The centromere is a specialized chromosomal structure essential for chromosome segregation. Centromere dysfunction leads to chromosome segregation errors and genome instability. In most eukaryotes, ...centromere identity is specified epigenetically by CENP-A, a centromere-specific histone H3 variant. CENP-A replaces histone H3 in centromeres, and nucleates the assembly of the kinetochore complex. Mislocalization of CENP-A to non-centromeric regions causes ectopic assembly of CENP-A chromatin, which has a devastating impact on chromosome segregation and has been linked to a variety of human cancers. How non-centromeric regions are protected from CENP-A misincorporation in normal cells is largely unexplored. Here, we review the most recent advances on the mechanisms underlying the prevention of ectopic centromere formation, and discuss the implications in human disease.
Non-alcoholic fatty liver disease (NAFLD) is currently related to a heavy socioeconomic burden and increased incidence. Since obesity is the most prevalent risk factor for NAFLD, weight loss is an ...effective therapeutic solution. Bariatric surgery (BS), which can achieve long-term weight loss, improves the overall health of patients with NAFLD. The two most common surgeries are the Roux-en-Y gastric bypass and sleeve gastrectomy. The gut-liver axis is the complex network of cross-talking between the gut, its microbiome, and the liver. The gut microbiome, involved in the homeostasis of the gut-liver axis, is believed to play a significant role in the pathogenesis of NAFLD and the metabolic improvement after BS. Alterations in the gut microbiome in NAFLD have been confirmed compared to that in healthy individuals. The mechanisms linking the gut microbiome to NAFLD have been proposed, including increased intestinal permeability, higher energy intake, and other pathophysiological alterations. Interestingly, several correlation studies suggested that the gut microbial signatures after BS become more similar to those of lean, healthy controls than that of patients with NAFLD. The resolution of NAFLD after BS is related to changes in the gut microbiome and its metabolites. However, confirming a causal link remains challenging. This review summarizes characteristics of the gut microbiome in patients with NAFLD before and after BS and accumulates existing evidence about the underlying mechanisms of the gut microbiome.
Gastric cancer (GC) is one of the most common malignant tumors with a high incidence and mortality. Microbiota play a significant role in human health and disease. We aimed to investigate the ...prognostic value of the gastric microbiota in different stomach microhabitats. We used our previously published 16S rRNA gene sequence data. We retrospectively enrolled a cohort of 132 patients with GC with complete prognostic information and selected 78 normal tissues, 49 peritumoral tissues, and 112 tumoral tissues for microbiota analysis. Patients with different prognoses showed different gastric microbiota compositions and diversity. The association network of the abundant gastric microbiota was more complicated in patients with poor prognoses. In the peritumoral microhabitat of patients with good prognoses, Helicobacter was significantly increased, whereas Halomonas and Shewanella were significantly decreased relative to that in the peritumoral microhabitat of patients with poor prognoses. PiCRUSt analysis revealed that the peritumoral microbiota had more different Kyoto Encyclopedia of Genes and Genomes pathways than did the tumoral and normal microbiota. This study evaluated the long‐term prognostic value of the gastric mucosal microbiota in patients with GC. These findings suggested that the characteristic alterations of the gastric mucosal microbiota may be markers for clinical outcomes in these patients.
Microbiota play a significant role in human health and disease. Gastric cancer (GC) patients with different prognoses showed different gastric microbiota compositions and diversity. The characteristic alterations of the gastric mucosal microbiota may be markers for clinical outcomes in these patients.
Curcumin is a natural polyphenol and is supposed to possess antioxidant, anti-inflammatory, anticancer, and antiapoptotic properties. Although some studies have reported the therapeutic effects of ...curcumin on ulcerative colitis (UC), the specific mechanism remains unclear. An in vitro coculture model of Caco-2 and differentiated THP-1 cells was established. After administration of curcumin (10 μM), Western blot analysis was performed to evaluate the protein levels of tight junction (TJ) proteins zonula occludens- (ZO-) 1 and claudin-1. Annexin V-APC/7-AAD assays and flow cytometry were conducted to assess Caco-2 cell apoptosis. The expression levels of oxidative stress and endoplasmic reticulum stress- (ERS-) related molecules were determined by Western blot analysis. Curcumin administration significantly upregulated ZO-1 and claudin-1 protein levels and reduced Caco-2 cell apoptosis. The protein levels of oxidative stress markers inducible nitric oxide synthase (iNOS) and γH2AX and ERS-induced apoptosis-related molecules C/EBP homologous protein (CHOP) and cleaved caspase-12 were significantly downregulated upon curcumin treatment. Furthermore, curcumin administration greatly blocked the protein kinase-like endoplasmic reticulum kinase- (PERK-) eukaryotic translation initiation factor 2α- (eIF2α-) activating transcription factor 4- (ATF4-) CHOP signaling pathway. Curcumin enhanced intestinal epithelial barrier integrity in the in vitro coculture model by upregulating TJ protein expressions and reducing intestinal epithelial cell apoptosis. The potential mechanisms may be suppression of ERS and subsequent apoptosis.
Background and objective
Endoscopic bariatric and metabolic therapies (EBMTs) are emerging minimally invasive therapeutic options for obesity and its related complications, including non-alcoholic ...fatty liver disease (NAFLD). This study aimed to evaluate the effects of EBMTs on NALFD in patients with obesity.
Methods
Four databases were searched until Nov 2021. Randomized controlled trials (RCTs) and observational studies reporting liver-related outcomes following Food and Drug Administration (FDA)-approved and non-FDA-approved EBMTs were included. Liver parameters, metabolic parameters, and weight loss were evaluated. Risk of bias was assessed using the “risk of bias” tool in the Cochrane Collaboration for RCTs and the Methodological Index for Non-Randomized Studies criteria for observational studies.
Results
Thirty-three studies with 1710 individuals were included. Regarding the effects of EBMTs on liver fibrosis, a significant decline of NAFLD Fibrosis Score, but not transient elastography-detected liver stiffness or Fibrosis-4 Index, was observed. EBMTs significantly improved liver steatosis (control attenuation parameter and Hepatic Steatosis Index), NAFLD Activity Score, and Homeostasis Model Assessment of Insulin Resistance. EBMTs reduced serum levels of alanine transaminase, aspartate aminotransferase, and gamma-glutamyl transpeptidase considerably. Moreover, EBMTs had reducing effects on the serum levels of triglycerides and total cholesterol as well as body weight.
Conclusions
Our meta-analysis suggested that EBMTs could ameliorate NAFLD based on the evidence of improved liver steatosis, liver function, and insulin resistance. Large-scale, prospective, long-term studies are warranted to clarify the role of EBMTs in patients with different stages of NAFLD.
Gastric cancer (GC) is the fifth most common neoplasm and the third most deadly cancer in humans worldwide.
infection is the most important causative factor of gastric carcinogenesis, and activates ...host innate and adaptive immune responses. As key constituents of the tumor immune microenvironment, plasmacytoid dendritic cells (pDCs) are increasingly attracting attention owing to their potential roles in immunosuppression. We recently reported that pDCs have vital roles in the development of immunosuppression in GC. Clarifying the contribution of pDCs to the development and progression of GC may lead to improvements in cancer therapy. In this review, we summarize current knowledge regarding immune modulation in GC, especially the roles of pDCs in GC carcinogenesis and treatment strategies.
Centromere is a specialized chromatin domain that plays a vital role in chromosome segregation. In most eukaryotes, centromere is surrounded by the epigenetically distinct heterochromatin domain. ...Heterochromatin has been shown to contribute to centromere function, but the precise role of heterochromatin in centromere specification remains elusive. Centromeres in most eukaryotes, including fission yeast (Schizosaccharomyces pombe), are defined epigenetically by the histone H3 (H3) variant CENP-A. In contrast, the budding yeast Saccharomyces cerevisiae has genetically-defined point centromeres. The transition between regional centromeres and point centromeres is considered as one of the most dramatic evolutionary events in centromere evolution. Here we demonstrated that Cse4, the budding yeast CENP-A homolog, can localize to centromeres in fission yeast and partially substitute fission yeast CENP-ACnp1. But overexpression of Cse4 results in its localization to heterochromatic regions. Cse4 is subject to efficient ubiquitin-dependent degradation in S. pombe, and its N-terminal domain dictates its centromere distribution via ubiquitination. Notably, without heterochromatin and RNA interference (RNAi), Cse4 fails to associate with centromeres. We showed that RNAi-dependent heterochromatin mediates centromeric localization of Cse4 by protecting Cse4 from ubiquitin-dependent degradation. Heterochromatin also contributes to the association of native CENP-ACnp1 with centromeres via the same mechanism. These findings suggest that protection of CENP-A from degradation by heterochromatin is a general mechanism used for centromere assembly, and also provide novel insights into centromere evolution.
CENP-A is a centromere-specific histone 3 variant essential for centromere specification. CENP-A partially replaces canonical histone H3 at the centromeres. How the particular CENP-A/H3 ratio at ...centromeres is precisely maintained is unknown. It also remains unclear how CENP-A is excluded from non-centromeric chromatin. Here, we identify Ccp1, an uncharacterized NAP family protein in fission yeast that antagonizes CENP-A loading at both centromeric and non-centromeric regions. Like the CENP-A loading factor HJURP, Ccp1 interacts with CENP-A and is recruited to centromeres at the end of mitosis in a Mis16-dependent manner. These data indicate that factors with opposing CENP-A loading activities are recruited to centromeres. Furthermore, Ccp1 also cooperates with H2A.Z to evict CENP-A assembled in euchromatin. Structural analyses indicate that Ccp1 forms a homodimer that is required for its anti-CENP-A loading activity. Our study establishes mechanisms for maintenance of CENP-A homeostasis at centromeres and the prevention of ectopic assembly of centromeres.
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•Ccp1 antagonizes CENP-A loading at both centromeric and non-centromeric regions•Ccp1 is recruited to centromeres at the end of mitosis in a Mis16-dependent manner•Ccp1 cooperates with H2A.Z to evict CENP-A assembled in euchromatin•Ccp1 forms a homodimer that is required for its anti-CENP-A loading activity
Dong et al. identify Ccp1, a NAP family protein, antagonizing the loading of CENP-A at both centromeric and non-centromeric regions. This study provides insights into both how the balance of CENP-A and histone H3 levels is achieved at centromeres and how non-centromeric regions are protected from mistakenly assembling CENP-A.
Background. Gastrointestinal stromal tumors (GISTs) are prevalent in elderly patients. Endoscopic resection has become popular for treating small (≤5 cm) gastric GISTs. However, little is known about ...the outcomes of endoscopic resection in elderly patients. Aim. To assess the efficacy and safety of endoscopic resection for small (≤5 cm) gastric GISTs in elderly patients (≥65 years old). Methods. A total of 260 patients (265 lesions) with gastric GISTs treated via endoscopic resection from January 2011 to May 2020 were retrospectively analyzed. Among them, 65 patients were ≥65 years old (elderly group), and 195 patients were <65 years old (nonelderly group). Clinicopathological characteristics, postoperative complications, and tumor recurrence rates between the two age groups were compared. Results. A total of 260 patients with primary small (≤5 cm) gastric GISTs were treated with endoscopic resection. The median ages of the elderly and nonelderly groups were 68 (range 65-83) years and 55 (range 32-64) years, respectively. Elderly patients showed a higher incidence of comorbidities compared with nonelderly patients (61.5% versus 32.3%s, respectively; p<0.001). All elderly patients and 99.0% of nonelderly patients underwent en bloc resection; only two nonelderly patients received piecemeal resection. No significant differences were found regarding postoperative complications or tumor recurrence rates between the two groups. Conclusions. Although elderly patients had more comorbidities than nonelderly patients, both groups had similar postoperative complications and recurrence rates. We suggest that endoscopic resection performed by experienced endoscopists is safe and effective for treating small (≤5 cm) gastric GISTs in elderly patients.
Gastric cancer (GC) is one of the most common types of cancer and continues to threaten human health. The microbiota plays an important role in health and disease, including GC. Dysbiosis of gut ...microbiota has been reported to be associated with various diseases. There are no published meta-analyses of gut microbiota alterations in patients with GC in China. A meta-analysis was performed by searching the PubMed, Web of Science, EMBASE, and Cochrane Library databases up to July 2022. Nine eligible studies, representing 405 patients, were included in the analysis. At the phylum level, Proteobacteria (mean difference 12.46 (3.06–21.87), p < 0.05) was significantly increased, and Firmicutes (mean difference −4.10 (−7.65 to −0.56), p < 0.05) was decreased in patients with GC. At the genus level, Desulfovibrio (mean difference 0.38 (0.16–0.59); p < 0.05) and Streptococcus (mean difference 1.92 (0.37–3.46), p < 0.05) were significantly increased in patients with GC. No significant difference was observed in gut microbial diversity between patients and non-GC controls. Subgroup analysis suggested that region, sample size, and quality of studies caused heterogeneity to different extents. In summary, our study indicated a difference in gut microbial composition between patients with GC and individuals without GC. No significant differences were observed in the diversity of the gut microbes. Changes in the gut microbiota of patients with GC could potentially be used for the non-invasive diagnosis of GC.
•Altered gut microbiota can be observed in Chinese patients with gastric cancer (GC).•Increased Proteobacteria and decreased Firmicutes were observed in patients with GC.•Specific gut microbe could potentially be used for GC non-invasive diagnosis.
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