N-Doping Effects On Electrocatalytic Water Splitting of Non-Noble High-Entropy Alloy Nanoparticles Prepared by Inert Gas Condensation.

The unique catalytic activities of high-entropy alloys (HEAs) emerge from the complex interaction among different elements in a single-phase solid solution. As a "green" nanofabrication technique, inert gas condensation (IGC) combined with laser source opens up a highly efficient avenue to develop HEA nanoparticles (NPs) for catalysis and energy storage. In this work, the novel N-doped non-noble HEA NPs are designed and successfully prepared by IGC. The N-doping effects of HEA NPs on oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are systematically investigated. The results show that N-doping is conducive to improving the OER, but unfavorable for HER activity. The FeCoNiCrN NPs achieve an overpotential of 269.7 mV for OER at a current density of 10 mA cm-2 in 1.0 M KOH solution, which is among the best reported values for non-noble HEA catalysts. The effects of the differences in electronegativity, ionization energy and electron affinity energy among mixed elements in N-doped HEAs are discussed as inducing electron transfer efficiency. Combined with X-ray photoelectron spectroscopy and the extended X-ray absorption fine structure analysis, an element-design strategy in N-doped HEAs electrocatalysts is proposed to improve the intrinsic activity and ameliorate water splitting performance.

Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing.

Kidney is one of the most important organs in maintaining the normal life activities. With the high abundance of mitochondria, renal tubular cell plays the vital role in functioning in the reabsorption and secretion of kidney. Reports have shown that mitochondrial dysfunction is of great importance to renal tubular cell senescence and subsequent kidney ageing. However, the underlying mechanisms are not elucidated. Cannabinoid receptor 2 is one of the two receptors responsible for the activation of endocannabinoid system. CB2 is primarily upregulated in renal tubular cells in chronic kidney diseases and mediates fibrogenesis. However, the role of CB2 in tubular mitochondrial dysfunction and kidney ageing has not been clarified. In this study, we found that CB2 was upregulated in kidneys in 24-month-old mice and d-galactose (d-gal)-induced accelerated ageing mice, accompanied by the decrease in mitochondrial mass. Furthermore, gene deletion of CB2 in d-gal-treated mice could greatly inhibit the activation of ß-catenin signalling and restore the mitochondrial integrity and Adenosine triphosphate (ATP) production. In CB2 knockout mice, renal tubular cell senescence and kidney fibrosis were also significantly inhibited. CB2 overexpression or activation by the agonist AM1241 could sufficiently induce the decrease in PGC-1α and a variety of mitochondria-related proteins and trigger cellular senescence in cultured human renal proximal tubular cells. CB2-activated mitochondrial dysfunction and cellular senescence could be blocked by ICG-001, a blocker for ß-catenin signalling. These results show CB2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing. The intrinsic mechanism may be related to its activation in ß-catenin signalling.

Tubule-derived exosomes play a central role in fibroblast activation and kidney fibrosis.

Extracellular vesicles such as exosomes are involved in mediating cell-cell communication by shuttling an assortment of proteins and genetic information. Here, we tested whether renal tubule-derived exosomes play a central role in mediating kidney fibrosis. The production of exosomes was found to be increased in the early stage of unilateral ureteral obstruction, ischemia reperfusion injury or 5/6 nephrectomy models of kidney disease. Exosome production occurred primarily in renal proximal tubular epithelium and was accompanied by induction of sonic hedgehog (Shh). In vitro, upon stimulation with transforming growth factor-ß1, kidney proximal tubular cells (HKC-8) increased exosome production. Purified exosomes from these cells were able to induce renal interstitial fibroblast (NRK-49F) activation. Conversely, pharmacologic inhibition of exosome secretion with dimethyl amiloride, depletion of exosome from the conditioned media or knockdown of Shh expression abolished the ability of transforming growth factor-ß1-treated HKC-8 cells to induce NRK-49F activation. In vivo, injections of tubular cell-derived exosomes aggravated kidney injury and fibrosis, which was negated by an Shh signaling inhibitor. Blockade of exosome secretion in vivo ameliorated renal fibrosis after either ischemic or obstructive injury. Furthermore, knockdown of Rab27a, a protein that is essential for exosome formation, also preserved kidney function and attenuated renal fibrotic lesions in mice. Thus, our results suggest that tubule-derived exosomes play an essential role in renal fibrogenesis through shuttling Shh ligand. Hence, strategies targeting exosomes could be a new avenue in developing therapeutics against renal fibrosis.

Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal ß-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated ß-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI.

Self-acceptance and associated factors among Chinese women with breast cancer.

AIMS AND OBJECTIVES: To identify self-acceptance and associated socio-demographic and disease factors among Chinese women with breast cancer. BACKGROUND: Although it is recognised that breast cancer can affect a woman's feelings of self-acceptance, there are few studies concerning the level of self-acceptance among women with breast cancer and factors associated with self-acceptance in this population. DESIGN: Cross-sectional research design. METHODS: Data were collected using the convenience sampling method. A total of 308 women with breast cancer were investigated using the Self-Acceptance Questionnaire. RESULTS: The mean score on the Self-Acceptance Questionnaire was 39·79 ± 5·14, indicating that the women in this study had low levels of self-acceptance. Multiple regression analysis indicated that self-acceptance was positively associated with the time since diagnosis, household income and the presence of medical insurance/government-funded medical treatment, while Tumour, Lymph Node, Metastasis stage was negatively associated with self-acceptance. With respect to work status, retired patients had the highest levels of self-acceptance, those who had returned to work had moderate levels of self-acceptance and those who had not yet returned to work had the lowest levels of self-acceptance. CONCLUSIONS: This study demonstrates that the level of self-acceptance among women with breast cancer in China is low, and suggests that there is room to improve. Several factors are significantly associated with the self-acceptance of women with breast cancer. RELEVANCE TO CLINICAL PRACTICE: Medical staff should realise that the level of self-acceptance among women with breast cancer in China is low and has room to improve. It is important to conduct appropriate interventions to improve self-acceptance among these women, based on an understanding of the factors associated with self-acceptance.

Efficacy of Two Combinations of Blood Purification Techniques for the Treatment of Multiple Organ Failure Induced by Wasp Stings.

BACKGROUND/AIMS: The aim of this study was to explore the clinical efficacy of 2 combinations of blood purification techniques in patients with sting venom-induced multiple organ dysfunction syndrome (MODS). METHODS: A total of 23 patients received 35 sessions of hemoperfusion (HP) + continuous veno-venous hemodiafiltration (CVVHDF) treatment and 22 sessions of plasma exchange (PE) + CVVHDF treatment, respectively. RESULTS: Both HP + CVVHDF and PE + CVVHDF reduced the levels of inflammation, thus improving our patients' health condition. Moreover, PE + CVVHDF was found to be significantly more effective in reducing the levels of specific liver function markers and inflammatory mediators, as well as shortening prothrombin time and increasing the levels of serum albumin. CONCLUSION: Both combinations of blood purification techniques were capable of improving MODS. However, the PE + CVVHDF approach was more efficient for the removal of wasp venom and inflammatory mediators from the blood.

Structural and physicochemical properties of rice starch from a variety with high resistant starch and low amylose content.

Research on the physicochemical properties of rice-derived endo-sperm high resistant starch (RS) with low amylose content (AC) is limited. In this study, we evaluated the physicochemical characteristics of such a starch variety and revealed that the starch granules exhibit a smoother, more refined surface with distinct edges, increased compactness, higher order of surface, and fewer cavities compared to those of a low RS rice variety. The starch crystal was classified as an A-type, which may be connected to the high amylose-lipid complex content. The branched internal long chains (B2 + B3) were abundant, allowing for easy entanglement with other molecular chains and a compact structure. Differential scanning calorimetry revealed the need for high temperature and energy to disrupt the double helix structure within the crystallization region of starch. Furthermore, starch viscosity analysis revealed a high cold paste viscosity, consistency, and setback value, with recrystallization yielding a stable structure, increased viscosity, and enhanced hydrolysis resistance to enzymes.

Assessing the current situation and the influencing factors affecting perceived stigma among older patients after leukemia diagnosis.

BACKGROUND: Psychological problems are becoming increasingly prominent among older patients with leukemia, with patients potentially facing stigmatization after diagnosis. However, there is limited research on the stigma experienced by these patients and the factors that may contribute to it. AIM: To investigate the stigma faced by older patients after being diagnosed with leukemia and to analyze the potential influencing factors. METHODS: A retrospective analysis was conducted using clinical data obtained from questionnaire surveys, interviews, and the medical records of older patients with leukemia admitted to the Hengyang Medical School from June 2020 to June 2023. The data obtained included participants' basic demographic information, medical history, leukemia type, family history of leukemia, average monthly family income, pension, and tendency to conceal illness. The Chinese versions of the Social Impact Scale (SIS), Perceived Social Support Scale (PSSS), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) were used to assess indicators related to stigma, social support, and mental health status. We used Pearson's correlation coefficient to analyze the strength and direction of the relationship between the scores of each scale, and regression analysis to explore the factors related to the stigma of older patients with leukemia after diagnosis. RESULTS: Data from 120 patients with leukemia aged 65-80 years were analyzed. The total score on the SIS and PSSS was 43.60 ± 4.07 and 37.06 ± 2.87, respectively. The SAS score was 58.35 ± 8.32 and the SDS score was 60.58 ± 5.97. The stigma experienced by older leukemia patients was negatively correlated with social support (r = -0.691, P < 0.05) and positively correlated with anxiety and depression (r = 0.506, 0.382, P < 0.05). Age, education level, smoking status, average monthly family income, pension, and tendency to conceal illness were significantly associated with the participants' level of stigma (P < 0.05). Age, smoking status, social support, anxiety, and depression were predictive factors of stigmatization among older leukemia patients after diagnosis (all P < 0.05), with a coefficient of determination (R2) of 0.644 and an adjusted R2 of 0.607. CONCLUSION: Older patients commonly experience stigmatization after being diagnosed with leukemia. Factors such as age, smoking status, social support, and psychological well-being may influence older patients' reported experience of stigma.

The CXCR4-AT1 axis plays a vital role in glomerular injury via mediating the crosstalk between podocyte and mesangial cell.

Glomeruli stand at the center of nephrons to accomplish filtration and albumin interception. Podocytes and mesangial cells are the major constituents in the glomeruli. However, their interdependency in glomerular injury has rarely been reported. Herein, we investigated the role of C-X-C chemokine receptor type 4 (CXCR4) in mediating the crosstalk between podocytes and mesangial cells. We found CXCR4 and angiotensin II (AngII) increased primarily in injured podocytes. However, type-1 receptor of angiotensin II (AT1) and stromal cell-derived factor 1α (SDF-1α), a ligand of CXCR4, were evidently upregulated in mesangial cells following the progression of podocyte injury. Ectopic expression of CXCR4 in 5/6 nephrectomy mice increased the decline of renal function and glomerular injury, accelerated podocyte injury and mesangial cell activation, and initiated CXCR4-AT1 axis signals. Additionally, treatment with losartan, an AT1 blocker, interrupted the cycle of podocyte injury and mesangial matrix deposition triggered by CXCR4. Podocyte-specific ablation of CXCR4 gene blocked podocyte injury and mesangial cell activation. In vitro, CXCR4 overexpression induced oxidative stress and renin angiotensin system (RAS) activation in podocytes, and triggered the communication between podocytes and mesangial cells. In cultured mesangial cells, AngII treatment induced the expression of SDF-1α, which was secreted into the supernatant to further promote oxidative stress and cell injury in podocytes. Collectively, these results demonstrate that the CXCR4-AT1 axis plays a vital role in glomerular injury via mediating pathologic crosstalk between podocytes and mesangial cells. Our findings uncover a novel pathogenic mechanism by which the CXCR4-AT1 axis promotes glomerular injury.

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity.

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD). Tubular cell injury plays a pivotal role in renal fibrosis. Commonly, injured tubular cells exhibit significant lipid accumulation. However, the underlying mechanisms remain poorly understood. Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry. 2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice. Lipid accumulation and renal fibrosis were tested. Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models. Tubular cell-specific MAGL knock-in mice were generated. Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice. Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used. Results: 2-AG was increased in the serum or kidneys from CKD patients and models. Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/ß-catenin signaling. ß-catenin knockout blocked 2-AG/CB2-induced fatty acid ß-oxidation (FAO) deficiency and lipid accumulation. Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis. Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis. Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis. Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.

The Self-growth Process of Hospice Volunteers in Ningbo, China.

Objective: The development process of self-growth among Chinese hospice volunteers is poorly understood. This study aimed to explore and delineate their dynamic progression toward self-growth. Methods: This qualitative study used grounded theory to analyze semi-structured interview data using individual in-depth face-to-face interviews with 15 volunteers at a hospice care center in Ningbo, China, between January 2021 and January 2022. Data analysis was based on the open, axial, and selective coding stages of grounded theory and used the constant comparative method. Results: From the interview data, we extracted 1 core category (Death awakening life), 4 categories, and 19 subcategories that pertained to the process of self-growth. The 4 categories delineated the process of self-growth; respondents progressed through self-salvation, self-reflection, self-healing, and self-transcendence stages. The 19 subcategories are introduced and illustrated with interview extracts. Conclusions: The study findings can inform the development of training projects aimed at improving hospice care volunteer services.

Early Rehabilitation and Nursing Intervention (ERNI) Accelerates the Recovery of Patients With Ischemic Stroke.

BACKGROUND: Ischemic stroke, a severe disease with high disability and mortality, causes an overburden in society and demands more effective treatments. Early rehabilitation and nursing intervention (ERNI) helps the postoperative recovery of patients with hypertensive intracerebral hemorrhage. However, the effect of ERNI on the recovery of people after ischemic stroke remains unclear. METHODS: Patients were treated with the ERNI program; subsequently, Mini-Mental State Examination, National Institute of Health stroke scale, Fugl-Meyer Assessment Scale, Daily living activity assessment, and Quality of life test were performed after the treatment of ERNI to evaluate the influence of ERNI on the cognitive function, motor function, and life quality of patients after ischemic stroke. RESULTS: We observed that following the treatment of ERNI, cognitive, neurological, and motor functions, daily life qualities, and life quality in the ERNI-treated group were significantly better than that in the control group. CONCLUSION: ERNI promoted the recovery of neurological function and improved the life qualities of patients after ischemic stroke.

Direct Urea/H2O2 Fuel Cell with a Hierarchical Porous Nanoglass Anode for High-Efficiency Energy Conversion.

Direct urea/H2O2 fuel cells (DUFCs) constitute a sustainable bifunctional energy conversion technique devoted to simultaneously eliminating environmental wastewater with urea and generating clean energy. However, exploring an efficient anode material for DUFCs still remains a huge challenge. In this work, a Ni-P hierarchical porous nanoglass (HPNG) catalytic electrode was developed via a low-cost, industrially available electrodeposition technique, which exhibits one of the best performances reported so far in the urea oxidation reaction (UOR), with a potential of 1.330 V at a current density of 10 mA cm-2 and a Tafel slope of 9.77 mV dec-1. The superior UOR performance of the HPNG electrode is attributed to the excellent intrinsic catalytic activity of NG with a high-energy state and an extremely enlarged surface area from the unique 3D hierarchical porous structure. Furthermore, a DUFC system with the HPNG anode shows a performance breakthrough as indicated by the maximum power density of 38.15 mW cm-2 for 0.5 M urea, representing one of the best yet reported DUFCs. Our work demonstrates the feasibility of the scalable production of HPNG electrodes and is expected to be a great contribution to the development of the practical use of DUFCs in the near future for bifunctional energy conversion.

Tenascin-C promotes the proliferation and fibrosis of mesangial cells in diabetic nephropathy through the ß-catenin pathway.

OBJECTIVE: To mechanistically assess the involvement of tenascin-C (TNC) in diabetic nephropathy (DN). METHODS: Renal specimens from DN patients were histopathologically examined, and their TNC expression patterns were evaluated via immunohistochemistry. Additionally, the hereditarily diabetic C57BL/KsJ db/db mice were induced to develop DN via adaptive feeding, and then their renal levels of TNC and ß-catenin were assessed via western blotting and immunohistochemistry. Furthermore, the TNC and ß-catenin levels in primary rat mesangial cells (RMCs) cultured with high glucose levels were assessed via western blotting. In parallel, RMCs cultured with TNC in the presence or absence of the ß-catenin blocker ICG-001 were analyzed for their fibronectin and collagen I levels via immunostaining, and for their fibronectin, α-SMA, vimentin, PDGFR-ß, PCNA, and ß-catenin levels via western blotting. RESULTS: The TNC levels in the specimens were associated with the pathological classification. In these DN specimens, TNC protein was highly detected in the MCs and slightly in the tubulointerstitium. Renal TNC (P < 0.05) and ß-catenin (P < 0.001) were upregulated in db/db vs. db/m mice. High-glucose treatment upregulated TNC (P < 0.01) and ß-catenin (P < 0.05) in RMCs. TNC treatment upregulated fibronectin (P < 0.05), α-SMA (P < 0.01), vimentin (P < 0.05), PCNA (P < 0.05), and ß-catenin (P < 0.05) in RMCs, as assessed via western blotting. Immunohistochemical analysis confirmed the fibronectin upregulation and showed collagen I upregulation. Western-blot results also showed that levels of fibronectin (P < 0.001), α-SMA (P < 0.01), vimentin (P < 0.001), PCNA (P < 0.05), PDGFR-ß (P < 0.05), and ß-catenin (P < 0.01) were lower in RMCs co-treated with TNC and ICG-001 than in TNC-treated cells. Immunofluorescence analysis confirmed the decreased fibronectin level and showed that the collagen I level was also decreased by ICG-001. CONCLUSION: TNC is upregulated in DN and induces MC proliferation and fibrosis through the ß-catenin pathway.

Effects of Transient Electrical Acupuncture Stimulation Combined With Rehabilitation Training on Hemorheology, Neurological Function and BDNF in Patients With Cerebral Infarction.

OBJECTIVE: To explore the effects of transient electric acupuncture stimulation combined with rehabilitation training on hemorheology, neurological function and brain-derived neurotrophic factor (BDNF) in patients with cerebral infarction (CI). METHODS: A total of 90 patients with CI were admitted to our hospital from March 2019 to March 2021. According to the random number table method, 90 patients were divided into a control group (was treated with transient electrical acupuncture stimulation intervention treatment) and a therapy group (was treated with rehabilitation training on the basis of the control group), with 45 cases in each group. NIHSS score to detect neurological deficit; FMA score to detect motor function recovery; the clinical efficacy of the two groups of patients were compared; blood rheology analyzer to detect whole blood high shear viscosity, whole blood low shear viscosity, platelet aggregation rate and fibrinogen indicators; ELISA detects the content of BDNF in serum. RESULTS: There was no significant difference in NIHSS score, FMA score, clinical efficacy, hemorheology index, and BDNF content between the two groups of patients before treatment (P > 0.05). After treatment, the NIHSS score, whole blood high shear visible, whole blood low shear visible, platelet aggregation rate and fibrinogen index of the two groups were lower than those before treatment, and the FMA score and BDNF content of the two groups were higher than those before treatment, and all the above indicators in the therapy group changed significantly compared with the control group (P < 0.05). After treatment, the clinical efficacy of the therapy group was better than that of the control group (P < 0.05). CONCLUSION: The combination of transient electrical acupuncture stimulation and rehabilitation training can inhibit the blood flow index of patients with CI, improve the nerve function, increase the content of BDNF in the patient's serum, and restore the patient's nerve function.

The Impact of Triangle Hierarchical Management on Self-Management Behavior and Quality of Survival in Parkinson's Patients.

Objective: To investigate the effect of Triangle tiered and graded management on the self-management behavior and quality of survival of Parkinson's Disease (PD) patients. Methods: Eighty ambulatory PD patients admitted to the neurology outpatient clinic of our hospital from June 2020 to January 2021 were selected for the study. Eighty patients were divided into 40 cases each in the test group and the control group using the random number table method. Patients in the control group were given conventional treatment and care, while in the test group, Triangle hierarchical management was applied on the basis of the control group. Non-motor symptoms [assessed by the Montreal Cognitive Inventory (MoCA), the Scale for Outcomes in PD for Autonomic Symptoms disability Scale (SCOPA-DS) and the Nocturnal Scale (SCOPA-NS)], motor symptoms [assessed by the Functional Gait Assessment (FGA), the Modified Ashworth Scale, and the Unified Parkinson's Disease Rating Scale (UPDRS-III)], quality of life (assessed by Barthel Index), medication adherence (self-administered medication adherence questionnaire), quality of survival (assessed by the 39-item Parkinson's Disease Quality of Survival Questionnaire, PDQ-39), and self-management effectiveness (assessed by the Chronic Disease Self-Efficacy Scale, symptom management and disease co-management) were compared between the two groups before and after the intervention. The two groups were also observed for satisfaction with care. Results: After the intervention, the MoCA score, FGA score, Barthel Index, Medication adherence and all scores of self-management effectiveness were significantly higher in the test group than in the control group (P < 0.05); the SCOPA-DS score, SCOPA-NS score, Ashworth score, UPDRS-III score and PDQ-39 score were significantly lower than in the control group (P < 0.05). Satisfaction with nursing care was significantly higher in the test group than in the control group (P < 0.05). Conclusion: The application of Triangle's tiered and graded management to the home care of ambulatory PD patients was effective in improving their non-motor and motor symptoms, their ability to perform daily activities, medication adherence and self-management effectiveness, and their overall survival outcome.

KYA1797K, a Novel Small Molecule Destabilizing ß-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging.

Introduction: Aged kidney is characterized by mitochondrial dysfunction, cellular senescence, and fibrogenesis. The activation of Wnt/ß-catenin signaling plays an important role in the initiation of kidney aging. However, the inhibiting strategies have not been discovered in detail. Here, we compared the therapeutic effects of two ß-catenin inhibitors, KYA1797K and ICG-001, to assess their superiority. Methods: Two-month-old male C57BL/6 mice which had undergone unilateral nephrectomy and received D-galactose (D-gal) injection were co-treated with KYA1797K or ICG-001 at 10 mg/kg/day for 4 weeks. Human proximal renal tubular cells were treated with D-gal and KYA1797K/ICG-001 to compare their effects. Results: Compared with ICG-001, which inhibits ß-catenin pathway through blocking the binding of ß-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP), KYA1797K, a novel small molecule destabilizing ß-catenin through activating Axin-GSK3ß complex, possesses the superior effects on protecting against kidney aging. In D-gal-treated accelerated aging mice, KYA1797K could greatly inhibit ß-catenin pathway, preserve mitochondrial homeostasis, repress cellular senescence, and retard age-related kidney fibrosis. In cultured proximal tubular cells, KYA1797K shows a better effect on inhibiting cellular senescence and could better suppress mitochondrial dysfunction and ameliorate the fibrotic changes, at the same dose as that in ICG-001. Conclusion: These results show that effectively eliminating ß-catenin is a necessity to target against age-related kidney injury, suggesting the multiple transcriptional regulation of ß-catenin in kidney aging besides T-cell factor/lymphoid enhancer-binding factor family of transcription factors (TCF/LEF-1).

Nanostructured Metallic Glass in a Highly Upgraded Energy State Contributing to Efficient Catalytic Performance.

Metallic glasses (MGs), with high density of low coordination sites and high Gibbs free energy state, are novel promising and competitive candidates in the family of electrochemical catalysts. However, it remains a grand challenge to modify the properties of MGs by control of the disordered atomic structure. Recently, nanostructured metallic glasses (NGs), consisting of amorphous nanometer-sized grains connected by amorphous interfaces, have been reported to exhibit tunable properties compared to the MGs with identical chemical composition. Here, it is demonstrated that electrodeposited Ni-P NG is characterized by an extremely high energy state due to its heterogeneous structure, which significantly promotes the catalytic performance. Moreover, the Ni-P NG with a heterogeneous structure is a perfect precursor for the fabrication of unique honey-like nanoporous structure, which displays superior catalytic performance in the urea oxidation reaction (UOR). Specifically, modified Ni-P NG requires a potential of mere 1.36 V at 10 mA cm-2 , with a Tafel slope of 13 mV dec-1 , which is the best UOR performance in Ni-based alloys. The present work demonstrates that the nanostructurization of MGs provides a universal and effective pathway to upgrade the energy state of MGs for the design of high-performance catalysts in energy conversion.

ß-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.

Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by ß-catenin in renal tubular cells. Osteopontin (OPN), especially its N-terminal fragment (N-OPN), was encapsulated in ß-catenin-controlled tubular cell-derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of ß-catenin in tubular cells (Ksp-ß-catenin-/- ) or gene ablation of CD44 (CD44-/- ) greatly ameliorated renal fibrosis. Notably, N-OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome-mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by ß-catenin.

A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells.

Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis. LKB1 dysfunction plays a key role in renal fibrosis. However, LKB1 activators are scarce in commercial nowadays. This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1. Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site. We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models). TGF-ß-stimulated renal tubular cell culture was also tested. Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD. As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux. PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling. Transcriptomics sequencing and mutation analysis further demonstrated our results. Conclusion: PA-S14 is a novel leading compound of LKB1 activator. PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.