed that CEMIP downregulation suppressed the proliferation and migration of GC cells and impaired the chemoresistance of GC cells to 5-fluorouracil.Our study effectively identified and validated prognostic biomarkers for GC, laying a new foundation for the therapeutic target, occurrence, and development of gastric cancer.

DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production.

Mitogen-activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma-related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage-induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38-MAPK signaling complex to drive ROS production in an S-nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4-inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38-MAPK signaling, and ameliorate liver injury by influencing DDIT4 S-nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S-nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription-based signaling cascade that contributes to ROS production in liver injury.

Blood lead levels and their associated risk factors in Chinese adults from 1980 to 2018.

In China, studies on lead exposure to grownup are scarce compared to children, although relevant disease burdens for adults are much severe than that in developed countries. The present study evaluated blood lead levels (BLLs) in Chinese adults by data mining using Monte Carlo simulation. A total of 115 scientific studies published between January 1980 and March 2021 reflecting 45,514 Chinese adults were included in the study. After a continuous increase in Chinese adult BLLs from 1980-1983 (GM 74.84 µg/L) to 1994-1996 (GM 92.27 µg/L), BLLs began to decline from 2000--2002 (GM 80.32 µg/L) to 2016-2018 (GM 21.57 µg/L). This decline implied that the lead phase-out policy in gasoline was effective over the past two decades. The study indicated that North, South, and Southwest China were still relatively high compared to other regions in the past decade. Statistical analysis showed that BLLs of males (GM 68.45 µg/L) were higher than females (GM 56.51 µg/L), smokers (GM 80.96 µg/L) higher than nonsmokers (GM 58.95 µg/L), and populations over 40 (GM 40.43 µg/L) higher than younger populations (GM 40.37 µg/L). The significantly positive correlation between the concentrations of PM2.5 and topsoil lead and BLLs in Chinese adults indicated that air and soil pollution affect adult BLLs. Taken together, our results showed that strict lead control strategies and regular bio-monitoring are needed to maintain low BLLs in the population.