Succinylation modification:a potential therapeutic target in stroke

Stroke is a leading cause of mortality and disability worldwide.Ischemic cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of strokeinduced brain injury.Impaired mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of neuropathology.Recently,a new type of posttranslational modification,known as lysine succinylation,has been recognized to play a significant role in mitochondrial energy metabolism after ischemia.However,the role of succinylation modification in cell metabolism after stroke and its regulation are not well understood.We aimed to review the effects of succinylation on energy metabolism,reactive oxygen species generation,and neuroinflammation,as well as Sirtuin 5 mediated desuccinylation after stroke.We also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of stroke.The succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by desuccinylases.Mounting evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic enzymes.Sirtuins,especially Sirtuin 5,are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic enzymes.Imbalance between succinylation and desuccinylation has been implicated in the pathophysiology of stroke.Pharmacological agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism,and neuroprotective effects of these agents have been observed in experimental stroke studies.However,their therapeutic efficacy in stroke patients should be validated.

Circular RNA circ_0003609 ameliorates hypertrophied ligamentum flavum by regulating the miR-155/SIRT1 axis

Background:Hypertrophy of the ligamentumflavum(HLF)is a common contributor to spinal stenosis which results in significant neurological impairments.Circular RNA(circRNA)circ_0003609 has been linked to HLF;however,the exact mechanism by which it causes this disease is unclear.Methods:Circ_0003609 expressions were regulated in HLF cells by overexpression vectors and RNA interference.Cell proliferation andfibrosis-related gene expression were checked by the Cell Counting Kit-8(CCK-8)assay and western blotting.CircBank’s prediction of the association between miR-155 and circ_0003609 was supported by a dual-luciferase reporter experiment.The function of the miR-155/sirtuin 1(SIRT1)axis in controlling HLFfibrosis was further examined.Results:Overexpression of circ_0003609 suppressed HLF cell propagation andfibrosis compared to its silencing.It was found that circ_0003609 served as the sponge for miR-155 and that the circ_0003609/miR-155 axis controlled thefibrosis of HLF cells.It was found that circ_0003609 acted as a sponge for miR-155,regulating thefibrosis of HLF cells.Further,miR-155 targets SIRT1,and the miR-155/SIRT1 axis promotes HLF cellfibrosis.Conclusion:Circ_0003609 ameliorates hypertrophied ligamentumflavum(LF)by modulating the miR-155/SIRT1 axis,indicating a potential treatment approach for HLF.

Epicardial adipose tissue in obesity with heart failure with preserved ejection fraction: Cardiovascular magnetic resonance biomarker study

BACKGROUND Obesity has become a serious public health issue,significantly elevating the risk of various complications.It is a well-established contributor to Heart failure with preserved ejection fraction(HFpEF).Evaluating HFpEF in obesity is crucial.Epicardial adipose tissue(EAT)has emerged as a valuable tool for validating prognostic biomarkers and guiding treatment targets.Hence,assessing EAT is of paramount importance.Cardiovascular magnetic resonance(CMR)imaging is acknowledged as the gold standard for analyzing cardiac function and mor-phology.We hope to use CMR to assess EAT as a bioimaging marker to evaluate HFpEF in obese patients.AIM To assess the diagnostic utility of CMR for evaluating heart failure with preserved ejection fraction[HFpEF;left ventricular(LV)ejection fraction≥50%]by measuring the epicardial adipose tissue(EAT)volumes and EAT mass in obese patients.METHODS Sixty-two obese patients were divided into two groups for a case-control study based on whether or not they had heart failure with HFpEF.The two groups were defined as HFpEF+and HFpEF-.LV geometry,global systolic function,EAT volumes and EAT mass of all subjects were obtained using cine magnetic resonance sequences.RESULTS Forty-five patients of HFpEF-group and seventeen patients of HFpEF+group were included.LV mass index(g/m2)of HFpEF+group was higher than HFpEF-group(P<0.05).In HFpEF+group,EAT volumes,EAT volume index,EAT mass,EAT mass index and the ratio of EAT/[left atrial(LA)left-right(LR)diameter]were higher compared to HFpEF-group(P<0.05).In multivariate analysis,Higher EAT/LA LR diameter ratio was associated with higher odds ratio of HFpEF.CONCLUSION EAT/LA LR diameter ratio is highly associated with HFpEF in obese patients.It is plausible that there may be utility in CMR for assessing obese patients for HFpEF using EAT/LA LR diameter ratio as a diagnostic biomarker.Further prospective studies,are needed to validate these proof-of-concept findings.

Prognostic assessment of different metastatic lymph node staging methods for gastric cancer after D2 resection

AIM: To compare the prognostic assessment of lymph node ratio and absolute number based staging system for gastric cancer after D2 resection. METHODS: The clinical, pathologic, and long-term follow-up data of 427 patients with gastric cancer that underwent D2 curative gastrectomy were retrospectively analyzed. The relationships between the metastatic lymph node ratio (MLR), log odds of positive lymph nodes (LODDS), and positive lymph nodes (pN) staging methods and the long-term prognoses of the patients were compared. In addition, the survival curves, accuracy, and homogeneity were compared with stratification to evaluate the prognostic assessment of the 3 methods when the number of tested lymph nodes was insufficient (< 10 and 10-15). RESULTS: MLR [hazard ratio (HR) = 1.401, P = 0.012], LODDS (HR = 1.012,P = 0.034), and pN (HR = 1.376, P = 0.005) were independent risk factors for gastric cancer patients. The receiver operating characteristic (ROC) curves showed that the prognostic accuracy of the 3 methods was comparable (P > 0.05). Spearman correlation analysis confirmed that MLR, LODDS, and pN were all positively correlated with the total number of tested lymph nodes. When the number of tested lymph node was < 10, the value of survival curves staged by MLR and LODDS was superior to those of pN staging. However, the difference in survival curves between adjacent stages was not significant. In addition, the survival rate of stage 4 patients using the MLR and LODDS staging methods was 26.7% and 27.3% with < 10 lymph node, respectively which were significantly higher than the survival rate of patients with > 15 tested lymph nodes (< 4%). The ROC curve showed that the accuracy of the prognostic assessment of MLR, LODDS, and pN staging methods was comparable (P > 0.05), and the area under the ROC curve of all 3 methods were increased progressively with the enhanced levels of examined lymph nodes. In addition, the homogeneity of the 3 methods in patients with ≤ 15 tested lymph nodes also showed no significant difference. CONCLUSION: Neither MLR or LODDS could reduce the staging bias. A sufficient number of tested lymph nodes is key to ensure an accurate prognosis for patients underwent D2 radical gastrectomy.

Recent advances in prevention of hepatitis B recurrence after liver transplantation

Liver transplantation is the only effective treatment for hepatitis B virus(HBV)-related end-stage liver disease.However,without antiviral prophylaxis,the recurrence rate of hepatitis B is as high as 80%-100%,which leads to a 50% mortality rate in the first 2 years after liver transplantation.Combination therapy of hepatitis B immunoglobulin(HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%.The strategy of HBIG combined with lamivudine has been the standard treatment in many centers.However,the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the longterm efficacy of this strategy for the prevention of HBV reinfection.Recently,new nucleos(t)ide analogues,such as entecavir and tenofovir,have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection.These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation.Various therapies that are composed of entecavir,tenofovir,and lamivudine plus adefovir,with or without HBIG have been adopted in several liver transplant centers.This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.

Different distributions of interstitial cells of Cajal and platelet-derived growth factor receptor-α positive cells in colonic smooth muscle cell/interstitial cell of Cajal/plateletderived growth factor receptor-α positive cell syncytium in mice

AIM To investigate the distribution and function of interstitialcells of Cajal(ICCs) and platelet-derived growth factor receptor-α positive(PDGFRα+) cells in the proximal and distal colon.METHODS The comparison of colonic transit in the proximal and distal ends was performed by colonic migrating motor complexes(CMMCs). The tension of the colonic smooth muscle was examined by smooth muscle spontaneous contractile experiments with both ends of the smooth muscle strip tied with a silk thread. Intracellular recordings were used to assess electrical field stimulation(EFS)-induced inhibitory junction potentials(IJP) on the colonic smooth muscle. Western blot analysis was used to examine the expression levels of ICCs and PDGFRα in the colonic smooth muscle.RESULTS Treatment with NG-nitro-L-arginine methyl ester hydrochloride(L-NAME) significantly increased the CMMC frequency and spontaneous contractions, especially in the proximal colon, while treatment with MRS2500 increased only distal CMMC activity and smooth muscle contractions. Both CMMCs and spontaneous contractions were markedly inhibited by NPPB, especially in the proximal colon. Accordingly, CyPPA sharply inhibited the distal contraction of both CMMCs and spontaneous contractions. Additionally, the amplitude of stimulationinduced nitric oxide(NO)/ICC-dependent slow IJPs(sIJPs) by intracellular recordings from the smooth muscles in the proximal colon was larger than that in the distal colon, while the amplitude of electric field stimulationinduced purinergic/PDGFRα-dependent fast IJPs(fIJPs) in the distal colon was larger than that in the proximal colon. Consistently, protein expression levels of c-Kit and anoctamin-1(ANO1) in the proximal colon were much higher, while protein expression levels of PDGFRα and small conductance calcium-activated potassium channel 3(SK3) in the distal colon were much higher.CONCLUSION The ICCs are mainly distributed in the proximal colon and there are more PDGFRα+ cells are in the distal colon, which generates a pressure gradient between the two ends of the colon to propel the feces to the anus.

Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats

BACKGROUND Portal hypertension(PHT)is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow.Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.AIM To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.METHODS Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride(CCl4)in both male and female integral and castrated rats(ovariectomized[OVX]in female rats,orchiectomy[ORX]in male rats).The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.RESULTS No significant difference in portal pressure was observed between integral and castrated male PHT rats(15.2±2.1 mmHg vs 16.7±2.7 mmHg,P>0.05).The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats(12.7±2.7 mmHg vs 16.5±2.4 mmHg,P<0.05).In PHT rats,the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right,and the maximal responses(Emax)values were decreased and effective concentrations causing half maximum responses(EC50)values were increased,compared to those of non-PHT rats,both in male and female rats.Compared to non-PHT integral male rats,the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased(P>0.05).However,there was no difference between integral and ORX male rats with PHT.In integral female PHT rats,the concentration response curves were shifted to the left(P<0.05),and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats.CONCLUSION Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats.Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.

Differential diagnosis of gallstones by using hypericin as a fluorescent optical imaging agent

AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones.METHODS: Cholesterol, mixed and pigment stones from cholecystectomy patients were incubated with hypericin or solvent. After 72 h, the stones were analysed for fluorescence(365 nm) and treated with 2-propanol/dimethyl sulfoxide for high performance liquid chromatography(HPLC) analysis. Rats with virtual gallbladder containing human cholesterol, mixed or pigment gallstones(VGHG) received 5 mg/kg hypericin or solvent and VGHG rats with cholesterol stones were given different hypericin doses(5-15 mg/kg). Twelve hours later, the stones were analysed at 365 nm. Biliary excretion and metabolites of hypericin were assessed in common bile duct(CBD) cannulated rats for 9 h using fluorospectrometry, HPLC and matrixassisted laser desorption/ionization-time-of-flight mass spectrometry(MALDI-TOF MS).RESULTS: Homogeneous high fluorescence was seen on cholesterol stones either pre-incubated with hypericin or extracted from VGHG rats receiving hypericin. Mixed stones showed a dotted fluorescent pattern, whereas pigment and solvent-treated ones lacked fluorescence. HPLC showed 7.68, 6.65 and 0.08 × 10^(-3) M of cholesterol in extracts from cholesterol, mixed, and pigment gallstones, respectively. Hypericin accounted for 2.0, 0.5 and 0.2 × 10-6 M in that order. On cholesterol stones from VGHG rats receiving different hypericin doses, a positive correlation was observed between dose and fluorescence. In the bile from CBD-cannulated rats, fluorescence represented 20% of the injected dose with two peaks in 9 h. HPLC analysis revealed that hypericin conjugates reached 60% of the peak area. By MALDI-TOF MS, hypericinglucuronide was detected. CONCLUSION: This study proves the potential use of hypericin for differential fluorescent detection of human gallstones regarding their chemical composition.

Vitamin E in the management of pancreatic cancer: A scoping review

Pancreatic cancer is the leading cause of cancer mortality worldwide.Research investigating effective management strategies for pancreatic cancer is ongoing.Vitamin E,consisting of both tocopherol and tocotrienol,has demonstrated debatable effects on pancreatic cancer cells.Therefore,this scoping review aims to summarize the effects of vitamin E on pancreatic cancer.In October 2022,a literature search was conducted using PubMed and Scopus since their inception.Original studies on the effects of vitamin E on pancreatic cancer,including cell cultures,animal models and human clinical trials,were considered for this review.The literature search found 75 articles on this topic,but only 24 articles met the inclusion criteria.The available evidence showed that vitamin E modulated proliferation,cell death,angiogenesis,metastasis and inflammation in pancreatic cancer cells.However,the safety and bioavailability concerns remain to be answered with more extensive preclinical and clinical studies.More in-depth analysis is necessary to investigate further the role of vitamin E in the management of pancreatic cancers.

CHRM3 is a novel prognostic factor of poor prognosis andpromotes glioblastoma progression via activation of oncogenicinvasive growth factors

Glioblastoma(GBM)is the most aggressive cancer of the brain and has a high mortality rate due to the lack of effective treatment strategy.Clarification of molecular mechanisms of GBM’s characteristic invasive growth is urgently needed to improve the poor prognosis.Single-nuclear sequencing of primary and recurrent GBM samples revealed that levels of M3 muscarinic acetylcholine receptor(CHRM3)were significantly higher in the recurrent samples than in the primary samples.Moreover,immunohistochemical staining of an array of GBM samples showed that high levels of CHRM3 correlated with poor prognosis,consistent with The Cancer Genome Atlas database.Knockdown of CHRM3 inhibited GBM cell growth and invasion.An assay of orthotopic GBM animal model in vivo indicated that inhibition of CHRM3 significantly suppressed GBM progression with prolonged survival time.Transcriptome analysis revealed that CHRM3 knockdown significantly reduced an array of classic factors involved in cancer invasive growth,including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8.Taken together,CHRM3 is a novel and vital factor of GBM progression via regulation of multiple oncogenic genes and may serve as a new biomarker for prognosis and therapy of GBM patients.

Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review

Liver transplantation(LT) has been accepted as an effective therapy for hepatocellular carcinoma(HCC). The Milan criteria(MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alphafetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.

Role of BMSCs in liver regeneration and metastasis after hepatectomy

Hepatocellular carcinoma(HCC),which develops from liver cirrhosis,is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis.While surgery is the preferred treatment for HCC,intervention and liver transplantation are also treatment options for end-stage liver disease.However,the success of partial hepatectomy and intervention is hindered by the decompensation of liver function.Conversely,liver transplantation is difficult to carry out due to its high cost and the lack of donor organs.Fortunately,research into bone-marrow stromal cells(BMSCs)has opened a new door in this field.BMSCs are a type of stem cell with powerful proliferative and differential potential that represent an attractive tool for the establishment of successful stem cell-based therapy for liver diseases.A number of different stromal cells contribute to the therapeutic effects exerted by BMSCs because BMSCs can differentiate into functional hepatic cells and can produce a series of growth factors and cytokines capable of suppressing inflammatory responses,reducing hepatocyte apoptosis,reversing liver fibrosis and enhancing hepatocyte functionality.Additionally,it has been shown that BMSCs can increase the apoptosis rate of cancer cells and inhibit tumor metastasis in some microenvironments.This review focuses on BMSCs and their possible applications in liver regeneration and metastasis after hepatectomy.

Operative link on gastritis assessment stage is an appropriate predictor of early gastric cancer

AIM: To assess the predictive value of Operative Link on Gastritis Assessment(OLGA) and Operative Link on Gastric Intestinal Metaplasia Assessment(OLGIM) stages in gastric cancer.METHODS: A prospective study was conducted with 71 patients with early gastric cancer(EGC) and 156 patients with non-EGC. All patients underwent endoscopic examination and systematic biopsy. Outcome measures were assessed and compared, including the Japanese endoscopic gastric atrophy(EGA) classification method and the modified OLGA method as well as the modified OLGIM method. Helicobacter pylori(H. pylori) status was determined for all study participants. Stepwise logistic regression modeling was performed to analyze correlations between EGC and the EGA, OLGA and OLGIM methods.RESULTS: For patients with EGC and patients with non-EGC, the proportions of moderate-to-severe EGA cases were 64.8% and 44.9%, respectively(P = 0.005), the proportions of OLGA stages Ⅲ-Ⅳ cases were 52.1% and 22.4%, respectively(P < 0.001), and the proportions of OLGIM stages Ⅲ-Ⅳ cases were42.3% and 19.9%, respectively(P < 0.001). OLGA stage and OLGIM stage were significantly related to EGA classification; specifically, logistic regression modeling showed significant correlations between EGC and moderate-to-severe EGA(OR = 1.95, 95% CI: 1.06-3.58, P = 0.031) and OLGA stages Ⅲ-Ⅳ(OR = 3.14, 95%CI: 1.71-5.81, P < 0.001), but no significant correlation between EGC and OLGIM stages Ⅲ-Ⅳ(P = 0.781). H. pylori infection rate was significantly higher in patients with moderate-to-severe EGA(75.0% vs 54.1%, P = 0.001) or OLGA/OLGIM stages Ⅲ-Ⅳ(OLGA: 83.6% vs 55.8%, P < 0.001; OLGIM: 83.6% vs 57.8%, P < 0.001).CONCLUSION: OLGA classification is optimal for EGC screening. A surveillance program including OLGA stage and H. pylori infection status may facilitate early detection of gastric cancer.

Endoscopic treatment of difficult extrahepatic bile duct stones, EPBD or EST: An anatomic view

Large bile duct stone(> 10 mm) or multiple stones(≥ 3) are challenging for endoscopists. Endoscopic sphincterotomy(EST) is a routine therapeutic endoscopic retrograde cholangiopancreatography(ERCP) procedure usually used. It is safe and effective, but severe perforation or massive bleeding are the main causes of mortality. Because of the permanent destroy ofOddi sphincter, the use of EST is still controversial. Endoscopic papillary balloon dilation(EPBD) gives another way to open the sphincter. Less incidence of bleeding, perforation and partly preserving the Oddi sphincter's function are the main advantages. But high incidence of post-ERCP pancreatitis becomes a predominant problem. According to the anatomical feature of Oddi sphincter, limited EST + EPBD seems a more reasonable procedure. Compared to the former two procedures, it makes the stone extraction process much easier with lower incidences of short-term and long-term complications.

Efficacy of mosapride plus proton pump inhibitors for treatment of gastroesophageal reflux disease: A systematic review

AIM:To assess the potential benefits of mosapride plus proton pump inhibitors(PPIs)in the treatment of gastroesophageal reflux disease.METHODS:A literature search was performed through MEDLINE,EMBASE,and the ISI Web of Knowledge.The clinical trials that compared the benefit of mosapride plus PPI treatment with that of PPI monotherapy were analyzed.The rate of responders was evaluated by the pooled relative risk(PRR)and improvement in symptom scores was assessed by single effect size of a standardized mean,while Hedges’g was used as the effect size.Pooled effect sizes with 95%CIs were calculated using a fixed-effects model.Between-study heterogeneity was assessed using Q test and I2analyses.In addition,studies that assessed the additional efficacy of mosapride in PPI-resistant patients were also reviewed.RESULTS:This systematic review included information on a total of 587 patients based on 7 trials.Four trials compared the efficacy of combination therapy of mosapride plus a PPI with that of PPI monotherapy.The statistical analysis for the effect of additional mosapride showed equivocal results(PRR=1.132;95%CI:0.934-1.372;P=0.205;Hedges’g=0.24;95%CI:0.03-0.46;P=0.023).No heterogeneity and publication bias were found among the studies.Three openlabeled trials assessed the additional efficacy of mosapride in PPI-resistant patients.However,since these trials did not set the control group,the results may be considerably biased.CONCLUSION:Mosapride combined therapy is not more effective than PPI alone as first-line therapy.Whether it is effective in PPI-resistant patients needs to be determined.

Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding:A meta-analysis

AIM: To analyze the accuracy of computed tomography (CT) angiography in the diagnosis of acute gastrointestinal (GI) bleeding. METHODS: The MEDLINE, EMBASE, Cancerlit, Cochrane Library database, Sciencedirect, Springerlink and Scopus, from January 1995 to December 2009, were searched for studies evaluating the accuracy of CT angiography in diagnosing acute GI bleeding. Studies were included if the ycompared CT angiography to a reference standard of upper GI endoscopy, colonoscopy, angiography or surgery in the diagnosis of acute GI bleeding. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver-operating characteristic. RESULTS: A total of 9 studies with 198 patients were included in this meta-analysis. Data were used to form 2 × 2 tables. CT angiography showed pooled sensi-tivity of 89% (95% CI: 82%-94%) and specificity of 85% (95% CI: 74%-92%), without showing significant heterogeneity (χ2 = 12.5, P = 0.13) and (χ2 = 22.95, P = 0.003), respectively. Summary receiver operating characteristic analysis showed an area under the curve of 0.9297. CONCLUSION: CT angiography is an accurate, costeffective tool in the diagnosis of acute GI bleeding and can show the precise location of bleeding, thereby directing further management.

Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation

AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid(PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids(SFAs) or PUFAs as well as combined with lipopolysaccharide(LPS). The expression of NOD-like receptor protein 3(NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B(NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: high-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid(PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid(Dh A) had thepotential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a highfat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but Dh A decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION:Hepatic NLRP 3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.

Clinicopathological,treatment,and prognosis study of 43 gastric neuroendocrine carcinomas

AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas(G-NECs) which occur rarely but are highly malignant and clinically challenging.METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria.RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half(48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases(72.09%), and liver metastasis was found in 6 cases(13.95%). Follow-up information was got for 40 patients. Twentythree die of this disease with a median survival of 31 mo(range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR(30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence.CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.

儿童期接受双侧斜疝手术所致梗阻性无精子症的临床特征及治疗策略

Childhood inguinal herniorrhaphy is one common cause of seminal tract obstruction. Vasovasostomy （VV） can reconstruct seminal deferens and result in appearance of sperm and natural pregnancy in some patients. Secondary epididymal obstruction caused by a relatively long-term vasal obstruction is a common cause of lower patency compared with VV due to vasectomy in adults. From July 2007 to June 2012, a total of 62 patients, with history of childhood inguinal herniorrhaphy and diagnosed as obstructive azoospermia were treated in our center. The overall patency rate and natural pregnancy rate were 56.5% （35/62） and 25.8% （16/62）, respectively. 48.4% （30/62） of the patients underwent bilateral VV in the inguinal region, with a patency rate of 76.7% （23/30） and a natural pregnancy rate of 36.7% （11/30）, respectively. 30.6% （19/62） of the patients underwent bilateral VV and unilateral or bilateral vasoepididymostomies due to ipsilateral epididymal obstruction with the patency and natural pregnancy rate decreasing to 63.2% （12/19） and 26.3% （5/19）. 21.0% （13/62） of the patients merely underwent vasal exploration without reconstruction due to failure to find distal vasal stump, etc. Our study indicate that microsurgical reanastomosis is an effective treatment for some patients with seminal tract obstruction caused by childhood inguinal herniorrhaphy.

Lobaplatin inhibits growth of gastric cancer cells by inducing apoptosis

AIM:To assess the anti-cancer effect of lobaplatin on human gastric cancer cells,and to explore the underlying molecular mechanisms.METHODS:The human gastric cancer cell lines MKN-28,AGS and MKN-45 were used.The cytotoxicity of lobaplatin was detected using an MTS cell proliferation assay.Flow cytometry was used to detect cell apoptosis using Annexin V-FITC Apoptosis Detection Kit.The expression of apoptosis-regulated genes was examined at the protein level using Western blot.RESULTS:Lobaplatin inhibited the proliferation of human gastric cancer cells and induced apoptosis,which may be associated with the up-regulation of Bax expression,poly(ADP-ribose)polymerase(PARP)cleavage,p53 expression and the reduction of Bcl-2 expression.CONCLUSION:The cytotoxicity of lobaplatin may be due to its ability of inducing apoptosis of gastric cancer cells,which would support the potential use of lobaplatin for the therapy of gastric cancer.