Suppression of aldehyde dehydrogenase 2 in kidney proximal tubules contributes to kidney fibrosis through Transforming Growth Factor-ß signaling.

Chronic kidney disease (CKD) is an increasingly prevalent disorder that poses a significant global health and socioeconomic burden. East Asian countries such as China, Taiwan, Japan, and South Korea have a higher incidence and prevalence of kidney failure when compared to Western nations, and the reasons for this discrepancy remain unclear. Aldehyde dehydrogenase 2 (ALDH2) is an essential detoxifying enzyme for exogenous and endogenous aldehyde metabolism in mitochondria. Inactivating mutations at E504K and E487K are found in 35-45% of East Asian populations and has been linked to a higher risk of various disorders, including cardiovascular diseases and cancer. However, little is known about the role of ALDH2 in CKD. Here, we characterized the expression pattern of ALDH2 in normal and CKD human and mouse kidneys and demonstrated that ALDH2 expression was significantly reduced, and that the protein level was inversely correlated with the degree of CKD and fibrosis. Further, we treated ALDH2*2 knock-in mice, a loss of ALDH2 function model, with aristolochic acid and found that these mice showed enhanced fibrosis. Moreover, ALDH2 deficiency was associated with kidney fibrosis involving epithelial cell differentiation process in vivo and in vitro. However, ALDH2 overexpression protected proximal tubule epithelial cells from transforming growth factor-ß-induced dedifferentiation or partial epithelial-mesenchymal transdifferentiation in vitro. Thus, our findings yield important clinical information regarding the development and progression of CKD involving ALDH2, especially among East Asian populations.

The initial experiences of junior nursing college students when communicating with children during pediatric clinical practicum: A phenomenological study.

PURPOSE: Nursing students feel stressed during pediatric clinical practicum due to limited communication encounters with hospitalized children. The purpose of this study was to describe junior nursing college students' experiences of communicating with children during pediatric clinical practicums. DESIGN AND METHODS: A qualitative phenomenological research design was used. Purposive sampling was used to recruit 18 junior nursing college students who completed their pediatric clinical practicum. Data were collected using semi-structured interviews and were analyzed using Colaizzi's seven-step method for data analysis. RESULTS: Three themes emerged from the data. (1) Difficulties in communicating during initial practicum: fear, rejection, self-doubt of communication abilities, and unfamiliarity with the application of communication techniques posed frustrations among nursing students. (2) Efforts to learn during practicum: self-empowerment, seeking a diverse support system, adjusting communication methods, and striving to establish good relationships allowed nursing students to adapt to the pediatric curriculum. (3) Effective communication at the later stages of practicum: mastering fundamental communication techniques and exercising pediatric therapeutic communication techniques allowed nursing students to feel accomplished. CONCLUSIONS: Junior nursing college students initially encountered difficulties and frustration when communicating with children during their pediatric clinical practicum. This study serves as a guide for educators of pediatric nursing to design courses on communication with hospitalized children. PRACTICE IMPLICATIONS: These findings could be used to develop foundation courses on communicating with children for first-time pediatric nursing practicum students; for example, formulating a course on therapeutic play for children that encompasses communication techniques, pediatric ward simulation, and introduction to therapeutic play.

Proof-of-Principle Experiment for Testing Strong-Field Quantum Electrodynamics with Exotic Atoms: High Precision X-Ray Spectroscopy of Muonic Neon.

To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and 5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.

Allogeneic adipose tissue-derived stem cells ELIXCYTE® in chronic kidney disease: A phase I study assessing safety and clinical feasibility.

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 â‰§ 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.

Genetic insight into primary glomerulonephritis.

Primary glomerulonephritis is a major global health concern and a disorder with significant heritable components. Rapid advances in sequencing technologies have led to genome-wide, high-throughput investigations of the genetic basis of complex human traits. Genetic studies have successfully mapped several susceptibility loci and disease-causing genes for different subtypes of primary glomerulonephritis. These studies have revealed that IgA nephropathy-associated genes have a highly complex, polygenic and pleiotropic genetic architecture and that genetic susceptibility to membranous nephropathy may be driven by a few large-effect loci. Furthermore, both susceptibility genes and high-penetrant gene mutations reportedly contribute to the development of the most heterogeneous phenotype of focal segmental glomerulosclerosis. The genetic heterogeneity between each glomerular disease type and within different populations has indicated disease-specific and ethnicity-specific underlying molecular mechanisms for the disorders. The findings from genome-wide association studies (GWAS) have mainly included variants on or near the major histocompatibility (MHC) loci, highlighting the molecular basis for the shared pathogenesis of the immune-mediated disease. Recent studies with increased sample sizes and higher resolutions of genome-wide imputation have provided novel insights into the pathogenesis of glomerular disorders. Further integration of results from genomic studies with functional genomics datasets can indicate novel targets for drug discovery as well as potential tools for patient diagnosis and stratification. However, larger GWASs and sequencing studies in independent cohorts and more standardized inclusion of phenotypes across studies are required for each subtype of glomerular disease.

Using Deep Transfer Learning to Detect Hyperkalemia From Ambulatory Electrocardiogram Monitors in Intensive Care Units: Personalized Medicine Approach.

BACKGROUND: Hyperkalemia is a critical condition, especially in intensive care units. So far, there have been no accurate and noninvasive methods for recognizing hyperkalemia events on ambulatory electrocardiogram monitors. OBJECTIVE: This study aimed to improve the accuracy of hyperkalemia predictions from ambulatory electrocardiogram (ECG) monitors using a personalized transfer learning method; this would be done by training a generic model and refining it with personal data. METHODS: This retrospective cohort study used open source data from the Waveform Database Matched Subset of the Medical Information Mart From Intensive Care III (MIMIC-III). We included patients with multiple serum potassium test results and matched ECG data from the MIMIC-III database. A 1D convolutional neural network-based deep learning model was first developed to predict hyperkalemia in a generic population. Once the model achieved a state-of-the-art performance, it was used in an active transfer learning process to perform patient-adaptive heartbeat classification tasks. RESULTS: The results show that by acquiring data from each new patient, the personalized model can improve the accuracy of hyperkalemia detection significantly, from an average of 0.604 (SD 0.211) to 0.980 (SD 0.078), when compared with the generic model. Moreover, the area under the receiver operating characteristic curve level improved from 0.729 (SD 0.240) to 0.945 (SD 0.094). CONCLUSIONS: By using the deep transfer learning method, we were able to build a clinical standard model for hyperkalemia detection using ambulatory ECG monitors. These findings could potentially be extended to applications that continuously monitor one's ECGs for early alerts of hyperkalemia and help avoid unnecessary blood tests.

Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

C-Reactive Protein Concentration Can Help to Identify Bacteremia in Children Visiting the Emergency Department: A Single Medical Center Experience.

BACKGROUND: For febrile children who are evaluated in a pediatric emergency department (PED), blood culture can be considered the laboratory criterion standard to detect bacteremia. However, high rates of negative, false-positive, or contaminated blood cultures in children often result in this testing being noncontributory. This study determined the factors associated with true-positive blood cultures in children. METHODS: This retrospective study was conducted at a tertiary medical center's PED. The blood culture use reports were prepared by an infectious disease specialist and were classified as bacteremia, nonbacteremia, and contamination. RESULTS: We registered a total of 239,459 PED visits during the 8-year period, and 21,841 blood culture samples were taken. Of the laboratory test studies, higher C-reactive protein (CRP) levels and lower hemoglobin levels were observed in the bacteremia group compared with other groups (all P < 0.001). The cut-off value calculated for each age group was adjusted for better clinical usage and significantly improved the blood culture clinical utility documented in the following age groups: 0 to 1 years (CRP level = 30 mg/L, odds ratio [OR] = 5.4, P < 0.001), 1 to 3 years (CRP level = 45 mg/L, OR = 3.7, P < 0.001), and 12 to 18 years (CRP level = 50 mg/L, OR = 6.3, P = 0.006). Using the CRP cut-off value established in this study, we could reduce the blood culture samples in the PED by 14,108 (64.6%). CONCLUSIONS: This study provides new evidence that CRP may be a useful indicator for blood culture sampling in certain age groups and may help improve the efficiency of blood culture in the PED.

Potent Impact of Plastic Nanomaterials and Micromaterials on the Food Chain and Human Health.

Plastic products are inexpensive, convenient, and are have many applications in daily life. We overuse plastic-related products and ineffectively recycle plastic that is difficult to degrade. Plastic debris can be fragmented into smaller pieces by many physical and chemical processes. Plastic debris that is fragmented into microplastics or nanoplastics has unclear effects on organismal systems. Recently, this debris was shown to affect biota and to be gradually spreading through the food chain. In addition, studies have indicated that workers in plastic-related industries develop many kinds of cancer because of chronic exposure to high levels of airborne microplastics. Microplastics and nanoplastics are everywhere now, contaminating our water, air, and food chain. In this review, we introduce a classification of plastic polymers, define microplastics and nanoplastics, identify plastics that contaminate food, describe the damage and diseases caused by microplastics and nanoplastics, and the molecular and cellular mechanisms of this damage and disease as well as solutions for their amelioration. Thus, we expect to contribute to the understanding of the effects of microplastics and nanoplastics on cellular and molecular mechanisms and the ways that the uptake of microplastics and nanoplastics are potentially dangerous to our biota. After understanding the issues, we can focus on how to handle the problems caused by plastic overuse.

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast-osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast-osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = -0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/ß-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid-bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast-osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

ICU admission following an unscheduled return visit to the pediatric emergency department within 72 hours.

INTRODUCTION: The purpose of this study was to describe the demographic characteristics and prognosis of children admitted to the intensive care unit (ICU) after a pediatric emergency department (PED) return visit within 72 h. METHOD: We conducted this retrospective study from 2010 to 2016 in the PED of a tertiary medical center in Taiwan and included patients under the age of 18 years old admitted to the ICU after a PED return visit within 72 h. Clinical characteristics were collected to perform demographic analysis. Pediatric patients who were admitted to the ICU on an initial visit were also enrolled as a comparison group for outcome analysis, including mortality, ventilator use, and length of hospital stay. RESULTS: We included a total of 136 patients in this study. Their mean age was 3.3 years old, 65.4% were male, and 36.0% had Chronic Health Condition (CHC). Disease-related return (73.5%) was by far the most common reason for return. Compared to those admitted on an initial PED visit, clinical characteristics, including vital signs at triage and laboratory tests on return visit with ICU admission, demonstrated no significant differences. Regarding prognosis, ICU admission on return visit has a higher likelihood of ventilator use (aOR:2.117, 95%CI 1.021~4.387), but was not associated with increased mortality (aOR:0.658, 95%CI 0.150~2.882) or LOHS (OR:-1.853, 95%CI -4.045~0.339). CONCLUSION: Patients who were admitted to the ICU on return PED visits were associated with an increased risk of ventilator use but not mortality or LOHS compared to those admitted on an initial visit.

High-level expression of ARID1A predicts a favourable outcome in triple-negative breast cancer patients receiving paclitaxel-based chemotherapy.

Paclitaxel-based chemotherapy is a common strategy to treat patients with triple-negative breast cancer (TNBC). As paclitaxel resistance is still a clinical issue in treating TNBCs, identifying molecular markers for predicting pathologic responses to paclitaxel treatment is thus urgently needed. Here, we report that an AT-rich interaction domain 1A (ARID1A) transcript is up-regulated in paclitaxel-sensitive TNBC cells but down-regulated in paclitaxel-resistant cells upon paclitaxel treatment. Moreover, ARID1A expression was negatively correlated with the IC50 concentration of paclitaxel in the tested TNBC cell lines. Kaplan-Meier analyses revealed that ARID1A down-regulation was related to a poorer response to paclitaxel-based chemotherapy in patients with TNBCs as measured by the recurrence-free survival probability. The pharmaceutical inhibition with p38MAPK-specific inhibitor SCIO-469 revealed that p38MAPK-related signalling axis regulates ARID1A expression and thereby modulates paclitaxel sensitivity in TNBC cells. These findings suggest that ARID1A could be used as a prognostic factor to estimate the pathological complete response for TNBC patients who decide to receive paclitaxel-based chemotherapy.

The influence of crowding on clinical practice in the emergency department.

BACKGROUND: This study aimed to clarify the association between the crowding and clinical practice in the emergency department (ED). METHODS: This 1-year retrospective cohort study conducted in two EDs in Taiwan included 70,222 adult non-trauma visits during the day shift between July 1, 2011, and June 30, 2012. The ED occupancy status, determined by the number of patients staying during their time of visit, was used to measure crowding, grouped into four quartiles, and analyzed in reference to the clinical practice. The clinical practices included decision-making time, patient length of stay, patient disposition, and use of laboratory examinations and computed tomography (CT). RESULT: The four quartiles of occupancy statuses determined by the number of patients staying during their time of visit were <24, 24-39, 39-62, and >62. Comparing >62 and <24 ED occupancy statuses, the physicians' decision-making time and patients' length of stay increased by 0.3h and 1.1h, respectively. The percentage of patients discharged from the ED decreased by 15.5% as the ED observation, general ward, and intensive care unit admissions increased by 10.9%, 4%, and 0.7%, respectively. CT and laboratory examination slightly increased in the fourth quartile of ED occupancy. CONCLUSION: Overcrowding in the ED might increase physicians' decision-making time and patients' length of stay, and more patients could be admitted to observation units or an inpatient department. The use of CT and laboratory examinations would also increase. All of these could lead more patients to stay in the ED.

Exploring the growth trajectory of cultural competence in Taiwanese paediatric nurses.

AIM: To explore the evolution of cultural competence in Taiwanese paediatric nurses. BACKGROUND: Because transnational marriage has become a social phenomenon in Taiwan, the proportion of newborns of new immigrant mothers accounts for 8%-10% of total births every year. As family-centred care is the core value of paediatric nursing, it is necessary to teach caregivers how to take care of hospitalised children and perform related nursing care as well as to determine what difficulties nurses will encounter when they care for patients from diverse cultures and to find solutions for these problems. Unfortunately, few nursing programmes provide elective transcultural courses. DESIGN: A phenomenological design was applied in the study. METHOD: A purposive sampling method was used. Nurses who had served in paediatric wards for over 1 year and who also had experience with taking care of the children of new immigrants were recruited as the informants. The data were collected through face-to-face in-depth interviews and analysed using Moustakas' method (1994). Rigour and trustworthiness was based on Yardley's evaluative criteria. RESULTS: The researcher interviewed ten paediatric nurses. Their average age was 31.6 years. The mean seniority of their service in paediatric wards was 6.3 years. Four major themes were obtained from the data, including perceiving difficulties related to caring for patients from diverse cultures, self-reflection on diverse cultures and the findings, finding approaches based on experiences with diverse cultures and new perceptions and identification with diverse cultures. CONCLUSIONS: In this study, clinical nurses were interviewed who had not had cultural competency training during their nursing education. It is suggested that such courses be provided for nurses to improve their cultural competence. RELEVANCE FOR CLINICAL PRACTICE: Accordingly, educational strategies could be generated to improve nurses' cultural competence related to clinical applications.

Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence.

Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.

The impact of prolonged waiting time for coronary care unit admission on patients with non ST-elevation acute coronary syndrome.

BACKGROUND: The boarding of patients in the emergency department consumes nursing and physician resources, and may delay the evaluation of new patients. It may also contribute to poor cardiovascular outcomes in patients with acute coronary syndrome (ACS). This study analyzed the relationship between the delay in coronary care unit (CCU) admission and the clinical outcomes of patients with ACS with non-ST-segment elevation (NSTE-ACS). METHODS: Patients were divided into 2 groups according to the CCU waiting time (<12h and >12h). Outcome variables including in-hospital mortality, gastrointestinal bleeding and stroke during hospitalization, and duration of hospital stay were compared between the 2 study groups. We used the GRACE risk scores to classify disease severity of the study patients for stratifying analysis. RESULT: A difference was found in the outcome of gastrointestinal bleeding. Among those with GRACE risk scores of <3 (low mortality risk) and 3 (high mortality risk), 5% and 3.1% of patients developed gastrointestinal bleeding, respectively, with CCU waiting time of >12h compared to CCU waiting time of <12h. However, there was no significant statistical difference (P=0.065 and 0.547). In addition, there were no significant differences in the in-hospital mortality rate, incidence of stoke, and duration of hospital stay between the 2 groups. CONCLUSION: There was no significant difference in the clinical outcomes of NSTE-ACS patients without profound shock between those with CCU waiting times of <12 and >12h. If necessary, CCU admission should be prioritized for patients whose hemodynamic instability or respiratory failure.

Peroxisome Proliferator-Activated Receptor α Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1.

Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor that has been reported to inhibit gentamicin-induced apoptosis in renal tubular cells. However, the antiapoptotic mechanism of PPARα is still unknown. In this study, we found that PPARα overexpression induced Na+/H+ exchanger-1 (NHE1) expression in the rat renal tubular cells NRK-52E. Beraprost, a PPARα ligand, also increased NHE1 expression in the renal tubules in normal mice, but not in PPARα knockout mice. Chromatin immunoprecipitation assays revealed that two PPARα binding elements were located in the rat NHE1 promoter region. Na+/H+ exchanger activity also increased in the PPARα-overexpressed cells. Flow cytometry showed that the PPARα-overexpressed cells were resistant to apoptosis-induced shrinkage. Cariporide, a selective NHE1 inhibitor, inhibited the antiapoptotic effect of PPARα in the gentamicin-treated cells. The interaction between NHE1 and ezrin/radixin/moesin (ERM) and between ERM and phosphatidylinositol 4,5-bisphosphate in the PPARα-overexpressed cells was more than in the control cells. ERM short interfering RNA (siRNA) transfection inhibited the PPARα-induced antiapoptotic effect. PPARα overexpression also increased the phosphoinositide 3-kinase (PI3K) expression, which is dependent on NHE1 activity. Increased PI3K further increased the phosphorylation of the prosurvival kinase Akt in the PPARα-overexpressed cells. Wortmannin, a PI3K inhibitor, inhibited PPARα-induced Akt activity and the antiapoptotic effect. We conclude that PPARα induces NHE1 expression and then recruits ERM to promote PI3K/Akt-mediated cell survival in renal tubular cells. The application of PPARα activation reduces the nephrotoxicity of gentamicin and may expand the clinical use of gentamicin.

The role of hypoxia-inducible factor-1α in zinc oxide nanoparticle-induced nephrotoxicity in vitro and in vivo.

BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of products, including rubber manufacture, cosmetics, pigments, food additives, medicine, chemical fibers and electronics. However, the molecular mechanisms underlying ZnO NP nephrotoxicity remain unclear. In this study, we evaluated the potential toxicity of ZnO NPs in kidney cells in vitro and in vivo. RESULTS: We found that ZnO NPs were apparently engulfed by the HEK-293 human embryonic kidney cells and then induced reactive oxygen species (ROS) generation. Furthermore, exposure to ZnO NPs led to a reduction in cell viability and induction of apoptosis and autophagy. Interestingly, the ROS-induced hypoxia-inducible factor-1α (HIF-1α) signaling pathway was significantly increased following ZnO NPs exposure. Additionally, connective tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1), which are directly regulated by HIF-1 and are involved in the pathogenesis of kidney diseases, displayed significantly increased levels following ZnO NPs exposure in HEK-293 cells. HIF-1α knockdown resulted in significantly decreased levels of autophagy and increased cytotoxicity. Therefore, our results suggest that HIF-1α may have a protective role in adaptation to the toxicity of ZnO NPs in kidney cells. In an animal study, fluorescent ZnO NPs were clearly observed in the liver, lungs, kidneys, spleen and heart. ZnO NPs caused histopathological lesions in the kidney and increase in serum creatinine and blood urea nitrogen (BUN) which indicate possible renal possible damage. Moreover, ZnO NPs enhanced the HIF-1α signaling pathway, apoptosis and autophagy in mouse kidney tissues. CONCLUSIONS: ZnO NPs may cause nephrotoxicity, and the results demonstrate the importance of considering the toxicological hazards of ZnO NP production and application, especially for medicinal use.