Identification of a Novel Parvovirus in the Arctic Wolf (Canis lupus arctos).

A novel virus, temporarily named "Arctic wolf parvovirus" (AWPV), was discovered in a pharyngeal metagenomic library derived from an Arctic wolf (Canis lupus arctos) in China. The genome sequence was assigned GenBase accession number C_AA071902.1. AWPV has a genome comprised of 4,920 base pairs with a nucleotide composition of 36.4% A, 23.4% T, 18.2% G, and 22.0% C, with a GC content of 40.2%. Its structure resembles parvoviruses, containing two open reading frames: the nonstructural (NS) region encoding replication enzymes and the structural (VP) region encoding capsid protein. Pairwise sequence comparison and phylogenetic analysis suggest AWPV may represent a novel species within the genus Protoparvovirus. This discovery enhances our understanding of mammalian virus ecology and potential future infectious diseases.

Network pharmacology prediction to discover the potential pharmacological action mechanism of Rhizoma Dioscoreae for liver regeneration.

Improving liver regeneration (LR) remains a medical issue, and there is currently a lack of safe and effective drugs for LR. Rhizoma Dioscoreae (SanYak, SY) is a traditional Chinese medicine. However, the underlying action mechanism of SY treatment for LR is yet to be fully elucidated. To explore the mechanism by which SY affects LR, we have conducted a series of methods for network pharmacological analysis, molecular docking, and in vivo experimental validation in mice. Overall, 9 compounds and 30 predicted target genes of SY were found to be associated with the therapeutic effects of LR. Compared with the model group, hematoxylin and eosin staining revealed that the mice with preoperative drug intervention possessed fewer postoperative hepatocyte bubbles and relatively regular morphology. Furthermore, the serum alanine transaminase and aspartate aminotransferase levels were reduced, immunohistochemistry revealed elevated proliferating cell nuclear antigen positivity rate, and Western blotting demonstrated that the phospho-protein kinase B (AKT)/AKT ratio was downregulated and that vascular endothelial growth factor A (VEGFA) expression levels were upregulated. This study explored dioscin, the main active ingredient of SY, and its potential therapeutic effects on LR. It repairs damaged liver following surgery and promotes liver cell proliferation. The action mechanism comprises reducing AKT phosphorylation levels and upregulating VEGFA expression levels. Thus, this study provides a new direction for further research on the mechanism of SY promoting LR.

Ciwujianoside E inhibits Burkitt lymphoma cell proliferation and invasion by blocking ENO1-plasminogen interaction and TGF-ß1 activation.

Burkitt's lymphoma (BL) is a rare and highly aggressive B-cell non-Hodgkin lymphoma. Although the outcomes of patients with BL have greatly improved, options for patients with relapsed and refractory BL are limited. Therefore, there is an urgent need to improve BL therapeutics and to develop novel drugs with reduced toxicity. In this study, we demonstrated that enolase 1 (ENO1) is a potential novel drug target for BL treatment. We determined that ENO1 was aberrantly upregulated in BL, which was closely related to its invasiveness and poor clinical outcomes. Furthermore, using RNA interference, we demonstrated that ENO1 depletion significantly inhibited cell proliferation and invasion both in vitro and in vivo. Mechanistically, we established that ENO1 knockdown suppressed the PI3K-AKT and epithelial-mesenchymal transition (EMT) signaling pathways by reducing plasminogen (PLG) recruitment, plasmin (PL) generation, and TGF-ß1 activation. Addition of activated TGF-ß1 protein to the culture medium of shENO1 cells reversed the inhibitory effects on cell proliferation and invasion, as well as those on the PI3K-AKT and EMT signaling pathways. Notably, our research led to the discovery of a novel ENO1-PLG interaction inhibitor, Ciwujianoside E (L-06). L-06 effectively disrupts the interaction between ENO1 and PLG, consequently reducing PL generation and suppressing TGF-ß1 activation. In both in vitro and in vivo experiments, L-06 exerted impressive antitumor effects. In summary, our study elucidated the critical role of ENO1 in BL cell proliferation and invasion and introduced a novel ENO1 inhibitor, which holds promise for improving the treatment of patients with BL in the future.

CRKL but not CRKII contributes to hemin-induced erythroid differentiation of CML.

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR-429-CT10 regulation of kinase-like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR-429-CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR-429-CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR-429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR-429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin-induced erythroid differentiation of K562 cells, whereas, miR-429 exhibited opposite effects to CRKL. Mechanistically, miR-429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL-3'-untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR-429 contribute to development, progression and erythropoiesis of CML, miR-429-CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients.

The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells.

The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif -1116 TTAAAA-1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif -1116 TTAAAA-1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif -1116TTAAAA-1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM.

Prognostic Significance and Functional Mechanism of UTS2 in Glioblastoma Multiforme

Aim: We aimed to explore the role of urotensin 2 (UTS2) in glioblastoma (GBM). Background: GBM is the most malignant primary brain cancer with a poor prognosis. Previous studies have suggested that GBM vessels undergo dynamic remodeling modulated by tumor vasodilation and vasoconstriction instead of tumor angiogenesis. Objective: Here, we have first investigated the expression and function of UTS2, a potent vasoconstrictor, in GBM. Methods: The mRNA expression profiles and clinical information of GBM patients were obtained from the TCGA database. The clinical relevance of UTS2 was explored by the Mann-Whitney U test and Cox hazard regression survival test. We further explored the role of UTS2 in GBM cell proliferation, migration, and tumor immune microenvironment. Moreover, we established the in vivo mice model to validate its oncogenic effects on GBM progression. Results: Although we did not find significant correlations between UTS2 expression and patients' clinical characteristics, UTS2 was identified as a valid independent prognostic indicator according to multivariate survival analysis. Knockdown of UTS2 resulted in decreased GBM cell proliferation and migration. In addition, functional enrichment analysis implied UTS2 to be involved in the regulation of the immune microenvironment. In vivo studies showed that UTS2 knockdown suppressed GBM xenograft growth, highlighting the tumor-promoting effects of UTS2 on GBM. Conclusion: Our study identified that UTS2 could predict the prognosis of GBM patients and provided evidence regarding its oncogenic effects both in vitro and in vivo.

Interspecies interactions of non-O1/O139 Vibrio cholerae and Salmonella typhimurium: a rare coinfection case report.

Infectious diseases are commonly demonstrated to be caused by polymicrobial infections, which correlate with increased infection severity and poorer clinical outcomes. In this study, we report a rare intestinal coinfection case of non-O1/O139 Vibrio cholerae and Salmonella typhimurium, along with V. cholerae septicemia. The data of quantitative real-time PCR and competition assay showed that V. cholerae may present enhanced virulence in the presence of S. typhimurium, and exerted an inhibitory growth effect over S. typhimurium in vitro.

NONHSAT021545/miR-330-3p/EREG: A Cooperative Axis in Breast Cancer Prognosis and Treatment.

Lymphatic metastasis is the most common form in breast cancer (BC) progression. Previously, we observed that lnc045874, a most conservative homology of Homo Sapiens NONHSAT021545 (lnc021545), miR-330-3p, and EREG may have some effects in mouse hepatocarcinoma cell lines with different lymphatic metastasis potentials. Through data from TCGA and GEO database analysis, we speculated that miR-330-3p might be a tumor promoter, while EREG could be a tumor suppressor in BC. MiR-330-3p was upregulated, while lnc021545 and EREG were downregulated in 50 BC tissues. MiR-330-3p advanced the metastatic behaviors of BC cells, whereas lnc021545 and EREG resulted in the opposite effects. The three molecules' expressions were correlated respectively and showed that miR-330-3p targeted lnc021545 and EREG to affect their expressions. Lnc021545/miR-330-3p axis affected BC metastasis by regulating EREG in epithelial-to-mesenchymal transition. In 50 BC patients, these three molecules and their cooperation are associated with aggressive tumor phenotypes, patient outcomes, and trastuzumab therapy. We finally discovered that lnc021545, miR-330-3p, and EREG formed a multi-gene co-regulation system that affected the metastasis of BC and the cooperation reflects the synergistic effects of the three molecules, recommending that their cooperation may provide a more accurate index for anti-metastasis therapeutic and prognostic evaluation of BC.

TRPV1: A promising therapeutic target for skin aging and inflammatory skin diseases.

TRPV1 is a non-selective channel receptor widely expressed in skin tissues, including keratinocytes, peripheral sensory nerve fibers and immune cells. It is activated by a variety of exogenous or endogenous inflammatory mediators, triggering neuropeptide release and neurogenic inflammatory response. Previous studies have shown that TRPV1 is closely related to the occurrence and/or development of skin aging and various chronic inflammatory skin diseases, such as psoriasis, atopic dermatitis, rosacea, herpes zoster, allergic contact dermatitis and prurigo nodularis. This review summarizes the structure of the TRPV1 channel and discusses the expression of TRPV1 in the skin as well as its role of TRPV1 in skin aging and inflammatory skin diseases.

Circulating GDF-15 in relation to the progression and prognosis of chronic kidney disease: A systematic review and dose-response meta-analysis.

BACKGROUND: Patients with chronic kidney disease (CKD) typically exhibit circulating growth differentiation factor-15 (GDF-15) at high levels. This meta-analysis aimed to evaluate the potential value of GDF-15 in predicting CKD progression and prognosis. Furthermore, when sufficient information was provided, the dose-response correlation was studied. METHODS: Studies were searched in Web of Science, Embase, and PubMed from inception until November 2022. By using random- or fixed-effects models, the pooled effect size was estimated in accordance with heterogeneity in existing research. RESULTS: This study covered 14 studies from 12 articles with 7813 subjects participating in the research. CKD patients in the top GDF-15 tertile had notably higher risks of CKD progression (HR 2.60, 95% CI 2.06-3.27), all-cause mortality (HR 2.05, 95% CI 1.44-2.92), cardiovascular mortality (HR 2.82, 95% CI 1.85-4.30), and cardiovascular events (HR 2.74, 95% CI 2.21-3.40), as compared to CKD patients in the bottom tertile. In the dose-response study, the risks for CKD progression, all-cause death, cardiovascular death, and cardiovascular events were increased by 31% (HR 1.31, 95% CI 1.06-1.61), 44% (HR 1.44, 95% CI 1.08-1.92), 67% (HR 1.67, 95% CI 1.37-2.03), and 55% (HR 1.55, 95% CI 1.31-1.83), respectively, with per 1 ng/mL increase in GDF-15. The positive linear correlations between GDF-15 and CKD progression and prognosis in a certain GDF-15 concentration range of approximately 0-3 ng/mL were indicated by the dose-response curve. CONCLUSIONS: Circulating GDF-15 independently predicted CKD progression and worse prognosis; however, the predicted correlations may fall into a specific range of GDF-15 concentrations.

RBM4 regulates cellular senescence via miR1244/SERPINE1 axis.

Cellular senescence serves as a powerful tumor suppressing mechanism that inhibits the proliferation of cancer cells bearing oncogenic mutations at the initial stage of cancer development. RNA-binding proteins (RBPs) play important roles in cancer progression and treatment through distinct functions. However, functions and mechanisms of RNA binding proteins in regulating senescence remain elusive. Here we reported that the RNA binding protein RBM4 contributed to cellular senescence. Depletion of RBM4 induced senescence in different types of cells, including multiple cancer cells. Meanwhile, RBM4 ablation inhibited cancer cell progression both in vitro and in vivo. Specifically, knockdown of RBM4 significantly increased the level of SERPINE1, a known promoter of senescence, thereby inducing the senescence of lung cancer cells. Mechanistically, miR-1244 bound to the 3'-UTR of SERPINE1 to suppress its expression, whereas depletion of RBM4 reduced the level of miR-1244 by promoting the degradation of primary miR-1244 transcripts (pri-miR1244), thus increasing the expression of SERPINE1 and inducing subsequent senescence. Moreover, either SERPINE1 inhibitor or miR-1244 mimics attenuated the RBM4 depletion-induced senescence. Altogether, our study revealed a novel mechanism of RBM4 in the regulation of cancer progression through controlling senescence, providing a new avenue for targeting RBM4 in cancer therapeutics.

Butyrate ameliorates colorectal cancer through regulating intestinal microecological disorders.

The occurrence and progression of colorectal cancer (CRC) are closely related to intestinal microecological disorders. Butyrate, the representative of short chain fatty acids, possess anti-inflammatory and antioxidant effects, and its antitumor effect has been gradually paid attention to. In this study, azoxymethane/dextran sodium sulfate induced mouse CRC model was used to explore the role and mechanism of butyrate in regulating colon cancer and its intestinal microecological balance. Outcomes exhibited that butyrate alleviated weight loss, disease activity index, and survival in CRC mice and inhibited tumor number and progression. Further research revealed that butyrate restrained the aggregation of harmful while promoting the colonization of beneficial flora, such as Actinobacteriota, Bifidobacteriales and Muribaculacea through 16S rDNA sequence analysis. This study confirmed that butyrate can ameliorate CRC by repairing intestinal microecology, providing ideas and evidence for chemical prophylactic agents, such as butyrate to remedy tumors and regulate tumor microbiota.

Complete mitochondrial genomes of Thyreophagus entomophagus and Acarus siro (Sarcoptiformes: Astigmatina) provide insight into mitogenome features, evolution, and phylogeny among Acaroidea mites.

Mites from the Acaroidea (Sarcoptiformes: Astigmatina) are important pests of various stored products, posing potential threats to preserved foods. In addition, mites can cause allergic diseases. Complete mitochondrial genomes (mitogenomes) are valuable resources for different research fields, including comparative genomics, molecular evolutionary analysis, and phylogenetic inference. We sequenced and annotated the complete mitogenomes of Thyreophagus entomophagus and Acarus siro. A comparative analysis was made between mitogenomic sequences from 10 species representing nine genera within Acaroidea. The mitogenomes of T. entomophagus and A. siro contained 37 genes, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs), and one control region. In Acaroidea species, mitogenomes have highly conserved gene size and order, and codon usage. Among Acaroidea mites, most PCGs were found to be under purifying selection, implying that most PCGs might have evolved slowly. Our findings showed that nad4 evolved most rapidly, whereas cox1 and cox3 evolved most slowly. The evolutionary rates of Acaroidea vary considerably across families. In addition, selection analyses were also performed in 23 astigmatid mite species, and the evolutionary rate of the same genes in different superfamilies exhibited large differences. Phylogenetic results are mostly consistent with those identified by previous phylogenetic studies on astigmatid mites. The monophyly of Acaroidea was rejected, and the Suidasiidae and Lardoglyphidae appeared to deviate from the Acaroidea branch. Our research proposed a review of the current Acaroidea classification system.

WTAP promotes oesophageal squamous cell carcinoma development by decreasing CPSF4 expression in an m6A-dependent manner.

m6A is a widespread RNA modification. However, the mechanism through which m6A regulated the progress of oesophageal squamous cell carcinoma (ESCC) remains undetermined. The levels and prognosis of WTAP were analysed using an ESCC tissue microarray (87 ESCC and 44 paracancerous tissues). TCGA and Oncolnc databases validate WTAP expression and prognosis. CCK8, colony formation (CF), wound healing, transwell cell invasion (CI), and migration (CM) assays were employed for the detection of the biological impacts of WTAP. Expression of tumour stemness-related genes was assessed via qRT-PCR and western blotting. The m6A RNA methylation (m6AMe) quantitative kit was employed for cellular methylation level detection. Arraystar m6A-mRNA and lncRNA epitranscriptomic microarray analyses were used to screen low methylation, high expression, and prognosis-related candidate gene CPSF4. KEGG enrichment analysis was used to screen the downstream signalling pathways of CPSF4. WTAP, a methyltransferase "writer", was markedly enhanced in ESCC and was strongly correlated with poor patient outcome. WTAP knockdown inhibited the cell proliferation (CP), CI, CM, and stemness of ESCC cells in vitro and reduced the overall m6A modification (m6AMo) percentage of ESCC cells. CPSF4 is a target of WTAP-based m6AMo. WTAP-based m6AMo of CPSF4 transcript reduced the stability of CPSF4 by relying on YTHDF2. We identified the significant role of WTAP-catalysed m6AMo in ESCC tumourigenesis, wherein it facilitates ESCC tumour growth and metastasis through decreasing CPSF4 expression in an m6A-dependent manner.

Low Testosterone Level and Risk of Adverse Clinical Events among Male Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Cohort Studies.

The phenomenon of low testosterone level is extremely common in male patients with chronic kidney diseases (CKDs). This meta-analysis aimed to evaluate whether the low circulating testosterone could independently predict adverse outcomes among male patients with chronic kidney diseases (CKDs). The data till May 2022 were systematically searched from Pubmed, Web of Science, and Embase from inception. Studies meeting the PICOS (population, intervention/exposure, control/comparison, outcomes, and study design) principles were included in this meta-analysis. Study-specific effect estimates were pooled using fixed-effects (I 2 > 50%) or random-effects models (I 2 < 50%). Ultimately, 9 cohort studies covering 5331 patients with CKDs were involved in this meta-analysis. The results suggested that per 1-standard deviation (SD) decrease in total testosterone independently increased the risk of all-cause mortality by 27% [hazard risk (HR) 1.27, 95% confidence interval (CI) 1.16-1.38], cardiovascular mortality by 100% (HR 2.00, 95% CI 1.39-2.86), cardiovascular events by 20% (HR 1.20, 95% CI 1.04-1.39), and infectious events by 41% (HR 1.41, 95% CI 1.08-1.84). Besides, with per 1-SD decrease in free testosterone, the risk of overall adverse events increased by 66% (HR 1.66, 95% CI 1.34-2.05). Stratified analyses indicated that the negative relationship of the total testosterone with all-cause death risk was independent of factors involving age, race, body mass index, diabetes, hypertension, C-reactive protein, creatinine, and sex hormone binding globulin. In conclusion, it was identified that low endogenous testosterone could serve as an independent predictor of adverse clinical events among male patients with CKDs.

The homeostatic malfunction of a novel feedback pathway formed by lncRNA021545, miR-330-3p and epiregulin contributes in hepatocarcinoma progression via mediating epithelial-mesenchymal transition.

A better understanding of tumor metastasis is urgently required for the treatment and prognosis of hepatocarcinoma patients. Current work contributes a novel ceRNA feedback regulation pathway composed of epiregulin (EREG), microRNA-330-3p (miR-330-3p) and long non-coding RNA 021545 (lncRNA021545) in regulating hepatocarcinoma malignancy via epithelial-mesenchymal transition (EMT) process. Closely correlated, the deficiencies of EREG and lncRNA021545 and the overexpression of miR-330-3p were involved in the clinical progression of hepatocarcinoma. In vitro results showed that 1) lncRNA021545 downregulation promoted, 2) miR-330-3p dysexpression positively correlated, and 3) EREG dysexpression reversely correlated with the migratory and invasive properties of hepatocarcinoma HCCLM3 and Huh7 cell lines. By directly binding to EREG and lncRNA021545, miR-330-3p expression change reversely correlated with their expressions in HCCLM3 and Huh7 cells, which was also confirmed in primary tumors from HCCLM3-xenograft mice in responding to miR-330-3p change. LncRNA021545 and EREG positively regulated each other, and lncRNA021545 negatively regulated miR-330-3p, while, EREG dysregulation unchanged miR-330-3p expression in hepatocarcinoma cells. Furthermore, systemic in vitro cellular characterizations showed that the malfunctions of the three molecules mediated the invasiveness of hepatocarcinoma cells via EMT process through affecting the expressions of E-cadherin, N-cadherin, vimentin, snail and slug, which was further confirmed by in vivo miR-330-3p promotion on the tumorigenicity and metastasis of HCCLM3 bearing nude mice and by in vitro miR-330-3p promotion on the migration and invasion of hepatocarcinoma cells to be antagonized by EREG overexpression through acting on EMT process. Our work indicates, that by forming a circuit signaling feedback pathway, the homeostatic expressions of lncRNA021545, miR-330-3p and EREG are important in liver health. Its collapse resulted from the downregulations of lncRNA021545 and EREG together with miR-330-3p overexpression promote hepatocarcinoma progression by enhancing the invasiveness of tumor cells through EMT activation. These discoveries suggest that miR-330-3p/lncRNA021545/EREG axis plays a critical role in hepatocarcinoma progression and as a candidate for its treatment.

Transient Receptor Potential Vanilloid1 (TRPV1) Channel Opens Sesame of T Cell Responses and T Cell-Mediated Inflammatory Diseases.

Transient receptor potential vanilloid1 (TRPV1) was primarily expressed in sensory neurons, and could be activated by various physical and chemical factors, resulting in the flow of extracellular Ca2+ into cells. Accumulating data suggest that the TRPV1 is expressed in some immune cells and is a novel regulator of the immune system. In this review, we highlight the structure and biological features of TRPV1 channel. We also summarize recent findings on its role in modulating T cell activation and differentiation as well as its protective effect in T cell-mediated inflammatory diseases and potential mechanisms.

Circulating Trimethylamine-N-Oxide and Risk of All-Cause and Cardiovascular Mortality in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Background: Trimethylamine-N-oxide (TMAO) is expected to be a prognostic biomarker among patients suffering from chronic kidney disease (CKD). However, investigations on the association between TMAO and CKD prognosis are conflicting. In the present article, we aimed to assess the relationship of circulating TMAO with the risk of all-cause and cardiovascular mortality among CKD patients by a meta-analysis. Methods: Data were collected from PubMed, EMBASE, and Web of Science for systematically searching related literature (last update: February 2022). The multivariable-adjusted hazard risks (HR) and their 95% confidence intervals (CI) were pooled using random effects models. Results: Eleven prospective cohort studies covering 7,899 CKD patients were enrolled in this meta-analysis. When comparing individuals in the top and bottom baseline TMAO levels thirds, the multivariate adjusted pooled HR was 1.29 (95% CI 1.11-1.51, P = 0.001) for all-cause mortality, and 1.45 (95% CI 1.01-2.09, P = 0.043) for cardiovascular death. For continuous variables, per 1 unit increase of circulating TMAO levels was associated with a 3% higher all-cause mortality (HR 1.03, 95% CI 1.00-1.06, P = 0.032), but not significantly associated with cardiovascular death (HR 1.08, 95% CI 0.92-1.27, P = 0.346). Stratified analyses revealed that the positive relationship between TMAO and all-cause mortality remained significant after adjusting for diabetes, blood pressure, blood lipid, renal function, or inflammatory parameters. Conclusion: Higher circulating TMAO was associated with an increased mortality risk among patients with CKD, and this relationship may be dependent on TMAO dose and independent of renal function, inflammation, diabetes, hypertension, and dyslipidemia. Systematic Review Registration: [https://www.INPLASY.COM], identifier [INPLASY2021100049].

ETV6 Regulates Hemin-Induced Erythroid Differentiation of K562 Cells through Mediating the Raf/MEK/ERK Pathway.

As a member of transcription factor E-Twenty Six (ETS) family, ETS variant 6 (ETV6) plays significant role in hematopoiesis and embryonic development. ETV6 dysexpression also involved in the occurrence, development and progression of cancers and leukemia. In current work, we hypothesized that ETV6 plays a role in erythroid differentiation of chronic myeloid leukemia (CML). We found the protein expression level of ETV6 was significantly upregulated during hemin-induced erythroid differentiation of K562 cells. Moreover, overexpression of ETV6 inhibited erythroid differentiation in hemin-induced K562 cells with decreased numbers of benzidine-positive cells and decreased expression levels of erythroid differentiation specific markers glycophorin (GPA), CD71, hemoglobin A (HBA), α-globin, γ-globin and ε-globin. Conversely, ETV6 knockdown promoted erythroid differentiation in hemin-induced K562 cells. Furthermore, ETV6 expression level slightly positively with the proliferation capacity of K562 cells treated with hemin. Mechanistically, ETV6 overexpression inhibited fibrosarcoma/mitogen activated extracellular signal-regulated kinase/extracellular regulated protein kinase (Raf/MEK/ERK) pathway, ETV6 knockdown activated the Raf/MEK/ERK pathway. Collectively, the current work demonstrates that ETV6 plays an inhibitory role in the regulation of K562 cell erythroid differentiation via Raf/MEK/ERK pathway, it would be a potentially therapeutic target for dyserythropoiesis.