The association between sodium/glucose cotransporter-2 inhibitors and adverse clinical events in patients with chronic kidney disease: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes. METHODS: Twelve articles were chosen via a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias. RESULTS: In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I2: 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I2: 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I2: 0.0%, P: 0.642). CONCLUSION: The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes.

Dihydropyrimidine Dehydrogenase (DPD) as a Bridge between the Immune Microenvironment of Colon Cancers and 5-FU Resistance.

BACKGROUND: The purpose of the present study was to investigate the role of the 5-Fluorouracil (5-FU) resistance-related factor dihydropyrimidine dehydrogenase (DPD) in tumor immunity and prognosis and to study the relationship between drug resistance and the immune microenvironment of colon cancer. METHODS: Bioinformatics methods were used to analyze the expression of DPD associated with prognosis, immunity, microsatellite instability, and tumor mutational burden in colon cancer. Immunohistochemistry (IHC) was used to detect DPD, MLH1, MSH2, MSH6, and PMS2 in 219 colon cancer tissue samples. Additional IHC analyses were conducted to detect CD4, CD8, CD20, and CD163 in 30 colon cancer tissue samples with the most extensive immune infiltration. The significance of the correlations and clinical significance of DPD with immune infiltration, immune-related markers, microsatellite instability-related indicators, and prognosis were evaluated. RESULTS: The major findings of the present study are as follows: (1) DPD was expressed in tumor and immune cells and associated with certain immune cell-related markers, particularly M2 macrophages that expressed CD163. (2) DPD expression significantly and positively correlated with immune cell markers and immune checkpoints PD-1 and PD-L1. High expression of DPD in immune cells, but not tumor cells, led to increased immune infiltration. (3) High expression of DPD in immune and tumor cells induced 5-FU resistance and was associated with unfavorable prognosis. (4) DPD expression closely correlated with microsatellite instability and tumor mutational burden and led to resistance to 5-FU in patients with microsatellite instability. (5) Bioinformatics analyses revealed that DPD was enriched in immune-related functions and pathways such as activation of T cells and macrophages. CONCLUSIONS: DPD plays an important role in the immune microenvironment and drug resistance of colon cancers and their functional association.

Beneficial Effects of Hordenine on a Model of Ulcerative Colitis.

Hordenine, a phenethylamine alkaloid, is found in a variety of plants and exhibits a broad array of biological activities and pharmacological properties, including anti-inflammatory and anti-fibrotic effects. However, the efficacy and underlying mechanisms of hordenine in treating ulcerative colitis (UC) remain unclear. To address this, we examined the therapeutic effects of hordenine on dextran sodium sulphate (DSS)-induced UC by comparing disease activity index (DAI), colon length, secretion of inflammatory factors, and degree of colonic histological lesions across diseased mice that were and were not treated with hordenine. We found that hordenine significantly reduced DAI and levels of pro-inflammatory factors, including interleukin (IL)-6, IL-1ß, and tumor necrosis factor alpha (TNF-α), and also alleviated colon tissue oedema, colonic lesions, inflammatory cells infiltration and decreased the number of goblet cells. Moreover, in vitro experiments showed that hordenine protected intestinal epithelial barrier function by increasing the expression of tight junction proteins including ZO-1 and occludin, while also promoting the healing of intestinal mucosa. Using immunohistochemistry and western blotting, we demonstrated that hordenine reduced the expression of sphingosine kinase 1 (SPHK1), sphingosine-1-phosphate receptor 1 (S1PR1), and ras-related C3 botulinum toxin substrate 1 (Rac1), and it inhibited the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in colon tissues. Thus, hordenine appears to be effective in UC treatment owing to pharmacological mechanisms that favor mucosal healing and the inhibition of SPHK-1/S1PR1/STAT3 signaling.

Hypertensive vascular and cardiac remodeling protection by allicin in spontaneous hypertension rats via CaMK â ¡/NF-κB pathway.

Allicin is the main active component of Traditional Chinese medicine, garlic. It is widely used to treat cardiovascular diseases. Our previous studies have confirmed that allicin significantly reduces blood pressure in Spontaneous Hypertension Rats (SHRs). However, the reports studying the effect of allicin on vascular and cardiac remodeling caused by hypertension are few, with their underlying mechanism not being studied in detail or fully elucidated. In this study, we treated 12-week-old SHRs with allicin for 4 weeks. After 4 weeks, allicin was shown to improve vascular and cardiac remodeling in SHRs, as evidenced by reduced cardiac left ventricular wall thickness, aortic vessel thickness, and reduced proliferating cell nuclear antigen (PCNA) and smooth muscle actin (α-SMA), and increased expression of and smooth muscle 22α (SM 22α). Additionally, allicin reduced serum IL-1ß, IL-6, and TNF-α levels, improved calcium homeostasis in cardiomyocytes, downregulated calcium transportation-related CaMK II and inflammation-related NF-κB and NLRP3, which were observed in smooth muscle cells and cardiomyocytes. Thus, we inferred that allicin protected hypertensive vascular and cardiac remodeling in Spontaneous Hypertensive Rats by inhibiting the activation of the CaMK II/ NF-κB pathway. This study also provided new mechanistic insights into the anti-hypertensive vascular and cardiac remodeling effects of allicin, highlighting its therapeutic potential.

Misdiagnosis of an elevated lesion in the esophagus: A case report.

BACKGROUND: Esophageal carcinosarcoma (ECS) is a rare biphasic tumor and a type of esophageal malignancy, which presents as protruding or elevated lesions. ECS patients are often not hospitalized until they have severe dysphagia. ECS is easily misdiagnosed as a benign tumor due to its atypical characteristics under endoscopy. With the popularization of endoscopic treatment, these patients are often referred to endoscopic treatment, such as endoscopic submucosal dissection (ESD). However, there is a lack of consensus on the endoscopic features and therapies for ECS. Here, we report a case of ECS and discuss the value of endoscopic diagnosis and therapeutic strategies. CASE SUMMARY: A 63-year-old man was admitted to the hospital with dysphagia. During the endoscopic examination, an elevated lesion was found with an erosive and hyperemic surface covered with white pseudomembranous inflammation. Endoscopic ultrasonography (EUS), biopsies, and enhanced thoracic computed tomography were performed, suggesting that it was a benign lesion and located within the submucosal layer. This lesion was diagnosed as a fibrovascular polyp with a Paris classification of 0-Ip. The patient was then referred to ESD treatment. However, the post-ESD pathological and immunohistochemical study showed that this lesion was ECS with a vertical positive margin (T1b stage), indicating that we made a misdiagnosis and achieved a noncurative resection. Due to the potential tumor residue, additional open surgery was performed at the patient's request. In the postoperative pathological study, no tumor remnants or metastases were discovered. The patient was followed for 1 year and had no recurrence. CONCLUSION: ECS can be misdiagnosed at the initial endoscopy. EUS can help to identify the tumor stage. Patients with T1b stage ECS cannot be routinely referred to ESD treatment due to the high risk of metastasis and recurrence rate.

A common tumor in an uncommon site: epithelioid Leiomyoma arising from the seminal vesicle-a case report.

BACKGROUND: Leiomyoma of the seminal vesicle is a rare leiomyoma characterized by the formation of benign leiomyomatous tissue within the seminal vesicle. Although histologically benign, excessive size can lead to urinary system disease if left untreated. Herein, we report a case of a seminal vesicle epithelioid leiomyoma. CASE PRESENTATION: A 36-year-old Chinese man sought medical attention at our hospital for urination pain and hemospermia. CT showed a 5.3 cm × 5.0 cm seminal vesicle mass with a mixed density in the right seminal vesicle. The gross specimen showed light yellow, gray, and white tissues, with softness and hemorrhage in some places. Histologically, it showed classic spindle cell proliferation, with spindle cells arranged in fascicles, and mitosis was rare. Immunohistochemistry showed frequent expression of smooth muscle markers, such as calponin, SMA, and desmin. A diagnosis of epithelioid leiomyoma was proposed according to the immunohistochemical findings and morphology. The patient did not receive adjuvant therapy. There was no evidence of tumor recurrence in the 10 months after surgery. CONCLUSIONS: We report the first case of epithelioid leiomyoma in the seminal vesicle. This disease should be included in the differential diagnostic list of seminal vesicle tumors with epithelioid morphology.

Efficacy and Mechanism of Quercetin in the Treatment of Experimental Colitis Using Network Pharmacology Analysis.

Quercetin, a flavonoid that is present in vegetables and fruits, has been found to have anti-inflammatory effects. However, the mechanism by which it inhibits colitis is uncertain. This study aimed to explore the effect and pharmacological mechanism of quercetin on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC). Mice were given a 4% (w/v) DSS solution to drink for 7 days, followed by regular water for the following 5 days. Pharmacological mechanisms were predicted by network pharmacology. High-throughput 16S rDNA sequencing was performed to detect changes in the intestinal microbiota composition. Enzyme-linked immunosorbent assay and western blotting were performed to examine the anti-inflammatory role of quercetin in the colon. Quercetin attenuated DSS-induced body weight loss, colon length shortening, and pathological damage to the colon. Quercetin administration modulated the composition of the intestinal microbiota in DSS-induced mice and inhibited the growth of harmful bacteria. Network pharmacology revealed that quercetin target genes were enriched in inflammatory and neoplastic processes. Quercetin dramatically inhibited the expression of phosphorylated protein kinase B (AKT) and phosphatidylinositol 3-kinase (PI3K). Quercetin has a role in the treatment of UC, with pharmacological mechanisms that involve regulation of the intestinal microbiota, re-establishment of healthy microbiomes that favor mucosal healing, and the inhibition of PI3K/AKT signaling.

Key Candidate Genes - VSIG2 of Colon Cancer Identified by Weighted Gene Co-Expression Network Analysis.

BACKGROUND: Colon adenocarcinoma (COAD) is one of the most common malignancies. To identify candidate genes that may be involved in colon adenocarcinoma development and progression, weighted gene co-expression network analysis (WGCNA) was used to construct gene co-expression networks to explore associations between gene sets and clinical features and to identify candidate biomarkers. Moreover, we intend to make a preliminary exploration on it. METHODS: Gene expression profiles and clinical information were collected from The Cancer Genome Atlas COAD database for analysis. The gene expression profiles of GSE106582 and GSE110224 were screened from the Gene Expression Omnibus database for verification. WGCNA analysis, functional pathway enrichment analysis, and prognosis analysis were performed on three databases. Target genes were selected from the key genes for experimental verification and research. RESULTS: Key genes obtained by WGCNA analysis were mainly enriched in key functions and pathways such as drug metabolism, steroid hormones, and retinol metabolism. A total of four prognostic genes were screened out: SELENBP1, NAT2, VSIG2, and CES2. VSIG2 was selected as the target gene for experimental verification, and its encoded protein was found to be mainly expressed in immune cells. Its expression was positively correlated with immune infiltration. CONCLUSIONS: VSIG2 was shown to be associated with immune invasion and antigen presentation in COAD, suggesting it plays an important role in COAD development and progression. It could be used as a potential biomarker or therapeutic target for COAD.

Dysregulation of Long Non-coding RNAs and mRNAs in Plasma of Clear Cell Renal Cell Carcinoma Patients Using Microarray and Bioinformatic Analysis.

Objective: The roles of long non-coding RNAs (lncRNAs) in the diagnosis of clear cell renal cell carcinoma (ccRCC) are still not well-defined. We aimed to identify differentially expressed lncRNAs and mRNAs in plasma of ccRCC patients and health controls systematically. Methods: Expression profile of plasma lncRNAs and mRNAs in ccRCC patients and healthy controls was analyzed based on microarray assay. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based approaches were used to investigate biological function and signaling pathways mediated by the differentially expressed mRNAs. SOCS2-AS1 was selected for validation using Real-Time PCR. The differentially expressed lncRNAs and mRNAs were further compared with E-MTAB-1830 datasets using Venn and the NetworkAnalyst website. The GEPIA and ULCAN websites were utilized for the evaluation of the expression level of differentially expressed mRNA and their association with overall survival (OS). Results: A total of 3,664 differentially expressed lncRNAs were identified in the plasma of ccRCC patients, including 1,511 up-regulated and 2,153 down-regulated lncRNAs (fold change ≥2 and P < 0.05), respectively. There were 2,268 differentially expressed mRNAs, including 932 up-regulated mRNAs and 1,336 down-regulated mRNAs, respectively (fold change ≥2 and P < 0.05). Pathway analysis based on deregulated mRNAs was mainly involved in melanogenesis and Hippo signaling pathway (P < 0.05). In line with the lncRNA microarray findings, the SOCS2-AS1 was down-regulated in ccRCC plasma and tissues, as well as in cell lines. Compared with the E-MTAB-1830 gene expression profiles, we identified 18 lncRNAs and 87 mRNAs differently expressed in both plasma and neoplastic tissues of ccRCC. The expression of 10 mRNAs (EPB41L4B, CCND1, GGT1, CGNL1, CYSLTR1, PLAUR, UGT3A1, PROM2, MUC12, and PCK1) was correlated with the overall survival (OS) rate in ccRCC patients based on the GEPIA and ULCAN websites. Conclusions: We firstly reported differentially expressed lncRNAs in ccRCC patients and healthy controls systemically. Several differentially expressed lncRNAs and mRNAs were identified, which might serve as diagnostic or prognostic markers. The biological function of these lncRNAs and mRNAs should be further validated. Our study may contribute to the future treatment of ccRCC and provide novel insights into cancer biology.

Expression of PHLPP2 correlates with clinicopathologic characteristics and prognosis in colorectal cancer.

PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) belongs to the phosphokinase family, that has been reported to play an important role in several cancers. However, the expression of PHLPP2 and its correlation with clinicopathologic characteristics in colorectal cancer (CRC) have yet to be determined. The aim of this study is to investigate the expression of PHLPP2 and explore its role in CRC. The expression of PHLPP2, PTEN, PI3KCA, and PI3KCB in 130 cases of CRC and normal tissues was assessed by immunohistochemistry. In addition, the expression of PHLPP2, PTEN, PI3KCA, and PI3KCB in 32 pairs of CRC tissues and their corresponding normal tissues was determined by RT-PCR and western blotting, respectively. PHLPP2 expression in CRC was significantly lower than that of normal tissues. However, PHLPP2 mRNA shows no significant difference between CRC and normal tissue. PTEN expression in left colorectal cancer (LCC) was absent, while PI3KCA and PI3KCB in right colorectal cancer (RCC) were significantly higher than those in LCC. PHLPP2 was negatively correlated with p-Akt1 in CRC. The expression of p-Akt1 in PHLPP2 (+)/PTEN (+) in CRC tissues was significantly lower than that in other groups. PHLPP2 expression was correlated with differentiation, invasion, and lymph node metastasis. Kaplan-Meier analysis and multivariate analysis reveal that PHLPP2 is closely related to prognosis; more importantly, it is an independent prognostic factor for CRC. In conclusion, PHLPP2 may play a major role in the development, metastasis, and prognosis of CRC.

Upregulation of syncytin-1 promotes invasion and metastasis by activating epithelial-mesenchymal transition-related pathway in endometrial carcinoma.

BACKGROUND: Endometrial carcinoma (EC) is the most common and lethal malignancy worldwide. Syncytin-1 is expressed in multiple types of cancer. However, the expression pattern and potential mechanism of syncytin-1 and its clinical significance in EC remain unclear. MATERIALS AND METHODS: We analyzed 130 primary EC specimens from Binzhou Medical University to investigate the clinical role of syncytin-1 in EC by using different advanced pathological stages of EC tissues. Kaplan-Meier analysis was used to measure the overall survival of EC patients. Syncytin-1 expression was analyzed by Western blot assays in HECCL-1 and RL-95-2 cells. Cell proliferation, cycle, migration, and invasion abilities were detected by cell counting kit-8, flow cytometry, and transwell assays. AKT and epithelial-mesenchymal transition (EMT)-related genes were assessed by Western blot assays in HECCL-1 and RL-95-2 cells. RESULTS: Syncytin-1 was upregulated in EC tissues and cells and was related to clinical stages, expression of ER, Ki-67, and overall survival of EC. Functional research revealed that overexpression of syncytin-1 can promote cell proliferation, cell cycle progression, and the migration and invasion of EC cells. Suppression of syncytin-1 expression also inhibited cell proliferation and apoptosis in vitro. The expression of syncytin-1 substantially improved the expression levels of EMT-related genes (vimentin, E-cadherin, slug, and ZEB1) but significantly decreased those of epithelial markers (N-cadherin and snail). In addition, we found that syncytin-1 was not correlated with AKT-related genes (total-AKT, p-AKT, and vinculin). CONCLUSION: Our results suggested that syncytin-1 may promote aggressive behavior and can serve as a novel prognostic biomarker for EC. Our study provides new insights into the regulatory mechanism of EMT signaling.

PIK3CA and PIK3CB silencing by RNAi reverse MDR and inhibit tumorigenic properties in human colorectal carcinoma.

Colorectal carcinoma (CRC) is the second most common and frequent cause of cancer-related deaths for men and women in the world. PIK3CA and PIK3CB that reverse multidrug resistance (MDR) can serve as predictive and prognostic markers as well as therapeutic targets for CRC treatment. In the present study, we showed that PIK3CA and PIK3CB are upregulated in CRCs and positively correlated with MDR-1, LRP, and GST-π. Long-term monitoring of 316 CRC patients showed that PIK3CA and PIK3CB were associated with poor survival time as shown by Kaplan-Meier analysis. Furthermore, we found that the downregulation of PIK3CA and PIK3CB reversed MDR; inhibited the capability of proliferation, migration, and invasion of CRC cells; and slowed down the CRC tumor growth in nude mice. Consistent with clinical observations, PIK3CA and PIK3CB significantly increase multidrug resistance of CRC cells in vivo. Together, these results suggest that PIK3CA and PIK3CB may be used as potential therapeutic drug targets for colorectal cancer.

PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma.

The phosphoinositide 3-kinases (PI3Ks) are a critical family of signaling enzymes that participate in many cellular processes that promote the transformation of a normal cell into a cancer cell. These processes include cancer cell proliferation, migration, and invasion. However, the correlation between PI3Ks and multidrug resistance (MDR) remains unclear. The prognostic value of PI3Ks has not been previously evaluated. Thus, this study aims to evaluate the association between PIK3CA and PIK3CB expression and the MDR gene in colorectal cancer (CRC) patients. Immunohistochemistry was employed to detect the expressions of PIK3CA, PIK3CB, MDR-1, LRP, GST-π, and Topo II in 316 CRC specimens. Patients were followed-up annually by telephone or at an outpatient clinic. Results revealed that PIK3CA and PIK3CB expression was correlated with the degree of tumor differentiation and lymph node metastasis (P < 0.05). The overexpression of MDR-1, LRP, Topo II, and GST-π was found to be 72.78%, 70.89%, 77.53%, and 76.58% of CRC, respectively. Correlation analysis showed that PIK3CA and PIK3CB expression exhibits a positive correlation with MDR-1, LRP, and GST-π with correlation coefficients of 0.288, 0.128, and 0.197, respectively (P < 0.05). Kaplan-Meier analysis revealed that the five-year survival rate of patients without lymph node metastasis, positive expression of PIK3CA and PIK3CB, and negative expression of GST-π and MDR-1 was higher than those with these characteristics. Multivariate analysis revealed that GST-π, MDR-1 expression, and lymph node metastasis could serve as independent predictive factors of overall survival. The expression of both PIK3CA and PIK3CB is increased and related to the development and progress of colorectal carcinoma and MDR. The combined detection of PIK3CA andPIK3CB is important for patients with colorectal carcinoma in prognosis and optimal therapy.