Activation of lipophagy is required for RAB7 to regulate ferroptosis in sepsis-induced acute kidney injury.

Sepsis-induced acute kidney injury (S-AKI) is the most common type of acute kidney injury (AKI), accompanied by elevated morbidity and mortality rates. This study investigated the mechanism by which lipid droplets (LDs) degraded via autophagy (lipophagy)required for RAB7 regulated ferroptosis in the pathogenesis of S-AKI. Here, we constructed the S-AKI model in vitro and in vivo to elucidate the potential relationship of lipophagy and ferroptosis, and we first confirmed that the activation of lipophagy promoted renal tubular epithelial cell ferroptosis and renal damage in S-AKI. The results showed that lipopolysaccharide (LPS) induced a marked increase in lipid peroxidation and ferroptosis, which were rescued by ferrstain-1 (Fer-1), an inhibitor of ferroptosis. In addition, LPS induced the remarkable activation of RAB7-mediated lipophagy. Importantly, silencing RAB7 alleviated LPS-induced lipid peroxidation and ferroptosis. Thus, the present study demonstrated the potential significant role of ferroptosis and lipophagy in sepsis-induced AKI, and contributed to better understanding of the pathogenesis and treatment targets of AKI.

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis.

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI-induced by contrast media, ischemia-reperfusion injury, cisplatin, and folic acid-to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

Pseudodonghicola flavimaris sp. nov. and Sedimentitalea xiamensis sp. nov., two novel species belonging to the family Roseobacteraceae.

Two Gram-stain-negative, chemoheterotrophic, aerobic bacteria, designated IC7T and JM2-8T, were isolated from seawater of the Yellow Sea of China and rhizosphere soil of mangroves in Xiamen, Fujian, respectively. Phylogenetic analyses based on 16S rRNA gene and genome sequences showed that these two novel strains belonged to the family Roseobacteraceae. Strain IC7T formed a coherent lineage within the genus Pseudodonghicola, showing 98.05 % 16S rRNA gene sequence similarity to Pseudodonghicola xiamenensis Y-2T. Strain JM2-8T was most closely related to members of the genus Sedimentitalea, showing 96.51 and 96.73 % 16S rRNA gene sequence similarities to Sedimentitalea nanhaiensis NH52FT and Sedimentitalea todarodis KHS03T, respectively. The two novel strains contained Q-10 as the major quinone, and phosphatidylethanolamine, aminophospholipid, phosphatidylglycerol and phosphatidylcholine as the principal polar lipids. The main fatty acid of strain IC7T was C19 : 0 cyclo ω8c, while the fatty acid profile JM2-8T was dominated by summed feature 8 containing C18 : 1 ω7c and/or C18 : 1 ω6c. The average nucleotide identity and digital DNA-DNA hybridization values between these two novel isolates and their closely related species were below the cut-off values of 95-96 and 70 %, respectively. The combined genotypic and phenotypic data show that strain IC7T represents a novel species of the genus Pseudodonghicola, for which the name Pseudodonghicola flavimaris sp. nov. is proposed, with the type strain IC7T (=MCCC 1A02763T=KCTC 82844T), and strain JM2-8T represents a novel species of the genus Sedimentitalea, for which the name Sedimentitalea xiamensis sp. nov. is proposed, with the type strain JM2-8T (=MCCC 1A17756T=KCTC 82846T).

Pseudophaeobacter profundi sp. nov., isolated from the Western Pacific Ocean.

A novel Gram-stain-negative, facultatively anaerobic and heterotrophic bacterium, designated strain ZH257T, was isolated from in situ enrichment samples incubated on the seamount floor of the Western Pacific Ocean. Cells were rod-shaped, oxidase- and catalase- positive, and motile by means of polar flagella. Strain ZH257T grew at 4-37 °C (optimum, 28-32 °C), pH 6.0-9.0 (optimum, pH 7.0) and with 2.0-9.0 % (w/v) NaCl (optimum, 3.0-4.0 %). Strain ZH257T was most closely related to members of the genus Pseudophaeobacter, sharing 99.13, 98.27 and 96.89 % 16S rRNA gene sequence identities with Pseudophaeobacter flagellatus GDMCC 1.2988T, Pseudophaeobacter arcticus DSM 23566T and Pseudophaeobacter leonis DSM 25627T, respectively. The DNA G+C content was 59.2 mol%. The estimated average nucleotide identity and digital DNA-DNA hybridization values between strain ZH257T and its closely related species were 79.61-93.04 % and 23.10-50.20 %, respectively. Strain ZH257T harboured complete denitrification and nitrate assimilation pathways. Strain ZH257T contained summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c) as major fatty acids (>5 %), and Q-10 as the major respiratory quinone. The polar lipid profile contained phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, an unidentified phospholipid, an unidentified aminolipid and four unidentified lipids. The combined phenotypic, genotypic and chemotaxonomic data showed that strain ZH257T represents a novel species of the genus Pseudophaeobacter, for which the name Pseudophaeobacter profundi sp. nov. is proposed, with the type strain ZH257T (=MCCC M29024T=KACC 23147T).

Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis.

Cisplatin is widely recommended in combination for the treatment of tumors, thus inevitably increasing the incidence of cisplatin-induced acute kidney injury. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. Ferroptosis, a new modality of programmed cell death, is characterized by iron-dependent phospholipid peroxidation and oxidative membrane damage. However, the role of mitophagy in ferroptosis in kidney disease is unclear. Here, we investigated the mechanism underlying both BNIP3-mediated and PINK1-PARK2-mediated mitophagy-induced attenuation of ferroptosis in cisplatin-induced acute kidney injury. The results showed that cisplatin induced mitochondrial injury, ROS release, intracellular iron accumulation, lipid peroxidation and ferroptosis in the kidney, which were aggravated in Bnip3 knockout, Pink1 knockout or Park2 knockout cisplatin-treated mice. Ferrstatin-1, a synthetic antioxidative ferroptosis inhibitor, rescued iron accumulation, lipid peroxidation and ferroptosis caused by inhibition of mitophagy. Thus, the present study elucidated a novel mechanism by which both BNIP3-mediated and PINK1-PARK2-mediated mitophagy protects against cisplatin-induced renal tubular epithelial cell ferroptosis through the ROS/HO1/GPX4 axis.

HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome.

Chronic kidney disease affects approximately 14.3% of people worldwide. Tubulointerstitial fibrosis is the final stage of almost all progressive CKD. To date, the pathogenesis of renal fibrosis remains unclear, and there is a lack of effective treatments, leading to renal replacement therapy. Mitophagy is a type of selective autophagy that has been recognized as an important way to remove dysfunctional mitochondria and abrogate the excessive accumulation of mitochondrial-derived reactive oxygen species (ROS) to balance the function of cells. However, the role of mitophagy and its regulation in renal fibrosis need further examination. In this study, we showed that mitophagy was induced in renal tubular epithelial cells in renal fibrosis. After silencing BNIP3, mitophagy was abolished in vivo and in vitro, indicating the important effect of the BNIP3-dependent pathway on mitophagy. Furthermore, in unilateral ureteral obstruction (UUO) models and hypoxic conditions, the production of mitochondrial ROS, mitochondrial damage, activation of the NLRP3 inflammasome, and the levels of αSMA and TGFß1 increased significantly following BNIP3 gene deletion or silencing. Following silencing BNIP3 and pretreatment with mitoTEMPO or MCC950, the protein levels of αSMA and TGFß1 decreased significantly in HK-2 cells under hypoxic conditions. These findings demonstrated that HIF1α-BNIP3-mediated mitophagy played a protective role against hypoxia-induced renal epithelial cell injury and renal fibrosis by reducing mitochondrial ROS and inhibiting activation of the NLRP3 inflammasome.

Slower progression of amyotrophic lateral sclerosis with external application of a Chinese herbal plaster-The randomized, placebo-controlled triple-blinded ALS-CHEPLA trial.

Background: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by gradually increasing damage to the upper and lower motor neurons. However, definitive and efficacious treatment for ALS is not available, and oral intake in ALS patients with bulbar involvement is complicated due to swallowing difficulties. Hypothesis/purpose: This study investigated whether the external plaster application of the herbal composition Ji-Wu-Li efficiently slows ALS progression because prior studies obtained promising evidence with oral herbal applications. Study design: The randomized, triple-blinded study compared the efficacy, safety, and tolerability of the application of Ji-Wu-Li plaster (JWLP) with placebo plaster (PLAP). Methods: In total, 120 patients with definite ALS, clinically probable ALS, or clinically probable laboratory-supported ALS were randomized in a 1:1 ratio to receive JWLP or PLAP. Patients were treated and observed for 20 weeks. The primary outcome was the ALSFRS-R score, while the secondary outcomes were the ALS-SSIT score and weight loss. Results: The mean±SD decrease in the ALSFRS-R over 20 weeks differed by 0.84 points in a group comparison (JWLP, -4.44 ± 1.15; PLAP, -5.28 ± 1.98; p = 0.005). The mean increase in the ALS-SSIT over 20 weeks differed by 2.7 points in a group comparison (JWLP, 5.361.15; PLAP, 8.06 ± 1.72; p < 0.001). The mean weight loss over 20 weeks differed by 1.65 kg in a group comparison (JWLP, -3.98 ± 2.61; PLAP, -5.63 ± 3.17; p = 0.002). Local allergic dermatitis suspected as causal to the intervention occurred in 10 of 60 participants in the JWLP group and 9 of 60 participants in the PLAP group. Systemic adverse events were mild, temporary, and considered unrelated to the intervention. Conclusion: The JWLP showed clinical efficacy in the progression of ALS, as measured by the ALSFRS-R, ALS-SSIT, and weight loss in a randomized, placebo-controlled trial. Because skin reactions occurred in both groups, the covering material needs improvement. All of the Ji Wu Li herbal ingredients regulate multiple mechanisms of neurodegeneration in ALS. Hence, JWLP may offer a promising and safe add-on therapy for ALS, particularly in patients with bulbar involvement, but a confirmative long-term multicentre study is required.

Naoxintong Capsule for Secondary Prevention of Ischemic Stroke: A Multicenter, Randomized, and Placebo-Controlled Trial.

OBJECTIVE: To examine whether the combination of Naoxintong Capsule with standard care could further reduce the recurrence of ischemic stroke without increasing the risk of severe bleeding. METHODS: A total of 23 Chinese medical centers participated in this trial. Adult patients with a history of ischemic stroke were randomly assigned in a 1:1 ratio using a block design to receive either Naoxintong Capsule (1.2 g orally, twice a day) or placebo in addition to standard care. The primary endpoint was recurrence of ischemic stroke within 2 years. Secondary outcomes included myocardial infarction, death due to recurrent ischemic stroke, and all-cause mortality. The safety of drugs was monitored. Results were analyzed using the intention-to-treat principle. RESULTS: A total of 2,200 patients were enrolled from March 2015 to March 2016, of whom 143 and 158 in the Naoxintong and placebo groups were lost to follow-up, respectively. Compared with the placebo group, the recurrence rate of ischemic stroke within 2 years was significantly lower in the Naoxintong group [6.5% vs. 9.5%, hazard ratio (HR): 0.665, 95% confidence interval (CI): 0.492-0.899, P=0.008]. The two groups showed no significant differences in the secondary outcomes and safety, including rates of severe hemorrhage, cerebral hemorrhage and subarachnoid hemorrhage (P>0.05). CONCLUSION: The combination of Naoxintong Capsule with standard care reduced the 2-year stroke recurrence rate in patients with ischemic stroke without increasing the risk of severe hemorrhage in high-risk patients. (Trial registration No. NCT02334969).

Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerulonephritis, and a major cause of end-stage renal disease; however, its pathogenesis requires elucidation. Here, a hub gene, FABP1, and signaling pathway, PPARα, were selected as key in IgAN pathogenesis by combined weighted gene correlation network analysis of clinical traits and identification of differentially expressed genes from three datasets. FABP1 and PPARα levels were lower in IgAN than control kidney, and linearly positively correlated with one another, while FABP1 levels were negatively correlated with urinary albumin-to-creatinine ratio, and GPX4 levels were significantly decreased in IgAN. In human mesangial cells (HMCs), PPARα and FABP1 levels were significantly decreased after Gd-IgA1 stimulation and mitochondria appeared structurally damaged, while reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, and glutathione and GPX4 decreased, relative to controls. GPX4 levels were decreased, and those of ACSL4 increased on siPPARα and siFABP1 siRNA treatment. In PPARα lentivirus-transfected HMCs stimulated by Gd-IgA1, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPARα and GPX4, increased; and damaged mitochondria reduced. Hence, PPARα pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

Effect of intravenous thrombolysis combined with mild hypothermia on the levels of IL-1ß, IL-6, ICAM-1 and MMP-2 in patients with acute cerebral infarction and clinical significance.

The present study aimed to explore the effects and clinical importance of serum interleukin (IL) IL-1ß, IL-6, C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1 and matrix metalloproteinase (MMP)-2 in patients with acute cerebral infarction undergoing intravenous thrombolysis during simultaneous hypothermia therapy. A total of 80 patients with acute cerebral infarction who were treated at our hospital were randomly selected. They were divided into groups A and B. The two groups were treated with intravenous thrombolysis, while group B received sub-hypothermia treatment. Prior to treatment and at 7 days after treatment, 5 ml of venous blood was collected and stored in a freezer at -80˚C. IL-1ß, IL-6, CRP, ICAM-1 and MMP-2 levels were detected by ELISA and compared between the groups and time-points. The results were as follows: i) At 7 days after treatment, the levels of IL-1ß, IL-6, CRP, ICAM-1 and MMP-2 in group B were significantly decreased compared with those in group A (P<0.05), while there was no significant difference of these levels between group A and B before treatment (P>0.05). The incidence of adverse reactions in group A and group B was 35 and 20% respectively, and the mortality rate was 10 and 5%, respectively. There were no significant differences in adverse events and mortality between the two groups (P>0.05). In addition, a positive correlation of the level of IL-1ß, IL-6, CRP, ICAM-1 and MMP-2 with the National Institutes of Health Stroke Scale score was determined in the patients prior to treatment. In conclusion, mild hypothermia treatment in addition to intravenous thrombolysis significantly reduced the levels of IL-1ß, IL-6, CRP, ICAM-1 and MMP-2 in patients with acute cerebral infarction and reduced inflammation, and should therefore be incorporated in clinical practice.

A Decreased Level of Soluble Klotho Can Predict Cardiovascular Death in No or Mild Abdominal Aortic Calcification Hemodialysis Patients.

Background: Soluble Klotho plays an important role in cardiovascular disease and death in chronic kidney disease (CKD). We assessed the relationship between serum soluble Klotho (sKL) level and outcome in MHD patients. Methods: Soluble Klotho was detected by ELISA. Cox regression analysis and Kaplan-Meier analysis showed the relationship between sKL and cardiovascular disease (CVD) mortality in maintenance hemodialysis (MHD) patients. Results: There were 45 cases (35.2%) of all-cause death and 36 cases (28.1%) of CVD mortality. Multivariate linear regression analysis showed that Log[iPTH] (γ = -0.224, P = 0.015) was an independent predictor of sKL level. Cox regression showed that lower sKL was associated with higher CVD mortality rate [OR = 0.401, 95% CI (0.183-0.867), P = 0.022]. Kaplan-Meier analysis showed that the CVD mortality rate increased significantly in patients with low sKL (P = 0.006). Compared with high sKL patients, low sKL patients with no or mild vascular calcification [aortic calcification score (AACs) ≤ 4] had no significant difference in all-cause mortality rate. The CVD mortality rate was significantly lower in high sKL patients (P = 0.004) than in those with low sKL. In the severe calcification group (AACs ≥ 5), all-cause and CVD mortality rates were similar between different sKL groups (P = 0.706 and 0.488, respectively). The area under the receiver-operating characteristic curve (AUC) of soluble Klotho for predicting the CVD in MHD patients with AACs ≤ 4 was 0.796 (0.647-0.946, P = 0.017), sensitivity was 0.921, and specificity was 0.50 for a cutoff value of 307.69 pg/ml. Conclusions: Lower sKL was associated with higher CVD mortality rate. Lower sKL concentration in MHD patients with no or mild calcification can predict CVD mortality.

αKlotho protein has therapeutic activity in contrast-induced acute kidney injury by limiting NLRP3 inflammasome-mediated pyroptosis and promoting autophagy.

Contrast-induced acute kidney injury (CI-AKI) is a main cause of hospital-acquired renal failure. Nevertheless, limited measures have been shown to be effective for the treatment of CI-AKI. Here, we demonstrated that αKlotho, which is highly expressed in kidney, has therapeutic activity in CI-AKI. Our data showed that αKlotho expression levels were decreased both in the kidney and serum of CI-AKI mice. Administration of αKlotho protein protected the kidney and HK-2 cells against contrast-induced injury. Mechanistically, αKlotho reduced contrast-induced renal tubular cells pyroptosis by limiting NLRP3 inflammasome activation. Meanwhile, αKlotho up-regulated autophagy via inhibiting the AKT/mTOR pathway and decreased mitochondrial ROS level. Inhibition of autophagy blunted the suppression effect of αKlotho on NLRP3 inflammasome activation and cell pyroptosis in contrast-treated HK-2 cells. Taken together, our data suggest that αKlotho protein protects against CI-AKI through inhibiting NLRP3 inflammasome-mediated pyroptosis, which is likely by promoting autophagy. αKlotho may be a promising therapeutic strategy for CI-AKI.

Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy.

The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.Abbreviations: BNIP3: BCL2/adenovirus E1B interacting protein 3; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EGLN2/PHD1: egl-9 family hypoxia-inducible factor 2; HIF1A: hypoxia inducible factor 1, alpha subunit; H-E: hematoxylin and eosin; IL18: interleukin 18; IL1B: interleukin 1 beta; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mRNA: messenger RNA; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family, pyrin domain containing 3; NS: normal saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RNA: ribonucleic acid; SEM: standard error of the mean; siRNA: small interfering RNA; TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin, alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VDAC: voltage-dependent anion channel; WT: wild-type.

Periostin Contributes to Immunoglobulin a Nephropathy by Promoting the Proliferation of Mesangial Cells: A Weighted Gene Correlation Network Analysis.

Immunoglobulin A nephropathy (IgAN) is a known cause of end-stage kidney disease, but the pathogenesis and factors affecting prognosis are not fully understood. In the present study, we carried out weighted gene correlation network analysis (WGCNA) to identify hub genes related to the occurrence of IgAN and validated candidate genes in experiments using mouse mesangial cells (MMCs) and clinical specimens (kidney tissue from IgAN patients and healthy controls). We screened the GSE37460 and GSE104948 differentially expressed genes common to both datasets and identified periostin (POSTN) as one of the five key genes using the cytoHubba plugin of Cytoscape software and by receiver-operating characteristic curve analysis. The top 25% of genes in the GSE93798 dataset showing variable expression between IgAN and healthy tissue were assessed by WGCNA. The royalblue module in WGCNA was closely related to creatinine and estimated glomerular filtration rate (eGFR) in IgAN patients. POSTN had very high module membership and gene significance values for creatinine (0.82 and 0.66, respectively) and eGFR (0.82 and -0.67, respectively), indicating that it is a co-hub gene. In MMCs, POSTN was upregulated by transforming growth factor ß1, and stimulation of MMCs with recombinant POSTN protein resulted in an increase in the level of proliferating cell nuclear antigen (PCNA) and a decrease in that of B cell lymphoma-associated X protein, which were accompanied by enhanced MMC proliferation. POSTN gene knockdown had the opposite effects. Immunohistochemical analysis of kidney tissue specimens showed that POSTN and PCNA levels were elevated, whereas the rate of apoptosis was reduced in IgAN patients relative to healthy controls. POSTN level in the kidney tissue of IgAN patients was positively correlated with creatinine level and negatively correlated with eGFR. Thus, POSTN promotes the proliferation of MCs to promote renal dysfunction in IgAN.

Association of abdominal aortic calcification estimated by plain radiography with outcomes in haemodialysis patients: A 6-year follow-up study.

AIM: Vascular calcification has played a vital role in increasing the prevalence of cardiovascular disease (CVD) and mortality in maintenance haemodialysis (MHD) patients. This study is aimed at exploring the prognostic value of abdominal aortic calcification (AAC) estimated by plain lateral abdominal radiography in MHD patients. METHODS: Lateral abdominal radiography was used to determine the abdominal aortic calcification score (AACS). The serum level of fibroblast growth factor-23 was tested by enzyme-linked immunosorbent assay. Patients were divided into two groups: no or minor calcification group (AACS < 5) and moderate to severe calcification group (AACS ≥ 5). All patients were followed up to death or the end of the study (30 November 2016). RESULTS: A total of 114 patients were enrolled in this study, including 64 males (56.1%), and the mean age was 57.42 ± 13.48 years. Seventy-six patients (66.7%) exhibited AAC. Independent predictors for moderate to severe calcification were older age (odds ratio (OR) 1.06 (1.02-1.10), P = 0.003), longer dialysis vintage (OR 1.01 (1.00-1.02), P = 0.039), presence of smoking (OR 3.01 (1.18-7.70), P = 0.021) and higher Log fibroblast growth factor-23 serum levels (OR 2.83 (1.01-7.94), P = 0.048). During a median follow-up of 6.0 (5.6, 6.1) years, 22 patients (19.3%) died of all-cause death, and 17 cases (14.9%) died of CVD. Kaplan-Meier survival curves showed that patients in the moderate to severe calcification group had significantly higher all-cause (28.3 vs 11.5%, P = 0.028) and CVD mortality (22.6 vs 8.2%, P = 0.035) than that in the no or minor calcification group. A multivariate Cox regression showed that AACS (hazard ratio 1.08 (1.01-1.15), P = 0.022) was an independent predictor of CVD mortality. Compared with the no or minor calcification group, the risk of CVD mortality was increased by a factor of 3.14 in patients in the moderate to severe calcification group (hazard ratio 3.14 (1.04-9.44), P = 0.042). CONCLUSION: Our data suggest that AAC is prevalent in MHD patients and could provide potential predictive information for CVD mortality. Plain lateral abdominal radiography, which is simple and cheap and involves lower radiation, might represent an appropriate screening method for evaluating vascular calcification in daily clinical practice.

Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction.

Mitophagy is a principle mechanism to degrade damaged mitochondria through PARK2-dependent or PARK2-independent pathway. Mitophagy has been identified to play an important role in acute kidney disease, whereas its role in renal fibrosis remains ill-defined. We sought to investigate the involvement and regulation of mitophagy in renal tubular epithelial cell(RTEC) injury and renal fibrosis after unilateral ureteral obstruction(UUO). Mitochondrial damageand mitochondrial reactive oxygen species (ROS) production was increased in kidney after obstruction of the left ureter. Mitophagy was increased in kidneys following UUO and HK-2 cells under hypoxia exposure, assessed by electron microscopy of mitophagosome, colocalization of MitotrackerRed-stained mitochondria and LC3 staining. The upregulation of PINK1, PARK2, and LC3 II in mitochondrial fraction was observed in the obstructed kidney and hypoxia-exposed HK-2 cells. Pink1 or Park2 gene deletion markedly increased mtROS production, mitochondrial damage, TGFß1 expression in RTEC, and renal fibrosis in UUO. Mitochondrial recruitment of Drp1 was also induced after UUO. The Drp1 inhibitor, Mdivi-1, decreased mitochondrial PINK1, PARK2 and LC3II level, increased mtROS production both in vivo and in vitro, activated TGFß1-Smad2/3 signaling in HK-2 cells under hypoxia and worsened renal fibrosis following UUO. The upregulation of TGFß1 signaling in hypoxia-treated HK-2 cells due to PINK1 or PARK2 silencing, or worsened renal fibrosis after UUO due to Pink1-or Park2-KO mice was rescued by mitoTEMPO, a mitochondria-targeted antioxidant. The findings of this study suggest that Drp1-regulated PARK2-dependent mitophagy plays a critical role in hypoxia-induced renal tubular epithelial cell injury and renal fibrosis in UUO.

The use of integrative therapies in patients with amyotrophic lateral sclerosis in shanghai, china.

Objective. To investigate the current use of integrative therapies (IT) in the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5%) of 258 patients with ALS were eligible for the study and 229 (99% of all) of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995) correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention.

[Protective effects of Chinese herbal medicine Naoshuantong on neurovascular unit in rats with cerebral ischemia/reperfusion injury].

OBJECTIVE: To investigate the protective effects of Naoshuantong, a compound traditional Chinese herbal medicine, on the main components of neurovascular unit in rats with cerebral ischemia/reperfusion injury. METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into sham-operated, ischemia/reperfusion, and ischemia/reperfusion plus Naoshuantong groups. The cerebral ischemia was induced by 1.5 h of middle cerebral artery occlusion, followed by unlocking the thread to induce reperfusion injury. After 24 h of reperfusion, neurological functional deficits were assessed, apoptosis of main components of neurovascular unit was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling combined with neuronal nuclei antigen, glial fibrillary acidic protein or CD31 immunofluorescence double staining. RESULTS: Naoshuantong significantly reduced neurological functional deficits, and reduced neuron, astrocyte and vascular endothelium cell apoptosis induced by ischemia/reperfusion injury in the border zone of ischemic cortex. CONCLUSION: Naoshuantong is effective in protecting the neurovascular unit including neurons, astrocytes and vascular endothelium cells against cerebral ischemia/reperfusion-induced apoptosis.