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Hydrogen sulfide (H2S) has been highlighted as an important gasotransmitter in mammals. A growing number of studies have indicated that H2S plays a key role in the pathophysiology of vascular diseases and physiological vascular homeostasis. Alteration in H2S biogenesis has been reported in a variety of vascular diseases and H2S supplementation exerts effects of vasodilation. Accumulating evidence has shown vascular potassium channels activation is involved in H2S-induced vasodilation. This review aimed to summarize and discuss the role of H2S in the regulation of vascular tone, especially by interaction with different vascular potassium channels and the underlying mechanisms.

PurposeThe purpose of the current study was to analyze the effect of intraoperative blood loss (IBL) and intraoperative blood transfusion (IBT) on the short-term outcomes and prognosis for patients who underwent primary colorectal cancer (CRC) surgery.MethodsWe retrospectively collected the patients' information from the database of a teaching hospital from January 2011 to January 2020. IBL and IBT were collected and analyzed, and the propensity score matching (PSM) analysis was performed.ResultsA total of 4,250 patients with CRC were included in this study. There were 1,911 patients in the larger IBL group and 2,339 patients in the smaller IBL group. As for IBT, there were 82 patients in the IBT group and 4,168 patients in the non-IBT group. After 1:1 ratio PSM, there were 82 patients in the IBT group and 82 patients in the non-IBT group. The larger IBL group had longer operation time (p = 0.000 < 0.01), longer post-operative hospital stay (p = 0.000 < 0.01), smaller retrieved lymph nodes (p = 0.000 < 0.01), and higher overall complication (p = 0.000 < 0.01) than the smaller IBL group. The IBT group had longer operation time (p = 0.000 < 0.01), longer hospital stay (p = 0.016 < 0.05), and higher overall complications (p = 0.013 < 0.05) compared with the non-IBT group in terms of short-term outcomes. Larger IBL (p = 0.000, HR = 1.352, 95% CI = 1.142–1.601) and IBT (p = 0.044, HR = 1.487, 95% CI = 1.011–2.188) were independent predictive factors of overall survival (OS). Larger IBL (p = 0.000, HR = 1.338, 95% CI = 1.150–1.558) was an independent predictor of disease-free survival (DFS); however, IBT (p = 0.179, HR = 1.300, 95% CI = 0.886–1.908) was not an independent predictor of DFS.ConclusionBased on the short-term outcomes and prognosis of IBL and IBT, surgeons should be cautious during the operation and more careful and proficient surgical skills are required for surgeons.

PurposeThe purpose of this meta-analysis was to analyze whether chronic kidney disease (CKD) affected the complications and prognosis after liver resection for hepatocellular carcinoma.MethodsThe PubMed, Embase, and Cochrane Library databases were searched from inception to 22 February 2022 to find eligible studies. Complications, overall survival (OS), and disease-free survival (DFS) were collected, and this meta-analysis was performed with RevMan 5.3.ResultsA total of nine studies including 6,541 patients were included in this meta-analysis. After pooling all baseline information, the CKD group had a higher rate of Child-Pugh grade B than the Non-CKD group (OR = 1.58, 95% CI = 1.3 to 1.93, P < 0.00001). As for surgery-related information, the CKD group had larger blood loss (MD = −404.79, 95% CI = −509.70 to −299.88, P < 0.00001), and higher rate of blood transfusion (OR = 2.47, 95% CI = 1.85 to 3.3, P < 0.00001). In terms of complications, the CKD group had a higher rate of overall complications (OR = 2.1, 95% CI = 1.57 to 2.81, P < 0.00001) and a higher rate of ≥ grade III complications (OR = 2.04, 95% CI = 1.57 to 2.81, P = 0.0002). The CKD group had poor OS compared with the non-CKD group (HR = 1.28, 95% CI = 1.1 to 1.49, P = 0.001). However, in terms of DFS, no significant difference was found (HR = 1.11, 95% CI = 0.96 to 1.28, P = 0.16).ConclusionPreexisting CKD was associated with higher ratio of complications and poor OS.

Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.

Atrial fibrillation (AF) is one of the most common arrhythmias in medical practice. Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation. The increased morbility of atrial fibrillation in diabetes mellitus is related to both structural and electrical remodeling of atrium. Based on studies of atrial electrophysiological changes in diabetes mellitus, this article focuses on the electrical remodeling of atrial cardiomyocytes, including remodeling of sodium channels, calcium channels, potassium channels and other channels, to provide the basis for the clinical management of antiarrhythmic drugs in diabetic patients with atrial fibrillation.

Abstract Background Thromboembolism is a life-threatening, limb-threatening or organ-threatening complication that occurs in patients with primary nephrotic syndrome (NS). There are few studies on the spectrum, complications and outcomes of thrombosis in children with NS. This study aimed to determine the spectrum of thrombosis and its relationship with the nephrotic state, treatment and outcomes in children and adolescents with primary NS. Methods The medical records of subjects aged 1–18 years with NS complicated with thromboembolism treated at our centre within the last 26 years were retrieved. Data on the status of NS, site, symptoms and signs, laboratory investigations, diagnosis, treatment, complications and outcomes of thrombosis were collected and reviewed retrospectively. A severe complication was defined as a condition associated with thrombosis requiring a special diagnostic modality to confirm or a specific treatment such as surgical intervention. The outcome of thrombosis was defined as the status of thrombosis, as determined by imaging methods and the functional status with respect to the anatomic sites of thrombosis at the last follow-up. The permanent dysfunction of an organ or limb related to thrombosis was defined as a sequela. Results We observed thrombosis in 1.4% (27/1995) of subjects with NS during the study period. There were 27 subjects with thrombosis, including 21 males and 6 females. Thrombosis was observed in 51.9% (14/27) of the study participants with steroid resistant NS. Most episodes of thrombosis occurred during the active stage of NS; however, 7.4% of thrombosis cases occurred during the remission of proteinuria. Renal vein thrombosis (33.3%) and pulmonary embolism (25.9%) were the most common types of thrombosis. Among the 17 subjects biopsied, minimal change disease and membranous nephropathy were the two most common findings. Six (22.2%) subjects experienced severe complications or sequelae; 1 had persistent intracranial hypertension, 1 had intestinal perforation, 1 had hypoxemia and pulmonary hypertension, 1 had lameness, 1 had epilepsy, and 1 had an askew mouth due to facial paralysis. In 19 (70.4%) subjects, the symptoms resolved completely or improved without severe complications or sequelae. Conclusions Thrombosis mostly occurred in males of school age during the active stage of NS. Renal vein thrombosis and pulmonary embolism were the most common types of thrombosis. In most patients with thrombosis, the symptoms improved completely without complications with standard anticoagulation therapy. However, 22.2% had severe complications or sequelae requiring an advanced diagnostic modality and aggressive treatment.

Dynamic arrangement of epigenetic modifications such as repressive H3K27 methylation is essential for zygote development. Here the authors show that establishment of genome-wide H3K27me3 in zygotes requires EZH2, that EZH1 partially compensates for EZH2 loss, and that EHMT1 is involved in H3K27me2 establishment.

PurposeThe current study aims to explore the outcomes of type 2 diabetes mellitus (T2DM) on gastric cancer patients following gastrectomy through propensity score matching (PSM) analysis.MethodsA retrospective study of gastric cancer patients following gastrectomy was conducted in a single clinical center from January 2014 to December 2019. The short-term outcomes, overall survival (OS) and disease-free survival (DFS) were analyzed between T2DM group and Non-T2DM group.ResultsA total of 703 patients were enrolled in this study. After 1:1 PSM, 84 patients in T2DM group and 84 patients in Non-T2DM were matched for final analysis. No significant difference was found in terms of operation time, intra-operative blood loss, retrieved lymph nodes, postoperative stay, blood transfusion and complications between T2DM group and Non-T2DM group (p > 0.05). The Kaplan-Meier curve implied that T2DM had no impact on OS or DFS. Cox regression was conducted to identify predictive factors for prognosis. Body mass index (BMI) (p = 0.039 < 0.05, HR = 0.725, 95% CI = 0.534–0.983), pre-operative lymphocyte (p = 0.017 < 0.05, HR = 0.678, 95% CI = 0.493–0.932), pathological tumor node metastasis (pTNM) stage (p = 0.000 < 0.05, HR = 2.619, 95% CI = 2.048–3.349) and complications (p = 0.006 < 0.05, HR = 1.528, 95% CI = 1.132–2.061) were predictive factors for OS, and BMI (p = 0.013 < 0.05, HR = 0.524, 95% CI = 0.315–0.872), pTNM stage (p = 0.000 < 0.05, HR = 2.619, 95% CI = 2.048–3.349) and complications (p = 0.008 < 0.05, HR = 1.892, 95% CI = 1.179–3.036) were independent predictive factors for DFS.ConclusionT2DM did not have an impact on gastric cancer patients following gastrectomy in terms of short-term outcomes and prognosis.

Background: YTHDF1 is highly expressed in multiple tumors and affects tumor progression. However, there are only a few comprehensive studies on the analysis of YTHDF1 in esophageal cancer.Methods: We analyzed YTHDF1 expression in pan-cancer by comparing both the GEPIA and TCGA cohorts, and further verified the differences in YTHDF1 expression between the ESCA and normal groups by the GEO ESCA cohort and in vitro experiments. The correlation of YTHDF1 expression and the clinical characteristics of ESCA patients was analyzed using the TCGA ESCA clinical data. The GO and KEGG enrichment analyses of the YTHDF1 coexpressed genes were completed by bioinformatics analysis, and the GGI and PPI were constructed for the YTHDF1, respectively. The relationship between YTHDF1 expression and the infiltration of ESCA immune cells was analyzed by using the TIMER database and the TCGA ESCA cohort. The relationships between YTHDF1 expression levels and glycolysis and ferroptosis-related genes were analyzed using the TCGA and GEPIA ESCA cohorts. Finally, the ceRNA network that may be involved in YTHDF1 in ESCA was predicted and constructed through a variety of databases.Results: YTHDF1 was overexpressed in various cancers, and in vitro experiments confirmed that YTHDF1 expression was higher in ESCA samples than in normal samples. The expression of YTHDF1 has some accuracy in predicting the tumor outcome. Expression of YTHDF1 was significantly associated with multiple clinical features in ESCA patients. GO and KEGG enrichment analyses indicated that YTHDF1 coexpressed genes involved multiple biological functions. There is a potential association between YTHDF1 expression and multiple immune cell infiltration, glycolysis, and ferroptosis-related genes in ESCA. YTHDF1 may be involved in multiple ceRNA regulatory networks in ESCA, including PAXIP1-AS1/hsa-miR-376c-3p/YTHDF1 axis, THUMPD3-AS1/hsa-miR-655-3p/YTHDF1 axis, and SNHG20/hsa-miR-655-3p/YTHDF1 axis, respectively.Conclusion: YTHDF1 can serve as a biomarker of ESCA, related to the immune cell infiltration of ESCA, regulation of glycolysis and ferroptosis, and the ceRNA regulatory network.

Background: Overexpression of solute carrier family 2 member 1 (SLC2A1) promotes glycolysis and proliferation and migration of various tumors. However, there are few comprehensive studies on SLC2A1 in colorectal cancer (CRC).Methods: Oncomine, The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases were used to analyze the expression of SLC2A1 in pan-cancer and CRC and analyzed the correlation between SLC2A1 expression and clinical characteristics of TCGA CRC samples. The expression level of SLC2A1 in CRC was certified by cell experiments and immunohistochemical staining analysis. The Genome Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses of SLC2A1 relative genes were completed by bioinformatics analysis. The correlation between SLC2A1 expression level and CRC immune infiltration cell was analyzed by Tumor IMmune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), and TCGA database. The correlation between SLC2A1 expression level and ferroptosis and m6A modification of CRC was analyzed by utilizing TCGA and GEO cohort. Finally, the possible competing endogenous RNA (ceRNA) networks involved in SLC2A1 in CRC are predicted and constructed through various databases.Results: SLC2A1 is highly expressed not only in CRC but also in many other tumors. ROC curve indicated that SLC2A1 had high predictive accuracy for the outcomes of tumor. The SLC2A1 expression in CRC was closely correlated with tumor stage and progression free interval (PFI). GO, KEGG, and GSEA analysis indicated that SLC2A1 relative genes were involved in multiple biological functions. The analysis of TIMER, GEPIA, and TCGA database indicated that the SLC2A1 mRNA expression was mainly positively associated with neutrophils. By the analysis of the TCGA and GEO cohort, we identified that the expression of SLC2A1 is closely associated to an m6A modification relative gene Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3) and a ferroptosis relative gene Glutathione Peroxidase 4 (GPX4).Conclusion: SLC2A1 can be used as a biomarker of CRC, which is associated to immune infiltration, m6A modification, ferroptosis, and ceRNA regulatory network of CRC.

Purpose. The purpose of this study is to analyze the effect of preoperative waiting time on the short-term outcomes and prognosis in colorectal cancer (CRC) patients. Methods. We retrospectively analyzed 3744 CRC patients who underwent primary CRC surgery at a single clinical medical center from Jan 2011 to Jan 2020. The baseline information, short-term outcomes, overall survival (OS), and disease-free survival (DFS) were compared among the short-waiting group, the intermediate-waiting group, and the long-waiting group. Results. A total of 3744 eligible CRC patients were enrolled for analysis. There were no significant differences in all of the baseline information and short-term outcomes among the three groups. In multivariate analysis, older age (OS: p=0.000, HR = 1.947, 95% CI = 1.631–2.324; DFS: p=0.000, HR = 1.693, 95% CI = 1.445–1.983), advanced clinical stage (OS: p=0.000, HR = 1.301, 95% CI = 1.161–1.457; DFS: p=0.000, HR = 1.262, 95% CI = 1.139–1.400), overall complications (OS: p=0.000, HR = 1.613, 95% CI = 1.303–1.895; DFS: p=0.000, HR = 1.560, 95% CI = 1.312–1.855), and major complications (OS: p=0.001, HR = 1.812, 95% CI = 1.338–2.945; DFS: p=0.006, HR = 1.647, 95% CI = 1.153–2.352) were independent factors of OS and DFS. In addition, no significant difference was found in all stages (OS, p=0.203; DFS, p=0.108), stage I (OS, p=0.419; DFS, p=0.579), stage II (OS, p=0.465; DFS, p=0.385), or stage III (OS, p=0.539; DFS, p=0.259) in terms of OS and DFS among the three groups. Conclusion. Preoperative waiting time did not affect the short-term outcomes or prognosis in CRC patients.

Abstract Purpose Hepatocellular carcinoma (HCC) is a common malignant cancer and the third leading cause of death worldwide. The molecular mechanism of HCC remains unclear. Recent studies have demonstrated that the ubiquitin‐proteasome system (UPS) is associated with HCC. Ubqln2, a member of the UPS, is abnormally expressed in HCC. However, whether Ubqln2 is associated with HCC prognosis remains unknown. Patients and Methods We analyzed the associations between overall survival and various risk factors in 355 HCC tissue samples obtained from the Cancer Genomic Atlas (TCGA) database at the mRNA level and in 166 HCC tissue samples from Southwest Hospital at the protein level. qRCR was used to determinate Ubqln2 expression in cancer and noncancerous tissues. The association between Ubqln2 and Ki‐67 was analyzed by immunohistochemistry. The association between Ubqln2 expression and survival was analyzed using Kaplan‐Meier curve and Cox proportional hazards models. A nomogram was used to predict the impact of Ubqln2 on prognosis. Mutated genes were analyzed to determine the potential mechanism. Results Ubqln2 highly expressed in HCC tissues. The Ubqln2 mRNA level had significant relations with UICC tumor stage (P = .022), UICC stage (P = .034) and resection potential (P = .017). Concordantly, the Ubqln2 protein was closely associated with tumor size (P = .005), UICC stage (P = .012), and recurrence (P = .009). Ubqln2 was highly expressed in HCC and positively associated with poor survival. The nomogram precisely predicted the prognosis of HCC patients with high or low Ubqln2 expression. A genomic waterfall plot suggested that Ubqln2 expression was closely associated with mutated CTNNB1. Conclusion Our findings reveal that Ubqln2, an independent risk factor for HCC, is a potential prognostic marker in HCC patients. Ubqln2 expression is positively associated with mutated CTNNB1.

Background: The incidence of silent cerebral embolisms (SCEs) has been documented after pulmonary vein isolation using different ablation technologies; however, it is unreported in patients undergoing with atrial fibrillation (AF) ablation using Robotic Magnetic Navigation (RMN). The purpose of this prospective study was to investigate the incidence, risk predictors and probable mechanisms of SCEs in patients with AF ablation and the potential impact of RMN on SCE rates.Methods and Results: We performed a prospective study of 166 patients with paroxysmal or persistent AF who underwent pulmonary vein isolation. Patients were divided into RMN group (n = 104) and manual control (MC) group (n = 62), and analyzed for their demographic, medical, echocardiographic, and risk predictors of SCEs. All patients underwent cerebral magnetic resonance imaging within 48 h before and after the ablation procedure to assess cerebral embolism. The incidence and potential risk factors of SCEs were compared between the two groups. There were 26 total cases of SCEs in this study, including 6 cases in the RMN group and 20 cases in the MC group. The incidences of SCEs in the RMN group and the MC group were 5.77 and 32.26%, respectively (X2 = 20.63 P < 0.05). Univariate logistic regression analysis demonstrated that ablation technology, CHA2DS2-VASc score, history of cerebrovascular accident/transient ischemic attack, and low ejection fraction were significantly associated with SCEs, and multivariate logistic regression analysis showed that MC ablation was the only independent risk factor of SCEs after an AF ablation procedure.Conclusions: Ablation technology, CHA2DS2-VASc score, history of cerebrovascular accident/transient ischemic attack, and low ejection fraction are associated with SCEs. However, ablation technology is the only independent risk factor of SCEs and RMN can significantly reduce the incidence of SCEs resulting from AF ablation.Clinical Trial Registration: ChiCTR2100046505.

Background: The purpose of this study was to explore the effect of abdominal shape on the short-term surgical outcomes.Methods: This was a retrospective study that included 425 patients undergoing laparoscopic distal gastrectomy plus D2 lymph node dissection (LADG) from January 2013 to January 2021. The abdominal parameters, including the shortest distance of the pancreas from the anterior abdominal skin (PAAD), the lower sternum angle (LSA), the thickness of the subcutaneous fat at the navel level (SFT), the anteroposterior diameters (APD) and the left-right diameters (LRD) at the navel level, the distance from the xiphoid process to the navel (XND) and the distance from the xiphoid process to the pubis (XBD), were calculated by preoperative abdominal computed tomography (CT) imaging. The parameters and short-term surgical outcomes were analyzed.Results: In males, the number of retrieved lymph nodes was significantly higher in patients with a lower APD group (p = 0.031). The operation time was significantly shorter in the lower body mass index (BMI) (p = 0.007), lower LSA (p = 0.035), lower PAAD (p = 0.000), lower SFT (p = 0.004), lower APD (p = 0.000) and lower LRD (p = 0.014) groups. The estimated blood loss was significantly less in the lower BMI (p = 0.035), lower LSA (p = 0.001), lower PAAD (p = 0.012), lower SFT (p = 0.003), lower APD (p = 0.000) and lower LRD (p = 0.005) groups. The complications were fewer in the lower LSA (p = 0.012), lower APD (p = 0.043) and lower LRD (p = 0.023) groups. In females, the postoperative hospital stay was shorter in the lower PAAD (p = 0.027) and lower SFT (p = 0.004) groups, and the lower SFT group had fewer complications (p = 0.020). Furthermore, in multivariate analysis, higher PAAD (p = 0.037, odds ratio = 1.030, 95% CI = 1.002–1.059) was an independent factor for predicting postoperative complications in males.Conclusion: Various abdominal shapes can affect the difficulty of LADG. Higher PAAD is a simple independent index for predicting postoperative complications in males.

The sodium pump α3 subunit is associated with colorectal liver metastasis. However, the underlying mechanism involved in this effect is not yet known. In this study, we found that the expression levels of the sodium pump α3 subunit were positively associated with metastasis in colorectal cancer (CRC). Knockdown of the α3 subunit or inhibition of the sodium pump could significantly inhibit the migration of colorectal cancer cells, whereas overexpression of the α3 subunit promoted colorectal cancer cell migration. Mechanistically, the α3 subunit decreased p53 expression, which subsequently downregulated PTEN/IGFBP3 and activated mTOR, leading to the promotion of colorectal cancer cell metastasis. Reciprocally, knockdown of the α3 subunit or inhibition of the sodium pump dramatically blocked this effect in vitro and in vivo via the downregulation of mTOR activity. Furthermore, a positive correlation between α3 subunit expression and mTOR activity was observed in an aggressive CRC subtype. Conclusions: Elevated expression of the sodium pump α3 subunit promotes CRC liver metastasis via the PTEN/IGFBP3-mediated mTOR pathway, suggesting that sodium pump α3 could represent a critical prognostic marker and/or therapeutic target for this disease.

Diutina catenulata (Candida catenulata) is an ascomycete yeast species widely used in environmental and industrial research and capable of causing infections in humans and animals. At present, there are only a few studies on D. catenulata, and further research is required for its more in-depth characterization and analysis. Eleven strains of D. catenulata collected from China Hospital Invasive Fungal Surveillance Net (CHIF-NET) and the CHIF-NET North China Program were identified using matrix-assisted laser desorption ionization–time of flight mass spectrometry and internal transcribed spacer sequencing. The antifungal susceptibility of the Diutina catenulata strains was tested using the Clinical and Laboratory Standards Institute broth microdilution method and Sensititre YeastOne™. Furthermore, ERG11 and FKS1 were sequenced to determine any mutations related to azole and echinocandin resistance in D. catenulata. All isolates exhibited low minimum inhibitory concentration (MIC) values for itraconazole (0.06–0.12 μg/ml), posaconazole (0.06–0.12 μg/ml), amphotericin B (0.25–1 μg/ml), and 5-flucytosine (range,

PurposeThe purpose of the current meta-analysis is to analyze whether extended intraoperative peritoneal lavage (EIPL) can bring benefit on short-term outcomes or survival for patients undergoing curative gastrectomy for gastric cancer.MethodsThe PubMed, Embase, and Cochrane Library databases were searched from inception to May 3, 2021, to find eligible studies. Postoperative complications, overall survival (OS), disease-free survival (DFS), and peritoneal recurrence–free survival (PRFS) were compared between EIPL group and No EIPL group.ResultsA total of five randomized controlled trials with 1,790 patients were included in the current meta-analysis. No difference was found in baseline information (p > 0.05). After pooling up the data of overall postoperative complications, no significant difference was found between EIPL group and No EIPL group (OR = 0.88, 95% CI = 0.51 to 1.53, P = 0.65). Furthermore, there was no significant difference between EIPL group and No EIPL group in terms of OS (HR = 0.77, 95% CI = 0.36 to 1.64, P = 0.49), DFS (HR = 0.97, 95% CI = 0.71 to 1.33, P = 0.87), and PRFS (HR = 1.03, 95% CI = 0.74 to 1.43, P = 0.86). In terms of subgroup analysis of OS, no significant difference was found as well (HR = 1.05, 95% CI = 0.82 to 1.34, P = 0.69).ConclusionsEIPL did not bring benefit in terms of short-term outcomes or survival. Therefore, EIPL is not recommended for patients undergoing curative gastrectomy for gastric cancer.

PurposeThe purpose of the current study was to evaluate the impact of colorectal cancer (CRC) surgery on type 2 diabetes mellitus (T2DM) and to analyze the change in T2DM on overall survival after CRC surgery.MethodsPatients who underwent CRC surgery were retrospectively enrolled from January 2013 to December 2019. The status of T2DM pre- and 1-year after CRC surgery was recorded, and predictive factors for T2DM remission and overall survival were analyzed.ResultsA total of 296 patients were included in this study. Thirty-eight patients experienced remission of T2DM 1 year after CRC surgery, and the remission rate was 12.8%. Weight loss was significantly higher in the T2DM remission group (p = 0.038), and the T2DM duration was significantly shorter in the T2DM remission group (p = 0.015). In the multivariate logistic regression analysis, higher weight loss (p = 0.046, odds ratio = 1.060, 95% CI = 1.001–1.122) and shorter T2DM duration (p = 0.019, odds ratio = 1007, 95% CI = 1.001–1.014) were predictive factors for remission of T2DM. Furthermore, in multivariate Cox regression analysis, lower TNM stage (p = 0.000, odds ratio = 2.147, 95% CI = 1.474–3.128) and T2DM remission (p = 0.033, odds ratio = 2.999, 95% CI = 1.091–8.243) were the predictive factors for better overall survival.ConclusionPatients with concurrent CRC and T2DM had a 12.8% remission 1 year after CRC surgery. Higher weight loss and shorter T2DM duration contributed to T2DM remission, and patients with T2DM remission could improve in terms of their overall survival.

BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (HNRNPC) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

Polyacrylamide (PAM)/polyethyleneimine (PEI) gels doped with graphene oxide (GO) were prepared. Their structure and properties were systematically studied by X-ray diffraction (XRD), Fourier transition infrared spectrum (FT-IR), Raman spectroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and rheological experiments. The results showed that the graphene oxide (GO) nanosheets were significantly involved in the cross-linking reaction between the main agent (PAM) and the cross-linker (PEI), serving as multi-functional cross-linker and effective reinforcing nanofillers. Increasing the main agent and cross-linker content, the strength of gels was enhanced effectively. The GO could effectively adjust the strength and the gelation time to exhibit characteristics of weak gel, thanks to the improved three-dimensional honeycombed structure with controllable pore size. The DSC confirmed that the PAM/PEI/GO gel exhibited excellent thermal stability and did not dehydrate above 170 °C. This work provides theoretical support for further optimization of polyacrylamide gel used in ultra-deep and high-temperature reservoirs for water control.

BackgroundGlucose transporter 1 (GLUT1) is encoded by the solute carrier family 2A1 (SLC2A1) gene and is one of the glucose transporters with the greatest affinity for glucose. Abnormal expression of GLUT1 is associated with a variety of cancers. However, the biological role of GLUT1 in esophageal carcinoma (ESCA) remains to be determined.MethodsWe analyzed the expression of GLUT1 in pan-cancer and ESCA as well as clinicopathological analysis through multiple databases. Use R and STRING to perform GO/KEGG function enrichment and PPI analysis for GLUT1 co-expression. TIMER and CIBERSORT were used to analyze the relationship between GLUT1 expression and immune infiltration in ESCA. The TCGA ESCA cohort was used to analyze the relationship between GLUT1 expression and m6A modification in ESCA, and to construct a regulatory network in line with the ceRNA hypothesis.ResultsGLUT1 is highly expressed in a variety of tumors including ESCA, and is closely related to histological types and histological grade. GO/KEGG functional enrichment analysis revealed that GLUT1 is closely related to structural constituent of cytoskeleton, intermediate filament binding, cell-cell adheres junction, epidermis development, and P53 signaling pathway. PPI shows that GLUT1 is closely related to TP53, GIPC1 and INS, and these three proteins all play an important role in tumor proliferation. CIBERSORT analysis showed that GLUT1 expression is related to the infiltration of multiple immune cells. When GLUT1 is highly expressed, the number of memory B cells decreases. ESCA cohort analysis found that GLUT1 expression was related to 7 m6A modifier genes. Six possible crRNA networks in ESCA were constructed by correlation analysis, and all these ceRNA networks contained GLUT1.ConclusionGLUT1 can be used as a biomarker for the diagnosis and treatment of ESCA, and is related to tumor immune infiltration, m6A modification and ceRNA network.

Diabetic cardiomyopathy (DCM) is characterized by cardiac hypertrophy, fibrosis, oxidative stress and inflammation. Trimetazidine (TMZ), a potent metabolism modulator, has been shown to be cardioprotective in experimental models of ischaemia-reperfusion and type 2 diabetes-induced cardiomyopathy. The present study examined whether TMZ inhibits cardiomyopathy induced by insulin-dependent type 1 diabetes. Wistar rats were randomly divided into control group (vehicle alone), diabetes mellitus (DM; induced by streptozocin (STZ) injection) group and DM treated with TMZ (DM/TMZ) group. Cardiac function, histology, plasma biochemistry and molecular mechanism were assessed. STZ induced diabetes in rats as indicated by hyperglycemia, increased and decreased levels of advanced glycation end products (AGEs) and insulin respectively. Diabetic rats were characterized by left ventricular dysfunction, cardiachypertrophy and fibrosis and signs of inflammation and oxidative stress in the myocardium, which were accompanied by elevated levels of NADPH oxidase 2 (Nox2) and transient receptor potential channel 3 (TRPC3) in the heart. TMZ treatment ameliorated diabetes-associated structural and functional alterations by inhibiting Nox2 and TRPC3 without having any effects on glucose, insulin and AGEs levels. These results suggest that TMZ could be used as a therapy to treat cardiomyopathy associated with type 1 induced diabetes mellitus. Keywords: Diabetic cardiomyopathy, Trimetazidine, NADPH oxidase 2, Transient receptor potential channel 3, Oxidative stress

Abstract It is well recognized that osteocytes communicate with each other via gap junctions and that connxin43 (Cx43) shows its great potential in gap junction for the contribution enabling transmission of small molecules and operating in an autocrine/a paracrine manner. Fibroblast growth factors (FGFs) play significant roles in new bone formation and adult bone remodeling, and FGF signaling is regulated by the precise spatiotemporal approaches. However, the influence of FGF7 on osteocyte cell processes is not well elucidated. In this study, we aimed to examine the impact of FGF7 on osteocyte cell processes by characterizing the expression of Cx43 and to reveal the underlying mechanism regulating this cell process. We first found that the mRNA level of FGF7 was higher relative to other FGF family members both in osteocytes cell line (MLO-Y4) and bone tissue. We then demonstrated that FGF7 could increase the expression of Cx43 in osteocytes and promote the cell processes in the form of gap junctions between osteocytes. This modulation was due to the FGF7-induced cytoplasmic accumulation and resultant nuclear translocation of β-catenin. Our results could help us to further understand the importance of FGF7 on bone cell behavior and bone physiology and even pathology.

Diabetic coronary arterial disease is a leading cause of morbidity and mortality in diabetic patients. The impaired function of large-conductance calcium-activated potassium channels (BK channels) is involved in diabetic coronary arterial disease. Many studies have indicated that the reduced BK channel expression in diabetic coronary artery is attributed to ubiquitin-mediated protein degradation by the ubiquitin–proteasome system. This review focuses on the influence and the mechanisms of BK channel regulation by E3 ubiquitin ligases in diabetic coronary arterial disease. Thus, BK channels regulated by E3 ubiquitin ligase may play a pivotal role in the coronary pathogenesis of diabetic mellitus and, as such, is a potentially attractive target for therapeutic intervention.

We aimed to profile the metabolism of soybean roots that were infected with soybean cyst nematodes and treated with Bacillus simplex to identify metabolic differences that may explain nematode resistance. Compared with control soybean roots, B. simplex-treated soybean roots contained lower levels of glucose, fructose, sucrose, and trehalose, which reduced the nematodes' food source. Furthermore, treatment with B. simplex led to higher levels of melibiose, gluconic acid, lactic acid, phytosphingosine, and noradrenaline in soybean roots, which promoted nematocidal activity. The levels of oxoproline, maltose, and galactose were lowered after B. simplex treatment, which improved disease resistance. Collectively, this study provides insight into the metabolic alterations induced by B. simplex treatment, which affects the interactions with soybean cyst nematodes.

Icariside II (ICA II), a flavonoid derived from Epimediumbrevicormum Maxin in, has multiple biological activities in Chinese traditional medicine. Our study aimed to investigate the potential activity of ICA II against cardiac remodeling and the underlying mechanism. Mice received aorta banding (AB) or sham surgery, and then were randomly divided into ICA II or vehicle (veh) group for 6 weeks. After echocardiography and pressure-volume loop examination, hearts were harvested for histopathological analysis and molecular mechanism investigation. Additionally, neonatal rat cardiomyocytes (NRCM) were used for in vitro experiments. ICA II attenuated the systolic and diastolic cardiac dysfunction, and protected mouse heart from hypertrophy and fibrosis. The underlying mechanism might involve in the regulation of Akt, AMPKα and mTORC. In in vitro experiment, ICA II prevented phenylephrine (PE) induced NRCM hypertrophy by regulating AMPKα/mTORC pathway. This protective effect was disappeared after treatment with Compound C (CpC), an AMPKα inhibitor. Moreover, ICA II activated AMPK at baseline. ICAII was superior to resveratrol in activating AMPKα and similar to AICAR. ICA II protected against cardiac remodeling and NRCM hypertrophy by regulating AMPK/mTORC pathway. ICA II may be a candidate for the treatment of malignant cardiac remodeling. Keywords: Icariside II, Cardiac remodeling, AMPK/mTORC, Cardiomyocyte

Objective To summarize clinical and pathological features, diagnosis and differential diagnosis, as well as treatment and prognosis through analyzing one case of collision tumor in the sellar region (pituitary adenoma combined with malignant triton tumor). Methods and Results A 59-year-old male was admitted to hospital with decreased vision, vision field defect and dizziness. Head MRI demonstrated space-occupying lesion in the sellar region. Therefore, the patient underwent a transsphenoidal surgery with subtotal tumor resection. Three months later, the patient was admitted to hospital again with vision loss and headache. Head CT demonstrated space-occupying lesions in sellar/suprasellar region, therefore, the patient underwent saddle tumor resection. Histological findings revealed that the tumor was composed of two different types of tumors, one was pituitary adenoma with epithelial cells arranged in nest-like and trabecular pattern, and the other was diffused spindle cell tumor. The two tumors were distributed separately or mixed togenther. The morphology of spindle cell tumor was bland with scarce mitosis in the first surgery, whereas additional features including increased cell density, dark nuclei, frequent mitosis and scattering distributed rhabdomyoblasts were found in the second surgery. Immunohistochemically, the pituitary adenoma (epithelial cell region) cells were positive for cytokeratin 8 (CK8), chromogranin A (CgA), synaptophysin (Syn) and thyroid stimulating hormone (TSH), while the malignant triton tumor cells (spindle cell region) were positive for CD56, CD57, calretinin (CR) and focally positive for S-100 protein (S-100), desmin (Des) and myogenin. Ultrastructural findings revealed abundant rough endoplasmic reticules and secretary granules in the cytoplasm of pituitary adenoma cells, and discontinuous basal lamina located outside the spindle cell membrane. The final pathological diagnosis was sellar collision tumor (non-functional TSH adenoma combined with malignant triton tumor). The patient died 6 months after the second surgery. Conclusions Collision tumor of the sellar region with pituitary adenoma and malignant triton tumor is a rare tumor which can hardly be diagnosed by clinical and neuroimaging examination. The diagnosis relies on morphological characteristics, immunophenotype and ultrastructural features. The prognosis of collision tumor with malignant triton tumor component is poor. DOI: 10.3969/j.issn.1672-6731.2017.11.009

Identifying molecular mechanisms that regulate insulin expression in bone marrow-derived mesenchymal stem cells (bmMSCs) can provide clues on how to stimulate the differentiation of bmMSCs into insulin-producing cells (IPCs), which can be used as a therapeutic approach against type 1 diabetes (T1D). As repression factors may inhibit differentiation, the efficiency of this process is insufficient for cell transplantation. In this study, we used the mouse insulin 2 (Ins2) promoter sequence and performed a DNA affinity precipitation assay combined with liquid chromatography-mass spectrometry to identify the transcription factor, chicken ovalbumin upstream promoter transcriptional factor I (COUP-TFI). Functionally, bmMSCs were reprogrammed into IPCs via COUP-TFI suppression and MafA overexpression. The differentiated cells expressed higher levels of genes specific for islet endocrine cells, and they released C-peptide and insulin in response to glucose stimulation. Transplantation of IPCs into streptozotocin-induced diabetic mice caused a reduction in hyperglycemia. Mechanistically, COUP-TFI bound to the DR1 (direct repeats with 1 spacer) element in the Ins2 promoter, thereby negatively regulating promoter activity. Taken together, the data provide a novel mechanism by which COUP-TFI acts as a negative regulator in the Ins2 promoter. The differentiation of bmMSCs into IPCs could be improved by knockdown of COUP-TFI, which may provide a novel stem cell-based therapy for T1D. Keywords: siRNAs, differentiation, stem cell transplantation, diabetes, mesenchymal stem cells

Objective To study the clinicopathologic features, diagnosis, differential diagnosis, treatment and prognosis of intramedullary melanotic schwannoma (IMS). Methods and Results A 47-year-old male underwent an excision of thoracic intraspinal space-occupying lesion 6 years ago and was admitted to the hospital with a history of low back pain for one year. Spinal MRI revealed an intramedullary mass at the level of T4-5. Gross total resection of the tumor was done. Histological findings revealed that spindle or epithelioid cells were arranged in sheets, nests or intersecting bundles. The cytoplasms contained varying amounts of melanin pigments. The nuclei were round to oval with small nucleoli but no mitotic figures. Immunohistochemically, the tumor cells were positive for S-100 protein (S-100), HMB45, Melan-A, and Collagen Ⅳ. They were negative for epithelial membrane antigen (EMA), glial fibrillary acidic protein (GFAP), CD57, progestrone receptor (PR), desmin (Des) and myogen. Ki-67 labeling index was about 10%. Ultrastructural findings revealed that the tumor cells were surrounded by continuous basal lamina, and melanin granules in different stages of maturity were present in the cytoplasms. Final pathological diagnosis was IMS. No recurrence of tumor was found after follow-up for 18 months. Conclusions Intramedullary melanotic schwannom is a rare neoplasm. The diagnosis relies on its morphological characteristics, immunophenotype and ultra microstructure, and should be differentiated from melanoma, melanocytoma and pigmentary neurofibroma. The biologic behavior of the tumor is difficult to predict. It may occur local recurrence. Therefore, long-term follow-up is required. DOI: 10.3969/j.issn.1672-6731.2016.09.013

Polycyclic and caged molecules are common in nature but present challenging targets for synthesis. Here, the authors report a route to caged diterpene cores and apply to the total synthesis of atropurpuran, with oxidative dearomatization/intramolecular Diels-Alder cascade, aldol and ketyl-olefin cyclizations as key steps.

Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques.Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of

Objective. The objective of this study was to investigate the impact of left atrial (LA) size for the ablation of atrial fibrillation (AF) using remote magnetic navigation (RMN). Methods. A total of 165 patients with AF who underwent catheter ablation using RMN were included. The patients were divided into two groups based on LA diameter. Eighty-three patients had small LA (diameter

Social functions of oxytocin (OT) have been explored extensively; however, relationship between the effect of intranasally applied OT (nasal OT) on the social preference (SP) and intracerebral actions of endogenous OT remains unclear. To resolve this question, we first observed effects of nasal OT on the SP of virgin young adult male rats toward unfamiliar virgin estrous female (EF) vs. virgin male rats. The results showed that the test male rats exhibited significantly more times and longer duration accessing the female than the male, which were acutely eliminated by nasal OT. Then, we examined the approaches mediating nasal OT effects on the activity of potential brain targets in Western blots and found that nasal OT activated the olfactory bulbs (OBs) and the supraoptic nucleus (SON), but not the piriform cortex, amygdala and hippocampus as shown by significant changes in the expression of c-Fos and/or phosphorylated extracellular signal-regulated protein kinase (pERK) 1/2. Moreover, microinjection of TTX into the OBs blocked nasal OT-evoked increases in pERK1/2 levels as well as the molecular association between ERK1/2 and OT-neurophysin in the SON. Electrolytic lesions of the lateral olfactory tract did not significantly change the basal levels of pERK 1/2 in the SON; however, upon nasal OT, pERK 1/2 levels in the SON reduced significantly. Lastly, microinjection of L-aminoadipic acid (gliotoxin) into the SON to reduce OT levels reduced the duration of the test male’s accessing the EF and blocked the nasal OT-evoked increase in the duration of test male’s accessing the male while significantly increasing pERK1/2 levels in the amygdala. These findings reveal for the first time that nasal OT acutely eliminates virgin males’ SP to EFs via the OB-SON route and that OT neurons could mediate the social effects of nasal OT by suppressing social phobia generated in the amygdala.

Ammonia oxidizing (AOB) and denitrifying bacteria (DNB) play an important role in soil nitrogen transformation in natural and agricultural ecosystems. Effects of long-term fertilization on abundance and community composition of AOB and DNB were studied with targeting ammonia monooxygenase (amoA) and nitrite reductase (nirK) genes using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and real-time PCR, respectively. A field trial with different fertilization treatments in a rice paddy from Tai Lake region, centre East China was used in this study, including no fertilizer application (NF), balanced chemical fertilizers (CF), combined organic/inorganic fertilizer of balanced chemical fertilizers plus pig manure (CFM), and plus rice straw return (CFS). The abundances and richnesses of amoA and nirK were increased in CF, CFM and CFS compared to NF. Principle component analysis of DGGE profiles showed significant difference in nirK and amoA genes composition between organic amended (CFS and CFM) and the non-organic amended (CF and NF) plots. Number of amoA copies was significantly positively correlated with normalized soil nutrient richness (NSNR) of soil organic carbon (SOC) and total nitrogen (T-N), and that of nirK copies was with NSNR of SOC, T-N plus total phosphorus. Moreover, nitrification potential showed a positive correlation with SOC content, while a significantly lower denitrification potential was found under CFM compared to under CFS. Therefore, SOC accumulation accompanied with soil nutrient richness under long-term balanced and organic/inorganic combined fertilization promoted abundance and diversity of AOB and DNB in the rice paddy.

Background: Resveratrol has shown potent antioxidant activity in ischemia models. The present study was performed to determine whether resveratrol protects against cerebral ischemia-induced neuronal and myocardial injury by interfering with mitochondrial homeostasis. Methods: Wistar rats were pretreated with resveratrol or vehicle intraperitoneally for one week and then subjected to cerebral ischemia via middle cerebral artery occlusion (MCAO) for 24 h. Oxidation was evaluated by quantitating SOD activity and MDA levels. Apoptosis and autophagy were measured based on TUNEL staining and the expression levels of Bcl-2, Bax and LC3II. Mitochondrial changes were evaluated by transmission electron microscopy and by analyzing the mitochondrial membrane potential. Results: Resveratrol significantly decreased mortality, neurological deficits, infarction volume and MDA levels and increased SOD activity. Furthermore, neurocyte apoptosis was alleviated by resveratrol as indicated by the increased Bcl-2/Bax ratio, increased LC3II expression and a decreased number of TUNEL-positive neurocytes. Resveratrol preserved the mitochondria in neurons and cardiomyocytes and significantly improved cardiac function. Conclusion: Resveratrol protected brain tissues against ischemic damage by interfering with mitochondrial homeostasis and inhibiting apoptosis. Furthermore, resveratrol attenuated myocardial damage, suggesting that it may be a novel therapy for cerebral ischemia diseases.

Parkinson's disease (PD) is a progressive neurodegenerative disease. A growing number of studies have shown that mitochondrial dysfunction plays an important role in the pathogenesis of PD. Therefore, this review will mainly discuss the research progress on the correlation between PD and abnormal mitochondrial dynamics, mitochondrial autophapy as well as mitochondrial DNA mutations and mitochondrial complex Ⅰ inhibition.doi：10.3969/j.issn.1672-6731.2014.02.012

Hepatitis C virus (HCV) is a major cause of human chronic liver disease and hepatocellular carcinoma. Our recent studies showed that α1,6-fucosyltransferase (FUT8), a key glycosyltransferase, was the most up-regulated glycosyltransferase after the HCV infection of human hepatocellular carcinoma Huh7.5.1 cells. Here, we further studied the effects and possible mechanism of FUT8 on the proliferation of HCV and chemotherapy-resistance of HCV-infected Huh7.5.1 cells. The effects of FUT8 on the proliferation and drug resistance of HCV-infected Huh7.5.1 cells were analyzed by flow cytometry analysis (FCM), quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis and lactate dehydrogenase (LDH) release assay. Results: We found that FUT8 not only promoted Huh7.5.1 proliferation by activating PI3K-AKT-NF-κB signaling, but also stimulated the expression of the drug-resistant proteins P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1) and enhanced the 5-fluorouracil (5-FU) chemo-resistance of Huh7.5.1 cells. Silencing of FUT8 reduced the cell proliferation and increased the 5-FU sensitivity of HCV-infected Huh7.5.1 cells. Inhibition of P-gp and MRP1 increased the 5-FU drug sensitivity in HCV infected Huh7.5.1 cells. HCV-induced FUT8 promotes proliferation and 5-FU resistance of Huh7.5.1 cells. FUT8 may serve as a therapeutic target to reverse chemotherapy resistance in HCV-infected Huh7.5.1 cells.

Three new pimarane diterpenes, eutypellenoids A–C (1–3), together with a known compound, eutypenoid C (4), were isolated from the culture extract of Eutypella sp. D-1 derived from the Arctic region. Compounds 1–3 possessed an uncommon tetrahydrofuran-fused pimarane diterpene skeleton. The structures of all compounds were determined by detailed spectroscopic analysis, electronic circular dichroism (ECD) analysis, as well as a comparison with the literature data. Antibacterial, antifungal, and cytotoxic activities of these compounds were evaluated. Compound 2 displayed antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 8 and 8 μg/mL, respectively. Additionally, compound 2 showed antifungal activity against Candida parapsilosis, Candida albicans, Candida glabrata, and Candida tropicalis with MIC values of 8, 8, 16, and 32 μg/mL, respectively. Furthermore, compound 2 exhibited moderate cytotoxic activity against HCT-116 cell line with IC50 value of 3.7 μM.

Antibody–drug conjugates (ADCs), constructed with monoclonal antibodies (mAbs), linkers, and natural cytotoxins, are innovative drugs developed for oncotherapy. Owing to the distinctive advantages of both chemotherapy drugs and antibody drugs, ADCs have obtained enormous success during the past several years. The development of highly specific antibodies, novel marine toxins’ applications, and innovative linker technologies all accelerate the rapid R&D of ADCs. Meanwhile, some challenges remain to be solved for future ADCs. For instance, varieties of site-specific conjugation have been proposed for solving the inhomogeneity of DARs (Drug Antibody Ratios). In this review, the usages of various natural toxins, especially marine cytotoxins, and the development strategies for ADCs in the past decade are summarized. Representative ADCs with marine cytotoxins in the pipeline are introduced and characterized with their new features, while perspective comments for future ADCs are proposed.

Loss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.Epithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.The established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.Psychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.

Eutypenoids A–C (1–3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A–C (1–3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities.

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism. METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p-Akt) in the small intestine was analyzed via Western blotting. RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine. CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]