The Potential Mechanism of the Anti-Liver Fibrotic Effect of Curcumin in the Gut-Liver Axis.

This study aimed to explore the curative effect of curcumin on liver fibrosis and its correlation with the gut-liver axis in animal models. Histological staining was utilized to conduct histological analysis of the liver and intestine. An automatic biochemical analyzer or enzyme-linked immunosorbent assay system was utilized for analyzing the biochemical indexes in mice. Western blotting was employed to examine the level of relevant proteins. Furthermore, 16S rRNA high-throughput sequencing was performed to explore the impact of curcumin on intestinal microorganisms in rats with liver fibrosis. Ultrahigh-performance liquid chromatography with quadrupole-orbitrap mass spectrometry was utilized to analyze the effect of curcumin on rat feces metabolites. Our results showed that curcumin reduced the formation of collagen fibers caused by carbon tetrachloride in a dose-dependent manner. In addition, curcumin was able to restore intestinal permeability in rats with liver fibrosis. By adopting α diversity analysis (Chao 1 index, Shannon index, and Simpson index), we observed that both the diversity and the abundance of intestinal flora in rats with liver fibrosis were increased. The principal component analysis diagram demonstrated that curcumin could enhance the abundance and diversity of intestinal flora, and also restore the composition of model rat flora, which was similar to that in normal rats, thereby correcting the imbalance of flora in rats with liver fibrosis. In addition, curcumin regulated feces metabolites and their signaling pathways, including glycerophospholipid metabolism, pantothenate and CoA biosynthesis. Our findings suggest that curcumin exhibits antiliver fibrosis effects, and its antiliver fibrosis effects might correlate with gut-liver axis.

Blood glucose fluctuation and in-hospital mortality among patients with acute myocardial infarction: eICU collaborative research database.

BACKGROUND: To assess the relationship between glycemic variability, glucose fluctuation trajectory and the risk of in-hospital mortality in patients with acute myocardial infarction (AMI). METHODS: This retrospective cohort study included AMI patients from eICU Collaborative Research Database. In-hospital mortality of AMI patients was primary endpoint. Blood glucose levels at admission, glycemic variability, and glucose fluctuation trajectory were three main study variables. Blood glucose levels at admission were stratified into: normal, intermediate, and high. Glycemic variability was evaluated using the coefficient of variation (CV), divided into four groups based on quartiles: quartile 1: CV≤10; quartile 2: 1030. Univariate and multivariate Cox regression models to assess the relationship between blood glucose levels at admission, glycemic variability, glucose fluctuation trajectory, and in-hospital mortality in patients with AMI. RESULTS: 2590 participants were eventually included in this study. There was a positive relationship between high blood glucose level at admission and in-hospital mortality [hazard ratio (HR) = 1.42, 95%confidence interval (CI): 1.06-1.89]. The fourth quartile (CV>30) of CV was associated with increased in-hospital mortality (HR = 2.06, 95% CI: 1.25-3.40). The findings indicated that only AMI individuals in the fourth quartile of glycemic variability, exhibited an elevated in-hospital mortality among those with normal blood glucose levels at admission (HR = 2.33, 95% CI: 1.11-4.87). Additionally, elevated blood glucose level was a risk factor for in-hospital mortality in AMI patients. CONCLUSION: Glycemic variability was correlated with in-hospital mortality, particularly among AMI patients who had normal blood glucose levels at admission. Our study findings also suggest early intervention should be implemented to normalize high blood glucose levels at admission of AMI.

Differential expression profiles of miRNA in granulomatous lobular mastitis and identification of possible biomarkers.

The etiology and pathogenesis of granulomatous lobular mastitis (GLM) remain largely elusive and the expression levels and regulatory roles of microRNAs (miRNAs or miRs) in GLM have remained mostly undetermined. In the present study, the miRNAs that were differentially expressed in breast biopsy samples from patients with GLM and normal tissue adjacent to fibroadenoma were analyzed, a comprehensive differential expression profile of miRNAs was provided and potential biomarkers were screened out. The expression profile of miRNAs was determined by high-throughput sequencing in the tissues of patients with GLM and healthy controls. Significantly differentially expressed miRNAs were screened by threshold setting and cluster analysis and their target genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, circulating differentially expressed miRNAs between the GLM and control groups were further analyzed by reverse transcription-quantitative PCR (RT-qPCR). A total of 31,077 miRNAs were detected by high-throughput sequencing. By using the cutoff criteria of |log2 fold change|>2.5 and q<0.001, 13 miRNAs that were indicated to be GLM biomarkers were screened out. The expression levels of these 13 miRNAs in the GLM group were higher than those in the control group. GO and KEGG enrichment analyses suggested that the occurrence and development of GLM may be associated with autoimmune inflammation, metabolism and pathogenic organisms. miR-451a and miR-5571-3p were confirmed to be significantly increased in the serum of patients with GLM compared with their levels in the serum of healthy volunteers, which suggests that they may be used as biomarkers of GLM. To the best of our knowledge, the present study was the first report detailing genome-wide miRNA profiling of patients with GLM compared with controls. The possible targets and pathways of GLM were evaluated by bioinformatics analysis. The present study identified 13 differentially expressed miRNAs with important theoretical significance and potential application. Furthermore, miR-451a and miR-5571-3p were verified by RT-qPCR as possible biomarkers of GLM.

Effective peroxymonosulfate activation by natural molybdenite for enhanced atrazine degradation: Role of sulfur vacancy, degradation pathways and mechanism.

In this study, natural molybdenite (MoS2) was applied to activate peroxymonosulfate (PMS) for the removal of atrazine (ATZ) and its degradation mechanism was investigated. Molybdenite exhibits superior catalytic performance. The best condition for atrazine degradation efficiency (>99%) was obtained with molybdenite concentration of 0.4 g/L, PMS concentration of 0.1 mM, and ATZ concentration of 12 µM within 10 min under experimental conditions. Electron paramagnetic resonance (EPR) test and chemical probe test further proved that HO• and SO4•- played important roles in the molybdenite/PMS system, and SO4•- was dominant. Meanwhile, Electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) tests showed that sulfur vacancies and edge sulfur played important roles in the system. Edge sulfur was conducive to Mo4+ exposure, while sulfur vacancy facilitated electron transfer and reduced Mo6+ back to Mo4+. Combined with DFT calculation, the role of sulfur in the degradation process was verified. Besides, five ATZ degradation pathways were proposed. Finally, the degradation ability of the molybdenite/PMS system for different pollutants and in actual water bodies was also explored. This work provided ideas for exploring the degradation of organic contaminants by natural minerals.

The intestinal microbiota as a therapeutic target in the treatment of NAFLD and ALD.

INTRODUCTION: Liver diseases are currently common disorders worldwide. Especially, the proportion of patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is growing globally. An increasing number of studies have revealed a close relationship between the intestinal microbiota and the development of NAFLD and ALD. A better understanding of the role of intestinal microbiota and the intestine-liver axis thus might lead to the development novel therapies for the treatment of these diseases.

Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy.

The massive production and activation of myofibroblasts (MFB) is key to the development of liver fibrosis. In many studies, it has been proven that hepatocytes are an important part of MFB, and can be transformed into MFB through epithelial-mesenchymal transition (EMT) during hepatic fibrogenesis. In our previous study, we confirmed that curcumin inhibited EMT procession and differentiation of hepatocytes into MFB. In addition, in previous studies, it has been shown that autophagy plays an important role in the regulation of cellular EMT procession. In the current study, we showed that curcumin inhibited TGF-ß/Smad signaling transmission by activating autophagy, thereby inhibiting EMT. The mechanism of degradative polyubiquitylation of Smad2 and Smad3 is likely through inhibiting tetratricopeptide repeat domain 3 (TTC3) and by inducing ubiquitylation and proteasomal degradation of Smad ubiquitination regulatory factor 2 (SMURF2), which on account of the increase of autophagy in hepatocytes. Curcumin inhibits levels of reactive oxygen species (ROS) and oxidative stress in hepatocytes by activating PPAR-α, and regulates upstream signaling pathways of autophagy AMPK and PI3K/AKT/mTOR, leading to an increase of the autophagic flow in hepatocytes. In this study, we confirm that curcumin effectively reduced the occurrence of EMT in hepatocytes and inhibited production of the extracellular matrix (ECM) by activating autophagy, which provides a potential novel therapeutic strategy for hepatic fibrosis.

Combined therapy with ligustrazine and paeonol mitigates hepatic fibrosis through destroying mitochondrial integrity of stellate cell.

This study investigates the inhibitory effect and potential mechanism of ligustrazine combined with paeonol on hepatic fibrosis, as to provide a new therapeutic strategy for clinical hepatic fibrosis. The degree of liver injury collagen deposition and inflammation was assessed by hematoxylin and eosin staining, Masson, Sirius red staining and biochemically serum analysis. ATP and ROS levels in each group were detected by chemical fluorescence method. The apoptotic rate was measured by Tunel assay. Mito-Tacker fluorescence staining and mitochondrial DNA copy number were measured to observe the effect of ligustrazine or/and paeonol on mitochondrial function of hepatic stellate cell (HSC). The expression of relevant proteins and genes were evaluated by using immunofluorescence RT-PCR and western blot. Ligustrazine or/and paeonol significantly improve the pathological changes in liver tissue induced by CCl4, however, they reduced the levels of liver and fibrosis markers in tissue and serum. ROS, NOX1 and NOX2 were significantly increased and GSH was decreased in HSC, with the intervention of Ligustrazine or/and paeonol. We further found that Ligustrazine or/and paeonol can effectively inhibit liver inflammation in vivo. The expression of TNF-α, IL-6 and IL-8 was upregulated in HSC. Moreover, Ligustrazine or/and paeonol promotes apoptosis and inhibit proliferation of HSC. Additionally, the inhibiting effects of the drug on collagen deposition was due to the interference with the expression of signaling pathway related proteins and genes such as, MMPS, TGF-ß, PDGF and BMP-2 in HSC. Mitochondrial activity of HSC was inhibited by Ligustrazine or/and paeonol. The inhibitory effects of ligustrazine or/and Paeonol on mitochondrial function is partially balanced by mitochondrial protective agent SS-31. Ligustrazine combined with paeonol exerts significant anti-hepatic fibrosis effect in vivo and in vitro. This may due to the disruption of HSC mitochondrial function, thereby induced promoting oxidative stress, apoptosis, inflammation and inhibiting the formation and deposition of extracellular matrix.

The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism.

Introduction: Epigenetic modification is a type of gene expression and regulation that does not involve changes in DNA sequences. An increasing number of studies have proven that epigenetic modifications play an important role in the occurrence and progression of liver diseases through the gene regulation and protein expressions of hepatocellular lipid metabolism, inflammatory reaction, cell proliferation, and activation, etc.Areas covered: In this study, we elaborated and analyzed the underlying functional mechanism of epigenetic modification in alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver fibrosis (LF), viral hepatitis, hepatocellular carcinoma (HCC), and research progress of recent years.Expert opinion: The further understanding of epigenetic mechanisms that can regulate gene expression and cell phenotype leads to new insights in epigenetic control of chronic liver disease. Currently, hepatologists are exploring the role of DNA methylation, histone/chromatin modification, and non-coding RNA in specific liver pathology. These findings have led to advances in direct epigenetic biomarker testing of patient tissue or body fluid specimens, as well as quantitative analysis. Based on these findings, drug validation of some targets involved in the epigenetic mechanism of liver disease is gradually being carried out clinically.

The potential signaling pathway between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha in renal interstitial fibrosis disease.

Peroxisome proliferator-activated receptorγ (PPARγ) can regulate the process of cell apoptosis and is related to the progression of renal disorders. Retinoic acid receptor alpha (RARα) is one of the nuclear receptors involved in a variety of kidney diseases. Renal interstitial fibrosis (RIF) is a common denominator of chronic kidney disease (CKD). This study investigated whether a potential signaling pathway existed between PPARγ and RARα in RIF rats with unilateral ureteral obstruction (UUO). The rats were randomly divided into four groups: a model group subjected to UUO (GU), and three other groups treated with rosiglitazone sodium (GRS), GW9662 and dimethyl sulfoxide (DMSO), n = 40, respectively. Renal tissues were collected two and four weeks after post-surgery. The relevant indicators were detected. In comparison with the GU group, the expressions of PPARγ and RARα (protein and mRNA) were increased in the GRS group, and decreased in the GW9662 group (all p < 0.01). The RIF index, mRNA and protein expression of transforming growth factor-ß1 (TGF-ß1), and the protein expressions of collagen-IV (Col-IV) and fibronectin (FN) in the GRS group were more markedly reduced than those in the GU group; their levels in the GW9662 group were elevated (all p < 0.01). PPARγ or RARα was negatively correlated to the RIF index, TGF-ß1, Col-IV and FN. PPARγ was positively correlated with RARα (all p < 0.01). In conclusion, PPARγ agonist can elevate the expression of PPARγ or RARα in RIF rats. There might be a potential signaling pathway between PPARγ and RARα in RIF disease.

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM homeodomain type and has been implicated in the development of diverse structures such as limbs, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, and the cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here, we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and tubule lining, including epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, cell apoptosis, ROS, and malondialdehyde (r = -0.756, -0.698, -0.921, -0.923, -0.843, -0.794, -0.883, and -0.825, all P < 0.01).

The role of retinoic acid receptors in the signal pathway of all-trans retinoic acid-induced differentiation in adriamycin-induced podocyte injury.

All-trans retinoic acid (ATRA) plays an essential role in cell survival and differentiation by binding to retinoic acid receptors (RARs), including RAR-α, RAR-ß, and RAR-γ. Injury to podocytes is the most frequent cause of glomerulosclerosis (GS). This study was performed to investigate which of the RAR subtypes is involved in the signal pathway of ATRA-induced differentiation of injured podocytes. ATRA (0.1 µM) was administered to Adriamycin (ADR)-induced, injured podocytes, in vitro. Morphological changes were observed. The protein/mRNA expression of podocin, nephrin, transforming growth factor ß1(TGF-ß1), and the RARs (RAR-α,ß,γ) was measured by RT-PCR and Western blotting. ATRA treatment ameliorated cell hypertrophy and reduced the shedding of the cytoplasm which was observed under light microscope and the extension of the foot processes was observed under scan electron microscope. Compared with the injured podocytes, ATRA exposure significantly increased the protein/mRNA expression of nephrin and podocin and it markedly reduced TGF-ß1 (all p < 0.05). Compared with the injured podocytes, the protein/mRNA expression of RAR-α and RAR-γ was significantly increased after ATRA exposure; however, the expression level of RAR-ß was not significantly different. The RAR-α/γ protein expression level was positively correlated with nephrin and podocin (-α, r = 0.637, 0.663; -γ, r = 0.882, 0.878; all p < 0.05), and negatively correlated with TGF-ß1 (-α, r = -0.650; -γ, r = -0.739; all p < 0.05). The RAR-ß protein expression level was not correlated with nephrin, podocin and TGF-ß1 (r = -0.312, 0.079, -0.279; all p > 0.05). In conclusion, RAR-α/γ (and RAR-ß to a lesser degree) may be involved in the signal pathway of ATRA-induced differentiation in injured podocytes.

Association of prohibitin-1 and 2 with oxidative stress in rats with renal interstitial fibrosis.

Prohibitins PHB1 and PHB2 are evolutionary conserved and pleiotropic proteins, which have been shown to be important factors in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Recently, we demonstrated that down-regulation promoted renal interstitial fibrosis (RIF) in ureteral obstructed rats. Furthermore, the hypoxic conditions and oxidative stress have been implicated in obstruction-mediated renal disease. This study was performed to explore the association of PHBs with oxidative stress in a rat model of RIF. PHBs, the pro-fibrotic transforming growth factor-ß1 (TGF-ß1), and the extracellular matrix proteins collagen-IV (Col-IV) and fibronectin (FN) were evaluated, as were markers of oxidative stress [total reactive oxygen species (ROS), malondialdehyde (MDA)] and antioxidative capacity (superoxide dismutase, glutathione), and apoptosis. Our results showed a progressive increase in oxidative stress and concomitant decrease in antioxidants over a period of 4 weeks ureteral obstruction. Concomitantly, profibrotic components increased and PHB expression decreased. Overall, both PHBs were negatively correlated with the extent of observed fibrosis, TGF-ß1, Col-IV, FN, ROS, MDA, and apoptosis.

LIM homeobox transcription factor 1B is associated with pro-fibrotic components and apoptosis in hypoxia/reoxygenation renal tubular epithelial cells.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM-homeodomain type, which plays an important role in foetal development during formation of the extremities, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30 % of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and pro-fibrotic components and apoptosis in hypoxic renal tubular epithelial cells (RTEC), we explored if LMX1B was associated with extracellular matrix components, profibrotic factors, and apoptosis induced by hypoxia/reoxygenation (H-R). In this cell system under hypoxic conditions, when the expression of LMX1B was inhibited in H-R RTEC, the expression of transforming growth factor-ßl, collagen-III, fibronectin, cleaved caspase-3, and cell apoptosis rate was increased. Consequently, overexpression of LMX1B was associated with reduced cell apoptosis, whilst downregulation of LMX1B was associated with increased cell apoptosis in H-R RTEC.

Prohibitin is associated with antioxidative protection in hypoxia/reoxygenation-induced renal tubular epithelial cell injury.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and prohibitin expression in a hypoxia/reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress prohibitin. Our results show that increased prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-ß1, collagen-IV, fibronectin, and apoptosis (r = -0.895, -0.764, -0.798, -0.826, -0.817, -0.735; each P < 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r = 0.807, 0.815, 0.739; each P < 0.01). We postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Prohibitin attenuates oxidative stress and extracellular matrix accumulation in renal interstitial fibrosis disease.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Both prohibitin over- and under-expression have been implicated in various diseases and cell types. We recently demonstrated that prohibitin down-regulation results in increased renal interstitial fibrosis (RIF). Here we investigated the role of oxidative stress and prohibitin expression in RIF in unilateral ureteral obstructed rats. Lentivirus-based delivery vectors were used to knockdown or over-express prohibitin. Our results show that increased prohibitin expression was negatively correlated with the RIF index, reactive oxygen species, malon dialdehyde, transforming growth factor ß1, collagen IV, fibronectin, and cell apoptosis index. In conclusion, we postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Association of PAX2 with cell apoptosis in unilateral ureteral obstruction rats.

Renal interstitial fibrosis (RIF) is the final common pathway for chronic kidney disease. Cell apoptosis is a critical detrimental event that leads to renal fibrosis. Paired box 2 (PAX2) plays a major role in the development of the kidney. This study was performed to investigate whether PAX2 was associated with cell apoptosis in the progression of RIF in unilateral ureteral obstruction (UUO) rats. Eighty Wistar male rats were divided into two groups randomly: sham operation group (SHO) and model group subjected to UUO (GU), n = 40, respectively. The model was established by left ureteral ligation. Renal tissues were collected 14 and 28 days after surgery. Protein expressions of PAX2, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), collagen-IV (Col-IV), fibronectin (FN), and caspase-3 were detected using immunohistochemical analysis; mRNA expression of PAX2 in renal tissue was detected by real-time reverse transcription polymerase chain reaction; and RIF index and cell apoptosis index in renal interstitium were also calculated. When compared with those in the SHO group, expressions of PAX2 (protein and mRNA) were markedly increased in the GU group (each p < 0.01). Protein expressions of TGF-ß1, α-SMA, Col-IV, FN, and caspase-3 and RIF index and cell apoptosis index in the GU group were remarkably increased when compared with those in the SHO group (each p < 0.01). The protein expression of PAX2 was positively correlated with the protein expressions of TGF-ß1, α-SMA, Col-IV, FN, and caspase-3 and with RIF index and cell apoptosis index (all p < 0.01). The apoptotic cell in our observation was mainly derived from renal tubular epithelial cells. In conclusion, the increased expression of PAX2 is associated with cell apoptosis in the progression of RIF in UUO rats, suggesting that PAX2 is a potentially therapeutic target for prevention of RIF. Tian-Biao Zhou and Yuan-Han Qin wish it to be known that, in their opinion, they should be regarded as joint first authors.

Less gelatinases is associated with apolipoprotein E accumulation in glomerulosclerosis rats.

BACKGROUND: Gelatinases include matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The abnormal expressions of gelatinases are implicated in the pathogenesis of extracellular matrix (ECM) accumulation. Apolipo-protein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether gelatinases were associated with the apoE accumulation in the pathological process of GS. METHODS: 40 Wistar rats were divided into two groups at random: sham operation group (SHO) and glomerulosclerosis model group (GS); n=20, respectively. The disease of GS was established by uninephrectomy and adriamycin (5 mg/kg) injection. At the end of 13 weeks, the 20 rats in each group were killed and the relevant samples were collected and measured. RESULTS: Serum total protein (TP) and serum albumin (Alb) in GS group were reduced compared to those of the SHO group (P<0.01). Compared with the SHO group, values of 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), blood urea nitrogen (BUN), serum creatinine (Scr) and glomerulosclerosis index (GSI) in GS group were significantly increased (P<0.01). The protein of MMP-2 or MMP-9 in the glomerulus, and mRNA expression of MMP-2 or MMP-9 in renal tissue were reduced when compared with those in SHO (P<0.01). Protein expressions of apoE, collagen IV (Col-IV), fibronectin (FN), α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1) in the glomerulus and expression of apoE mRNA in renal tissue were significantly up-regulated in GS group when compared with those in the SHO group (P<0.01). CONCLUSIONS: Lower expression of gelatinases is associated with the increased expression of apoE in the glomerulus, and increases the accumulation of ECM and takes part in the pathological change of GS.

Less expression of prohibitin is associated with increased caspase-3 expression and cell apoptosis in renal interstitial fibrosis rats.

AIMS: Prohibitin (PHB), a ubiquitous protein, is involved in a variety of molecular functions. Renal interstitial fibrosis (RIF) is a hallmark of common progressive chronic diseases that lead to renal failure. This study was performed to investigate whether PHB was associated with caspase-3 expression/cell apoptosis in RIF rats. METHODS: Twenty-four male Wistar rats were randomly divided into two groups: sham operation group (SHO) and model group subjected to unilateral ureteral obstruction (GU), n = 12, respectively. The model was established by left ureteral ligation. Renal tissues were collected at 14 days and 28 days after surgery. RIF index, cell apoptosis index, protein expression of PHB, transforming growth factor-ßl (TGF-ß1), collagen-IV (Col-IV), fibronectin (FN) or caspase-3 in renal interstitium, and mRNA expression of PHB in renal tissue were detected. RESULTS: Compared with that in the SHO group, the PHB expression (mRNA and protein) was significantly reduced (P < 0.01). Protein expressions of TGF-ß1, Col-IV, FN and caspase-3, and RIF index or cell apoptosis index in GU group were markedly elevated compared with those in SHO group (all P < 0.01). The protein expression of PHB had a negative correlation with the protein expression of TGF-ß1, Col-IV, FN or caspase-3, and RIF index or cell apoptosis index (each P < 0.01). CONCLUSIONS: Less expression of PHB is associated with increased caspase-3 expression/cell apoptosis in RIF rats. However, further research is needed to determine the effect of PHB on caspase-3 expression/cell apoptosis and to determine the potential of PHB as a therapeutic target.

A meta-analysis of the association between angiotensin-converting enzyme insertion/deletion gene polymorphism and steroid-sensitive nephrotic syndrome in children.

BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism correlates with circulating and cellular ACE concentration. Association between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) risk in children is still controversial. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and SSNS susceptibility in children. METHODS: The relevant investigations were screened from the search engines of PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) as of 1 March 2011, and eligible studies were synthesized using meta-analysis methods. RESULTS: Ten studies were identified for the analysis of association between ACE I/D gene polymorphism and SSNS risk in children, including seven in Asians, one for Caucasians and two in Africans. There was no markedly positive association between D allele or DD genotype and SSNS susceptibility in Asians, Caucasians and Africans (D: Asians OR = 1.24, p = 0.28; Caucasians OR = 1.61, p = 0.15; Africans OR = 1.61, p = 0.53; DD: Asians OR = 1.72, p = 0.15; Caucasians OR = 1.39, p = 0.48; Africans OR = 1.80, p = 0.56). Furthermore, II homozygous seemed not to play a protective role against SSNS onset for Asians, Caucasians and Africans (Asians OR = 0.95, p = 0.85; Caucasians OR = 0.30, p = 0.11; Africans OR = 0.60, p = 0.65). CONCLUSIONS: There was no association between ACE I/D gene polymorphism and SSNS susceptibility in Asians, Caucasians and Africans. However, the conclusions for Caucasians and Africans were less powerful.

Association of angiotensin converting enzyme insertion/deletion gene polymorphism with idiopathic nephrotic syndrome susceptibility in children: a meta-analysis.

BACKGROUND AND OBJECTIVE: Angiotensin converting enzyme (ACE) gene contains either an insertion (I) allele or a deletion (D) allele forming three potential genotypes: II, ID and DD. The D allele or DD genotype has been reported to be associated with higher plasma ACE level. An assessment of the association between ACE I/D gene polymorphism and idiopathic nephrotic syndrome (INS) susceptibility in children is still controversial. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and the onset of INS. METHOD: A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases, and eligible investigations were synthesized using the meta-analysis method. RESULTS: Nine investigations were identified for the analysis of association between ACE I/D gene polymorphism and INS risk in children, including six in Asians, one study for Caucasians and two for Africans. There was positive association between D allele or DD genotype and INS susceptibility in Asians (OR = 1.75, p = 0.01; OR = 2.01, p = 0.02), but not for Caucasian children and Africans (for Caucasians, D: OR=1.35, p = 0.27, DD: OR = 0.95, p = 0.91; for Africans, D: OR = 1.70, p = 0.56, DD: OR = 1.60, p = 0.73). Furthermore, II homozygous seemed to play a positive role against INS onset for Asians (OR = 0.59, p = 0.02), but the link between II genotype and INS risk was not observed in Caucasian children and Africans (Caucasians: OR = 0.31, p = 0.06; Africans: OR = 0.50, p = 0.59). CONCLUSIONS: D allele and DD homozygous might become significant genetic molecular markers for INS susceptibility in Asian children, but the association was not observed in Caucasians or Africans. However, the conclusion from our study cannot be sustained and more investigations on larger sample in different populations are required to further clarify the role of D allele or DD homozygous in the onset of INS in difference races.