Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion.

In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.

Farnesoid X receptor activation protects against renal fibrosis via modulation of ß-catenin signaling.

OBJECTIVE: Activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice. METHODS: We investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and ß-catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and ß-catenin was further verified. RESULTS: Mice were fed by a 60% kcal fat diet for 20 weeks developed the typical traits of metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal ß-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected ß-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox-LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) ß-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) ß-catenin, nuclear translocation and ß-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with ß-catenin via the AF1 domain, and disrupt the assembly of the core ß-catenin/TCF4 complex. CONCLUSION: These experimental data suggest that FXR activation, via modulating ß-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.

Prognostic model for the prediction of cancer-specific survival in elderly patients with stage I-III gastric cancer.

Elderly patients with gastric cancer (GC) exhibit unique physiological conditions and population characteristics. However, no efficient predictive tools have been developed for this patient subgroup. We extracted data on elderly patients diagnosed with stage I-III GC between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database, and applied Cox regression analysis to examine factors associated with cancer-specific survival (CSS). A prognostic model was developed and validated to predict CSS. We assessed the performance of the prognostic model and stratified patients based on their prognostic scores. Notably, 11 independent prognostic factors, including age, race, grade, the tumor-node-metastasis (TNM) stage, T-stage, N-stage, operation, tumor size, regional nodes, radiation, and chemotherapy, associated with CSS were identified using multivariate Cox regression. A nomogram was constructed based on these predictors. The C-index score of the nomogram was 0.802 (95% (confidence interval) [CI]: 0.7939-0.8114), which is superior to the American Joint Commission on Cancer (AJCC) TNM staging prediction ability in the training cohort (C-index: 0.589; 95% CI: 0.5780-0.6017). Based on the receiver operating characteristic (ROC) and calibration curve, the predicted value of the nomogram demonstrated a satisfactory accuracy with the actual observation value. Additionally, decision curve analysis (DCA) showed that the nomogram had a more ideal clinical net benefit than TNM staging. Survival analysis of the different risk groups confirmed the noteworthy clinical and statistical utility of the nomogram in prognosis stratification. This retrospective study reports the successful creation and validation of a nomogram for predicting CSS at 1-, 3- and 5-years in elderly patients with stage I-III GC. This nomogram critically guides personalized prognostic assessments and may contribute to clinical decision-making and consultation for postoperative survival.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

Socioeconomic deprivation and survival outcomes in patients with colorectal cancer.

Socioeconomic deprivation has been linked to detrimental healthcare outcomes. We sought to examine whether patients with colorectal cancer (CRC) from socioeconomically disadvantaged areas experience worse survival outcomes and how it interacts with other factors. In this population-based study, patients with CRC diagnosed between 2007 to 2015 in the SEER program were reviewed. Socioeconomic deprivation was measured using the Area Deprivation Index (ADI) linked to patients' residence addresses. The effect of ADI on cancer-specific survival and overall survival was evaluated using survival analysis. The Inverse Probability of Weighted (IPW) method and multiple regression was performed to account for the confounding bias. Subgroup analyses were used to test interactions. Multiple mediation analysis was used to estimate the mediating effects. Overall, 266,620 eligible patients were included in further analyses. Compared with low ADI patients, high ADI patients had more unfavorable characteristics and worse cancer-specific (hazard ratio [HR] 1.14, 95% CI 1.12-1.16, P<.001) and overall survival (HR 1.11, 95% CI 1.09-1.12, P<0.001). The results were similar after accounting for confounding factors using the IPW and multiple regression methods. Subgroup analyses revealed the relative robustness of ADI as a prognostic factor. They detected significant interactions between ADI and other covariates on cancer survival, such as age, race, insurance status, disease stage, and receipt of treatment. Multiple mediation analyses identified several factors mediating survival disparities, including anticancer therapy, insurance status, race, marital status, and age. This study suggested that high ADI CRC patients were associated with more unfavorable characteristics at presentation and lower cancer and noncancer survival after treatment than their low ADI counterparts. Multiple factors interacted and mediated these survival disparities associated with the ADI.

Calpain 6 inhibits autophagy in inflammatory environments: A preliminary study on myoblasts and a chronic kidney disease rat model.

A non­classical calpain, calpain 6 (CAPN6), can inhibit skeletal muscle differentiation and regeneration. In the present study, the role of CAPN6 in the regulation of the autophagy of myoblasts in vitro was investigated. The underlying molecular events and the CAPN6 level in atrophic skeletal muscle in a rat model of chronic kidney disease (CKD) were also investigated. In vitro, CAPN6 was overexpressed, or knocked down, in rat L6 myoblasts to assess autophagy and related gene expression and co­localization. Subsequently, myoblasts were treated with a mixture of cytokines, and relative gene expression and autophagy were assessed. A rat model of CKD for muscle atrophy was established, and blood chemical level and the expression of CAPN6 in muscle were assessed. The data revealed that the knockdown of CAPN6 in rat myoblasts resulted in increased microtubule­associated protein 1 light chain 3 (LC3) levels, while its overexpression decreased LC3 levels and impaired autophagy. Additionally, it was observed that the co­localization of mammalian target of rapamycin (mTOR) and lysosomal­associated membrane protein 1 (LAMP1), a lysosomal marker, proteins was increased. In addition, mTOR, Raptor and α­tubulin (a marker of microtubules) increased in the CAPN6 overexpression group. However, inflammatory cytokines, such as interleukin (IL)­6, tumor necrosis factor (TNF)­α, interferon (INF)­Î³ and lipopolysaccharides upregulated CAPN6 expression, inhibited L6 myoblast autophagy and stabilized mTOR activity. Furthermore, the animal model successfully mimicked human disease as regards an increase in body weight, and a reduction in muscle mass, cross­sectional area and blood biomarker concentrations; a slight increase in CAPN6 mRNA and protein levels in muscles was observed. Finally, the data of the present study suggested that CAPN6 reduced autophagy via the maintenance of mTOR signaling, which may play a role in CKD­related muscle atrophy. However, future studies are required to determine whether CAPN6 may be used as an intervention target for CKD­related skeletal muscle atrophy.

The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Several susceptibility gene variants predisposing to nonalcoholic fatty liver disease (NAFLD) have been identified in chronic kidney disease (CKD). Evidence supports that 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) rs72613567 plays a role in NAFLD development by affecting lipid homeostasis. Since lipid droplets may accumulate in the kidneys and contribute to renal injury, we investigated the association between the HSD17B13 rs72613567 variant and markers of renal function/injury in NAFLD. METHODS AND RESULTS: We measured estimated glomerular filtration rate (eGFR), urinary/serum neutrophil gelatinase-associated lipocalin (NGAL), and urinary albumin-to-creatinine ratio (u-ACR) in individuals with biopsy-proven NAFLD. Multivariable regression analyses were undertaken to examine the associations between the HSD17B13 rs72613567 variant and markers of renal function/injury. Individuals were stratified by HSD17B13 rs72613567 genotypes into -/-, A/- and A/A groups. HSD17B13 rs72613567 genotypes were not significantly associated with eGFR and urinary/serum NGAL levels. Conversely, the prevalence of abnormal albuminuria in the A/- + A/A group was lower than in the -/- group (4.92% vs. 19.35%, p = 0.001). Additionally, the mean u-ACR levels were lower among carriers of the A/- or A/A genotypes with coexisting hypertension or diabetes, than among those with the -/- genotype. The risk of abnormal albuminuria (adjusted-odds ratio 0.16, p = 0.001) remained significantly lower in the A/- + A/A group after adjustment for established renal risk factors and histologic severity of NAFLD. CONCLUSION: HSD17B13 rs72613567: A allele is associated with a lower risk of having abnormal albuminuria, but not with lower eGFR or urinary/serum NGAL levels, in patients with biopsy-proven NAFLD.

MAFLD and risk of CKD.

BACKGROUND/AIMS: Whereas nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and extra-hepatic diseases is not known. The aim of this cross-sectional study was to compare the prevalence of chronic kidney disease (CKD) in patients with either MAFLD or NAFLD, and then to examine the association between the presence and severity of MAFLD and CKD and abnormal albuminuria. METHODS: A total of 12,571 individuals with complete biochemical and liver ultrasonography data from the Third National Health and Nutrition Examination Survey (1988-1994) were included in the analysis. Multivariable logistic regression analyses were performed to test the independence of associations between MAFLD or MAFLD severity as the key exposures and CKD (defined as either CKD stage ≥1 or stage ≥3) or abnormal albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol) as the outcomes. RESULTS: The prevalence of MAFLD and NAFLD was 30.2% (n = 3794) and 36.2% (n = 4552), respectively. MAFLD individuals had a lower eGFR (74.96 ±â€¯18.21 vs. 76.46 ±â€¯18.24 ml/min/1.73 m2, P < 0.001) and a greater prevalence of CKD (29.60% vs. 26.56%, P < 0.05) than NAFLD individuals. Similarly, there was a higher prevalence CKD in MAFLD than in non-metabolic dysfunction-associated NAFLD (P < 0.05). Notably, after adjustment for sex, age, ethnicity, alcohol intake and diabetes, the severity of MAFLD (i.e. NAFLD fibrosis score ≥ 0.676) was associated with 1.34-fold higher risk of prevalent CKD (P < 0.05). CONCLUSIONS: MAFLD identifies patients with CKD better than NAFLD. MAFLD and MAFLD with increased liver fibrosis score are strongly and independently associated with CKD and abnormal albuminuria.

Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-ß1 pathway.

It has been reported that butyrate played an protect role in diabetic kidney disease (DKD) while the mechanism was still not clear. Transforming growth factor-ß1 (TGF-ß1) is the initial factor which triggers the profibrotic signaling cascades. P311 is an RNA-binding protein, which could stimulate TGF-ß1 translation in several cell types. In our study, we found that supplementary of butyrate alleviated fibrosis and suppressed the expression of TGF-ß1 and P311 in the kidney of db/db mice as well as high glucose (HG)-induced SV40-MES-13 cells. Overexpression of P311 offset the inhibition of butyrate on TGF-ß1 in SV40-MES-13 cells. To make clear the mechanism of butyrate in regulating P311, microRNAs (miRNAs) of the SV40-MES-13 cells were sequenced. We found that miR-7a-5p was significantly decreased in the HG-induced SV40-MES-13 cells and the kidney of db/db mice, while giving butyrate reversed this change. Besides, miR-7a-5p could specifically target the 3' UTR of P311's mRNA and suppressed the expression of P311 in the SV40-MES-13 cells. Giving miR-7a-5p inhibitor blocked the inhibition of butyrate on P311 and TGF-ß1. Introducing the miR-7a-5p agomir into db/db mice alleviated renal fibrosis and inhibit the expression of P311 and TGF-ß1. In conclusion, butyrate alleviated DKD by mediating the miR-7a-5p/P311/TGF-ß1 pathway.

Effect of Sheng Xue Ning Tablets on Renal Anemia in Patients Subject to Maintenance Hemodialysis and Safety Evaluation: A Multi-setting Prospective Randomized Study.

This study compared Sheng Xue Ning (SXN) tablets with ferrous succinate (FS) tablets in terms of their efficacy for the treatment of iron-deficient renal anemia and safety in patients subject to maintenance hemodialysis (MHD). A total of 94 patients undergoing MHD were randomly assigned to an experiment group (receiving oral SXN tablets, SXN group) and a control group (orally given FS tablets, FS group) and followed up for 12 weeks. Erythropoietin (EPO) was used in both groups. The efficacy was assessed by detecting the subsequent changes in hemoglobin (Hb), serum iron (SI), SF and transferrin saturation (TSAT). At the 12th week, Hb and TSAT levels in both groups were significantly increased compared to those in the screening period (P<0.05). However, no significant difference in Hb and TSAT was found between the two groups. The average weekly EPO dosage used was lower in SXN group than in FS group (P<0.05) at the 10th week and the 12th week. Our study showed that SXN tablets can effectively ameliorate renal anemia and keep iron metabolism stable in MHD patients, and its efficacy is virtually close to that of FS tablets. Meanwhile, SXN tablets can reduce the dosage of EPO and have a good safety profile.

PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.

BACKGROUND & AIMS: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. METHODS: Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. RESULTS: The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P < .001), higher albuminuria (P = .039) and greater prevalence of chronic kidney disease (CKD; P = .046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (ß-coefficient: 22.29, 95% CI: 0.99-43.60, P = .041). CONCLUSION: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI.

Metabolic Acidosis in Critically Ill Cirrhotic Patients with Acute Kidney Injury.

Background and Aims: The metabolic acid-base disorders have a high incidence of acute kidney injury (AKI) in critically ill cirrhotic patients (CICPs). The aims of our study were to ascertain the composition of metabolic acidosis of CICPs with AKI and explore its relationship with hospital mortality. Methods: Three-hundred and eighty consecutive CICPs with AKI were eligible for the cohort study. Demographic, clinical and laboratory parameters were recorded and arterial acid-base state was analyzed by the Stewart and Gilfix methodology. Results: Net metabolic acidosis, lactic acidosis, acidosis owing to unmeasured anions, acidemia, and dilutional acidosis were less frequent in the non-survival group compared to the survival group of CICPs. The presence of acidemia, acidosis owing to unmeasured anions, and lactic acidosis were independently associated with increased risk of intensive care unit 30-day mortality, with hazard ratios of 2.11 (95% confidence interval (CI): 1.43-3.12), 3.38 (95% CI: 2.36-4.84), and 2.16 (95% CI: 1.47-3.35), respectively. After full adjustment for confounders, the relationship between acidosis owing to unmeasured anions with hospital mortality was still significant, with hazard ratio of 2.29 (95% CI: 1.22-4.30). Furthermore, arterial lactate concentration in combination with chronic liver failure-sequential organ failure assessment and BEUMA had the strongest ability to differentiate 30-day mortality (area under the receiver operating characteristic curve: 0.79, 95% CI: 0.74-0.83). Conclusions: CICPs with AKI exhibit a complex metabolic acidosis during intensive care unit admission. Lactic acidosis and BEUMA, novel markers of acid-base disorders, show promise in predicting mortality rate of CICPs with AKI.

The histone demethylase LSD1 promotes renal inflammation by mediating TLR4 signaling in hepatitis B virus-associated glomerulonephritis.

Renal inflammation significantly contributes to the progression of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN), but the mechanisms that control its precise regulation remain largely unknown. In this study, we showed that the lysine-specific demethylase 1 (LSD1) was significantly upregulated in renal tissue of HBV-GN patients, and its expression was positively correlated with inflammation. Functionally, LSD1 could promote HBV-induced release of proinflammatory mediators in HK-2 cells, a human renal tubular epithelial (RTE) cell line. Mechanistic investigations suggested that LSD1 directly promoted the transcription of the inflammatory-related gene Tlr4 by eliminating the mono- or di-methylation of H3K9 near its promoter. Knockdown of Lsd1 further inhibited TLR4-NF-κB/JNK signaling cascades, and subsequently decreased HBV-induced production of proinflammatory mediators in HK-2 cells. Co-transfection with Tlr4-expressing plasmids counteracted these effects. Meanwhile, downregulation of abovementioned TLR4-related pathways using small-molecule inhibitors attenuated inflammation. Importantly, LSD1 inhibitor tranylcypromine (TCP) could inhibit TLR4-NF-κB/JNK signaling axis and alleviate renal inflammation in HBV transgenic mice. Taken together, our data identify LSD1 as a novel regulator of renal inflammation and as a potential therapeutic target in HBV-GN.

CKD autophagy activation and skeletal muscle atrophy-a preliminary study of mitophagy and inflammation.

BACKGROUND/OBJECTIVES: Long-lived proteins and organelles, such as mitochondria and the sarcoplasmic reticulum, are degraded by autophagy. However, the specific role of autophagy in chronic kidney disease (CKD) muscle atrophy is still undefined. SUBJECTS/METHODS: This was a cross-sectional study with 20 subjects and 11 controls. Autophagy induction was studied in human skeletal muscle biopsies from CKD patients and controls by comparing the cross-sectional areas of muscle fibers, protein, and mRNA expression of autophagy-related genes and the appearance of autophagosomes. RESULTS: The cross-sectional area of muscle fibers was decreased in CKD patients as compared with the control group. CKD was associated with activated autophagy and mitophagy, as measured by the elevated mRNA and protein expression of BNIP3, (microtubule-associated proteins 1 A/1B light chain 3, also MAP1LC3) LC3, p62, PINK1, and PARKIN in the skeletal muscle and isolated mitochondria of the CKD group. Electron microscopy and immunohistofluorescence analysis showed mitochondrial engulfment by autophagosomes. Mitophagy was further demonstrated by the colocalization of LC3 and p62 puncta with the mitochondrial outer membrane protein TOM20. In addition, degradative FOXO3 (Forkhead box O3) was activated and synthetic mTOR (mammalian target of rapamycin) was inhibited, whereas the upstream mediators VPS34 (class III PI3-kinase) and AKT (protein kinase B, PKB) were activated in CKD patients. CONCLUSIONS: Hyperactive autophagy and mitophagy may play important roles in CKD muscle atrophy. Autophagy was activated by FOXO3 translational factors in the skeletal muscle tissues of CKD patients, which maybe a new way of intervention for CKD muscle atrophy.

Upregulated Expression of Long Non-Coding RNA, LINC00460, Suppresses Proliferation of Colorectal Cancer.

Through bioinformatics analysis, a novel lncRNA, LINC00460, was implicated in the development of multiple cancers. However, the precise expression pattern, clinical significance and biological function of LINC00460 in colorectal cancer (CRC) remain unknown. Network databases were used to investigate the correlation between LINC00460 and CRC. In situ hybridization was performed to verify the precise expression pattern and clinical significance of LINC00460 in a CRC tissue microarray, which included 92 pairs of CRC and adjacent normal tissues. The effect of LINC00460 on proliferation was evaluated by MTT, colony formation assays and flow cytometry employing SW620 and HCT116 cell lines. Cell migration and matrigel invasion assays were performed to investigate whether LINC00460 is involved in the metastasis of CRC. The expression of LINC00460 was significantly upregulated in CRC tissues and cells, associated with early stage CRC and low disease-free survival. The downregulated of LINC00460 expression increased cell proliferation by regulating the cell cycles of SW620 and HCT116 cells. LINC00460 knockdown did not affect cell migration or invasion in vitro. These findings suggest that LINC00460 may be an interesting target for the development of CRC.

Phosphate stimulates myotube atrophy through autophagy activation: evidence of hyperphosphatemia contributing to skeletal muscle wasting in chronic kidney disease.

BACKGROUND: Accelerated muscle atrophy is associated with a three-fold increase in mortality in chronic kidney disease (CKD) patients. It is suggested that hyperphosphatemia might contribute to muscle wasting, but the underlying mechanisms remain unclear. Although evidence indicates that autophagy is involved in the maintenance of muscle homeostasis, it is not known if high phosphate levels can result in activation of autophagy, leading to muscle protein loss. METHODS: Immortalized rat L6 myotubes were exposed to a high concentration of phosphate, with or without autophagy inhibition. Myotube atrophy was examined by phase contrast microscopy. Autophagic activity was assessed by measuring the expression of microtubule-associated protein 1 light chain 3 (LC3) and p62 using quantitative real-time polymerase chain reaction and western blot. RESULTS: Phosphate induced cell atrophy in L6 myotubes in a dose- and time-dependent manner, and these responses were not associated with calcification or osteogenesis. Phosphate also dose- and time-dependently increased the LC3-II/LC3-I ratio. Inhibition of autophagy with wortmannin or knockdown of Atg5 significantly suppressed myotube atrophy caused by high phosphate concentration. CONCLUSIONS: High phosphate concentration induces muscle cell atrophy through the activation of autophagy. Targeting autophagy could be a therapeutic strategy for preventing muscle wasting caused by hyperphosphatemia.

Helicobacter pylori cytotoxin-associated gene A impairs the filtration barrier function of podocytes via p38 MAPK signaling pathway.

Helicobacter pylori (Hp) specific antigens were found deposited in the glomeruli in some kidney diseases. However, the underlying molecular mechanisms remain to be elucidated. The aim of this study was to investigate the effect of cytotoxin associated gene A protein (CagA), a key virulence factor of Hp, on mouse podocytes. Cells were cultured and treated with recombinant CagA protein. The expression of the tight junction protein ZO-1 and p38 MAPK signaling pathway activation were measured with real-time RT-PCR and western blotting. The filtration barrier function of podocytes was evaluated with albumin influx assay. CagA decreased the expression and membrane distribution of ZO-1, impaired the filtration barrier function of podocytes, while activating p38 MAPK signaling pathway in these cells. Selective p38 MAPK inhibition partly prevented CagA-induced filtration barrier dysfunction of podocytes through ameliorating ZO-1 downregulation. Taken together, the results suggested that CagA, at least via p38 MAPK signaling pathway, may induce podocyte injury. Anti-Hp therapy may be beneficial for the treatment of kidney diseases related to Hp antigen deposition.

Combination therapy with lamivudine and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker for hepatitis B virus-associated glomerulonephritis with mild to moderate proteinuria: a clinical review of 38 cases.

PURPOSE: The treatment of HBV-associated glomerulonephritis (HBV-GN) is still a challenge in clinical practice now. The objective of this study was to report the pathological characteristics of HBV-GN presenting with mild to moderate proteinuria and to evaluate the therapeutic efficacy of lamivudine (LAM) in combination with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) as compared to ACEI/ARB monotherapy. METHODS: We conducted a retrospective observational study in HBV-GN patients between 2005 and 2014. The patients were classified into two groups: Group 1 included patients treated with LAM plus ACEI/ARB (n = 20), and group 2, patients treated with ACEI/ARB alone (n = 18). Their clinical and pathological characteristics were collected; we analyzed the therapeutic responses and assessed the correlation between renal and liver pathologies. RESULTS: Our results showed that the most common type of HBV-GN was IgA nephropathy. LAM plus ACEI/ARB therapy was better in reducing 24-h urinary protein excretion, alanine aminotransferase, and aspartate aminotransferase levels, while maintaining the level of kidney function. The proportion of patients who achieved remission (CR + PR) was higher in the LAM plus ACEI/ARB group than in the ACEI/ARB monotherapy group (χ 2 = 5.371, P = 0.035). CONCLUSION: In the HBV-GN patients with mild to moderate proteinuria, LAM plus ACEI/ARB not only improved liver function but also better reduced 24-h proteinuria.

Prevalence, awareness, and treatment of anemia in Chinese patients with nondialysis chronic kidney disease: First multicenter, cross-sectional study.

This was the first multicenter, cross-sectional survey to assess the prevalence of anemia, patient awareness, and treatment status in China. Data of patients with chronic kidney disease (CKD; age, 18-75 years; both out- and inpatients) from 25 hospitals in Shanghai, seeking medical treatment at the nephrology department, were collected between July 1, 2012 and August 31, 2012. The prevalence, awareness, and treatment of anemia in patients with nondialysis CKD (ND-CKD) were assessed. Anemia was defined as serum hemoglobin (Hb) levels ≤12 g/dL in women and ≤13 g/dL in men. A total of 2420 patients with ND-CKD were included. Anemia was established in 1246 (51.5%) patients: 639 (51.3%) men and 607 (48.7%) women. The prevalence of anemia increased with advancing CKD stage (χtrend = 675.14, P < 0.001). Anemia was more prevalent in patients with diabetic nephropathy (68.0%) than in patients with hypertensive renal damage (56.6%) or chronic glomerulonephritis (46.1%, both P < 0.001). Only 39.8% of the anemic patients received treatment with erythropoietin and 27.1% patients received iron products; furthermore, 22.7% of the patients started receiving treatment when their Hb level reached 7 g/dL. The target-achieving rate (Hb at 11-12 g/dL) was only 8.2%. Of the 1246 anemia patients, only 7.5% received more effective and recommended intravenous supplementation. Anemia is highly prevalent in patients with ND-CKD in China, with a low target-achieving rate and poor treatment patterns. The study highlights the need to improve multiple aspects of CKD management to delay the progression of renal failure.

Passive Smoking and Risk of Colorectal Cancer: A Meta-analysis of Observational Studies.

We conducted this meta-analysis to explore the association between passive smoking and the risk of colorectal cancer. A literature search of online databases, including MEDLINE, EMBASE, the Cochrane Library, and Web of Science was performed up to June 30, 2015. A fixed-effects meta-analysis using Stata 12.0 was carried out to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the associations. Eleven articles, including 6 case-control studies and 6 cohort studies, were included in our analysis according to inclusion and exclusion criteria. The pooled RR of all studies showed a statistically significant association between passive smoking and colorectal cancer (RR = 1.14; 95% CI = 1.05-1.24). Results of subgroup analysis showed a positive association between passive smoking and rectal cancer ((RR = 1.33; 95% CI = 1.15-1.53) and that male passive smokers were at greater risks of colorectal cancer (RR = 1.73; 95% CI = 1.37-2.19) than females. Results suggested that passive smoking is associated with an increased risk of colorectal cancer.