Lectin Complement Protein Collectin 11 (CL-K1) and Susceptibility to Urinary Schistosomiasis

BackgroundUrinary Schistosomiasis is a neglected tropical disease endemic in many sub Saharan -African countries. Collectin Kidney 1 (CL-K1, encoded by COLEC11 on chromosome 2p25.3), a member of the vertebrate C-type lectin super family, has recently been identified as pattern-recognition molecule (PRR) of the lectin complement pathway. CL-K1 is preferentially expressed in the kidneys, but also in other organs and it is considered to play a role in host defense to some infectious agents. Schistosome teguments are fucosylated and CL-K1 has, through its collagen-like domain, a high binding affinity to fucose.ConclusionsIn agreement with findings from our earlier published study, our findings support the observation that CL-K1 and their functional variants may be host factors associated with protection in schistosomiasis and may be a useful marker for further investigations.     

Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity

Collectins play important roles in the innate immune defense against microorganisms. Recently, a new collectin, collectin 11 (CL-11 or CL-K1), was identified via database searches. In present work, we characterize the structural and functional properties of CL-11. Under nonreducing conditions, in gel permeation chromatography recombinant CL-11 forms disulfide-linked oligomers of 100 and 200 kDa. A mAb-based ELISA estimates the concentration of CL-11 in plasma to be 2.1 μg/ml, and the presence of CL-11 in plasma was further verified by Western blotting and mass spectrometry. Mannan-binding lectin-associated serine protease 1 (MASP-1) copurified with CL-11 and the interaction in plasma with MASP-1 and/or MASP-3 was further demonstrated using ELISA. We identified the adrenal glands, the kidneys, and the liver as primary sites of expression. CL-11 lectin activity was demonstrated by ELISA and showed that CL-11 has preference for l-fucose and d-mannose. We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA. On the basis of the significant concentration of CL-11 in circulation and CL-11's interaction with various microorganisms and MASP-1 and/or MASP-3, it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms.     

Association of IL-15 and IP-10 Serum Levels with Cytomegalovirus Infection,CMV Viral Load and Cyclosporine Level after Kidney Transplantation

Background:Cytomegalovirus (CMV) infection is the most common complications following kidney transplantation. Natural killer (NK) cells demonstrated critical anti-viral role in controlling and elimination of CMV after transplantation. Interleukin-15 (IL-15) is a pleiotropic cytokine that promotes the activity of NK cells and strengthens the acquired immune system. Also, IP10 (CXCL10) is a chemotactic factor which regulates NK cell recruitment and antiviral immune response. We aimed to determine the correlation between the serum levels of IL-15 and IP-10 cytokines with CMV infection, CMV viral load, and cyclosporine as a major immunosuppressive treatment after transplantation.Methods:Fifty-eight kidney transplant recipient patients without evidence of CMV virus disease before transplantation surgery were included in the study. From the day of transplant surgery, the patients were evaluated based on the presence of CMV Ag pp65, CMV viral load, serum levels of IL-15 & IP-10, Cyclosporine levels (C0 & C2), Glomerular Filtration Rate (GFR), and hematological & biochemical Index, up to 75 days.Results:Comparison analysis of serum levels of IL-15 and IP-10 showed no significant association with CMV infection in kidney transplant recipients. In addition, CMV viral load and cyclosporine levels at C0 and C2 did not affect patients'' IL-15 and IP-10 levels.Conclusion:The levels of IP-10 and IL-15 cytokines are not affected with CMV infection, even if a viral infection occurs in the early days after transplantation or long afterwards. In addition, taking the different levels of cyclosporine did not affect the cytokines levels. Other mechanisms may play a role in maintaining the levels of these cytokines.Key Words: Cytokine, Cytomegalovirus, IP-10, Interleukin-15, Transplantation     

Association of Genetic Variation in Adaptor Protein APPL1/APPL2 Loci with Non-Alcoholic Fatty Liver Disease

The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR = 2.50 95% CI 1.45–4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff = 15.08 [7.60–22.57] p = 0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR = 3.88; 95% CI 1.582–9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.     

Association of Ficolin-2 Serum Levels and FCN2 Genetic Variants with Indian Visceral Leishmaniasis

BackgroundVisceral leishmaniasis (VL), one of the neglected tropical diseases, is endemic in the Indian subcontinent. Ficolins are circulating serum proteins of the lectin complement system and involved in innate immunity.MethodsWe have estimated ficolin-2 serum levels and analyzed the functional variants of the encoding gene FCN2 in 218 cases of VL and in 225 controls from an endemic region of India.ResultsElevated levels of serum ficolin-2 were observed in VL cases compared to the controls (adjusted P<0.0001). The genetic analysis revealed that the FCN2 structural variant +6359 C>T (p.T236M) was associated with VL (OR=2.2, 95% CI=1.23-7.25, P=0.008) and with high ficolin-2 serum levels. We also found that the FCN2*AAAC haplotype occurred more frequently among healthy controls when compared to cases (OR=0.59, 95%CI=0.37-0.94, P=0.023).ConclusionsOur findings indicate that the FCN2 variant +6359C>T is associated with the occurrence of VL and that ficolin-2 serum levels are elevated in Leishmania infections.     

肾脏部分切除手术对T1a期肾癌患者炎性因子与肝肾功能的影响

目的:探讨肾脏部分切除手术对T_(1a)期肾癌患者炎性因子与肝肾功能的影响。方法:回顾性分析我院2013年6月至2016年12月收治的91例T_(1a)期肾癌患者的临床资料,按治疗方式不同分为对照组与试验组,对照组48例接受后腹腔镜根治性肾癌切除术治疗,试验组43例接受后腹腔镜肾脏部分切除手术治疗。比较两组的手术指标、治疗前后血清炎性因子、肝肾功能的变化及并发症发生情况。结果:对照组的手术时间、术中出血量均少于试验组(P0.05)。治疗后,试验组血清IL-1变化值低于对照组[(-19.47±-2.57)μg/L比(-41.61±-6.38)μg/L]、IL-6变化值低于对照组[(-8.71±-1.05)ng/L比(-18.96±-3.10)ng/L]、CRP变化值低于对照组[(-12.72±-1.54)mg/L比(-17.46±-2.64)mg/L]、TNF-α变化值低于对照组[(-5.66±-0.15)ng/L比(-14.33±-2.04)ng/L]、BUN变化值低于对照组[(-1.53±-0.19)mmol/L比(-3.01±-0.79)mmol/L]、AST变化值低于对照组[(-15.29±-2.46)U/L比(-33.70±-3.78)U/L]、ALT变化值低于对照组[(-19.46±-2.27)U/L比(-34.02±-5.51)U/L],试验组Ccr变化值低于对照组[(19.78±2.94)mL/min比(28.26±3.52)mL/min]、GFR变化值低于对照组[(14.45±1.48)mL/min比(29.36±1.91)mL/min],除CRP和GFR外,其余指标差异均有统计学意义(P0.05)。对照组和试验组并发症发生率分别为16.67%(8/48)和9.30%(4/43),两组比较差异无统计学意义(P0.05)。结论:后腹腔镜肾脏部分切除手术治疗T_(1a)期肾癌患者的临床效果优于后腹腔镜根治性肾癌切除术治疗,其对患者炎性因子及肝肾功能的影响较小,安全性更高。     

Association between Serum Irisin Levels and Non-Alcoholic Fatty Liver Disease in Health Screen Examinees

Irisin is a recently found myokine that aids obesity control and improves glucose homeostasis by acting on white adipose tissue cells and increases total energy consumption. The aim of this study was to evaluate serum irisin levels in patients with non-alcoholic fatty liver disease (NAFLD) and to compare these levels with those of normal controls. Among 595 health screen examinees who had visited our institute between January 2013 to March 2013, 355 patients (84 NAFLD patients and 271 normal controls) were enrolled depending on whether they gave written informed consents and their history of alcohol intake, blood tests, and abdominal ultrasonographic findings. Age; sex; laboratory test parameters; homeostasis model assessment-insulin resistance; and levels of leptin, adiponectin, and irisin were assessed. Serum irisin levels (ng/ml) were significantly higher in the NAFLD group than in normal controls (63.4±32.6 vs. 43.0±29.7, p<0.001) and higher in the mild fatty liver group than in the moderate-to-severe fatty liver group (68.3±38.2 vs. 56.6±21.2, p<0.001). Additionally, serum irisin levels were not different between the non-obese and obese groups (48.4±34.2 vs. 45.8±22.9, p = 0.492); however, the levels were significantly lowest in normal controls and highest in the mild fatty liver group in the non-obese (44.9±31.7 vs. 73.1±48.5 vs 59.7±18.0, p<0.001) and obese groups (35.0±17.0 vs. 62.9±21.2 vs. 54.6±23.3, p<0.001). Serum irisin levels were significantly higher in NAFLD patients, which is not consistent with the results of previously published studies. Therefore, more studies are needed to confirm the role of irisin in NAFLD.     

Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis

In human pathology, several diseases are associated with somatic mutations in the mitochondrial genome (mtDNA). Even though mitochondrial dysfunction leads to increased oxidative stress, the role of mitochondrial mutations in atherosclerosis has not received much attention so far. In this study we analyzed the association of mitochondrial genetic variation with the severity of carotid atherosclerosis, as assessed by carotid intima-media thickness (cIMT) and the presence of coronary heart disease (CHD) in 190 subjects from Moscow, Russia, a population with high CHD occurrence. cIMT was measured by high-resolution B-mode ultrasonography and mtDNA heteroplasmies by a pyrosequencing-based method. We found that heteroplasmies for several mutations in the mtDNA in leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly (p<0.001) associated with both the severity of carotid atherosclerosis and the presence of CHD. These findings indicate that somatic mitochondrial mutations have a role in the development of atherosclerosis.     

Association between Serum Growth Hormone Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

Growth hormone (GH) is an important regulator of metabolism and body composition. GH deficiency is associated with increased visceral body fat and other features of the metabolic syndrome. Here we performed a cross-sectional study to explore the association of GH levels with nonalcoholic fatty liver disease (NAFLD), which is considered to be the hepatic manifestation of the metabolic syndrome. A total of 1,667 subjects were diagnosed as NAFLD according the diagnostic criteria, and 5,479 subjects were defined as the controls. The subjects with NAFLD had significantly lower levels of serum GH than the controls. Those with low GH levels had a higher prevalence of NAFLD and the metabolic syndrome. A stepwise logistic regression analysis showed that GH levels were significantly associated with the risk factor for NAFLD (OR = 0.651, 95%CI = 0.574–0.738, P<0.001). Our results showed a significant association between lower serum GH levels and NAFLD.     

Serum Complement Component C3 Levels in Cattle: Genetic Influence and Association with Total Haemolytic Activity

Serum C3 levels and total haemolytic complement (HC) activity were determined simultaneously in young bulls (130 animals, 14 sire families). 3 of the 14 families show considerable deviation in C3 levels and there was significant correlation between G3 and HC.     

重度子痫前期患者血清CXCL10、CXCL16水平与肝肾功能损害的相关性研究

摘要 目的：探讨重度子痫前期患者血清趋化因子配体（CXCL）10、CXCL16水平与肝肾功能损害的相关性。方法：选取我院于2016年9月至2019年9月收治的轻度子痫前期患者65例（轻度组）、重度子痫前期患者80例（重度组）,另选取同期60例正常妊娠孕妇为对照组,对比各组血清CXCL10、CXCL16、肝功能、肾功能相关指标水平,Pearson相关性分析重度组患者血清CXCL10、CXCL16水平与肝功能、肾功能相关指标间的关系。结果：重度组患者血清CXCL10、CXCL16、丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、谷氨酰转肽酶（GGT）、尿酸（UA）、肌酐（Cr）、尿素氮（BUN）、胱抑素C（Cys-C）水平及24h尿蛋白均高于轻度组和对照组（P＜0.05）,直接胆红素（DBIL）、白蛋白（ALB）、碱性磷酸酶（ALP）、肌酐清除率（CCr）均低于轻度组和对照组（P＜0.05）;轻度组血清CXCL10、CXCL16、ALT、AST、UA、Cr水平及24 h尿蛋白高于对照组（P＜0.05）,ALP和CCr低于对照组（P＜0.05）,轻度组和对照组的ALB、DBIL、GGT、BUN、Cys-C水平比较无差异（P>0.05）。Pearson相关性分析结果显示,重度子痫前期患者CXCL10、CXCL16与ALT、AST、UA、Cr、24h尿蛋白呈正相关（P＜0.05）,与ALP呈负相关（P＜0.05）。结论：血清CXCL10、CXCL16水平升高与重度子痫前期患者肝肾功能改变有关,临床可能通过检测二者水平来辅助评估重度子痫前期患者的病情以便及时予以治疗。     

Genetic Factors in Susceptibility: Serum PON1 Variation Between Individuals and Species

In mammals, serum paraoxonase (PON1) is tightly associated with high-density lipoprotein (HDL) particles. In human populations, PON1 exhibits a substrate dependent activity polymorphism determined by an Arg/Gln (R/Q) substitution at amino acid residue 192. The physiological role of this protein appears to be involvement in the metabolism of oxidized lipids. Several studies have suggested that the PON1_R192 allele may be a risk factor in coronary artery disease. PON1 also plays an important role in the metabolism of organophosphates including insecticides and nerve agents. The PON1_R192 isoform hydrolyzes paraoxon rapidly, but diazoxon, soman and sarin slowly compared with the PON1_Q192 isoform. Both PON1 isoforms hydrolyze phenylacetate at approximately the same rate, while PON1_R192 hydrolyzes chlorpyrifos oxon slightly faster than PON_Q192. Animal model studies involving injection of purified rabbit PON1 into mice clearly demonstrated the ability of PON1 to protect cholinesterases from inhibition by OP compounds. The consequence of having low PON1 levels has been addressed with toxicology studies in PON1 knockout mice. These mice showed dramatically increased sensitivity to chlorpyrifos oxon, diazoxon and some increased sensitivity to the respective parent compounds. These observations are consistent with earlier studies that showed a good correlation between high rates of OP hydrolysis by serum PON1 and resistance to specific OP compounds. They are also consistent with the observations that newborns have an increased sensitivity to OP toxicity, due in part to their not expressing adult PON1 levels for weeks to months after birth, depending on the species. Together, these studies point out the importance of considering the genetic variability of PON1₁₉₂ isoforms and levels as well as the developmental time course of PON1 appearance in serum in developing risk assessment models     

Association of Ghrelin Gene Polymorphisms and Serum Ghrelin Levels with the Risk of Hepatitis B Virus-Related Liver Diseases in a Chinese Population

Background

The functions of ghrelin (GHRL) include anti-inflammatory effects, reduction of the fibrogenic response, protection of liver tissue, and regulation of cell proliferation. Genetic variations in the GHRL gene may play an important role in the development of chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Therefore, we investigated whether GHRL gene polymorphisms and its serum levels are associated with hepatitis B virus (HBV)-related diseases risk in a Chinese population.

Methods

176 patients with CHB, 106 patients with HBV-related LC, 151 patients with HBV-related HCC, and 167 healthy controls were recruited in the study. Genotyping of GHRL rs26311, rs27647, rs696217, and rs34911341 polymorphisms were determined with the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing. The serum GHRL concentrations were determined using enzyme-linked immunosorbent assay (ELISA).

Results

Binary logistic regression analyses adjusting for gender and age revealed that a significant increased risk of LC was found in the GHRL rs26311 GC genotype and combined GC+CC genotypes when compared with the GG genotype (GC vs. GG: OR = 1.671, 95% CI = 1.013–2.757, P = 0.044; GC+CC vs. GG: OR = 1.674, 95% CI = 1.040–2.696, P = 0.034). In subgroup analysis by gender, binary logistic regression analyses adjusting for age showed that the GHRL rs26311 C allele and combined GC+CC genotypes were associated with a significantly increased risk to LC in males (C vs. G OR = 1.416, 95% CI = 1.017–1.972, P = 0.040; GC+CC vs. GG: OR = 1.729, 95% CI = 1.019–2.933, P = 0.042). In addition, we found significant decreased serum GHRL levels in LC patients compared with the healthy controls. However, there was no significant association of the GHRL rs26311 polymorphism with serum GHRL levels in LC patients.

Conclusions

These observations suggest that the GHRL rs26311 polymorphism is associated with an increased risk to HBV-related LC, especially in men. We also found an inverse association of serum GHRL levels with LC.     

血液中肾损伤分子-1(KIM-1)和血清肌酐(SCr)对AKI的生物标志物作用

为了探讨血液中肾损伤分子-1 (KIM-1)和血清肌酐(SCr)的表达对外科术后急性肾损伤(AKI)的早期诊断价值,本研究选取医院内2018年3月至2019年3月进行外科手术的患者48例,分为AKI组患者即实验组12例,非AKI组患者即对照组36例,收集所有患者手术后0、3 h、6 h、9 h、12 h、24 h、48 h和72 h的血液样本,检测各个时间点血液中KIM-1和血清肌酐SCr水平,将血液中KIM-1与血清肌酐SCr水平进行相关统计学分析,绘制受试者工作特征曲线(ROC),探究并对比血液中KIM-1和血清肌酐的表达对外科手术后患者发生AKI的早期诊断价值。本研究数据显示,AKI组患者在手术后(3 h, 6 h, 9 h, 12 h)血液中KIM-1水平都高于0 h基准值,并且在6 h达到最大值;与此同时,AKI组患者手术后(0, 3 h, 6 h, 9 h)血液中KIM-1水平明显高于非AKI组患者。AKI组患者手术后血液中KIM-1 (0, 3 h, 6 h, 9 h)水平和手术后24 h的血清肌酐SCr水平呈正相关。本研究表明,3~9 h血液中KIM-1水平升高对患者外科手术后AKI的发生具备较高的诊断价值,血液中KIM-1可以作为早期诊断患者外科手术后发生AKI的一项生物标志物,且血清肌酐SCr的观测效率明显低于血液中KIM-1,可作为辅助诊疗手段。     

Association of Aldosterone Synthase Polymorphism (CYP11B2 -344T>C) and Genetic Ancestry with Atrial Fibrillation and Serum Aldosterone in African Americans with Heart Failure

The objective of this study was to examine the extent to which aldosterone synthase genotype (CYP11B2) and genetic ancestry correlate with atrial fibrillation (AF) and serum aldosterone in African Americans with heart failure. Clinical data, echocardiographic measurements, and a genetic sample for determination of CYP11B2 -344T>C (rs1799998) genotype and genetic ancestry were collected from 194 self-reported African Americans with chronic, ambulatory heart failure. Genetic ancestry was determined using 105 autosomal ancestry informative markers. In a sub-set of patients (n = 126), serum was also collected for determination of circulating aldosterone. The CYP11B2 −344C allele frequency was 18% among the study population, and 19% of patients had AF. Multiple logistic regression revealed that the CYP11B2 −344CC genotype was a significant independent predictor of AF (OR 12.7, 95% CI 1.60–98.4, p = 0.0150, empirical p = 0.011) while holding multiple clinical factors, left atrial size, and percent European ancestry constant. Serum aldosterone was significantly higher among patients with AF (p = 0.036), whereas increased West African ancestry was inversely correlated with serum aldosterone (r = −0.19, p = 0.037). The CYP11B2 −344CC genotype was also overrepresented among patients with extreme aldosterone elevation (≥90th percentile, p = 0.0145). In this cohort of African Americans with chronic ambulatory heart failure, the CYP11B2 −344T>C genotype was a significant independent predictor of AF while holding clinical, echocardiographic predictors, and genetic ancestry constant. In addition, increased West African ancestry was associated with decreased serum aldosterone levels, potentially providing an explanation for the lower risk for AF observed among African Americans.     

Assessing Interactions between the Association of Common Genetic Variant at 1p11 (rs11249433) and Hormone Receptor Status with Breast Cancer Risk

Background

The association between rs11249433 polymorphism on 1p11 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the 1p11-rs11249433 polymorphism and BC.

Methods

Databases including Pubmed, SCOPUS, ISI web of knowledge, Embase and Cochrane databases were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias.

Results

A total of 15 articles involving 90,291 cases and 137,525 controls were included. In a combined analysis, the summary per-allele odds ratio (OR) for BC of 1p11-rs11249433 polymorphism was 1.09 (95% CI: 1.06–1.12; P<10⁻⁵). Significant associations were also observed under dominant and recessive genetic models. In the subgroup analysis by ethnicity, significantly increased risks were found in Caucasians; whereas no significant associations were found among Asians and Africans. In addition, our data indicate that 1p11-rs11249433 polymorphism is involved in BC susceptibility and confer its effect primarily in estrogen receptor-positive and progesterone receptor-positive tumors.

Conclusions

In conclusion, this meta-analysis demonstrated that the G allele of 1p11-rs11249433 is a risk factor associated with increased breast cancer susceptibility, but these associations vary in different ethnic populations.