Xiezhuo Tiaozhi formula inhibits macrophage pyroptosis in the non-alcoholic fatty liver disease by targeting the SIRT1 pathway.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a challenging disease to interfere with and represents a potential long-term risk factor for hepatic fibrosis and liver cancer. The Xiezhuo Tiaozhi (XZTZ) formula, a water extract from crude herbs, has been widely used as an anti-NAFLD agent through clinical observation. However, the underlying pharmacological mechanisms of the XZTZ formula and its impact on the potential pathways against NAFLD have not been elucidated. PURPOSE: Our study aims to investigate the pharmacological effects and underlying regulatory mechanisms of the XZTZ formula to treat NAFLD. METHODS: The possible active components and pharmacological mechanisms of the XZTZ formula against NAFLD were identified using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and molecular docking. To further explore the potential mechanisms, forty-eight 6-week-old male C57BL/6 J mice were given individual attention with high-fat and high-sugar diet (HFHSD) or relevant control (Ctrl) diets for 16 weeks to successfully construct a NAFLD mouse model. Subsequently, the levels of serum biochemicals, pathological changes in the liver, and pyroptosis levels were assessed in mice to investigate the therapeutic effects of the XZTZ formula. Further, LPS-induced RAW264.7 cells and Immortalized Mouse Kupffer cells (ImKC) were used to verify the potential mechanisms of the XZTZ formula against NAFLD in vitro. RESULTS: We identified 7 chemical compounds and 2 potential therapeutic targets as plausible therapeutic points for the treatment of NAFLD using the XZTZ formula. Subsequent histopathological analysis revealed marked hepatic steatosis and lipid accumulation in the HFHSD mice liver, while conditions were effectively ameliorated by administration of the XZTZ formula. Additionally, our work demonstrated that the XZTZ formula could attenuate M1 polarization, promote M2 polarization, and suppress pyroptosis via the SIRT1 pathway in tissue samples. Moreover, validation performed through LPS-induced RAW264.7 and ImKC cells by showing that silencing SIRT1 weaken the effects of the XZTZ formula on relative pyroptosis affirmed that its role was associated with the SIRT1 pathway in macrophage. CONCLUSION: These findings suggest that the XZTZ formula alleviated hepatic steatosis and lipid accumulation in NAFLD mice. These ameliorations are associated with mechanisms involving the attenuation of M1 polarization, promotion of M2 polarization, and anti-pyroptosis effects through the SIRT1 pathway.

CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway.

CBLC (CBL proto-oncogene C) is an E3 ubiquitin protein ligase that plays a key role in cancers. However, the function and mechanism of CBLC in colorectal cancer (CRC) has not been fully elucidated. The aim of this study was to investigate the function of CBLC in CRC and its underlying molecular mechanism. High CBLC levels were certified in tumor tissues of CRC patients, and its expression was positively associated with TNM stage. Next, we explored the role of CBLC in CRC using gain or loss of function. For biological function analysis, CCK-8 cell proliferation, colony formation, flow cytometry, scratch, and transwell assays collectively suggested that CBLC overexpression promoted cell proliferation, cell cycle progression, migration and invasion. As observed, CBLC knockdown exhibited exactly opposite effects, resulting in impaired tumorigenicity in vitro. Xenograft studies displayed that CBLC overexpression accelerated tumor growth and promoted tumor metastasis to the lung, while the inhibitory effects of CBLC knockdown on tumorigenicity and metastasis ability of CRC cells was also confirmed. Furthermore, the molecular mechanism of CBLC in CRC was explored. CBLC induced the activation of ERK signaling pathway, further leading to its pro-tumor role. Notably, CBLC decreased ABI1 (Abelson interactor protein-1, a candidate tumor suppressor) protein levels through its ubiquitin ligase activity, while ABI1 upregulation abolished the effects of CBLC on the tumorigenesis of CRC. Taken together, these results demonstrate that CBLC acts as a tumor promoter in CRC through triggering the ubiquitination and degradation of ABI1 and activating the ERK signaling pathway. CBLC may be a potential novel target for CRC.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

MICDnet: Multimodal information processing networks for Crohn's disease diagnosis.

Crohn's disease (CD) is a chronic inflammatory disease with increasing incidence worldwide and unclear etiology. Its clinical manifestations vary depending on location, extent, and severity of the lesions. In order to diagnose Crohn's disease, medical professionals need to comprehensively analyze patients' multimodal examination data, which includes medical imaging such as colonoscopy, pathological, and text information from clinical records. The processes of multimodal data analysis require collaboration among medical professionals from different departments, which wastes a lot of time and human resources. Therefore, a multimodal medical assisted diagnosis system for Crohn's disease is particularly significant. Existing network frameworks find it hard to effectively capture multimodal patient data for diagnosis, and multimodal data for Crohn's disease is currently lacking. In addition,a combination of data from patients with similar symptoms could serve as an effective reference for disease diagnosis. Thus, we propose a multimodal information diagnosis network (MICDnet) to learn CD feature representations by integrating colonoscopy, pathology images and clinical texts. Specifically, MICDnet first preprocesses each modality data, then uses encoders to extract image and text features separately. After that, multimodal feature fusion is performed. Finally, CD classification and diagnosis are conducted based on the fused features. Under the authorization, we build a dataset of 136 hospitalized inspectors, with colonoscopy images of seven areas, pathology images, and clinical record text for each individual. Training MICDnet on this dataset shows that multimodal diagnosis can improve the diagnostic accuracy of CD, and the diagnostic performance of MICDnet is superior to other models.

Mucosal esophageal carcinoma following endoscopic submucosal dissection with giant gastric metastasis: A case report and review of literature.

BACKGROUND: Esophageal carcinoma is a highly aggressive digestive cancer responsible for a notable proportion of cancer-related deaths worldwide. Its elevated metastatic rate contributes to a poor prognosis in affected patients. In this case review, we aim to summarize the metastatic characteristics of intramural gastric metastasis (IGM) in mucosal esophageal squamous carcinoma. CASE SUMMARY: A 56-year-old man was admitted to our hospital because of a dry cough with an esophageal sensation for one year. Endoscopic examination revealed a 2.0 cm 1.0 cm, superficial esophageal squamous cell carcinoma, and the patient underwent endoscopic submucosal dissection (ESD). Fifteen months after ESD, positron emission tomography/computed tomography revealed that the metabolism of the stomach cardia wall had increased slightly. However, the mucosa of the gastric cardia was smooth under gastroendoscopy. Two years after ESD, endoscopic examination revealed a giant gastric cardia carcinoma, while the esophageal mucosa was smooth, and no advanced cancer was found. A biopsy of the gastric cardia indicated squamous-cell carcinoma. The patient received immunochemotherapy and radiotherapy for esophageal cancer for 8 mo and is currently under follow-up. CONCLUSION: Early-stage esophageal carcinoma with IGM is rare. Despite the ESD of the primary lesion, IGM may still occur and should be closely monitored after ESD.

Long noncoding RNA PSMA3-AS1 functions as a competing endogenous RNA to promote gastric cancer progression by regulating the miR-329-3p/ALDOA axis.

LncRNA PSMA3-AS1 functions as an oncogene in several cancers, including ovarian cancer, lung cancer, and colorectal cancer. However, its role in gastric cancer (GC) progression remains unclear. In this study, the levels of PSMA3-AS1, miR-329-3p, and aldolase A (ALDOA) in 20 paired human GC tissues and adjacent nontumorous tissues were measured by real-time PCR. GC cells were transfected with recombinant plasmid carrying full-length PSMA3-AS1 or shRNA targeting PSMA3-AS1. The stable transfectants were selected by G418. Then, the effects of PSMA3-AS1 knockdown or overexpression on GC progression in vitro and in vivo were evaluated. The results showed that PSMA3-AS1 was highly expressed in human GC tissues. Stable knockdown of PSMA3-AS1 significantly restrained proliferation/migration/invasion, enhanced cell apoptosis, and induced oxidative stress in vitro. Tumor growth and matrix metalloproteinase expression in tumor tissues were markedly inhibited, while oxidative stress was enhanced in nude mice after stable PSMA3-AS1 knockdown. Additionally, PSMA3-AS1 negatively regulated miR-329-3p while positively regulated ALDOA expression. MiR-329-3p directly targeted ALDOA-3'UTR. Interestingly, miR-329-3p knockdown or ALDOA overexpression partially attenuated the tumor-suppressive effects of PSMA3-AS1 knockdown. Conversely, PSMA3-AS1 overexpression exhibited the opposite effects. PSMA3-AS1 promoted GC progression by regulating the miR-329-3p/ALDOA axis. PSMA3-AS1 might serve as a promising and effective target for GC treatment.

Polygenic risk for termination of the 'healthspan' and its interactions with lifestyle factors: A prospective cohort study based on 288,359 participants.

OBJECTIVES: To investigate whether a polygenic risk score (PRS) and its interactions with lifestyle factors are associated with termination of the 'healthspan' (the number of years living without serious diseases or degeneration). DESIGN, EXPOSURES AND PARTICIPANTS: Death or the incidence of any of seven independent morbidities (cancer, congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, and diabetes) strongly associated with aging were considered to define the termination of the healthspan. A total of 288,359 healthy participants from the UK Biobank were included in this prospective cohort study to evaluate the associations between PRS, lifestyle, and healthspan. The PRS was generated by weighting 12 healthspan-related genetic loci, which and scores were then categorized into three groups in Cox regression models. A lifestyle index was developed that incorporated body mass index (BMI), alcohol consumption, diet, smoking, and physical activity, and these scores were also categorized into three groups. The risk of termination of the healthspan was calculated across the different PRS and lifestyle index groups using Cox regression models. Interactions were estimated with the marginal effect of lifestyle on the risk of termination of healthspan across values of the moderator PRS using kernel estimation. RESULTS: During an average follow-up of 9.83 years, 68,903 healthspan-termination events occurred. It was calculated that people with high polygenic risk could reduce their risk of healthspan termination by 40 % if they maintain a favorable lifestyle. The marginal effect of lifestyle on the risk of healthspan termination increased with growing genetic risk. Smoking and diet showed monotonic changes in opposite directions, while BMI, physical activity, and alcohol had a U-shaped interaction with genetic risk. CONCLUSIONS: Favorable lifestyle can attenuate the risk of termination of the healthspan, especially for people with high genetic risk. The improvement afforded by ideal lifestyle behaviors varies for each individual.

Endoscopic and pathological characteristics of de novo colorectal cancer: Retrospective cohort study.

BACKGROUND: Endoscopy has rapidly developed in recent years and has enabled further investigation into the origin and features of intestinal tumors. The small size and concealed position of these tumors make it difficult to distinguish them from nonneoplastic polyps and carcinoma in adenoma (CIA). The invasive depth and metastatic potential determine the operation regimen, which in turn affects the overall survival and distant prognosis. The previous studies have confirmed the malignant features and clinicopathological features of de novo colorectal cancer (CRC). AIM: To provide assistance for diagnosis and treatment, but the lack of a summary of endoscopic features and assessment of risk factors that differ from the CIA prompted us to conduct this retrospective study. METHODS: In total, 167 patients with small-sized CRCs diagnosed by endoscopy were reviewed. The patients diagnosed as advanced CRCs and other malignant cancers or chronic diseases that could affect distant outcomes were excluded. After screening, 63 cases were excluded, including 33 de novo and 30 CIA cases. Patient information, including their follow-up information, was obtained from an electronic His-system. The characteristics between two group and risk factors for invasion depth were analyzed with SPSS 25.0 software. RESULTS: Nearly half of the de novo CRCs were smaller than 1 cm (n = 16, 48.5%) and the majority were located in the distal colon (n = 26, 78.8%). The IIc type was the most common macroscopic type of de novo CRC. In a Pearson analysis, the differential degree, Sano, JNET, and Kudo types, surrounding mucosa, and chicken skin mucosa (CSM) were correlated with the invasion depth (P < 0.001). CSM was a significant risk factor for deep invasion and disturbed judgment of endoscopic ultrasound. A high degree of tumor budding and tumor-infiltrating lymphocytes are accompanied by malignancy. Finally, de novo CRCs have worse outcomes than CIA CRCs. CONCLUSION: This is the first comprehensive study to analyze the features of de novo CRCs to distinguish them from nonneoplastic polyps. It is also the first study paying attention to CSM invasive depth measurement. This study emphasizes the high metastatic potential of de novo CRCs and highlights the need for more research on this tumor type.

Oxygen-Vacancy-Rich Piezoelectric BiO2- x Nanosheets for Augmented Piezocatalytic, Sonothermal, and Enzymatic Therapies.

Piezocatalytic therapy is a new-emerging reactive oxygen species (ROS)-enabled therapeutic strategy that relies on built-in electric field and energy-band bending of piezoelectric materials activated by ultrasound (US) irradiation. Despite becoming a hot topic, material development and mechanism exploration are still underway. Herein, as-synthesized oxygen-vacancy-rich BiO2- x nanosheets (NSs) demonstrate outstanding piezoelectric properties. Under US, a piezo-potential of 0.25 V for BiO2- x NSs is sufficient to tilt the conduction band to be more negative than the redox potentials of O2 /• O2 - , • O2 - /H2 O2 , and H2 O2 /• OH, which initiates a cascade reaction for ROS generation. Moreover, the BiO2- x NSs exhibit peroxidase and oxidase-like activities to augment ROS production, especially in the H2 O2 -overexpressed tumor microenvironment. Density functional theory calculations show that the generated oxygen vacancies in BiO2- x NSs are favorable for H2 O2  adsorption and increasing the carrier density to produce ROS. Furthermore, the quick movement of electrons enables an excellent sonothermal effect, for example, rapid rise in temperature to nearly 65 °C upon US with low power (1.2 W cm-2 ) and short time (96 s). Therefore, this system realizes a multimode synergistic combination of piezocatalytic, enzymatic, and sonothermal therapies, providing a new direction for defect engineering-optimized piezoelectric materials for tumor therapy.

The Interaction Between Epigenetic Changes, EMT, and Exosomes in Predicting Metastasis of Colorectal Cancers (CRC).

Worldwide, colorectal cancer (CRC) ranks as the third most common malignancy, and the second most deadly with nearly one million attributable deaths in 2020. Metastatic disease is present in nearly 25% of newly diagnosed CRC, and despite advances in chemotherapy, less than 20% will remain alive at 5 years. Epigenetic change plays a key role in the epithelial-to-mesenchymal transition (EMT), which is a crucial phenotype for metastasis and mainly includes DNA methylation, non-coding RNAs (ncRNAs), and N 6-methyladenosine (m6A) RNA, seemingly valuable biomarkers in CRCs. For ncRNAs, there exists a "molecular sponge effect" between long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). The detection of exosomes is a novel method in CRC monitoring, especially for predicting metastasis. There is a close relationship between exosomes and EMT in CRCs. This review summarizes the close relationship between epigenetic changes and EMT in CRCs and emphasizes the crucial function of exosomes in regulating the EMT process.

The incidence of psoriasis among smokers and/or former smokers inflammatory bowel diseases patients treated with tumor necrosis factor antagonist: A systematic review and meta-analysis.

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) refer to the classic drugs to treat moderate-severe inflammatory bowel disease (IBD), which have been proven to be effective to control IBD. However, the side effects exerted by IFX and ADA should be monitored in therapies, especially the paradoxical reaction of the skin system (e.g., psoriasis). Psoriasis is recognized as the most common skin lesion, capable of significantly affecting the quality of patients' life. METHODS: This study searched literatures published in English language with the qualifications on PubMed, Embase, Web of Science, Google, and Geenmedical databases. Over 2 co-authors assessed the quality of the articles and extracted the data independently. The data acquired were statistically analyzed with the statistical software of Revman and Stata. RESULTS: The ADA Group achieved a higher incidence of psoriasis (odds ratio [OR] = 0.658, 95% confidence interval [CI] [0.471-0.919]); Females achieved a higher incidence of psoriasis than males (OR = 1.941, 95%CI [1.326-2.843], P < .05); Smoking up-regulated the incidence of psoriasis (OR = 1.679, 95%CI [1.237-2.279], P < .05); The interval of medication was over 1 year, and the interval of medication applying IFX was longer than that of the ADA Group; most cases could be relieved by using local hormone, phototherapy, or systemic hormone therapy under the strategy of biological agents. CONCLUSIONS: The frequency of reported in IBD exceeds those of other autoimmune diseases, and the ADA treatment for IBD is safer than IFX. Psoriasis is more common in females than in males. Smoking refers to one of risk factors of psoriasis.

Identification of key genes and pathways associated with cholangiocarcinoma development based on weighted gene correlation network analysis.

BACKGROUND: As the most frequently occurred tumor in biliary tract, cholangiocarcinoma (CCA) is mainly characterized by its late diagnosis and poor outcome. It is therefore urgent to identify specific genes and pathways associated with its progression and prognosis. MATERIALS AND METHODS: The differentially expressed genes in The Cancer Genome Atlas were analyzed to build the co-expression network by Weighted gene co-expression network analysis (WGCNA). Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted for the selected genes. Module-clinical trait relationships were analyzed to explore the association with clinicopathological parameters. Log-rank tests and cox regression were used to identify the prognosis-related genes. RESULTS: The most related modules with CCA development were tan module containing 181 genes and salmon module with 148 genes. GO analysis suggested enrichment terms of digestion, hormone transport and secretion, epithelial cell proliferation, signal release, fibroblast activation, response to acid chemical, wnt, Nicotinamide adenine dinucleotide phosphate metabolism. KEGG analysis demonstrated 15 significantly altered pathways including glutathione metabolism, wnt, central carbon metabolism, mTOR, pancreatic secretion, protein digestion, axon guidance, retinol metabolism, insulin secretion, salivary secretion, fat digestion. Key genes of SOX2, KIT, PRSS56, WNT9A, SLC4A4, PRRG4, PANX2, PIR, RASSF8, MFSD4A, INS, RNF39, IL1R2, CST1, and PPP3CA might be potential prognostic markers for CCA, of which RNF39 and PRSS56 also showed significant correlation with clinical stage. DISCUSSION: Differentially expressed genes and key modules contributing to CCA development were identified by WGCNA. Our results offer novel insights into the characteristics in the etiology, prognosis, and treatment of CCA.