Therapeutic potential of Pien Tze Huang in colitis-associated colorectal cancer: mechanistic insights from a mouse model.

BACKGROUND: Pien Tze Huang (PZH), a traditional Chinese medicine formulation, is recognized for its therapeutic effect on colitis and colorectal cancer. However, its protective role and underlying mechanism in colitis-associated colorectal cancer (CAC) remain to be elucidated. METHODS: A CAC mouse model was established using AOM/DSS. Twenty mice were randomly divided into four groups (n = 5/group): Control, PZH, AOM/DSS, and AOM/DSS + PZH groups. Mice in the PZH and AOM/DSS + PZH group were orally administered PZH (250 mg/kg/d) from the first day of experiment, while the control and AOM/DSS group received an equivalent volume of distilled water. Parameters such as body weight, disease activity index (DAI), colon weight, colon length, colon histomorphology, intestinal tumor formation, serum concentrations of pro-inflammatory cytokines, proliferation and apoptosis in colon tissue were assessed. RNA sequencing was employed to identify the differentially expressed transcripts (DETs) in colonic tissues and related signaling pathways. Wnt/ß-Catenin Pathway-Related genes in colon tissue were detected by QPCR and immunohistochemistry (IHC). RESULTS: PZH significantly attenuated AOM/DSS-induced weight loss, DAI elevation, colonic weight gain, colon shortening, histological damage, and intestinal tumor formation in mice. PZH also notably decreased serum concentration of IL-6, IL-1ß, and TNF-α. Furthermore, PZH inhibited cell proliferation and promote apoptosis in tumor tissues. RNA-seq and KEGG analysis revealed key pathways influenced by PZH, including Wnt/ß-catenin signaling pathway. IHC staining confirmed that PZH suppressed the expression of ß-catenin, cyclin D1 and c-Myc in colonic tissues. CONCLUSIONS: PZH ameliorates AOM/DSS-induced CAC in mice by suppressing the activation of Wnt/ß-catenin signaling pathway.

Qing Hua Chang Yin ameliorates chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and the NF-κB signalling pathway.

CONTEXT: Ulcerative colitis has been clinically treated with Qing Hua Chang Yin (QHCY), a traditional Chinese medicine formula. However, its precise mechanisms in mitigating chronic colitis are largely uncharted. OBJECTIVE: To elucidate the therapeutic efficiency of QHCY on chronic colitis and explore its underlying molecular mechanisms. MATERIALS AND METHODS: A total ion chromatogram fingerprint of QHCY was analysed. Chronic colitis was induced in male C57BL/6 mice using 2% dextran sodium sulphate (DSS) over 49 days. Mice were divided into control, DSS, DSS + QHCY (0.8, 1.6 and 3.2 g/kg/d dose, respectively) and DSS + mesalazine (0.2 g/kg/d) groups (n = 6). Mice were intragastrically administered QHCY or mesalazine for 49 days. The changes of disease activity index (DAI), colon length, colon histomorphology and serum pro-inflammatory factors in mice were observed. RNA sequencing was utilized to identify the differentially expressed transcripts (DETs) in colonic tissues and the associated signalling pathways. The expression of endoplasmic reticulum (ER) stress-related protein and NF-κB signalling pathway-related proteins in colonic tissues was detected by immunohistochemistry staining. RESULTS: Forty-seven compounds were identified in QHCY. Compared with the DSS group, QHCY significantly improved symptoms of chronic colitis like DAI increase, weight loss, colon shortening and histological damage. It notably reduced serum levels of IL-6, IL-1ß and TNF-α. QHCY suppressed the activation of PERK-ATF4-CHOP pathway of ER stress and NF-κB signalling pathways in colonic tissues. DISCUSSION AND CONCLUSIONS: The findings in this study provide novel insights into the potential of QHCY in treating chronic colitis patients.

Research Progress of Long Non-Coding RNA in Tumor Drug Resistance: A New Paradigm.

In the past few decades, chemotherapy has been one of the most effective cancer treatment options. Drug resistance is currently one of the greatest obstacles to effective cancer treatment. Even though drug resistance mechanisms have been extensively investigated, they have not been fully elucidated. Recent genome-wide investigations have revealed the existence of a substantial quantity of long non-coding RNAs (lncRNAs) transcribed from the human genome, which actively participate in numerous biological processes, such as transcription, splicing, epigenetics, the cell cycle, cell differentiation, development, pluripotency, immune microenvironment. The abnormal expression of lncRNA is considered a contributing factor to the drug resistance. Furthermore, drug resistance may be influenced by genetic and epigenetic variations, as well as individual differences in patient treatment response, attributable to polymorphisms in metabolic enzyme genes. This review focuses on the mechanism of lncRNAs resistance to target drugs in the study of tumors with high mortality, aiming to establish a theoretical foundation for targeted therapy.

Identification of a membrane-associated element (MAE) in the C-terminal region of SARS-CoV-2 nsp6 that is essential for viral replication.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has rapidly spread worldwide since its emergence in late 2019. Its ongoing evolution poses challenges for antiviral drug development. Coronavirus nsp6, a multiple-spanning transmembrane protein, participates in the biogenesis of the viral replication complex, which accommodates the viral replication-transcription complex. The roles of its structural domains in viral replication are not well studied. Herein, we predicted the structure of the SARS-CoV-2 nsp6 protein using AlphaFold2 and identified a highly folded C-terminal region (nsp6C) downstream of the transmembrane helices. The enhanced green fluorescent protein (EGFP)-fused nsp6C was found to cluster in the cytoplasm and associate with membranes. Functional mapping identified a minimal membrane-associated element (MAE) as the region from amino acids 237 to 276 (LGV-KLL), which is mainly composed of the α-helix H1 and the α-helix H2; the latter exhibits characteristics of an amphipathic helix (AH). Mutagenesis studies and membrane flotation experiments demonstrate that AH-like H2 is required for MAE-mediated membrane association. This MAE was functionally conserved across MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63, all capable of mediating membrane association. In a SARS-CoV-2 replicon system, mutagenesis studies of H2 and replacements of H1 and H2 with their homologous counterparts demonstrated requirements of residues on both sides of the H2 and properly paired H1-H2 for MAE-mediated membrane association and viral replication. Notably, mutations I266A and K274A significantly attenuated viral replication without dramatically affecting membrane association, suggesting a dual role of the MAE in viral replication: mediating membrane association as well as participating in protein-protein interactions.IMPORTANCESevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) assembles a double-membrane vesicle (DMV) by the viral non-structural proteins for viral replication. Understanding the mechanisms of the DMV assembly is of paramount importance for antiviral development. Nsp6, a multiple-spanning transmembrane protein, plays an important role in the DMV biogenesis. Herein, we predicted the nsp6 structure of SARS-CoV-2 and other human coronaviruses using AlphaFold2 and identified a putative membrane-associated element (MAE) in the highly conserved C-terminal regions of nsp6. Experimentally, we verified a functionally conserved minimal MAE composed of two α-helices, the H1, and the amphipathic helix-like H2. Mutagenesis studies confirmed the requirement of H2 for MAE-mediated membrane association and viral replication and demonstrated a dual role of the MAE in viral replication, by mediating membrane association and participating in residue-specific interactions. This functionally conserved MAE may serve as a novel anti-viral target.

Integration analysis of ATAC-seq and RNA-seq provides insight into fatty acid biosynthesis in Schizochytrium limacinum under nitrogen limitation stress.

BACKGROUND: Schizochytrium limacinum holds significant value utilized in the industrial-scale synthesis of natural DHA. Nitrogen-limited treatment can effectively increase the content of fatty acids and DHA, but there is currently no research on chromatin accessibility during the process of transcript regulation. The objective of this research was to delve into the workings of fatty acid production in S. limacinum by examining the accessibility of promoters and profiling gene expressions. RESULTS: Results showed that differentially accessible chromatin regions (DARs)-associated genes were enriched in fatty acid metabolism, signal transduction mechanisms, and energy production. By identifying and annotating DARs-associated motifs, the study obtained 54 target transcription factor classes, including BPC, RAMOSA1, SPI1, MYC, and MYB families. Transcriptomics results revealed that several differentially expressed genes (DEGs), including SlFAD2, SlALDH, SlCAS1, SlNSDHL, and SlDGKI, are directly related to the biosynthesis of fatty acids, meanwhile, SlRPS6KA, SlCAMK1, SlMYB3R1, and SlMYB3R5 serve as transcription factors that could potentially influence the regulation of fatty acid production. In the integration analysis of DARs and ATAC-seq, 13 genes were identified, which were shared by both DEGs and DARs-associated genes, including SlCAKM, SlRP2, SlSHOC2, SlTN, SlSGK2, SlHMP, SlOGT, SlclpB, and SlDNAAF3. CONCLUSIONS: SlCAKM may act as a negative regulator of fatty acid and DHA synthesis, while SlSGK2 may act as a positive regulator, which requires further study in the future. These insights enhance our comprehension of the processes underlying fatty acid and DHA production in S. limacinum. They also supply a foundational theoretical framework and practical assistance for the development of strains rich in fatty acids and DHA.

A planar tracking strategy based on multiple-interpretable improved PPO algorithm with few-shot technique.

Facing to a planar tracking problem, a multiple-interpretable improved Proximal Policy Optimization (PPO) algorithm with few-shot technique is proposed, namely F-GBQ-PPO. Compared with the normal PPO, the main improvements of F-GBQ-PPO are to increase the interpretability, and reduce the consumption for real interaction samples. Considering to increase incomprehensibility of a tracking policy, three levels of interpretabilities has been studied, including the perceptual, logical and mathematical interpretabilities. Detailly speaking, it is realized through introducing a guided policy based on Apollonius circle, a hybrid exploration policy based on biological motions, and the update of external parameters based on quantum genetic algorithm. Besides, to deal with the potential lack of real interaction samples in real applications, a few-shot technique is contained in the algorithm, which mainly generate fake samples through a multi-dimension Gaussian process. By mixing fake samples with real ones in a certain proportion, the demand for real samples can be reduced.

Pien Tze Huang Inhibits Proliferation of Colorectal Cancer Cells through Suppressing PNO1 Expression and Activating p53/p21 Signaling Pathway.

OBJECTIVE: To explore the regulatory effect of Pien Tze Huang (PZH) on targeting partner of NOB1 (PNO1) and it's down-stream mediators in colorectal cancer (CRC) cells. METHODS: Quantitative polymerase chain reaction was performed to determine mRNA levels of PNO1, TP53, and CDKN1A. Western blotting was performed to determine protein levels of PNO1, p53, and p21. HCT-8 cells were transduced with a lentivirus over-expressing PNO1. Colony formation assay was used to detect cell survival in PNO1 overexpression of HCT-8 cells after PZH treatment. Cell-cycle distribution, cell viability and cell apoptosis were performed to identify the effect of PNO1 overexpression on cell proliferation and apoptosis of HCT-8 cells after PZH treatment. Xenograft BALB/c nude mice bearing HCT116 cells transduced with sh-PNO1 or sh-Ctrl lentivirus were evaluated. Western blot assay was performed to detect PNO1, p53, p21 and PCNA expression in tumor sections. Terminal deoxynucleotidyl transferase dUTP nick end labling (TUNEL) assay was used to determine the apoptotic cells in tissues. RESULTS: PZH treatment decreased cell viability, down-regulated PNO1 expression, and up-regulated p53 and p21 expressions in HCT-8 cells (P<0.05). PNO1 overexpression attenuated the effects of PZH treatment, including the expression of p53 and p21, cell growth, cell viability, cell cycle arrest and cell apoptosis in vitro (P<0.05). PNO1 knockdown eliminated the effects of PZH treatment on tumor growth, inhibiting cell proliferation inhibition and apoptosis induction in vivo (P<0.05). Similarly, PNO1 knockdown attenuated the effects of PZH treatment on the down-regulation of PNO1 and up-regulation of p53 and p21 in vivo (P<0.05). CONCLUSION: The mechanism by which PZH induces its CRC anti-proliferative effect is at least in part by regulating the expression of PNO1 and its downstream targets p53 and p21.

Qing Hua Chang Yin alleviates chronic colitis of mice by protecting intestinal barrier function and improving colonic microflora.

Background: Qing Hua Chang Yin (QHCY) is a famous formula of traditional Chinese medicine (TCM) and has been proven to have protective effect on ulcerative colitis. However, its protective effect and potential therapeutic mechanisms in chronic colitis remain unclear. The purpose of this study is to explore the effects and underlying mechanisms of QHCY on dextran sulfate sodium (DSS)-induced chronic colitis mice model. Methods: The chronic colitis model was established by administration of 2% DSS for three consecutive cycles of 7 days with two intervals of 14 days for recovery by drinking water. The experiment lasted 49 days. The DSS + QHCY group received QHCY administration by oral gavage at doses of 1.6 g/kg/d, DSS + Mesalazine group was administrated Mesalazine by oral gavage at doses of 0.2 g/kg/d. The control and DSS group were given equal volume of distilled water. The body weight, stool consistency and blood in stool were monitored every 2 days. The disease activity index (DAI) was calculated. The colon length was measured after the mice were sacrificed. The histomorphology of colonic tissues was checked by the HE and PAS staining. Immunohistochemistry was performed to detect the expressions of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), tight junction proteins (ZO-1, occludin) and Mucin2 (MUC2). 16S rRNA sequencing analysis was conducted to study the diversity and abundance of gut microbiota changes. Results: QHCY treatment not only significantly attenuated DSS-induced the weight loss, DAI score increase, colon shortening and histological damage in mice, but also decreased the expression of pro-inflammatory cytokines in colonic tissues and increased the expression of ZO-1, occludin, and MUC2. Furthermore, QHCY enhanced the diversity of gut microbes and regulated the structure and composition of intestinal microflora in mice with chronic colitis. Conclusion: QHCY has a therapeutic effect on a murine model of chronic colitis. It can effectively reduce the clinical and pathological manifestations of colitis and prevent alterations in the gut microbiota.

Seasonal variation in diurnal blood pressure pattern.

AIMS: To explore the relationship between diurnal blood pressure (BP) pattern and season. METHODS: A total of 6765 eligible patients (average age 57.35 ± 15.53 years; male 51.8%; hypertensives 68.8%) from 1 October 2016 to 6 April 2022 were enrolled, who were divided into four dipper groups, dipper, non-dipper, riser, and extreme-dipper, according to the diurnal BP pattern calculated using their ambulatory BP monitoring data. The season which the patient was in was determined by the time of ambulatory BP monitoring examination. RESULTS: Among the 6765 patients, 2042 (31.18%) were grouped into dipper, 380 (5.6%) into extreme-dipper, 1498 (22.1%) into riser and 2845 (42.1%) into non-dipper. Only the dipper subjects showed age difference among seasons, with the average age significantly lower in winter. There was no seasonal difference in age for the other types. No seasonal difference was revealed in gender, BMI, hypertension or not. Diurnal BP patterns significantly differed among seasons (P < .001). Post hoc tests with Bonferroni correction indicated the significantly different diurnal BP pattern between any two seasons (P < .001), but not between spring and autumn (P = .257), and the significance of the P value was assessed at 0.008 (0.05/6) after Bonferroni correction. Multinomial logistic regression suggested season as an independent contributor to diurnal BP pattern. CONCLUSION: Diurnal BP pattern is influenced by season.

Establishing Transition Metal Phosphides as Effective Sulfur Hosts in Lithium-Sulfur Batteries through the Triple Effect of "Confinement-Adsorption-Catalysis".

Structurally optimized transition metal phosphides are identified as a promising avenue for the commercialization of lithium-sulfur (Li-S) batteries. In this study, a CoP nanoparticle-doped hollow ordered mesoporous carbon sphere (CoP-OMCS) is developed as a S host with a "Confinement-Adsorption-Catalysis" triple effect for Li-S batteries. The Li-S batteries with CoP-OMCS/S cathode demonstrate excellent performance, delivering a discharge capacity of 1148 mAh g-1 at 0.5 C and good cycling stability with a low long-cycle capacity decay rate of 0.059% per cycle. Even at a high current density of 2 C after 200 cycles, a high specific discharge capacity of 524 mAh g-1 is maintained. Moreover, a reversible areal capacity of 6.56 mAh cm-2 is achieved after 100 cycles at 0.2 C, despite a high S loading of 6.8 mg cm-2 . Density functional theory (DFT) calculations show that CoP exhibits enhanced adsorption capacity for sulfur-containing substances. Additionally, the optimized electronic structure of CoP significantly reduces the energy barrier during the conversion of Li2 S4 (L) to Li2 S2 (S). In summary, this work provides a promising approach to optimize transition metal phosphide materials structurally and design cathodes for Li-S batteries.

Series of Halogen Engineered Ni(OH)2 Nanosheet for Pseudocapacitive Energy Storage with High Energy Density.

Ni(OH)2 nanosheet, acting as a potential active material for supercapacitors, commonly suffers from sluggish reaction kinetics and low intrinsic conductivity, which results in suboptimal energy density and long cycle life. Herein, a convenient electrochemical halogen functionalization strategy is applied for the preparation of mono/bihalogen engineered Ni(OH)2 electrode materials. The theoretical calculations and experimental results found that thanks to the extraordinarily high electronegativity, optimal reversibility, electronic conductivity, and reaction kinetics could be achieved through F functionalization . However, benefiting from the largest ionic radius, INi(OH)2 contributes the best specific capacity and morphology transformation, which is a new finding that distinguishes it from previous reports in the literature. The exploration of the interaction effect of halogens (F, INi(OH)2 , F, BrNi(OH)2 , and Cl, INi(OH)2 ) manifests that F, INi(OH)2 delivers a higher specific capacity of 200.6 mAh g-1 and an excellent rate capability of 58.2% due to the weaker electrostatic repulsion, abundant defect structure, and large layer spacing. Moreover, the F, INi(OH)2 //FeOOH@NrGO device achieves a high energy density of 97.4 Wh kg-1 and an extremely high power density of 32426.7 W kg-1 , as well as good cycling stability. This work develops a pioneering tactic for designing energy storage materials to meet various demands.

TAF15 exacerbates nonalcoholic steatohepatitis progression by regulating lipid metabolism and inflammation via FASN and p65 NF-κB.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) consists of a broad spectrum of conditions, and nonalcoholic steatohepatitis (NASH) is the advanced form of NAFLD. TAF15 is a DNA and RNA binding protein and is involved in crucial inflammatory signalling pathways. We aimed to investigate the role of TAF15 in the progression of NASH and the underlying molecular mechanism. METHODS: We generated mice with hepatocyte-specific knockdown and overexpression of TAF15 using a specific adeno-associated virus (AAV). NASH models were established by feeding mice high-fat and high-cholesterol diets and methionine- and choline-deficient diets. Cleavage under targets and tagmentation and dual-luciferase reporter assays were performed to investigate the effect of TAF15 on FASN transcription. Coimmunoprecipitation and immunofluorescence assays were conducted to explore the interaction of TAF15 and p65. In vitro coculture systems were established to study the interactions of hepatocytes, macrophages and HSCs. RESULTS: TAF15 was significantly increased in the livers of mouse NASH models and primary hepatocyte NASH model. Knockdown of TAF15 inhibited steatosis, inflammation and fibrosis, while overexpression of TAF15 promoted NASH phenotypes. Mechanistically, TAF15 bound directly to the promoter region of FASN to facilitate its expression, thereby promoting steatosis. Moreover, TAF15 interacted with p65 and activated the NF-κB signalling pathway, increasing the secretion of proinflammatory cytokines and triggering M1 macrophage polarization. Treatment with the FASN inhibitor orlistat partially reversed the phenotypes. CONCLUSIONS: These results suggested that TAF15 exacerbated NASH progression by regulating lipid metabolism and inflammation via transcriptional activation of FASN and interacting with p65 to activate the NF-κB signalling pathway.

Mesoporous Carbon-Based Materials for Enhancing the Performance of Lithium-Sulfur Batteries.

The most promising energy storage devices are lithium-sulfur batteries (LSBs), which offer a high theoretical energy density that is five times greater than that of lithium-ion batteries. However, there are still significant barriers to the commercialization of LSBs, and mesoporous carbon-based materials (MCBMs) have attracted much attention in solving LSBs' problems, due to their large specific surface area (SSA), high electrical conductivity, and other unique advantages. The synthesis of MCBMs and their applications in the anodes, cathodes, separators, and "two-in-one" hosts of LSBs are reviewed in this study. Most interestingly, we establish a systematic correlation between the structural characteristics of MCBMs and their electrochemical properties, offering recommendations for improving performance by altering the characteristics. Finally, the challenges and opportunities of LSBs under current policies are also clarified. This review provides ideas for the design of cathodes, anodes, and separators for LSBs, which could have a positive impact on the performance enhancement and commercialization of LSBs. The commercialization of high energy density secondary batteries is of great importance for the achievement of carbon neutrality and to meet the world's expanding energy demand.

Takotsubo cardiomyopathy induced by pheochromocytoma: a case report.

Pheochromocytoma presents various clinical manifestations and imprecise signs and symptoms. Along with other diseases, it is considered to be 'the great mimic'. This is the case of a 61-year-old man who on arrival presented with extreme chest pain accompanied by palpitations, and with a blood pressure of 91/65 mmHg. An echocardiogram showed an ST-segment elevation in the anterior leads. The cardiac troponin was 1.62 ng/ml, 50 times the upper limit of normal. Bedside, echocardiography revealed global hypokinesia of the left ventricle, with an ejection fraction of 37%. Because ST-segment elevation myocardial infarction-complicated cardiogenic shock was suspected, an emergency coronary angiography was performed. It showed no significant coronary artery stenosis, while left ventriculography demonstrated left ventricular hypokinesia. Sixteen days after admission, the patient suddenly presented with palpitations, headache and hypertension. A contrast-enhanced abdominal CT showed a mass in the left adrenal area. Pheochromocytoma-induced takotsubo cardiomyopathy was suspected.

Combined analysis of chromatin accessibility and gene expression profiles provide insight into Fucoxanthin biosynthesis in Isochrysis galbana under green light.

Isochrysis galbana, as a potential accumulator of fucoxanthin, has become a valuable material to develop functional foods for humans. Our previous research revealed that green light effectively promotes the accumulation of fucoxanthin in I. galbana, but there is little research on chromatin accessibility in the process of transcriptional regulation. This study was conducted to reveal the mechanism of fucoxanthin biosynthesis in I. galbana under green light by analyzing promoter accessibility and gene expression profiles. Differentially accessible chromatin regions (DARs)-associated genes were enriched in carotenoid biosynthesis and photosynthesis-antenna protein formation, including IgLHCA1, IgLHCA4, IgPDS, IgZ-ISO, IglcyB, IgZEP, and IgVDE. The motifs for the MYB family were also identified as candidates controlling metabolic regulation responses to green light culture of I. galbana, including IgMYB1, IgMYB2, IgMYB33, IgMYB42, IgMYB98, IgMYB118, and IgMYB119. The results of differential expression analysis and WGCNA showed that several genes or transcription factors (TFs) related to carotenoid metabolism and photosynthesis exhibited a higher expression level and were significantly upregulated in A-G5d compared with A-0d and A-W5d, including IgMYB98, IgLHCA1, IgLHCX2, IgLHCB4, and IgLHCB5. This suggests that upregulation of these genes by green light may be the key factor leading to fucoxanthin accumulation by regulating the photosynthesis-antenna protein pathway. An integrated analysis of ATAC-seq and RNA-seq showed that 3 (IgphoA, IgPKN1, IgOTC) of 34 DARs-associated genes displayed obvious changes in their chromatin regions in ATAC-seq data, suggesting that these genes specific for green light may play a key role in fucoxanthin biosynthesis in I. galbana through a complex regulatory network of multiple metabolic pathways interacting with each other. These findings will facilitate in-depth understanding the molecular regulation mechanisms of fucoxanthin in I. galbana and its role in response to green light regulation, providing technical support for the construction of high fucoxanthin content strains.

No evidence for a causal link between Helicobacter pylori infection and Irritable bowel syndrome: a Mendelian randomization study.

Background: Although clinical studies have revealed a potential link between Helicobacter pylori (H. pylori) infection and irritable bowel syndrome (IBS), the causal relationship between them remains unknown. The objective of this study was to investigate whether H. pylori infection is causally associated with IBS. Method: A two-sample Mendelian randomization (MR) analysis using the inverse variance weighted (IVW), weighted mode, weighted median and MR-Egger methods was performed. We used the publicly available summary statistics data sets of genome-wide association studies (GWAS) for H. pylori infection in individuals of European descent (case = 1,058, control = 3,625) as the exposure and a GWAS for non-cancer illness code self-reported: IBS (case = 10,939, control = 451,994) as the outcome. Results: We selected 10 single nucleotide polymorphisms at genome-wide significance from GWASs on H. pylori infection as the instrumental variables. The IVW, weighted mode, weighted median and MR-Egger methods all provided consistent evidence that suggests a lack of causal association between H. pylori and IBS. MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = -1e-04; P = 0.831). Cochran's Q-test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy. Conclusion: The results of MR analysis support that H. pylori infection may not be causally associated with an increased risk of IBS.

CCT6A knockdown suppresses osteosarcoma cell growth and Akt pathway activation in vitro.

We assessed the role of the protein-coding gene chaperonin-containing TCP1 subunit 6A (CCT6A) in osteosarcoma, as this is currently unknown. Using data from the R2 online genomic analysis and visualization application, we found that CCT6A messenger ribonucleic acid (RNA) expression is increased in osteosarcoma tissue and cells. Transfection of CCT6A small interfering RNA into cultured osteosarcoma cells revealed that CCT6A knockdown attenuates cell growth, cell viability, cell survival, and induced apoptosis and cell cycle progression at the G0/G1 phases. Moreover, CCT6A knockdown downregulated phospho-protein kinase B (p-Akt), cyclinD1 and B-cell lymphoma-2, whereas upregulated Bcl-2-associated X-protein expression. Thus, CCT6A knockdown inhibits cell proliferation, induces cell apoptosis, and suppresses the Akt pathway.

Endoplasmic reticulum-resident protein Sec62 drives colorectal cancer metastasis via MAPK/ATF2/UCA1 axis.

OBJECTIVE: Metastasis is responsible for the poor prognosis of patients with colorectal cancer (CRC), and the role of aberrant expression of endoplasmic reticulum (ER) receptors in tumour metastasis has not been fully elucidated. The aim of the study is to ensure the role of ER-resident protein Sec62 in CRC metastasis and illuminate associated molecular mechanisms. MATERIALS AND METHODS: Bioinformatics analysis, qRT-PCR, western blot and immunohistochemistry assays were performed to evaluate the expression level and clinical significance of Sec62 in CRC. The specific role of Sec62 in CRC was identified by a series of functional experiments. We conducted RNA sequencing and rescue experiments to analyse the differentially expressed genes and identified UCA1 as a novel pro-metastasis target of Sec62 in CRC. Besides, the efficacy of MAPK/JNK inhibitor or agonist on Sec62-mediated CRC metastasis was evaluated by trans-well and wound healing assays. Finally, luciferase reporter and ChIP assay were employed to further explore the potential mechanisms. RESULTS: The abnormally elevated expression of Sec62 predicted poor prognosis of CRC patients and facilitated malignant metastasis of CRC cells. Mechanistically, Sec62 enhanced UCA1 expression through activating MAPK/JNK signalling pathway. And the p-JNK activating ATF2 could transcriptionally regulate UCA1 expression. Furthermore, blocking or activating MAPK/JNK signalling with JNK inhibitor or agonist potently suppressed or enhanced Sec62 mediated CRC metastatic process. CONCLUSIONS: Our study reports for the first time that the Sec62/MAPK/ATF2 /UCA1 axis exists in CRC metastatic process, which could be a potential treatment target of metastatic CRC.

Corrigendum: Swimming attenuates muscle wasting and mediates multiple signaling pathways and metabolites in CT-26 bearing mice.

[This corrects the article DOI: 10.3389/fmolb.2021.812681.].

Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2.

Ferroptosis, a novel regulated cell death induced by iron-dependent lipid peroxidation, plays an important role in tumor development and drug resistance. Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumorigenesis remain elusive. Here we explored the transcriptomic profiles of lncRNAs in primary CRC tissues and corresponding paired adjacent non-tumor tissues by RNA-seq and found that LINC00239 was significantly overexpressed in colorectal cancer tissues. Abnormally high expression of LINC00239 predicts poorer survival and prognosis in colorectal cancer patients. Concurrently, we elucidated the role of LINC00239 as a tumor-promoting factor in CRC through in vitro functional studies and in vivo tumor xenograft models. Importantly, overexpression of LINC00239 decreased the anti-tumor activity of erastin and RSL3 by inhibiting ferroptosis. Collectively, these data suggest that LINC00239 plays a novel and indispensable role in ferroptosis by nucleotides 1-315 of LINC00239 to interact with the Kelch domain (Nrf2-binding site) of Keap1, inhibiting Nrf2 ubiquitination and increasing Nrf2 protein stability. Considering the recurrence and chemoresistance constitute the leading cause of death in colorectal cancer (CRC), ferroptosis induction may be a promising therapeutic strategy for CRC patients with low LINC00239 expression.