Variants of tumor necrosis factor-induced protein 3 gene are associated with left ventricular hypertrophy in hypertensive patients

Background Tumor necrosis factor-induced protein 3 （TNFAIP3） gene has been shown important in cardiac remodeling. The aim of the present study was to investigate whether the variants of TNFAIP3 gene are associated with left ventricular hypertrophy （LVH） in hypertensive patients.Methods Four representatives of all the other single nucleotide polymorphisms （SNPs） in TNFAIP3 gene were tested for association with hypertrophy in two independent hypertensive populations （n=2120 and n=324）.Results We found that only the tag SNP （rs5029939） was consistently lower in the hypertensives with cardiac hypertrophy than in those without cardiac hypertrophy in the two study populations, indicating a protective effect on LVH （odds ratio （OR） （95% confidence interval （CI））0.58 （0.358-0.863）, P=0.035; OR （95% CI）=0.477 （0.225-0.815）, P〈0.05,respectively）. Multiple regression analyses confirmed that the patients with G allele of rs5029939 had less thickness in inter-ventricular septum, left ventricular posterior wall, relative wall thickness and left ventricular mass index than did those with CC allele in the hypertensive patients in both study populations （all P〈0.01）.Conclusion These findings indicate that the SNP （rs5029939） in the TNFAIP3 gene may serve as a novel protective genetic marker for the development of LVH in patients with hypertension

Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein I Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population

Background： Psoriasis is a common immune-mediated inflammatory dermatosis. Generalized pustular psoriasis （GPP） is the severe and rare type of psoriasis. The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 （TNIP1） gene and psoriasis was confirmed in people with multiple ethnicities. This study was to investigate the association between TNIP1 gene polymorphisms and pustular psoriasis in Chinese Hart population. Methods： Seventy-three patients with GPP, 67 patients with palmoplantar pustulosis （PPP）, and 476 healthy controls were collected from Chinese Hart population. Six single nucleotide polymorphisms （SNPs） of the TNIP1 gene, namely rs3805435, rs3792798, rs3792797, rs869976, rs 17728338, and rs999011 were genotyped by using polymerase chain reaction-ligase detection reaction. Statistical analyses were performed using the PLINK 1.07 package. Allele frequencies and genotyping frequencies for six SNPs were compared by using Chi-square test, odd ratio （OR） （including 95% confidence interval） were calculated. The haplotype analysis was conducted by Haploview software. Results： The frequencies of alleles of five SNPs were significantly different between the GPP group and the control group （P ≤ 7.22 × 10^-3）, especially in the GPP patients without psoriasis vulgaris （PsV）. In the haplotype analysis, the most significantly different haplotype was H4： ACGAAC, with 13.1% frequency in the GPP group but only 3.4% in the control group （OR = 4.16, P = 4.459 × 10^-7）. However, no significant difference in the allele frequencies was found between the PPP group and control group for each of the six SNPs （P 〉 0.05）. Conclusions： Polymorphisms in TNIP1 are associated with GPP in Chinese Han population. However, no association with PPP was found. These findings suggest that TNIPI might be a susceptibility gene for GPE

Protein induced by vitamin K absence or antagonist-Ⅱ versus alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: A systematic review with meta-analysis

Background: As a promising biomarker of hepatocellular carcinoma(HCC), protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-Ⅱ with alpha-fetoprotein(AFP) in the diagnosis of HCC. Data sources: A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-Ⅱ and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve(ROC) was employed to evaluate the diagnostic accuracy of each marker. Results: Thirty-one studies were included. The pooled sensitivity(95% CI) of PIVKA-Ⅱ and AFP was 0.66(0.65–0.68) and 0.66(0.65–0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity(95% CI) was 0.89(0.88–0.90) and 0.84(0.83–0.85), respectively. The area under the ROC curve(AUC) of PIVKA-Ⅱ and AFP was 0.856(0.817–0.895) and 0.770(0.728–0.811), respectively. Subgroup analysis showed that PIVKA-Ⅱ was superior to AFP in terms of the AUC for both small HCC( < 3 cm) [0.863(0.825–0.901) vs 0.717(0.658–0.776)] and large HCC( ≥ 3 cm) [0.854(0.811–0.897) vs 0.729(0.682–0.776)]; for American [0.926(0.897–0.955) vs 0.698(0.594–0.662)], European [0.772(0.743–0.801) vs 0.628(0.594–0.662)], Asian [0.838(0.812–0.864) vs 0.785(0.764–0.806)] and African [0.812(0.794–0.840) vs 0.721(0.675–0.767)] HCC patients; and for HBV-related [0.909(0.866–0.951) vs 0.714(0.673–0.755)] and mixed-etiology [0.847(0.821–0.873) vs 0.794(0.772–0.816)] HCC. Conclusion: This meta-analysis indicates that PIVKA-Ⅱ is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.

Expression of Peroxiredoxins and Pulmonary Surfactant Protein A Induced by Silica in Rat Lung Tissue

Silicosis is one of the most serious occupational diseases in China and dates back to centuries ago. In this study, we successfully established a rat model of silicosis by intratracheal silica injection for 28 days and determined hydroxyproline levels to evaluate collagen metabolism in lung homogenates. Oxidative stress status was evaluated by detecting catalase and glutathione peroxidase activities.

Analysis of Salicylic Acid Induced Proteins in Rice

An analysis using SDS\|PAGE of acidic and basic protein fractions extracted from rice seedling treated with salicylic acid (SA) yielded several new proteins, some of which are similar in relative molecular mass to PR\|1a,c, PR\|2, 2e and PR\|3d, 3e of tobacco. Direct assays for peroxidases and β\|1,3\|glucanases demonstrated that the activities of the two enzymes in the rice seedlings increased rapidly with time after SA treatment, reaching a maximum 6 days after treatment.Disease resistance tests showed that SA treated rice seedlings stunted the development of blight lesions and displayed higher resistance to rice blight pathogen ( Xanthomonas oryzea pv. oryzea ). The data suggest that the treatment with SA, even for plants with high endogenous SA levels such as rice, may induce the appearance of new proteins and the formation of disease resistance. The results contribute to the analysis of the SA role in rice systemic acquired resistance.

Des-gamma-carboxy prothrombin and alpha-fetoprotein levels as biomarkers for hepatocellular carcinoma and their correlation with radiological characteristics

BACKGROUND Alpha-fetoprotein(AFP),a commonly used biomarker for hepatocellular carcinoma(HCC),is normal in up to one-third of patients.AIM To evaluate the diagnostic performance of des-gamma-carboxy-prothrombin(DCP)alone and in combination with AFP.METHODS In this study,202 patients with radiologically proven HCC were enrolled,and their DCP and AFP levels were evaluated for their diagnostic performance.RESULTS The mean age of the enrolled patients was 58.5 years;72.0%were male.DCP was elevated in 86.6%(n=175)of all patients,100.0%(n=74)of patients with portal vein thrombus,and 87.4%(n=111)of patients with multicentric HCC.AFP was elevated in 64.3%(n=130)of all the patients,74%(n=55)of the patients with portal vein thrombus,and 71.6%(n=91)of the patients with multicentric HCC(P=0.030,0.001,and 0.015,respectively).In tumors less than 2 cm in size(n=46),DCP was increased in 32(69.5%)patients,and AFP was increased in 25(54.3%)patients(P=0.801).There was good pairing between DCP and AFP for HCCs of 2 cm size or larger(P<0.001);however,the pairing among tumors<2 cm size was not significant(P=0.210).In 69 of the patients(34.1%),only one of the tumor markers was positive;DCP was elevated alone in 57/202(28.2%)of all patients,and AFP alone was elevated in 12/202(5.9%)of the patients.The areas under receiver operating characteristic curves(AUROC)for tumors>2 cm was 0.74 for DCP and 0.59 for AFP;combining both markers resulted in an AUROC of 0.73.For tumors<2 cm,the AUROC was 0.25 for DCP and 0.40 for AFP.CONCLUSION DCP,as an individual marker,had a better diagnostic performance in many cases of HCC.Hence,DCP may replace AFP as the primary HCC biomarker.

BH3-only protein Bim is involved in myocardial injury induced by co-stress of ischemia and cold stress in rats

Objectives To investigate the effect of co-exposure of myocardial ischemia and cold stress on myocardial injury in rats and the relative mechanism.Methods Myocardial ischemia model was established by ligation of left coronary artery.SD rats were randomly allocated to 4 groups; sham+normal temperature(S group),sham+cold stress(SC group),myocardial ischemia+ normal temperature(Ⅰgroup), myocardial ischemia+cold stress(IC group).On the condition of 26℃,SC and IC groups were keeped in a 4℃artificial chamber for 8h(8;00-16:00) for 4 consecu- tive days.Car diac function was assessed by echocardiography;pathological change was analyzed by HE staining;myocardial infarct size was determined by TTC staining;Bim,Caspase-3 expression in myocardium was determined by western blotting.Results It was demonstrated that co-exposure of myocardial ischemia and cold stress could significantly make the cardiac muscle in abnormal shape,increase the infarct size and the expression of Bim and Caspase-3.Conclusions Co-exposure of myocardial ischemia and cold stress may aggravate the cardiac injury,pro- apoptosis protein Bim is involved.

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma

BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma(HCC)was not fully investigated.AIM To evaluate the diagnostic accuracy of alpha-fetoprotein(AFP),the Lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),and protein induced by vitamin K absence or antagonist-II(PIVKA-II)and their combination for HCC diagnosis.METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible.Serum AFP level,AFP-L3 fraction,and PIVKA-II level were measured at the first visit.RESULTS In total,622 patients were included;355 patients(57.1%)had chronic liver disease,and 208(33.4%)had liver cirrhosis.HCC was diagnosed in 160 patients(25.7%).The area under the receiver operating characteristics curves(AUROCs)of the serum AFP,AFP-L3 fraction,AFP-L3,and PIVKA-II levels for the diagnosis of HCC were 0.775,0.792,0.814,and 0.834,respectively.A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets.Using the binary regression analysis of the training cohort,the AFP,AFP-L3 fraction,and PIVKA-II(ALPs)score was calculated as follows:ALPs score=3.8×[serum AFP level(ng/mL)×AFP-L3 fraction(%)×0.01]+0.2×PIVKA-II level(mAU/mL).The AUROC of the ALPs score for diagnosis of HCC was 0.878,significantly higher than that of serum AFP level(P<0.001),AFP-L3 fraction(P<0.001),PIVKA-II level(P=0.036),and AFP-L3 level(P=0.006).The optimal ALPs score cut-off was 5.3(sensitivity,85.0%,specificity 80.1%).The validation cohort showed similar results.CONCLUSION The ALPs score calculated using serum AFP level,AFP-L3 fraction,and PIVKA-II level showed improved accuracy in HCC diagnosis.

Malarial pigment does not induce MMP-2 and TIMP-2 protein release by human monocytes

Dear editor, In the recent years growing evidence on the involvement of human matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases(TIMPs) in cerebral malaria (CM) has been reported[1]and a role for malarial pigment haemozoin(HZ) has been proposed[2,3].In a recent work my group showed that in human microvascular endothelial

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

BACKGROUND The GALAD score has improved early hepatocellular carcinoma(HCC)detection rate.The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest.AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis,tumor features,and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers.METHODS This prospective,diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital.Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer(BCLC)categorization.Demographics,HCC etiology,and HCC features were recorded.Biomarkers and the GALAD score were obtained at baseline.The performance of the GALAD score and biomarkers were prospectively assessed.RESULTS Exactly 115 individuals were diagnosed with HCC.The GALAD score increased with disease severity.Between BCLC-0/A and BCLC-B/C/D,the GALAD score predicted HCC staging with an area under the curve(AUC)of 0.868(95%CI:0.80–0.93).For identifying the curative HCC,the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein(AFP)(0.753)and Lens culinaris agglutinin-reactive fraction of AFP-L3(0.706),and as good as that of Protein induced by vitamin K absence-II(PIVKA-II)(0.897).For detecting aggressive features,the GALAD score gave an AUC of 0.839(95%CI:0.75–0.92)and significantly outperformed compared to that of AFP(0.761)and AFP-L3(0.697),with a trend of superiority to that of PIVKA-II(0.772).The performance to predict 1-year mortality of GALAD score(AUC:0.711,95%CI:0.60–0.82)was better than that of AFP(0.541)and as good as that of PIVKA-II(0.736).The optimal cutoff value of GALAD score was≥6.83,with a specificity of 72.63%for exhibiting substantial reduction in the 1-year mortality.CONCLUSION The GALAD model can diagnose HCC at the curative stage,including the characteristic of advanced disease,more than that by AFP and AFP-L3,but not PIVKA-II.The GALAD score can be used to predict the 1-year mortality of HCC.

Biomarkers in kidney transplantation: From bench to bedside

Immunosuppressive drug level monitoring and serum creatinine are widely used for kidney transplantation （KT） monitoring. Monitoring of drug level is not the direct measurement of the immune response while the rising of creatinine is too late for detection of allograft injury. Kidney biopsy, the gold standard for KT monitoring, is invasive and may lead to complications. Many biomarkers have been discovered for direct monitoring of the immune system in KT and the beneft of some biomarkers has reached clinical level. In order to use biomarkers for KT monitoring, physicians have to understand the biology including kinetics of each marker. This can guide biomarker selection for specific condition. Herein, we summarize the recent fndings of donor specifc anti-human leukocyte antigen antibody, B lymphocyte stimulator, interferon-gamma induced protein of 10 kDa, and intracellular adenosine triphosphate monitoring, all of which have very strong evidence support for the clinical use in KT.

Usefulness of determining a protein induced by vitamin K absencein detection of hepatocelluar carcinoma

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Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin

BACKGROUND Serum protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) is a promising biomarker for hepatocellular carcinoma(HCC) surveillance.AIM To identify the contributing factors related to the abnormal elevation of PIVKA-Ⅱ level and assess their potential influence on the performance of PIVKA-Ⅱ in detecting HCC.METHODS This study retrospectively enrolled in 784 chronic liver disease(CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve(AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-Ⅱ for HCC, respectively.RESULTS Elevated PIVKA-Ⅱ levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase(ALP), and total bilirubin(TBIL) for CLD patients and aspartate aminotransferase(AST) and tumor size for HCC patients(all P < 0.05). Serum PIVKA-Ⅱ were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal(ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST(all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-Ⅱ was significantly higher compared to that in patients with TBIL > 1 × ULN(0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant(0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone.CONCLUSION Serum PIVKA-Ⅱ has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Giant simple hepatic cyst with multiple elevated serum tumormarkers: A case report

BACKGROUND Simple hepatic cysts are relatively common in adults, and mostly appear asasymptomatic incidental radiologic findings. Occasionally, a large cyst will causesymptoms. Elevations in the serum biomarkers protein induced by vitamin Kabsence (PIVKA)-II, cancer antigen (CA) 12-5, and CA19-9 are often associatedwith malignant tumors in the liver or bile ducts. This is the first report to describea case of hepatic cyst with elevated levels of PIVKA-II and CA12-5.CASE SUMMARY An 84-year-old Chinese woman was admitted with gradual abdominal distension.Her symptoms started 1 year ago, and she had poor appetite and a weight loss of5 kg within the past 2 wk. She denied any symptoms associated with abdominalpain, fever and chills, nausea and vomiting, etc. The abdomen was enlarged, morein the right upper quadrant, without tenderness. Laboratory examination showedsignificantly increased serum levels of PIVKA-II, CA12-5, and CA19-9. Acomputed tomography scan revealed multiple round cysts in the liver with clearboundaries. The largest cyst was 20.1 cm × 12.2 cm × 19.6 cm in size, located in theright lobe of the liver with mild dilatation of the intrahepatic bile duct, but therewas no contrast enhancement. Percutaneous drainage on the largest hepatic cystand polycinnamol sclerosing agent injection into the cyst cavity were performed.After treatment, the patient’s symptoms relieved and the elevated serum tumormakers reduced to the normal levels dramatically.CONCLUSION The present report identifies an unusual case of a giant hepatic cyst with markedelevation of serum tumor marker levels of PIVKA-II, CA12-5, and CA19-9. Aftertreatment, these three serum markers dramatically decreased to normal levels.The mechanisms for the elevation of these tumor markers may be as follows: (1) Agiant hepatic cyst compresses the liver, causing injury to the hepatocytes, whichmay lead to secretion of a large amount of PIVKA-II;and (2) Some tumorassociatedantigens, such as carcinoembryonic antigen, CA19-9, CA12-5, andCA15-3, are expressed on inflammatory cells.

Comprehensive evaluation of microRNA as a biomarker for the diagnosis of hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer. Current guidelines for HCC management recommend surveillance of high-risk patients every 6 mo using ultrasonography. Serum biomarkers, like alpha-fetoprotein(AFP), protein induced by vitamin K absence/antagonist-Ⅱ(PIVKA-Ⅱ) and lectin-reactive AFP, show suboptimal performance for detection of HCC, which is crucial for successful resection or treatment. Thus, there is a significant need for new biomarkers to aid early diagnosis of HCC. Studies have shown that the expression level of human microRNAs(miRNAs), a small, non-coding RNA species released into the blood, can serve as an early marker for various diseases, including HCC.AIM To evaluate the diagnostic role of miRNAs in HCC as single markers, signatures or in combination with known protein biomarkers.METHODS Our prospective, multicenter, case-control study recruited 660 participants(354 controls with chronic liver disease and 306 participants with HCC) and employed a strategy of initial screening by two independent methods, real-time quantitative PCR(n = 60) and next-generation sequencing(n = 100), to assess a large number of miRNAs. The results from the next-generation sequencing and real-time quantitative PCR screening approaches were then combined to select 26 miRNAs(including two putative novel miRNAs). Those miRNAs were analyzed for their diagnostic potential as single markers or in combination with other miRNAs or established protein biomarkers AFP and PIVKA-Ⅱ via real-time quantitative PCR in training(n = 200) and validation cohorts(n = 300).RESULTS We identified 26 miRNAs that differentiated chronic liver disease controls from(early) HCC via two independent discovery approaches. Three miRNAs, miR-21-5p(miR-21), miR-320a and miR-186-5p, were selected by both methods. In the training cohort, only miR-21, miR-320d and miR-423could significantly distinguish(Q < 0.05) between the HCC and chronic liver disease control groups. In the multivariate setting, miR-21 with PIVKA-Ⅱ was selected as the best combination,resulting in an area under the curve of 0.87 for diagnosis and area under the curve of 0.74 for early diagnosis of HCC. In the validation cohort, only miR-21 and miR-423 could be confirmed as potential HCC biomarkers. A combination of miRNAs did not perform better than any single miRNA. Improvement of PIVKA-Ⅱ performance through combination with miRNAs could not be confirmed in the validation panel. Two putative miRs, put-miR-6 and put-miR-99, were tested in the training and validation panels, but their expression could only be detected in very few samples and at a low level(cycle threshold between 31.24 and 34.97).CONCLUSION miRNAs alone or as a signature in combination with protein biomarkers AFP and PIVKA-Ⅱ do not improve the diagnostic performance of the protein biomarkers.

Is thioredoxin reductase involved in the defense againsi DNA fragmentation in varicocele？

We aimed to investigate the role of thioredoxin reductase （TR） and inducible heat shock protein 70 （iHsp70） and their relationship with sperm quality in varicocele （VAR） patients. Semen samples were obtained from 16 subfertile men diagnosed as VAR and 10 fertile men who applied to the Andrology Laboratory of Istanbul Medical Faculty of Istanbul University. The sperm TR and iHsp 70 expression levels were determined using Western blot analysis. The TR activity of the sperm was assayed spectrophometrically. The sperm quality was evaluated both by conventional sperm analysis and by a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling （TUNEL） technique that assayed DNA-fragmented spermatozoa in semen samples. The percentage of TUNELopositive spermatozoa in the VAR group （16.3%±5.6%） was higher than that in the fertile group （5.5%±1.9%）. Significant inverse correlations were detected between the percentage of TUNEL-positive cells and both the concentration （r=--0.609; P=0.001） and motility （r=--0.550; P=-0.004） of spermatozoa. Both the TR expression and activity were increased significantly in the VAR group （U=22.0; P=0.001 and U=33.5 P=0.012, respectively） as analyzed using the Mann-Whitney UWilcoxon rank sum Wtest. Furthermore, significant positive correlations were found between TR expression and activity （r=-0.406; P=O.040） and between TR expression and the percentage of TUNEL-positive cells （r=0.665; P=-0.001）. Sperm iHsp70 expression did not differ between the VAR and fertile groups. In conclusion, increased sperm TR expression might be a defense mechanism against apoptosis in the spermatozoa of men with VAR.

Microbiota-host interplay at the gut epithelial level,health and nutrition

Growing evidence suggests the implication of the gut microbiota in various facets of health and disease. In this review, the focus is put on microbiota-host molecular cross-talk at the gut epithelial level with special emphasis on two defense systems： intestinal alkaline phosphatase（IAP） and inducible heat shock proteins（iHSPs）. Both IAP and iHSPs are induced by various microbial structural components（e.g. lipopolysaccharide, flagellin, CpG DNA motifs）,metabolites（e.g. n-butyrate） or secreted signal molecules（e.g., toxins, various peptides, polyphosphate）. IAP is produced in the small intestine and secreted into the lumen and in the interior milieu. It detoxifies microbial components by dephosphorylation and, therefore, down-regulates microbe-induced inflammation mainly by inhibiting NF-κB pro-inflammatory pathway in enterocytes. IAP gene expression and enzyme activity are influenced by the gut microbiota. Conversely, IAP controls gut microbiota composition both directly, and indirectly though the detoxification of pro-inflammatory free luminal adenosine triphosphate and inflammation inhibition. Inducible HSPs are expressed by gut epithelial cells in proportion to the microbial load along the gastro-intestinal tract. They are also induced by various microbial components, metabolites and secreted molecules. Whether iHSPs contribute to shape the gut microbiota is presently unknown. Both systems display strong anti-inflammatory and anti-oxidant properties that are protective to the gut and the host. Importantly, epithelial gene expressions and protein concentrations of IAP and iHSPs can be stimulated by probiotics, prebiotics and a large variety of dietary components, including macronutrients（protein and amino acids, especially L-glutamine, fat, fiber）, and specific minerals（e.g. calcium）and vitamins（e.g. vitamins K1 and K2）. Some food components（e.g. lectins, soybean proteins, various polyphenols） may inhibit or disturb these systems. The general cel ular and molecular mechanisms involved in the microbiota-host epithelial crosstalk and subsequent gut protection through IAP and iHSPs are reviewed along with their nutritional modulation.Special emphasis is also given to the pig, an economically important species and valuable biomedical model.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

Alpha-fetoprotein,protein induced by vitamin K absence or antagonist-Ⅱ,lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease:A multicenter analysis

Background:Current surveillance strategies for hepatocellular carcinoma(HCC)among patients with non-alcoholic fatty liver disease(NAFLD)are insufficient.This study aimed to investigate the diagnostic perfor-mance of alpha-fetoprotein(AFP),protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ),lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),and their combinations in HCC underlying NAFLD patients.Methods:Serologic AFP,AFP-L3,and PIVKA-Ⅱ levels in NAFLD patients with and without HCC were mea-sured.By receiver operating characteristic(ROC)analyses,the area under the curve(AUC),sensitivity,and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations.Results:This study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls.The eleva-tion of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls(all P<0.001).When they were analyzed individually,PIVKA-Ⅱ showed the best performance in diagnosing any-stage HCC with an AUC of 0.869,followed by AFP(0.763;vs.PIVKA-Ⅱ,P<0.001)and AFP-L3(0.689;vs.PIVKA-II,P<0.001).When they were analyzed in combination,AFP+PIVKA-Ⅱ yielded the highest AUC(0.906),followed by AFP+PIVKA-II+AFP-L3(0.904;vs.AFP+PIVKA-Ⅱ,P=0.086),PIVKA-Ⅱ+AFP-L3(0.881;vs.AFP+PIVKA-II,P<0.001),and AFP+AFP-L3(0.759;vs.AFP+PIVKA-II,P<0.001).Similar findings were obtained in the subgroup with early-stage NAFLD-HCC,as well as the non-cirrhotic subgroup.Conclusions:These data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD,and the combination of AFP+PIVKA-II signifi-cantly improved the diagnostic accuracy of NAFLD-HCC.