This study investigated the characteristics of patients with different chronic kidney disease (CKD) stages according to various body mass index (BMI) categories and determined the influence of BMI in ...renal function deterioration. We conducted a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of CKD project (2008-2013) and National Health Insurance Research Database (2001-2013). A total of 7357 patients with CKD aged 20-85 years from 14 hospitals were included in the study. A higher male sex, diabetes mellitus (DM) and hypertension were noted among overweight and obese CKD patients, while more cancer prevalence was noted among underweight CKD patients. Charlson comorbidity index was significantly higher and correlated with BMI among late CKD patients. Patients with BMI < 18.5 kg/m
exhibited non-significantly higher events of eGFR decline events in both early and late CKD stages than other BMI groups. BMI alone is not a determinant of CKD progression among our Taiwanese CKD patients. Obesity should be re-defined and body weight manipulation should be individualized in CKD patients.
Highlights • HDAC1 and HDAC7 are downstream effectors of miR-34a pathway in breast cancer. • Deacetylation of HSP70 K246 by HDAC1 and HDAC7 regulates therapy resistance. • Deacetylation of HSP70 K246 ...promotes therapy resistance by inhibiting autophagy. • The miR-34a–HDAC1/HDAC7–HSP70 K246 axis is a potential therapy resistant pathway.
Billions of tons of keratin bio-wastes are generated by poultry industry annually but discarded that result in serious environmental pollution. Keratinase is a broad spectrum protease with the unique ...ability to degrade keratin, providing an eco-friendly way to convert keratin wastes to valuable amino acids. In this report, a feather-degrading thermophilic bacterium, Meiothermus taiwanensis WR-220, was investigated due to its ability to apparently complete feather decay at 65 °C in two days. By genomics, proteomics, and biochemical approaches, the extracellular heat-stable keratinase (MtaKer) from M. taiwanensis WR-220 was identified. The recombinant MtaKer (rMtaKer) possesses keratinolytic activities at temperatures ranging from 25 to 75 °C and pH from 4 to 11, with a maximum keratinolytic activity at 65 °C and pH 10. The phylogenetic and structural analysis revealed that MtaKer shares low sequence identity but high structural similarity with known keratinases. Accordingly, our findings have enabled the discovery of more keratinases from other extremophiles, Thermus and Deinococcus. Proteins encoded in the extremophiles shall be evolved to be functional in the extreme conditions. Hence, our study expands the current boundary of hunting keratinases that can tolerate extreme conditions for keratin wastes biorecycle and other industrial applications.
The purpose of this phase I clinical trial is to assess the safety and tolerability of allogeneic adipose tissue‐derived stem cells (ADSCs) among chronic kidney disease (CKD) patients. 12 eligible ...CKD patients with an estimated glomerular filtration rate (eGFR) of 15–44 ml/min/1.73 m2 received one dose of intravenous allogeneic ADSCs (ELIXCYTE®), as 3 groups: 3 low dose (6.4 × 107 cells in total of 8 ml), 3 middle dose (19.2 × 107 cells in total of 24 ml) and 6 high dose (32.0 × 107 cells in total of 40 ml) of ELIXCYTE® and evaluated after 48 weeks. Primary endpoint was the safety profiles in terms of incidence of adverse events (AEs) and serious adverse event (SAE). Two subjects in high dose group experienced a total of 2 treatment‐related AEs which are Grade 1 slow speech and Grade 1 bradyphrenia after the infusion. One subject in middle dose group experienced an SAE unlikely related to treatment, grade 2 proteinuria. No fatal AE was reported in this study. An increase in eGFR was observed in 7 out of 12 subjects (58%) at Week 24 and in 6 of 12 subjects (50%) by Week 48. By Week 24, an increase in eGFR by more than 20% among all CKD patients with baseline eGFR ≧ 30 ml/min/1.73 m2 as compared to only 2 subjects in baseline eGFR < 30 ml/min/1.73 m2 group. No significant reduction in proteinuria was noted among all subjects. This phase I trial demonstrated single‐dose intravenous ELIXCYTE was well tolerated in moderate‐to‐severe CKD patients and its preliminary efficacy warrants future studies.
Background Anticoagulation of the extracorporeal circuit is required in continuous renal replacement therapy (CRRT). Heparin is the classic choice for anticoagulation, although it may increase the ...risk of bleeding. Regional citrate anticoagulation reduces the risk of bleeding, but may cause hypocalcemia and metabolic disturbances. Study Design Systematic review and meta-analysis of randomized controlled trials (RCTs). Setting & Population Patients admitted to the intensive care unit with acute kidney injury that required CRRT. Selection Criteria for Studies RCTs regardless of publication status or language. Intervention Regional citrate versus heparin anticoagulation in CRRT. Outcomes The primary outcomes were circuit survival time, the occurrence of major bleeding defined as a site of gross bleeding with a decrease in blood pressure or requiring transfusion of 2 or more units of red blood cells, metabolic alkalosis, hypocalcemia, and thrombocytopenia. The secondary outcome was cost. Results 6 RCTs with 488 patients were identified. Citrate anticoagulation was associated with a significant decrease in bleeding (RR, 0.34; 95% CI, 0.17-0.65). Circuit survival time, the incidence of metabolic alkalosis, and thrombocytopenia showed no significant difference between groups. Hypocalcemia was more common in patients receiving citrate, although no clinical adverse event was reported in the included studies. Limitations Significant heterogeneity in the primary outcome. Conclusion The efficacy of citrate and heparin anticoagulation for CRRT was similar. However, citrate anticoagulation decreased the risk of bleeding with no significant increase in the incidence of metabolic alkalosis. We recommend citrate as an anticoagulation agent in patients who require CRRT but are at high risk of bleeding.
MicroRNA (miRNA) are small noncoding RNAs that play vital roles in post-transcriptional gene regulation by inhibiting mRNA translation or promoting mRNA degradation. The dysregulation of miRNA has ...been implicated in numerous human diseases, including cancers. miR-34 family members (miR-34s), including miR-34a, miR-34b, and miR-34c, have emerged as the most extensively studied tumor-suppressive miRNAs. In this comprehensive review, we aim to provide an overview of the major signaling pathways and gene networks regulated by miR-34s in various cancers and highlight the critical tumor suppressor role of miR-34s. Furthermore, we will discuss the potential of using miR-34 mimics as a novel therapeutic approach against cancer, while also addressing the challenges associated with their development and delivery. It is anticipated that gaining a deeper understanding of the functions and mechanisms of miR-34s in cancer will greatly contribute to the development of effective miR-34-based cancer therapeutics.
Toll‐like receptors (TLRs) are important sensors that recognize pathogen‐associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an ...immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV‐induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side‐by‐side comparison of TLR9 and cyclic GMP‐AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV‐induced immune activation. The significance of TLR9 in DENV‐induced immune response is also confirmed in examination with the bone marrow‐derived DCs prepared from Tlr9‐knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.
Synopsis
Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol.
Infection of human DCs with DENV induces ROS generation, inflammasome activation, oxidization of mtDNA and opening of the mitochondrial permeability transition pores resulting in the release of both non‐oxidized and oxidized mtDNA into the cytosol.
Cytosolic mtDNA increases TLR9 expression, binds to TLR9 and induces immune activation such as anti‐viral interferon production.
The significance of TLR9 in DENV infection is confirmed by examining bone marrow‐derived dendritic cells prepared from Tlr9‐knockout mice.
Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol.
Acute kidney disease (AKD) comprises acute kidney injury (AKI). However, whether the AKD staging system has prognostic values among AKI patients with different baseline estimated glomerular ...filtration (eGFR) remains a controversial issue. Algorithm-based approach was applied to identify AKI occurrence and to define different AKD stages. Risk ratio for major adverse kidney events (MAKE), including (1) eGFR decline > 35% from baseline, (2) initiation of dialysis, (3) in-hospital mortality of different AKD subgroups were identified by multivariable logistic regression. Among the 4741 AKI patients identified from January 2015 to December 2018, AKD stages 1-3 after AKI was common (53% in the lower baseline eGFR group and 51% in the higher baseline eGFR group). In the logistic regression model adjusted for demographics and comorbidities at 1-year follow-up, AKD stages 1/2/3 (AKD stage 0 as reference group) were associated with higher risks of MAKE (AKD stage: odds ratio, 95% confidence interval 95% CI, AKD 1: 1.85, 1.56-2.19; AKD 2: 3.43, 2.85-4.12; AKD 3: 10.41, 8.68-12.49). Regardless of baseline eGFR, staging criteria for AKD identified AKI patients who were at higher risk of kidney function decline, dialysis and mortality. Post-AKI AKD patients with severer stage need intensified care and timely intervention.
Abstract Background Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events. Objectives This study ...performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause. Methods We performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. Results Thirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses. Conclusions Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.
The rice SUB1A-1 gene, which encodes a group VII ethylene response factor (ERFVII), plays a pivotal role in rice survival under flooding stress, as well as other abiotic stresses. In Arabidopsis, ...five ERFVII factors play roles in regulating hypoxic responses. A characteristic feature of Arabidopsis ERFVIIs is a destabilizing N terminus, which functions as an N-degron that targets them for degradation via the oxygen-dependent N-end rule pathway of proteolysis, but permits their stabilization during hypoxia for hypoxia-responsive signaling. Despite having the canonical N-degron sequence, SUB1A-1 is not under N-end rule regulation, suggesting a distinct hypoxia signaling pathway in rice during submergence. Herein we show that two other rice ERFVIIs gene, ERF66 and ERF67, are directly transcriptionally up-regulated by SUB1A-1 under submergence. In contrast to SUB1A-1, ERF66 and ERF67 are substrates of the N-end rule pathway that are stabilized under hypoxia and may be responsible for triggering a stronger transcriptional response to promote submergence survival. In support of this, overexpression of ERF66 or ERF67 leads to activation of anaerobic survival genes and enhanced submergence tolerance. Furthermore, by using structural and protein-interaction analyses, we show that the C terminus of SUB1A-1 prevents its degradation via the N-end rule and directly interacts with the SUB1A-1 N terminus, which may explain the enhanced stability of SUB1A-1 despite bearing an N-degron sequence. In summary, our results suggest that SUB1A-1, ERF66, and ERF67 form a regulatory cascade involving transcriptional and N-end rule control, which allows rice to distinguish flooding from other SUB1A-1–regulated stresses.
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