Regioselective Synthesis of α-Quaternary Amino Acid Derivatives Enabled by Photoinduced Energy Transfer.

α-Quaternary amino acids have found application in many biologically relevant compounds and pharmaceuticals. Although there are many methods for the synthesis of α-quaternary amino acids, most of them are mainly realized with the aid of transition metals and complex ligands. We present herein a 2,7-Br-4CzIPN catalyzed regioselective alkylation of azlactones with redox-active esters via radical-radical couplings. Strikingly, this approach is devoid of any metal or additive and shows broad scope and superior sensitive functional group compatibility.

Classic congenital adrenal hyperplasia with unilateral functional adrenal cortical adenoma: case report.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to adrenal steroid biosynthesis, and mainly caused by mutations in the CYP21A2 gene encoding 21-hydroxylase. Adrenal tumors are common in CAH, but functional adrenal tumors are rare. Here, we report a 17-year-old female with virilized external genitalia and primary amenorrhea, accompanied by a right adrenal tumor. Her 17-OHP level was normal, cortisol and androgen levels were significantly elevated, and the tumor pathology showed adrenal cortical adenoma. Gene testing for CYP21A2 showed c.518T > A in exon 4 and c.29313C > G in intron 2. The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.

Epidemiological characteristics and hospitalization burden analysis of pediatric inpatients with melanocytic nevi in China from 2016 to 2021: A nationwide retrospective study of 13,396 cases.

BACKGROUND: Melanocytic nevi typically appear in early childhood, and their removal is a common plastic surgery procedure performed on children. However, the epidemiological characteristics and hospitalization burden of children with melanocytic nevi have rarely been described in detail. METHODS: Medical records of pediatric inpatients with melanocytic nevi from January 1, 2016, to December 31, 2021, were collected from the Futang Research Center of Pediatric Development database in China. We then extracted and statistically analyzed the relevant information, including demographic characteristics, clinical information, hospitalization burden, and other basic information for each inpatient. RESULTS: Among the 13,396 inpatients with melanocytic nevi, the highest number of cases was found in East China, and most patients were residents of urban areas. Most hospitalized patients consisted of boys aged 7-12 years with melanocytic nevi. Lesion sites in the buttocks and lower limbs were most common among pediatric inpatients with melanocytic nevi. Compound nevi were the most common (38.50 %) histological subtype and the rate of conversion into melanoma was 1.02 % (137 inpatients) among pediatric inpatients with melanocytic nevi. The hospitalization burden for patients varied significantly based on factors such as the age of the patients undergoing surgery, year of hospitalization, site of the lesion, histological subtype, and surgical method. In general, if the patients' age was under 1 year, lesion site was located in face, and there was a need for excision combined with tissue expander can significantly increase the treatment fees for pediatric inpatients with melanocytic nevi. CONCLUSION: Given the increasing number and relatively large hospitalization burden among children with melanocytic nevi hospitalized in China, the government needs to pay more attention to this group and provide corresponding economic and policy support.

Identifying the risk of depression in a large sample of adolescents: An artificial neural network based on random forest.

BACKGROUND: This study aims to develop an artificial neural network (ANN) prediction model incorporating random forest (RF) screening ability for predicting the risk of depression in adolescents and identifies key risk factors to provide a new approach for primary care screening of depression among adolescents. METHODS: The data were from a large cross-sectional study conducted in China from July to September 2021, enrolling 8635 adolescents aged 10-17 with their parents. We used the Patient health questionnaire (PHQ-9) to rate adolescent depression symptoms, using scales and single-item questions to collect demographic information and other variables. Initial model variables screening used the RF importance assessment, followed by building prediction model using the screened variables through the ANN. RESULTS: The rate of depression symptoms in adolescents was 24.6%, and the depression risk prediction model was built based on 70% of the training set and 30% of the test set. Ten variables were included in the final prediction model with a model accuracy of 85.03%, AUC of 0.892, specificity of 89.79%, and sensitivity of 70.81%. The top 10 significant factors of depression risk were adolescent rumination, adolescent self-esteem, adolescent mobile phone addiction, peer victimization, care in parenting styles, overprotection in parenting styles, academic pressure, conflict in parent-child relationship, parental rumination, and relationship between parents. CONCLUSIONS: The ANN model based on the RF effectively identifies depression risk in adolescents and provides a methodological reference for large-scale primary screening. Cross-sectional studies and single-item scales limit further improvements in model accuracy.

Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Enhanced Tunability of Dual-Band Chiral Metasurface in the Mid-Infrared Range via Slotted Nanocircuit Design.

Multi-band circular dichroism (CD) response and tunability on the chiral metasurface are crucial for this device's applications in sensing and detection. This work proposes a dual-band CD Au-CaF2-Au dimer elliptical metasurface absorber, where chiroptical sensing is realized by breaking the geometric symmetry between two ellipses. The proposed metasurface can achieve high CD values of 0.8 and -0.74 for the dual-band within the 3-5 µm region, and the CD values can be manipulated by independently adjusting the geometric parameters of the metasurface. Furthermore, a slotted nanocircuit is introduced onto the metasurface to enhance its tunability by manipulating the geometry parameter in the design process, and the related mechanism is explained using an equivalent circuit model. The simulation of the sensing model revealed that the slotted nanocircuit enhances the sensor's tunability and significantly improves its bandwidth and sensitivity, achieving peak enhancements at approximately 753 nm and 1311 nm/RIU, respectively. Due to the strong dual-band positive (and negative) responses of the CD values, flexible wavelength tunability, and nonlinear sensitivity enhancement, this design provides a new approach for the development and application of mid-infrared chiroptical devices.

Fasudil attenuates oxidative stress-induced partial epithelial-mesenchymal transition of tubular epithelial cells in hyperuricemic nephropathy via activating Nrf2.

Anti-partial epithelial-mesenchymal transition (pEMT) treatment of renal tubular epithelial cells (TECs) represents a promising therapeutic approach. Hyperuricemia nephropathy (HN) arises as a consequence of hyperuricemia (HUA)-induced tubulointerstitial fibrosis (TIF). Studies have suggested that the Ras homolog member A (RhoA)/Rho-associated kinase (ROCK) pathway is a crucial signaling transduction system in renal fibrosis. Fasudil, a RhoA/ROCK inhibitor, has exhibited the potential to prevent fibrosis progress. However, its impact on the pEMT of TECs in HN remains unclear. Here, an HN rat model and an uric acid (UA)-stimulated human kidney 2 (HK2) cell model were established and treated with Fasudil to explore its effects. Furthermore, the underlying mechanism of action involved in the attenuation of pEMT in TECs by Fasudil during HN was probed by using multiple molecular approaches. The HN rat model exhibited significant renal dysfunction and histopathological damage, whereas in vitro and in vivo experiments further confirmed the pEMT status accompanied by RhoA/ROCK pathway activation and oxidative stress in tubular cells exposed to UA. Notably, Fasudil ameliorated these pathological changes, and this was consistent with the trend of ROCK silencing in vitro. Mechanistically, we identified the Neh2 domain of nuclear factor erythroid 2-related factor 2 (Nrf2) as a target of Fasudil for the first time. Fasudil targets Nrf2 activation and antagonizes oxidative stress to attenuate the pEMT of TECs in HN. Our findings suggest that Fasudil attenuates oxidative stress-induced pEMT of TECs in HN by targeting Nrf2 activation. Thus, Fasudil is a potential therapeutic agent for the treatment of HN.

Assessment of the Risk of Malnutrition or Frailty Among Patients Undergoing Liver Transplantation: A Hospital-Based Prospective Study.

Objective: We aimed to explore the status of nutritional and frailty in patients undergoing liver transplantation and the associated influencing factors. Methods: We conducted a follow-up analysis of 44 patients who underwent liver transplantation between 2021 and 2022. We followed up and recorded the nutritional status and risk of weakness at different time-points (days 1, 2, 3, 6, 9, and 12) postoperatively. Patient information regarding demographics, physical examination, medical history, and perioperative blood tests were collected. Binary logistic regression was applied to identify risk factors for weakness after liver transplantation. Results: The cohort comprised 44 liver transplant recipients, with a mean age of 47.66 years (standard deviation=9.49 years). Initial analysis revealed that, compared to the group without nutritional risks, the group with nutritional risks displayed elevated age and preoperative blood ammonia levels one week post-surgery. Moreover, this group had reduced levels of albumin and total bile acid preoperatively. Patients with preoperative nutritional risks were also prone to similar risks 2 weeks postoperatively. Further, a correlation was observed between preoperative pulmonary infections and increased frailty risk 6 days postoperatively. At both 9 and 12 days postoperatively, patients with frailty risk exhibited higher preoperative white blood cell counts and ammonia levels than those without. Multivariable analysis, controlling for confounding factors, indicated a significant association between preoperative nutritional status and nutritional risk 2 weeks postoperatively, as well as a link between preoperative white blood cell count and frailty risk at 12 days postoperatively. Conclusion: There was a significant correlation between preoperative nutritional status and nutritional risk 2 weeks after liver transplantation, and preoperative white blood cell count was an independent risk factor for weakness 12 days postoperatively. Preoperative nutritional management for patients could potentially mitigate the likelihood of adverse clinical outcomes.

Hospitalization information and burden of pediatric inpatients in transport accidents.

BACKGROUND: Transport accidents are one of the leading causes of child morbidity and mortality worldwide and represent a significant public health burden. This study aimed to investigate the hospitalization information and burden of pediatric inpatients in transport accidents in China. METHODS: In this study, we collected the cover page of the medical records of pediatric inpatients in transport accidents using the Futang Research Center of Pediatric Development (FRCPD) database from January 1, 2016 to December 31, 2021. Then, we extracted the epidemiological characteristics, including demographic characteristics, cases distribution, disease information, and hospitalization burden. RESULTS: Among 36,455 included inpatients, males, aged 1-3 years, East China, July were dominant in different subgroups. In transport accidents, pedestrians were the most frequently type of injury (65.69%). Of all known lesions, craniocerebral/nerve injury was the more common results in pediatric inpatients in transport accidents (33.93%). In addition to pedal cyclists more susceptible to sport system injury, other types of injured person with transport accidents were mainly craniocerebral/nerve injury. In terms of the type of discharge, occupant of heavy transport vehicle or bus and people with craniocerebral/nerve injury had the highest mortality rate after hospitalization in all type and lesion of injured person groups, respectively. The largest hospitalization burden in the type of injured person was occupant of heavy transport vehicle or bus. CONCLUSIONS: This study revealed that epidemiological characteristics and the main factor influencing the hospitalization information and burden of children with traffic accidents in China.

scMoresDB: A comprehensive database of single-cell multi-omics data for human respiratory system.

The human respiratory system is a complex and important system that can suffer a variety of diseases. Single-cell sequencing technologies, applied in many respiratory disease studies, have enhanced our ability in characterizing molecular and phenotypic features at a single-cell resolution. The exponentially increasing data from these studies have consequently led to difficulties in data sharing and analysis. Here, we present scMoresDB, a single-cell multi-omics database platform with extensive omics types tailored for human respiratory diseases. scMoresDB re-analyzes single-cell multi-omics datasets, providing a user-friendly interface with cross-omics search capabilities, interactive visualizations, and analytical tools for comprehensive data sharing and integrative analysis. Our example applications highlight the potential significance of BSG receptor in SARS-CoV-2 infection as well as the involvement of HHIP and TGFB2 in the development and progression of chronic obstructive pulmonary disease. scMoresDB significantly increases accessibility and utility of single-cell data relevant to human respiratory system and associated diseases.

Arachidonic acid metabolism as a therapeutic target in AKI-to-CKD transition.

Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A2 into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum.

Trends and Preferences of Rhinoplasty Among Chinese Patients: A Social Media Analysis.

BACKGROUND: This study investigated the trends, motivations and preferences of rhinoplasty in China. METHODS: Data on rhinoplasty were collected from Xiaohongshu and analyzed for trends. Text analysis and word frequency statistics were performed on the notes and comments using Python modules. RESULTS: We obtained 1065 notes with 102,153 comments, 239,383 collections and 640,579 likes. The number of rhinoplasty-related publications increased annually, correlating with per capita disposable income of households (DI) growth (r2 = 0.609, P = 0.041 < 0.05). In the Southern provinces, there was a notably higher volume of publications compared to the Northern provinces (P = 0.001). Furthermore, a significant correlation was observed between publication data, population size, and the DI (r2 = 0.786, P < 0.001). The nasal tip (3197) and nasion (1409) were the most mentioned nasal subunits. "Good-looking" (9672) and "natural" (2811) were the most used words to describe the nose shape. The "doctor" (4377), the "hospital" (2182) and "hyaluronic acid" (2106) were the most mentioned rhinoplasty procedure related vocabulary. CONCLUSIONS: Discussions about rhinoplasty in China are increasing, and more people express their desire for rhinoplasty on social networks, related to China's DI growth. The Southern provinces show a higher inclination toward these discussions, a trend that correlates with our findings of a positive association between NOPs and both DI and population size. Netizens pay more attention to the shape of nasal tip and nasion, and prefer the good-looking and natural appearance. Most people consider autologous cartilage or hyaluronic acid injection for rhinoplasty. Doctors are the primary consideration for patients. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The clinical characteristics and risk factors for necrotizing soft tissue infection in children.

Importance: Necrotizing soft tissue infection (NSTI) is a serious infectious disease. However, the early clinical manifestations and indicators of NSTI in children are still unclear. Objective: The purpose of this study was to analyze the clinical characteristics and risk factors of NSTI in pediatric patients. Methods: A total of 127 children with skin and soft tissue infection (SSTI) were treated at our hospital and divided into two groups: the NSTI group and the non-NSTI group, based on their discharge diagnosis from January 2011 to December 2022. Then, we collected and analyzed the clinical characteristics and risk factors of all patients, including sex and age, disease inducement, admission temperature, local skin manifestations, infection site, the presence of sepsis, bacterial culture, and laboratory indicators. Results: In our study, there was a statistical difference in the age distribution and disease inducement between NSTI and non-NSTI groups. The occurrence of local skin manifestations (blisters/bullae and ecchymosis) and the presence of sepsis significantly increased in the NSTI group compared to the non-NSTI group. Additionally, only the platelet count on laboratory tests was statistically different between the NSTI and non-NSTI groups. Finally, the logistic regression analysis suggested that local skin manifestations such as blisters/bullae, and ecchymosis, as well as the presence of sepsis, were identified as risk factors for NSTI. Interpretation: Children with SSTI and skin manifestations such as blisters/bullae, ecchymosis, and the presence of sepsis are at a higher risk of developing NSTI. These symptoms serve as useful indicators for early detection of NSTI.

Electrical injuries in children-a 6-year retrospective study.

BACKGROUND: This study aimed to assess the clinical epidemiological characteristics of children with electrical injuries and discuss the countermeasures for the prevention of electrical injuries in children. METHODS: The children with electrical injuries were grouped according to whether or not they were admitted to the hospital for treatment into inpatient and outpatient groups. Clinical data such as gender, causes of injury and injury-causing voltage distribution in different age groups were analyzed. The factors affecting hospitalization were subjected to χ2 test, Kruskal-Wallis H test, and logistic regression analysis. RESULTS: A total of 321 children were included with 37 divided into inpatient group and 284 divided into outpatient group. The incidence of electrical injuries was highest in children ≤6 years old and in the summer. There were significantly different in gender, place of occurrence, cause of injury and injury-causing voltage between the two groups (p < 0.05). Injury-causing voltage is an independent risk factor affecting hospitalization of children with electrical injuries (OR = 0.116, 95 %CI = 0.040-0.334, p = 0.000). In children ≤6 years old, boys suffered electrical injuries more frequently than girls; battery powered vehicle (47.53 %) was primarily the cause of injury; most of the patients (64.64 %) were exposed to low voltage below 100 Vs, mainly in the case of adolescent children. CONCLUSION: Male preschoolers accounted for the majority of electrical injury cases, and these accidents mostly happened in household electrical appliances and household battery cars. Overall, it is necessary to improve family electrical safety education and reinforce protective measures against electric injury to children.

MiR-9-enriched mesenchymal stem cells derived exosomes prevent cystitis-induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice.

BACKGROUND: Inflammatory response of central nervous system is an important component mechanism in the bladder pain of interstitial cystitis/bladder pain syndrome (IC/BPS). Exosomes transfer with microRNAs (miRNA) from mesenchymal stem cell (MSCs) might inhibit inflammatory injury of the central nervous system. Herein, the purpose of our study was to explore the therapeutic effects by which extracellular vesicles （EVs） derived from miR-9-edreched MSCs in IC/BPS and further investigate the potential mechanism to attenuate neuroinflammation. METHODS: On the basis of IC/BPS model, we used various techniques including bioinformatics, cell and molecular biology, and experimental zoology, to elucidate the role and molecular mechanism of TLR4 in regulating the activation of NLRP3 inflammasome in bladder pain of IC/BPS, and investigate the mechanism and feasibility of MSC-EVs enriched with miR-9 in the treatment of bladder pain of IC/BPS. RESULTS: The inflammatory responses in systemic and central derived by TLR4 activation were closely related to the cystitis-induced pelvic/bladder nociception in IC/BPS model. Intrathecal injection of miR-9-enreched MSCs derived exosomes were effective in the treatment of cystitis-induced pelvic/bladder nociception by inhibiting TLR4/NF-κb/NLRP3 signal pathway in central nervous system of IC/BPS mice. CONCLUSIONS: This study demonstrated that miR-9-enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis-induced bladder pain by inhibiting TLR4/NF-κb/NLRP3 signal pathway in interstitial cystitis mice, which is a promising strategy against cystitis-induced bladder pain.

Prognostic and predictive value of angiogenesis-associated serum proteins for immunotherapy in esophageal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved patient survival in multiple cancers. However, therapy response in esophageal cancer is limited to subgroups of patients and clinically useful predictive biomarkers are lacking. METHODS: We collected a series of plasma samples from 91 patients with esophageal cancer before and after ICI treatment. The Olink Immuno-Oncology panel (92 proteins) with proximity extension assays was used to detect the dynamic changes in plasma and potential biomarkers associated with treatment outcomes. We screened all survival-related proteins and established a risk score model to better predict the prognosis and treatment response in patients with esophageal cancer immunotherapy. RESULTS: We found that 47 out of 92 quantified proteins had significant changes in plasma levels during ICI treatment (p<0.050), and these changed proteins were involved in immune-related reactions, such as intercellular adhesion and T-cell activation. Notably, the baseline levels of three angiogenesis-related proteins (IL-8, TIE2, and HGF) were significantly associated with the survival outcomes of patients treated with ICIs (p<0.050). According to these prognostic proteins, we established an angiogenesis-related risk score, which could be a superior biomarker for ICI response prediction. In addition, antiangiogenic therapy combined with ICIs significantly improved overall survival compared with ICI monotherapy (p=0.044). CONCLUSIONS: An angiogenesis-related risk score based on three proteins (IL-8, TIE2, and HGF) could predict ICI response and prognosis in patients with esophageal cancer, which warrants verification in the future. Our study highlights the potential application of combining ICIs and antiangiogenic therapy and supports Olink plasma protein sequencing as a liquid biopsy method for biomarker exploration.

Characteristics and risk factors for electrical burn injuries: a study based on World Health Organization Global Burn Registry.

OBJECTIVE: Electrical burn injuries (EBIs) represent an important subset of burn injuries, but the information on them from the global level is limited. We aimed to investigate the characteristics and risk factors for EBIs reported to the World Health Organization Global Burn Registry. METHODS: Patients with EBIs and non-EBIs were identified from the registry. Patient demographics, income of the country, setting of the injury occurred, and outcomes were described and compared. Multivariable analysis was performed to identify risk factors associated with the EBIs and their outcomes. RESULTS: Of the 9276 patients, 814 (8.8%) were grouped as EBIs. EBIs patients had a median age of 28 years, and they were predominantly males (89.2%). EBIs were more likely to occur in lower-middle- and low-income countries (60.9% versus 43.4%) and in an occupational setting (49.1% versus 6.7%) than the non-EBIs. Older age, male, lower-income, and occupational and public setting were risk factors for EBIs. For EBIs patients, adolescents and young adults, those from low-middle and low-income countries, and those injured by high-voltage electricity were more likely to have more than 15% of the total body surface area. In addition, those from low-middle and low-income countries and those injured by high-voltage electricity were more likely to die. CONCLUSION: The characteristics of EBIs are significantly different from that of non-EBIs. To prevent EBIs and avoid unpleasant outcomes, particular attention should be given to adolescent boys and young adult men who are employed in electrical jobs in lower-income countries.

A Deep-Learning Model for Diagnosing Fresh Vertebral Fractures on Magnetic Resonance Images.

BACKGROUND: The accurate diagnosis of fresh vertebral fractures (VFs) was critical to optimizing treatment outcomes. Existing studies, however, demonstrated insufficient accuracy, sensitivity, and specificity in detecting fresh fractures using magnetic resonance imaging (MRI), and fall short in localizing the fracture sites. METHODS: This prospective study comprised 716 patients with fresh VFs. We obtained 849 Short TI Inversion Recovery (STIR) image slices for training and validation of the AI model. The AI models employed were yolov7 and resnet50, to detect fresh VFs. RESULTS: The AI model demonstrated a diagnostic accuracy of 97.6% for fresh VFs, with a sensitivity of 98% and a specificity of 97%. The performance of the model displayed a high degree of consistency when compared to the evaluations by spine surgeons. In the external testing dataset, the model exhibited a classification accuracy of 92.4%, a sensitivity of 93%, and a specificity of 92%. CONCLUSIONS: Our findings highlighted the potential of AI in diagnosing fresh VFs, offering an accurate and efficient way to aid physicians with diagnosis and treatment decisions.

Sirtuin 6 protects against podocyte injury by blocking the renin-angiotensin system by inhibiting the Wnt1/ß-catenin pathway.

Sirtuins (Sirts) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases that share diverse cellular functions. Increasing evidence shows that Sirts play a critical role in podocyte injury, which is a major determinant of proteinuria-associated renal disease. Membranous nephropathy (MN) is a typical glomerular disease in which podocyte damage mediates proteinuria development. In this study we investigated the molecular mechanisms underlying the regulatory roles of Sirt in podocyte injury in MN patients, rats with cationic bovine serum albumin (CBSA)-induced MN and zymosan activation serum (ZAS)-stimulated podocytes. Compared with healthy controls, MN patients showed significant reduction in intrarenal Sirt1 and Sirt6 protein expression. In CBSA-induced MN rats, significant reduction in intrarenal Sirt1, Sirt3 and Sirt6 protein expression was observed. However, only significant decrease in Sirt6 protein expression was found in ZAS-stimulated podocytes. MN patients showed significantly upregulated protein expression of Wnt1 and ß-catenin and renin-angiotensin system (RAS) components in glomeruli. CBSA-induced MN rats exhibited significantly upregulated protein expression of intrarenal Wnt1 and ß-catenin and their downstream gene products as well as RAS components. Similar results were observed in ZAS-stimulated podocytes. In ZAS-stimulated podocytes, treatment with a specific Sirt6 activator UBCS039 preserved the protein expression of podocin, nephrin and podocalyxin, accompanied by significant inhibition of the protein expression of ß-catenin and its downstream gene products, including Snail1 and Twist; treatment with a ß-catenin inhibitor ICG-001 significantly preserved the expression of podocyte-specific proteins and inhibited the upregulation of downstream ß-catenin gene products accompanied by significant suppression of the protein expression of RAS components. Thus, we demonstrate that Sirt6 ameliorates podocyte injury by blocking RAS signalling via the Wnt1/ß-catenin pathway. Sirt6 is a specific therapeutic target for the treatment of podocyte damage-associated renal disease.