Small nucleolar RNA and its potential role in the oncogenesis and development of colorectal cancer.

Small nucleolar RNAs (snoRNAs) represent a class of non-coding RNAs that play pivotal roles in post-transcriptional RNA processing and modification, thereby contributing significantly to the maintenance of cellular functions related to protein synthesis. SnoRNAs have been discovered to possess the ability to influence cell fate and alter disease progression, holding immense potential in controlling human diseases. It is suggested that the dysregulation of snoRNAs in cancer exhibits differential expression across various cancer types, stages, metastasis, treatment response and/or prognosis in patients. On the other hand, colorectal cancer (CRC), a prevalent malignancy of the digestive system, is characterized by high incidence and mortality rates, ranking as the third most common cancer type. Recent research indicates that snoRNA dysregulation is associated with CRC, as snoRNA expression significantly differs between normal and cancerous conditions. Consequently, assessing snoRNA expression level and function holds promise for the prognosis and diagnosis of CRC. Nevertheless, current comprehension of the potential roles of snoRNAs in CRC remains limited. This review offers a comprehensive survey of the aberrant regulation of snoRNAs in CRC, providing valuable insights into the discovery of novel biomarkers, therapeutic targets, and potential tools for the diagnosis and treatment of CRC and furnishing critical cues for advancing research into CRC and the judicious selection of therapeutic targets.

NOTCH3 inhibits transcription factor ZEB1 expression and metastasis of breast cancer cells via transcriptionally upregulating miR-223.

Background: NOTCH receptor 3 (NOTCH3) and zinc finger E-box binding protein 1 (ZEB1) play important roles in breast cancer respectively. NOTCH3 maintains the luminal phenotype and inhibits epithelial-mesenchymal transition (EMT) in breast cancer, while ZEB1 and NOTCH3 have the opposite effects. Methods: Public databases were used to predict the expression of NOTCH3 and ZEB1 in breast cancer cell lines. The regulatory effect of NOTCH3 on ZEB1 expression was verified by western blot and RT-PCR. MiRNAs regulating ZEB1 expression were identified by using multiple databases and confirmed by reporter gene experiments. Cellular function experiments were conducted to evaluate the role of NOTCH3/miR-223/ZEB1 in the proliferation and invasion of triple-negative breast cancer (TNBC). Results: NOTCH3 and ZEB1 have opposite expression pattern in MCF-7 cells that over-express LncATB or were incubated in TGF-ß to induce EMT. Western blotting and RT-PCR showed that NOTCH3 could regulate expression of ZEB1. MiR-223 inhibited the proliferation and invasion of breast cancer cells via down-regulating the expression of ZEB1. NOTCH3 inhibited the proliferation and invasion of breast cancer cells via up-regulating the expression of miR-223. Clinically, high expression of NOTCH3, miR-223 or low expression of ZEB1 were related to good prognosis of breast cancer patients. Conclusion: The current study reports a novel NOTCH3/miR-223/ZEB1 axis, which can inhibit the proliferation and invasion of breast cancer cells, and may serve as a potential biomarker for the prognosis of breast cancer.

Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications.

Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.

Network Pharmacology-Based Identification of Key Pharmacological Mechanism of Shen-qi-di-huang Decoction Acting on Uremia.

This study employs network pharmacology to uncover the pharmacological mechanisms underlying Shen-qi-di-huang decoction's efficacy in treating uremia. We identified a total of 927 differentially expressed genes (DEGs) through differential expression analysis and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform, of which 607 were downregulated and 320 were upregulated. We also obtained the effective biological components and related target gene information of Chinese herbal medicines such as Renshen, Huangqi, shudihuang, Shanyao, Fuling, Mudanpi, and Shanzhuyu in Shen-qi-di-huang decoction and constructed a regulatory relationship network between molecular components and target genes in Shen-qi-di-huang decoction. We then constructed a protein-protein interaction (PPI) network of 15 targeted genes (RXRA, ND6, CYP1B1, SLPI, CDKN1A, RB1, HIF1A, MYC, HSPB1, IFNGR1, NQO1, IRF1, RASA1, PSMG1 and MAP2K4) using the STRING database and visualized the PPI network using the software Cytoscape. In addition, we revealed the key molecular functions of uremia through Gene Ontology (GO) enrichment analysis, mainly including neuron apoptotic process, cellular response to oxidative stress, regulation of neuron apoptotic process, neuron projection cytoplasm, RNA polymerase II transcription regulator complex, plasma membrane bounded cell projection cytoplasm, NADH and NADPH dehydrogenase (quinone) activity, protein kinase inhibitor and ubiquitin protein ligase binding, etc. Finally, we identified important biological pathways in uremia through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which mainly concentrated in Kaposi sarcoma-associated, small cell lung cancer, Gastric cancer, Hepatitis B and C, Hepatocellular carcinoma, Thyroid cancer, Bladder cancer, MAPK signaling pathway, ErbB signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, Thyroid hormone signaling pathway and Cell cycle, etc. Using integrated bioinformatical analysis, we elucidated key pharmacological mechanisms based on targeted genes, which was enable early identification of patients with uremia and would contribute to early clinical diagnosis and treatment of patients.

Washed microbiota transplantation: a case report of clinical success with skin and gut microbiota improvement in an adolescent boy with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, recurrent inflammatory disease characterized by itching. The gut microbiome can help maintain skin immune homeostasis by regulating innate and adaptive immunity. Here, we report a case of AD in a 15-year-old adolescent boy who benefited from washed microbiota transplantation (WMT). WMT was performed for three courses, with each course lasting for three consecutive days and an interval of one month between two courses. Clinical assessments were conducted at each WMT course, and skin, blood, and stool samples were collected for microbial analysis. After three months of WMT treatment, the boy's itchiness was effectively controlled: his skin showed noticeable improvement, with reduced Staphylococcus aureus in the skin lesions. The scores of SCORAD (SCORing Atopic Dermatitis), EASI (Eczema Area and Severity Index), NRS (Numerical Rating Scale), and DLQI (Dermatology Life Quality Index) significantly decreased compared to the baseline. Serum levels of eosinophil ratio, tumor necrotic factor-α, and interleukin-6 also reduced to the normal levels. There was a significant decrease in S. aureus in the skin lesions. Additionally, the intestinal flora became more diverse, and the abundance of Bifidobacterium species, significantly increased after WMT. No adverse events were reported during the treatment and the 1-year follow-up period. This case report provides direct clinical evidence for WMT as a novel promising treatment strategy for AD, and preliminary experimental data suggests the existence of an intestinal-skin axis in terms of the gut microbiota and the skin immune homeostasis.

Washed microbiota transplantation improves renal function in patients with renal dysfunction: a retrospective cohort study.

BACKGROUND: Changes in the gut microbiota composition is a hallmark of chronic kidney disease (CKD), and interventions targeting the gut microbiota present a potent approach for CKD treatment. This study aimed to evaluate the efficacy and safety of washed microbiota transplantation (WMT), a modified faecal microbiota transplantation method, on the renal activity of patients with renal dysfunction. METHODS: A comparative analysis of gut microbiota profiles was conducted in patients with renal dysfunction and healthy controls. Furthermore, the efficacy of WMT on renal parameters in patients with renal dysfunction was evaluated, and the changes in gut microbiota and urinary metabolites after WMT treatment were analysed. RESULTS: Principal coordinate analysis revealed a significant difference in microbial community structure between patients with renal dysfunction and healthy controls (P = 0.01). Patients with renal dysfunction who underwent WMT exhibited significant improvement in serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen (all P < 0.05) compared with those who did not undergo WMT. The incidence of adverse events associated with WMT treatment was low (2.91%). After WMT, the Shannon index of gut microbiota and the abundance of several probiotic bacteria significantly increased in patients with renal dysfunction, aligning their gut microbiome profiles more closely with those of healthy donors (all P < 0.05). Additionally, the urine of patients after WMT demonstrated relatively higher levels of three toxic metabolites, namely hippuric acid, cinnamoylglycine, and indole (all P < 0.05). CONCLUSIONS: WMT is a safe and effective method for improving renal function in patients with renal dysfunction by modulating the gut microbiota and promoting toxic metabolite excretion.

[Identification and validation of novel biomarkers for cold-dampness syndrome of rheumatoid arthritis based on integration of multiple bioinformatics methods].

This study aims to identify the novel biomarkers of cold-dampness syndrome(RA-Cold) of rheumatoid arthritis(RA) by gene set enrichment analysis(GSEA), weighted gene correlation network analysis(WGCNA), and clinical validation. Firstly, transcriptome sequencing was carried out for the whole blood samples from RA-Cold patients, RA patients with other traditional Chinese medicine(TCM) syndromes, and healthy volunteers. The differentially expressed gene(DEG) sets of RA-Cold were screened by comparison with the RA patients with other TCM syndromes and healthy volunteers. Then, GSEA and WGCNA were carried out to screen the key DEGs as candidate biomarkers for RA-Cold. Experimentally, the expression levels of the candidate biomarkers were determined by RT-qPCR for an independent clinical cohort(not less than 10 cases/group), and the clinical efficacy of the candidates was assessed using the receiver operating characteristic(ROC) curve. The results showed that 3 601 DEGs associated with RA-Cold were obtained, including 106 up-regulated genes and 3 495 down-regulated genes. The DEGs of RA-Cold were mainly enriched in the pathways associated with inflammation-immunity regulation, hormone regulation, substance and energy metabolism, cell function regulation, and synovial pannus formation. GSEA and WGCNA showed that recombinant proteasome 26S subunit, ATPase 2(PSMC2), which ranked in the top 50% in terms of coefficient of variation, representativeness of pathway, and biological modules, was a candidate biomarker of RA-Cold. Furthermore, the validation results based on the clinical independent sample set showed that the F1 value, specificity, accuracy, and precision of PSMC2 for RA-Cold were 70.3%, 61.9%, 64.5%, and 81.3%, respectively, and the area under the curve(AUC) value was 0.96. In summary, this study employed the "GSEA-WGCNA-validation" integrated strategy to identify novel biomarkers of RA-Cold, which helped to improve the TCM clinical diagnosis and treatment of core syndromes in RA and provided an experimental basis for TCM syndrome differentiation.

Washed microbiota transplantation improves patients with metabolic syndrome in South China.

Background: Metabolic syndrome (MS) is a growing public health problem worldwide. The clinical impact of fecal microbiota transplantation (FMT) from healthy donors in MS patients is unclear, especially in southern Chinese populations. This study aimed to investigate the effect of washed microbiota transplantation (WMT) in MS patients in southern China. Methods: The clinical data of patients with different indications receiving 1-3 courses of WMT were retrospectively collected. The changes of BMI, blood glucose, blood lipids, blood pressure and other indicators before and after WMT were compared, such as fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c)), high-density lipoprotein cholesterol (HDL-c), non-high-density lipoprotein (non-HDL-c), systolic blood pressure (SBP), diastolic blood pressure (DBP), etc. At the same time, comprehensive efficacy evaluation and atherosclerotic cardiovascular disease (ASCVD) grade assessment were performed on MS patients. Finally, 16S rRNA gene amplicon sequencing was performed on fecal samples of MS patients before and after transplantation. Results: A total of 237 patients were included, including 42 in the MS group and 195 in the non-MS group. For MS patients, WMT significantly improved the comprehensive efficacy of MS in short term 40.48% (p<0.001), medium term 36.00% (p=0.003), and long term 46.15% (p=0.020). Short-term significantly reduced FBG (p=0.023), TG (p=0.030), SBP (p=0.026) and BMI (p=0.031), and increased HDL-c (p=0.036). The medium term had a significant reduction in FBG (p=0.048), TC (p=0.022), LDL-c (p=0.043), non-HDL-c (p=0.024) and BMI (p=0.048). WMT had a significant short term (p=0.029) and medium term (p=0.011) ASCVD downgrading effect in the high-risk group of MS patients. WMT improved gut microbiota in MS patients. Conclusion: WMT had a significant improvement effect on MS patients and a significant downgrade effect on ASCVD risk in the high-risk group of patients with MS. WMT could restore gut microbiota homeostasis in MS patients. Therefore, the regulation of gut microbiota by WMT may provide a new clinical approach for the treatment of MS.

Potential of six-transmembrane epithelial antigen of the prostate 4 as a prognostic marker for colorectal cancer.

BACKGROUND: Immune cells play a role in the regulation of tumor cell behavior, and accumulating evidence supports their significance in predicting outcomes and therapeutic efficacy in colorectal cancers (CRC). Human six-transmembrane epithelial antigen of the prostate (STEAP) proteins have been recognized and utilized as promising targets for cell- and antibody-based immunotherapy. One STEAP family member, STEAP4, is expected to be an attractive biomarker for the immunotherapy of prostate and breast cancer. However, the immunotherapeutic role of STEAP4 for colorectal carcinomas has not been demonstrated. AIM: To explore the expression pattern of STEAPs in CRC and their relationship with immune infiltration, and investigate the potential utilization of STEAPs as novel prognostic indicators in colorectal carcinomas. METHODS: The expression level of STEAPs in CRC was evaluated using various open-resource databases and online tools to explore the expression characteristics and prognostic significance of STEAPs, as well as their correlation with immune-related biomarkers, such as immune infiltration. Immunohistochemical (IHC) experiments were subsequently performed to verify the database conclusions. RESULTS: The levels of STEAPs in CRC were inconsistent. The expression of STEAPs 1-3 in CRC was not significantly different from that in normal tissues. However, STEAP4 mRNA levels were significantly lower in CRC than in normal tissue and were positively correlated with immune-related biomarkers, such as immune cell infiltration, immune stimulation, major histocompatibility complex levels, and chemokines. Interestingly, the expression of STEAP4 in microsatellite instability-high CRC subtype was higher than that in microsatellite stability subtype. IHC staining was performed on colon cancer tissue samples and showed that high expression of STEAP4 in adjacent tissues positively correlated with immune-related biomarkers, including MLH1, MLH6, and PMS2, but negatively correlated with programmed death ligand 1, to varying degrees. CONCLUSION: Our results provide an analysis of the expression of STEAP family members in CRC. Among different STEAP family members, STEAP4 plays a different role in CRC compared to STEAPs 1-3. In CRC, STEAP4 expression is not only lower than that in normal tissues, but it is also positively correlated with immune infiltration and immune-related biomarkers. These findings suggest that STEAP4 may be a potential biomarker for predicting CRC immune infiltration status.

[Mechanism of Tianhe Zhuifeng Ointment in treating rheumatoid arthritis with syndrome of internal obstruction and cold-dampness and compatibility principles based on "disease-syndrome-formula" association network].

This study aims to explore the mechanism of Tianhe Zhuifeng Ointment in treating rheumatoid arthritis(RA) with syndrome of internal obstruction and cold-dampness and the compatibility characteristics based on the "disease-syndrome-formula" association network. A gene set associated with the clinical symptoms of RA was collected from Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine v2.0(TCMIP v2.0). The different expression gene set of RA with syndrome of internal obstruction and cold-dampness was screened out by transcriptomic expression profile detection and bioinformatics data mining of the comparison of RA patients with syndrome of internal obstruction and cold-dampness and healthy volunteers. The chemical composition information of 35 Chinese medicines from Tianhe Zhuifeng Ointment was collected from TCMIP v2.0 and Traditional Chinese Medicine Bank(TCMBank). The candidate targets were predicted based on the similarity principle of compounds structure. The interactive network of "related gene of RA with syndrome of internal obstruction and cold-dampness-candidate target of Tianhe Zhuifeng Ointment" was constructed. The core network targets were screened out by topological characteristics of calculating network, and the functional exploration was carried out based on Kyoto Encyclopedia of Genes and Genomes(KEGG) and Reactome Pathway Database. The compatibility mechanisms of various efficacy groups of Tianhe Zhuifeng Ointment were further explored. The results showed that the candidate targets of Tianhe Zhuifeng Ointment were mainly involved into the modules of "immune-inflammation" regulation, nervous system function, cell function, and substance and energy metabolism, etc. The mechanisms of various efficacy groups emphasized on different aspects. The group of dispelling wind and removing dampness-dredging channels and activating collaterals, the group of extinguishing wind and stopping convulsions, and the group of pungent analgesia regulated "immune-inflammation" system by warming meridians and dissipating cold. The group of activating blood and resolving stasis and the group of strengthening sinews and bones regulated "immune-inflammation" system by activating blood and dredging channels. The group of dispelling wind and removing dampness-dredging channels and activating collaterals, the group of extinguishing wind and stopping convulsions, the group of activating blood and resolving stasis, the group of strengthening sinews and bones, and the group of clearing heat and draining water affected the nervous system by invigorating Qi-blood and benefiting spirit. The group of dispelling wind and removing dampness-dredging channels and activating collaterals and the group of extinguishing wind and stopping convulsions regulated cell function and substance and energy metabolism by dispelling wind and eliminating cold-dampness. The group of activating blood and resolving stasis and the group of strengthening sinews and bones regulated the cell function and substance and energy metabolism by activating blood and strengthening sinews and bones. The results showed that Tianhe Zhuifeng Ointment exerted the comprehensive efficacy of dispelling wind, removing dampness, activating blood, removing stasis, warming meridians, dredging channels, and strengthening sinews and bones through adjusting the imbalance of "immune-inflammation", regulating nervous system, cell function, and interfering with substance and energy metabolism, thus improving the syndrome of internal obstruction and cold-dampness. The findings of this study laid foundations for clarifying the therapeutic characteristics and clinical orientation of Tianhe Zhuifeng Ointment.

Induced Cell Cycle Arrest in Triple-Negative Breast Cancer by Combined Treatment of Itraconazole and Rapamycin.

Triple-negative breast cancer (TNBC) is the aggressive molecular type of breast carcinoma, with a high metastasis/relapse incidence and cancer-related death rate, due to lack of specific therapeutic targets in the clinic. Exploring potential therapeutic targets or developing novel therapeutic strategies are the focus of intense research to improve the survival and life quality of patients with TNBC. The current study focused on drugs targeting the mTOR signaling pathway by investigating the potential utilization of itraconazole (ITZ) combined with rapamycin in the treatment of TNBC. CCK-8, colony formation and transwell assays were conducted to evaluate the effect of ITZ with rapamycin in combination on MDA-MB-231 and BT-549 TNBC cells. Synergistic inhibition was found in terms of proliferation and motility of TNBC cells. However, apoptosis was not enhanced by the combined treatment of ITZ and rapamycin. Flow cytometry analysis showed that ITZ and/or rapamycin arrested cells in G0/G1 phase and prevented G1/S phase transition. Reduced cyclin D1 protein levels were consistent with G0/G1 phase arrest, especially when resulting from the combination of ITZ with rapamycin. In conclusion, the combination of ITZ with rapamycin is a promising therapeutic strategy for patients with TNBC through synergistically arresting cells in the G0/G1 phase of the cell cycle, rather than inducing apoptosis.

[Biological connotation of four traditional Chinese medicine syndromes of rheumatoid arthritis based on "disease-syndrome-symptom" association network].

The present study explored the biological connotation of traditional Chinese medicine(TCM) syndromes of rheumatoid arthritis(RA) from the "disease-syndrome-symptom" association network. RA patients with four TCM syndromes(dampness-heat obstruction, phlegm-stasis obstruction, Qi-blood deficiency, and liver and kidney deficiency), three for each type, were assigned as the RA TCM syndrome group, and three healthy volunteers as the normal control group. The differential gene sets of four syndromes were screened out through transcriptome expression profiling and bioinformatics mining. The relevant gene sets of syndrome-related clinical symptoms were collected from TCMIP v2.0(http://www.tcmip.cn/). The "disease-syndrome-symptom" association networks of four RA syndromes were established by using the intersection genes of syndrome-related differential genes and symptom-related genes, and the key network target genes of each syndrome were screened out and the corresponding biological functions were mined through topological feature calculation and enrichment analysis. The genes associated with clinical symptoms such as vasculitis, joint pain, and fever in the damp-heat obstruction syndrome ranked the top, and the key network target genes of this syndrome were most significantly enriched in the pathways related to material and energy metabolism and thermal reaction biological processes. The clinical symptom-related genes of the phlegm-stasis obstruction syndrome were most significantly enriched in the pathways related to "immunity-inflammation", nervous system regulation, and sensory response. The clinical symptoms such as hypoglycemia, hypotension, weight loss, palpitation, and arrhythmia in Qi-blood deficiency syndrome were predominant, and its key network target genes were most significantly enriched in the pathways related to the nervous system and "immunity-inflammation" response. The abnormal symptoms in the liver and kidney in the liver and kidney deficiency syndrome were commonly seen, and its key network target genes were most significantly enriched in the "immunity-inflammation" regulatory pathways, and liver and kidney development and metabolic response. In conclusion, the differences and connections of the biological basis between different TCM syndromes of RA are in line with the theoretical interpretation of TCM on the etiology and pathogenesis of RA. This study summarized the objective essence of syndromes to a certain extent from the "disease-syndrome-symptom" association network and is expected to provide a theoretical basis for the discovery of serum biomarkers of RA syndromes.

Regulatory Roles of Six-Transmembrane Epithelial Antigen of the Prostate Family Members in the Occurrence and Development of Malignant Tumors.

The human six-transmembrane epithelial antigen of the prostate (STEAP) proteins, which include STEAP1-4 and atypical STEAP1B, contain six transmembrane domains and are located in the cell membrane. STEAPs are considered archaeal metal oxidoreductases, based on their heme groups and F420H2:NADP+ oxidoreductase (FNO)-like structures, and play an important role in cell metal metabolism. Interestingly, STEAPs not only participate in biological processes, such as molecular transport, cell cycling, immune response, and intracellular and extracellular activities, but also are closely related to the occurrence and development of several diseases, especially malignant tumors. Up to now, the expression patterns of STEAPs have been found to be diverse in different types of tumors, with controversial participation in different aspects of malignancy, such as cell proliferation, migration, invasion, apoptosis, and therapeutic resistance. It is clinically important to explore the potential roles of STEAPs as new immunotherapeutic targets for the treatment of different malignant tumors. Therefore, this review focuses on the molecular mechanism and function of STEAPs in the occurrence and development of different cancers in order to understand the role of STEAPs in cancer and provide a new theoretical basis for the treatment of diverse cancers.

Diverse roles of FOXO family members in gastric cancer.

Gastric cancer (GC) is the fifth most diagnosed cancer and the third leading cause of cancer-related death worldwide. Although progress has been made in diagnosis, surgical resection, systemic chemotherapy, and immunotherapy, patients with GC still have a poor prognosis. The overall 5-year survival rate in patients with advanced GC is less than 5%. The FOXO subfamily, of the forkhead box family of transcription factors, consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6. This subfamily plays an important role in many cellular processes, such as cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism, in both normal tissue and malignant tumors. Various studies support a role for FOXOs as tumor suppressors based on their ability to inhibit angiogenesis and metastasis, and promote apoptosis, yet several other studies have shown that FOXOs might also promote tumor progression in certain circumstances. To elucidate the diverse roles of FOXOs in GC, this article systematically reviews the cellular functions of FOXOs in GC to determine potential therapeutic targets and treatment strategies for patients with GC.

Diverse expression patterns of mucin 2 in colorectal cancer indicates its mechanism related to the intestinal mucosal barrier.

BACKGROUND: Abnormal expression patterns of mucin 2 (MUC2) have been reported in a variety of malignant tumors and precancerous lesions. Reduced MUC2 expression in the intestinal mucosa, caused by various pathogenic factors, is related to mechanical dysfunction of the intestinal mucosa barrier and increased intestinal mucosal permeability. However, the relationship between MUC2 and the intestinal mucosal barrier in patients with colorectal cancer (CRC) is not clear. AIM: To explore the relationship between MUC2 and intestinal mucosal barrier by characterizing the multiple expression patterns of MUC2 in CRC. METHODS: Immunohistochemical staining was performed on intestinal tissue specimens from 100 CRC patients, including both cancer tissues and adjacent normal tissues. Enzyme-linked immunosorbent assays were performed on preoperative sera from 66 CRC patients and 20 normal sera to detect the serum levels of MUC2, diamine oxide (DAO), and D-lactate (D-LAC). The relationship between MUC2 expression and clinical parameters was calculated by the χ 2 test or Fisher's exact test. Prognostic value of MUC2 was evaluated by Kaplan-Meier curve and log-rank tests. RESULTS: Immunohistochemical staining of 100 CRC tissues showed that the expression of MUC2 in cancer tissues was lower than that in normal tissues (54% vs 79%, P < 0.05), and it was correlated with tumor-node-metastasis (TNM) stage and lymph node metastasis in CRC patients (P < 0.05). However, the serum level of MUC2 in CRC patients was higher than that in normal controls, and was positively associated with serum levels of human DAO (χ 2 = 3.957, P < 0.05) and D-LAC (χ 2 = 7.236, P < 0.05), which are the biomarkers of the functional status of the intestinal mucosal barrier. And the serum level of MUC2 was correlated with TNM stage, tumor type, and distant metastasis in CRC patients (P < 0.05). Kaplan-Meier curves showed that decreased MUC2 expression in CRC tissues predicted a poor survival. CONCLUSION: MUC2 in tissues may play a protective role by participating in the intestinal mucosal barrier and can be used as an indicator to evaluate the prognosis of CRC patients.

Bioinformatics analysis reveals that ANXA1 and SPINK5 are novel tumor suppressor genes in patients with oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a solid tumor of squamous epithelial origin. Currently, surgery is still the main treatment for OSCC, with radiotherapy and chemotherapy as important adjuvant treatments. However, the problem of poor prognosis of OSCC patients still exists in clinical practice. To explore further potential biomarkers or treatment targets in OSCC patients, this study used a high-throughput gene expression database to study the potential molecular mechanisms of OSCC carcinogenesis. METHODS: The GEO database related to OSCC was searched and analyzed using GEO2R. Oncomine and the Human Protein Atlas were used to evaluate the expression level of differentially-expressed genes (DEGs). The cBioPortal dataset was used to analyze the mutations of the potential DEGs and patient survival. RESULTS: Three GEO datasets, GSE146483, GSE138206, and GSE148944, were downloaded and 7 DEGs were found in common in OSCC tissues. Using Oncomine and the Human Protein Atlas, ANXA1, IL1RN, and SPINK5 were decreased in cancer tissues, while protein levels of APOE and IFI35 were increased accordingly. Interestingly, low levels of ANXA1 and SPINKS were associated with the TNM stage of OSCC patients. No mutations in DEGs were found in OSCC patients, based on the cBioPortal dataset. Survival analysis indicated OSCC patients with high MSR1 had poor overall survival (OS), while low expression of CXCR4, ANXA1, IL1RN, and SPINK5 also predicted poor OS in OSCC patients. CONCLUSIONS: Our findings uncovered 7 potential biomarkers of OSCC patients, with ANXA1 and SPINK5 serving as potential tumor suppressor genes in OSCC.

Neutrophil extracellular traps exacerbate coagulation and endothelial damage in patients with essential hypertension and hyperhomocysteinemia.

Patients with essential hypertension (EH) and hyperhomocysteinemia (HHCY) suffer from more increased thrombotic events than those in EH alone. However, the underlying mechanisms for this effect are not well understood. This study hypothesized that neutrophil extracellular trap (NET) releasing may be triggered by HHCY in patients in EH, thereby predisposing them to a more hypercoagulable state. Using a modified-capture enzyme-linked immunosorbent assay (ELISA) method, we observed that cell-free DNA (CF-DNA) and myeloperoxidase DNA (MPO-DNA) in patients With EH and HHCY were significantly higher. The NET formation was also positively correlated with homocysteine levels, neutrophil-lymphocyte ratio (NLR), and hypercoagulable markers (thrombin-antithrombin complex, D-dimers). Furthermore, neutrophils from patients in EH with HHCY were found to be predisposed to amplified NET release when compared to patients in EH without HHCY or CTR. Coagulation function assays showed that NETs in patients With EH and HHCY resulted in a significantly increased ability to generate thrombin and fibrin than in those in EH without HHCY or CTR. These procoagulant effects of NETs in patients With EH and HHCY were markedly inhibited (approximately 70%) by the cleavage of NETs with DNase I. Isolated NETs from patients With EH and HHCY neutrophils also exerted a strong cytotoxic effect on endothelial cells (ECs), converted them to apoptosis. This study revealed a previously unrecognized association between the hypercoagulable state and neutrophils in patients With EH and HHCY. Therefore, blocking NETs may represent a new therapeutic objective for preventing thrombosis in these patients.

Regulation of N6-Methyladenosine in the Differentiation of Cancer Stem Cells and Their Fate.

N6-methyladenosine (m6A) is one of the most common internal RNA modifications in eukaryotes. It is a dynamic and reversible process that requires an orchestrated participation of methyltransferase, demethylase, and methylated binding protein. m6A modification can affect RNA degradation, translation, and microRNA processing. m6A plays an important role in the regulation of various processes in living organisms. In addition to being involved in normal physiological processes such as sperm development, immunity, fat differentiation, cell development, and differentiation, it is also involved in tumor progression and stem cell differentiation. Curiously enough, cancer stem cells, a rare group of cells present in malignant tumors, retain the characteristics of stem cells and play an important role in the survival, proliferation, metastasis, and recurrence of cancers. Recently, studies demonstrated that m6A participates in the self-renewal and pluripotent regulation of these stem cells. However, considering that multiple targets of m6A are involved in different physiological processes, the exact role of m6A in cancer progression remains controversial. This article focuses on the mechanism of m6A and its effects on the differentiation of cancer stem cells, to provide a basis for elucidating the tumorigenesis mechanisms and exploring new potential therapeutic approaches.

MicroRNA-488 inhibits proliferation and motility of tumor cells via downregulating FSCN1, modulated by Notch3 in breast carcinomas.

As important modulators in multiple physiological processes, microRNAs (miRNAs) have been reported in various malignant tumors, including breast cancer. The current study investigated the function of a new tumor suppressor microRNA, miR-488, and its molecular mechanism of metastasis in breast cancers. CCK8 and transwell assays revealed that the upregulated miR-488 level significantly inhibited the proliferation and migration of breast cancer cells. As a potential downstream gene, the mRNA and protein level of FSCN1 was suppressed by increased miR-488 and vice versa. Luciferase assay showed that miR-488 directly bind to the 3'UTR of FSCN1 and suppressed the translation process of FSCN1. The promoter region of miR-488 was directly bound by Notch3 and promoted the expression of miR-488 transcriptionally. Immunohistochemistry results revealed that in patients with breast cancer, the expression of Notch3 and were negatively correlated with the FSCN1 levels significantly. Therefore, the current finding predicted miR-488 as a tumor suppressor molecule in breast cancer, and demonstrated that Notch3/miR-488/FSCN1 axis is established and involved in regulating the metastasis of breast cancers, providing novel therapeutic targets for patients with breast cancers.

The Tumor Suppressive Roles and Prognostic Values of STEAP Family Members in Breast Cancer.

OBJECTIVE: To investigate the expression patterns and prognostic values of STEAP family members in the occurrence and development of breast cancer. MATERIALS AND METHODS: The Human Protein Atlas was used to analyze the expression level of STEAPs in human normal tissues and malignant tumors. ONCOMINE datasets were analyzed for the comparison of the STEAPs levels between malignant cancers and corresponding normal tissues. Kaplan-Meier plotter was used to analyze the prognostic value of STEAPs in breast cancer patients. RESULTS: STEAPs were widely distributed in human normal tissues with diverse levels. Normally, it is predicted that STEAP1 and STEAP2 were involved in the mineral absorption process, while STEAP3 participated in the TP53 signaling pathway and iron apoptosis. The results from ONCOMINE showed downregulation of STEAP1, STEAP2, and STEAP4 in breast cancers. Survival analysis revealed that breast cancer patients with high levels of STEAP1, STEAP2, and STEAP4 had a good prognosis, while those with low expression had high overall mortality. CONCLUSION: STEAP1, STEAP2, and STEAP4 are predicted to be the potential prognostic biomarkers for breast cancer patients, providing novel therapeutic strategies for them.