Prognostic effects of the gastric mucosal microbiota in gastric cancer.

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.

Gut microbiome and microbial metabolites in NAFLD and after bariatric surgery: Correlation and causality.

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.

Effects of Bariatric Endoscopy on Non-Alcoholic Fatty Liver Disease: A Comprehensive Systematic Review and Meta-Analysis.

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.

Efficacy and Safety of Endoscopic Resection for Small Gastric Gastrointestinal Stromal Tumors in Elderly Patients.

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.

Roles of Plasmacytoid Dendritic Cells in Gastric Cancer.

Gastric cancer (GC) is the fifth most common neoplasm and the third most deadly cancer in humans worldwide. Helicobacter pylori 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.

Curcumin Improves Epithelial Barrier Integrity of Caco-2 Monolayers by Inhibiting Endoplasmic Reticulum Stress and Subsequent Apoptosis.

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.

Recent insights into mechanisms preventing ectopic centromere formation.

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.

Role of the Gastric Microbiome in Gastric Cancer: From Carcinogenesis to Treatment.

The development of sequencing technology has expanded our knowledge of the human gastric microbiome, which is now known to play a critical role in the maintenance of homeostasis, while alterations in microbial community composition can promote the development of gastric diseases. Recently, carcinogenic effects of gastric microbiome have received increased attention. Gastric cancer (GC) is one of the most common malignancies worldwide with a high mortality rate. Helicobacter pylori is a well-recognized risk factor for GC. More than half of the global population is infected with H. pylori, which can modulate the acidity of the stomach to alter the gastric microbiome profile, leading to H. pylori-associated diseases. Moreover, there is increasing evidence that bacteria other than H. pylori and their metabolites also contribute to gastric carcinogenesis. Therefore, clarifying the contribution of the gastric microbiome to the development and progression of GC can lead to improvements in prevention, diagnosis, and treatment. In this review, we discuss the current state of knowledge regarding changes in the microbial composition of the stomach caused by H. pylori infection, the carcinogenic effects of H. pylori and non-H. pylori bacteria in GC, as well as the potential therapeutic role of gastric microbiome in H. pylori infection and GC.

Bochdalek hernia masquerading as severe acute pancreatitis during the third trimester of pregnancy: A case report.

BACKGROUND: The occurrence of a diaphragmatic hernia during the third trimester of pregnancy is rare; to our knowledge, there has only been a single case report related to congenital Bochdalek hernia complicated with mild acute pancreatitis during pregnancy. Nonspecific symptoms and lack of experience due to its rarity make the diagnosis of this condition very challenging. We report a case of diaphragmatic hernia accompanied by mild acute pancreatitis in the third trimester of pregnancy, which was misdiagnosed as severe acute pancreatitis. CASE SUMMARY: A 19-year-old woman presented at gestation of 31+2 weeks with continuous distension pain for 3 d in the left lumbar region of no obvious cause. Ultrasonographic findings of left ureterectasis, with nonspecific lumbago and abdominal pain, led to the misdiagnosis of renal colic. Increased serum amylase and/or lipase levels indicated acute pancreatitis. Following the treatment of pancreatitis, her condition deteriorated. The patient was finally diagnosed with a diaphragmatic hernia complicated with mild acute pancreatitis on magnetic resonance imaging at our hospital. Caesarean section was performed at gestation of 31+6 weeks, followed by hernia repair, and the pancreatitis was treated sequentially. The patient was discharged in good condition 20 d after the surgery. CONCLUSION: In this case, surgical treatment was not the same as that for non-pregnant diaphragmatic hernia repair. It is important to first perform a cesarean section before commencing the therapy.

Resveratrol synergizes with cisplatin in antineoplastic effects against AGS gastric cancer cells by inducing endoplasmic reticulum stress­mediated apoptosis and G2/M phase arrest.

Gastric cancer (GC) is a common gastrointestinal malignancy, and cisplatin (DDP) is an important component of chemotherapeutic regimens for GC. However, the application of DDP is limited by its dose­dependent systemic toxicity. Resveratrol (RES) is a natural polyphenol compound that has chemopreventive and therapeutic effects against various cancers, including GC. However, whether RES can sensitize GC cells to DDP remains unknown. Following RES/DDP combination treatment, cell viability was determined by Cell Counting Kit­8 and colony­forming assays, and cell apoptosis and the cell cycle were detected by FITC­Annexin V/PI staining assay and PI staining assay, respectively, followed by flow cytometry. Moreover, western blotting was performed to evaluate the protein expression levels, and the intracellular free Ca2+ concentration was determined by a Fluo­4 AM probe after cell cotreatment with RES and DDP. The present results demonstrated that RES/DDP combination treatment significantly inhibited cell viability, promoted cell apoptosis and induced G2/M phase arrest in AGS cells. In addition, it was determined that RES combined with DDP significantly increased the levels of Bax, cleaved poly­ADP­ribose polymerase (PARP), glucose­regulated protein 78 (GRP78), PRKR­like ER kinase (PERK), p­eukaryotic translation initiation factor 2α (p­eIF2α), CCAAT/enhancer binding protein homologous protein (CHOP) and cleaved caspase­12, whereas Bcl­2 expression was downregulated following RES/DDP cotreatment. Moreover, RES/DDP cotreatment significantly upregulated phosphorylated cyclin­dependent kinase 1 (p­CDK1, Tyr15), p21Waf1/Cip1 and p27Kip1 protein levels and downregulated Cdc25C protein levels. In conclusion, RES and DDP synergistically inhibited the growth of the gastric adenocarcinoma cell line AGS by inducing endoplasmic reticulum stress­mediated apoptosis and G2/M phase arrest via activation of the PERK/eIF2α/activating transcription factor 4 (ATF4)/CHOP signaling pathway and caspase­12 and by inactivating the CDK1­cyclin B1 complex. These results indicated that RES is a promising adjuvant for DDP during GC chemotherapy.

Cell Cycle-Regulated Transcription of CENP-A by the MBF Complex Ensures Optimal Level of CENP-A for Centromere Formation.

The centromere plays an essential role in chromosome segregation. In most eukaryotes, centromeres are epigenetically defined by the conserved histone H3 variant CENP-A. Proper centromere assembly is dependent upon the tight regulation of CENP-A level. Cell cycle regulation of CENP-A transcription appears to be a universal feature across eukaryotes, but the molecular mechanism underlying the temporal control of CENP-A transcription and how such regulation contributes to centromere function remains elusive. CENP-A in fission yeast has been shown to be transcribed before S phase. Using various synchronization methods, we confirmed that CENP-A transcription occurs at G1, leading to an almost twofold increase of the protein during S phase. Through a genetic screen, we identified the MBF (MluI box-binding factors) complex as a key regulator of temporal control of CENP-A transcription. The periodic transcription of CENP-A is lost in MBF mutants, resulting in CENP-A mislocalization and chromosome segregation defects. We identified the MCB (MluI cell cycle box) motif in the CENP-A promoter, and further showed that the MBF complex binds to the motif to restrict CENP-A transcription to G1. Mutations of the MCB motif cause constitutive CENP-A expression and deleterious effects on cell survival. Using promoters driving transcription to different cell cycle stages, we found that timing of CENP-A transcription is dispensable for its centromeric localization. Our data instead indicate that cell cycle-regulated CENP-A transcription is a key step to ensure that a proper amount of CENP-A is generated across generations. This study provides mechanistic insights into the regulation of cell cycle-dependent CENP-A transcription, as well as its importance on centromere function.

Urban-rural environmental exposure during childhood and subsequent risk of inflammatory bowel disease: a meta-analysis.

BACKGROUND: The relationship between living conditions in urban and rural areas during childhood and subsequent inflammatory bowel disease (IBD) remains controversial. AIM: To explore the association between environmental exposures early in life and the subsequent risk of IBD. METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, and Conference Proceedings Citation Index. Studies were analyzed separately using rate ratios (RRs) or odds ratios (ORs) with 95% confidence intervals. RESULTS: The search strategy identified 15 studies. Of these, 9 studies explored the association between urban exposure during childhood and ulcerative colitis (UC), and 12 and 4 studies explored this relationship with Crohn's disease (CD) and IBD, respectively. A meta-analysis showed that the pooled ORs estimated for the case-control studies of UC, CD, and IBD were 1.16 (0.83, 1.61), 1.45 (1.45, 1.85), and 1.34 (1.11, 1.62), respectively. The pooled RR estimated for the cohort studies of CD and IBD was 1.48 (1.17, 1.87). The stratified analysis and meta-regression showed significant relationships between CD and living conditions in case-control studies published during 2010-2017 and in non-European countries (P < 0.05). CONCLUSIONS: Living conditions during childhood are positively associated with the subsequent development of IBD. Urban living environment is more common among those with CD than UC.

Heterochromatin and RNAi regulate centromeres by protecting CENP-A from ubiquitin-mediated degradation.

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.

Andrographolide Inhibits Mechanical and Thermal Hyperalgesia in a Rat Model of HIV-Induced Neuropathic Pain.

Aim: In this study, we investigated whether andrographolide (Andro) can alleviate neuropathic pain induced by HIV gp120 plus ddC treatment and the mechanism of its action. Methods: The paw withdrawal threshold and the paw withdrawal latency were observed to assess pain behaviors in all groups of the rats, including control group, control combined with Andro treatment group, sham group, gp120 combined with ddC treatment group, gp120 plus ddC combined with A438079 treatment group, and gp120 plus ddC combined with Andro treatment by intrathecally injecting at a dose of 25 µg/20 µl group. The protein expression levels of the P2X7 receptor, tumor necrosis factor-α-receptor (TNFα-R), interleukin-1ß (IL-1ß), IL-10, phospho-extracellular regulated protein kinases (ERK) (p-ERK) in the L4-L6 dorsal root ganglia (DRG) were measured by western blotting. Real-time quantitative polymerase chain reaction was used to test the mRNA expression level of the P2X7 receptor. Double-labeling immunofluorescence was used to identify the co-localization of the P2X7 receptor with glial fibrillary acidic protein (GFAP) in DRG. Molecular docking was performed to identify whether the Andro interacted perfectly with the rat P2X7 (rP2X7) receptor. Results: Andro attenuated the mechanical and thermal hyperalgesia in gp120+ddC-treated rats and down-regulated the P2X7 receptor mRNA and protein expression in the L4-L6 DRGs of gp120+ddC-treated rats. Additionally, Andro simultaneously decreased the expression of TNFα-R and IL-1ß protein, increased the expression of IL-10 protein in L4-L6 DRGs, and inhibited the activation of ERK signaling pathways. Moreover, Andro decreased the co-expression of GFAP and the P2X7 receptor in the SGCs of L4-L6 DRG on 14th day after surgery. Conclusion: Andro decreased the hyperalgesia induced by gp120 plus ddC.

In Situ Chromatin-Binding Assay Using Epifluorescent Microscopy in S. pombe.

Chromatin-associated proteins play critical roles in many cellular processes, including gene expression, epigenetic regulation, DNA repair, recombination, and replication. Especially, epigenetic landscape, shaped by a variety of chromatin-binding proteins, is dynamic and regulated in a context-dependent manner. In situ chromatin-binding assay is a powerful but simple tool to investigate how proteins, such as epigenetic components, associate with chromatin. This approach relies on the fact that chromatin bound proteins are more resistant to detergent extraction. Here, we describe a protocol for the in situ chromatin-binding assay used in Schizosaccaromyces pombe.

Effects of nanoparticle-encapsulated curcumin on HIV-gp120-associated neuropathic pain induced by the P2X3 receptor in dorsal root ganglia.

HIV-1 envelope glycoprotein (Glycoprotein 120, gp120) can directly stimulate primary sensory afferent neurons and cause chronic neuropathic pain. The P2X3 receptor in the dorsal root ganglia (DRG) is associated with the transmission of neuropathic pain. Curcumin isolated from the herb Curcuma rhizome has anti-inflammatory and anti-tumor effects. The water solubility, targeting and bioavailability of curcumin can be improved by nanoparticle encapsulation. In this study, we sought to explore the effects of nanoparticle-encapsulated curcumin (nano curcumin) on HIV-gp120-induced neuropathic pain mediated by the P2X3 receptor in DRG neurons. The results showed that mechanical and thermal hyperalgesia in rats treated with gp120 were increased compared to those in the control group. The expression levels of P2X3 mRNA and protein in rats treated with gp120 were higher than those in the control group. Nano curcumin treatment decreased mechanical hyperalgesia and thermal hyperalgesia and upregulated the expression levels of P2X3 mRNA and protein in rats treated with gp120. Nano curcumin treatment also reduced the ERK1/2 phosphorylation levels in gp120-treated rat DRG. In addition, P2X3 agonist α,ß-methylene ATP (α,ß-meATP)-induced currents in DRG neurons cultured with gp120 significantly decreased after co-treatment with nano curcumin. Therefore, nano curcumin treatment may inhibit P2X3 activation, decrease the sensitizing DRG primary afferents and relieve mechanical hyperalgesia and thermal hyperalgesia in gp120-treated rats.

Inhibition of Histone Methyltransferase, Histone Deacetylase, and ß-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells.

Previously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the histone deacetylase inhibitor trichostatin A (TSA) with BIX01294 synergistically enhances MSC cardiogenesis. Although TSA by itself had no effect on cardiac gene expression, coaddition of TSA to MSC cultures enhanced BIX01294-induced levels of Mesp1 and brachyury expression 5.6- and 7.2-fold. Moreover, MSCs exposed to the cardiogenic stimulus Wnt11 generated 2.6- to 5.6-fold higher levels of the cardiomyocyte markers GATA4, Nkx2.5, and myocardin when pretreated with TSA in addition to BIX01294. MSC cultures also showed a corresponding increase in the prevalence of sarcomeric protein-positive cells when treated with these small molecule inhibitors. These results correlated with data showing synergism between (1) TSA and BIX01294 in promoting acetylation of lysine 27 on histone H3 and (2) BIX01294 and Wnt11 in decreasing ß-catenin accumulation in MSCs. The implications of these findings are discussed in light of observations in the early embryo on the importance of ß-catenin signaling and histone modifications for cardiomyocyte differentiation and heart development.

A317491 relieved HIV gp120-associated neuropathic pain involved in P2X3 receptor in dorsal root ganglia.

Glycoprotein 120 (gp120) is an HIV envelope glycoprotein. Gp120 can directly stimulate the primary sensory afferent neurons and cause hyperalgesia. The P2X3 receptor in dorsal root ganglia (DRG) is involved in the transmission of pain. In this study, we aimed to explore the role of the P2X3 receptor in gp120-induced neuropathic pain. Our data showed that mechanical and thermal hyperalgesia in rats treated with gp120 were increased compared to those in the control group. The expression levels of the P2X3 mRNA and protein in rats treated with gp120 were higher than those in the control group. The P2X3 antagonist A317491 decreased mechanical hyperalgesia and thermal hyperalgesia and the up-regulated expression levels of P2X3 mRNA and protein in rats treated with gp120. A317491 decreased ERK1/2 phosphorylation levels in the gp120-treated rat DRG. In addition, P2X3 agonist α,ß-methylene ATP (α,ß-meATP)-activated currents in DRG neurons cultured with gp120 were higher than those in control neurons. The inhibitory effect of A317491 on α,ßme-ATP-induced currents in DRG neurons from the gp120-treated neurons was larger than that for control neurons. Molecular docking data showed that A317491 may be acted in the gp120 protein to inhibit the gp120 initiated the P2X3 activation, decrease the sensitizing DRG primary afferents and reduce the signal transmission of neuropathic pain in gp120-treated rats. Therefore, the inhibition of the P2X3 receptor in rat DRG neurons relieved gp120-induced mechanical hyperalgesia.

Are all repeats created equal? Understanding DNA repeats at an individual level.

Repetitive DNA sequences, comprising up to 50 % of the genome in all eukaryotes, play important roles in a wide range of cellular functions, such as transcriptional regulation, genome stability, and cellular differentiation. However, due to technical difficulties in differentiating their sequences, DNA repeats remain one of the most mysterious parts of eukaryotic genomes. Key questions, such as how repetitive entities behave at individual level and how the internal architecture of these repeats is organized, are still poorly understood. Recent advances from our group reveal unexpected position-dependent variation within tandem DNA repeats in fission yeast. Despite sharing identical DNA sequences, the peri-centromeric repeats are organized into diverse epigenetic states and chromatin structures. We demonstrate that this position-dependent variation requires key heterochromatin factors and condensin. Our works further suggest that the peri-centromeric repeats are organized into distinct higher order structures that ensure a proper positioning of CENP-A, the centromere-specific histone H3 variant, to centromeres. These most recent developments offer insights into the mechanisms underlying the position effect within tandem DNA arrays, and have broad implications in the field of epigenetics and chromatin biology.