Abundance of Modifications in Mature miRNAs Revealed by LC-MS/MS Method Coupled with a Two-Step Hybridization Purification Strategy.

Accurate detection of endogenous miRNA modifications, such as N6-methyladenosine (m6A), 7-methylguanosine (m7G), and 5-methylcytidine (m5C), poses significant challenges, resulting in considerable uncertainty regarding their presence in mature miRNAs. In this study, we demonstrate for the first time that liquid chromatography coupled with a tandem mass spectrometry (LC-MS/MS) nucleoside analysis method is a practical tool for quantitatively analyzing human miRNA modifications. The newly designed liquid-solid two-step hybridization (LSTH) strategy enhances specificity for miRNA purification, while LC-MS/MS offers robust capability in recognizing modifications and sufficient sensitivity with detection limits ranging from attomoles to low femtomoles. Therefore, it provides a more reliable approach compared to existing techniques for revealing modifications in endogenous miRNAs. With this approach, we characterized m6A, m7G, and m5C modifications in miR-21-5p, Let-7a/e-5p, and miR-10a-5p isolated from cultured cells and observed unexpectedly low abundance (<1% at each site) of these modifications.

Urinary Profile of Alkylated DNA Adducts and DNA Oxidative Damage in Sulfur Mustard-Exposed Rats Revealed by Mass Spectrometry Quantification.

Alkylation reagents, represented by sulfur mustard (SM), can damage DNA molecules directly as well as lead to oxidative stress, causing DNA lesions indirectly. Correspondingly, two types of biomarkers including alkylated DNA adducts and oxidative DNA adducts are commonly involved in the research of DNA damage evaluation caused by these agents. However, the correlations and differences of the occurrence, duration, severity, and traceability between alkylation and oxidation lesions on the DNA molecular level reflected by these two types of biomarkers have not been systematically studied. A simultaneous determination method for four alkylated DNA adducts, i.e., N7-(2-hydroxyethylthioethyl)2'-guanine (N7-HETEG), O6-(2-hydroxyethylthioethyl)-2'-guanine (O6-HETEG), N3-(2-hydroxyethylthioethyl)-2'-adenine (N3-HETEA), and bis(2-ethyl-N7-guanine)thioether (Bis-G), and the oxidative adduct 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in urine samples by isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (ID-HPLC-MS/MS) was built with a lower limit of detection of 0.02 ng/mL (except Bis-G, 0.05 ng/mL) and a recovery of 79-111%. The profile of these adducts was simultaneously monitored in urine samples after SD rats' dermal exposure to SM in three dose levels (1, 3, and 10 mg/kg). The time-effect and dose-effect experiments revealed that when exposed to SM, DNA alkylation lesions would happen earlier than those of oxidation. For the two types of biomarkers, alkylated DNA adducts showed an obvious dose-effect relationship and could be used as internal exposure dose and effect biomarkers, while 8-OH-dG did not show a correlation with exposure dose, demonstrating that it was more suitable as a biomarker for DNA oxidative lesions but not an indicator for the extent of cytotoxicity and internal exposure.

NAD(P)H: quinone oxidoreductase 1 attenuates oxidative stress and apoptosis by regulating Sirt1 in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is one of the main complications of diabetes, and oxidative stress plays an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and toxic quinone damage. In the present study, we aimed to investigate the protective effects and underlying mechanisms of NQO1 on diabetes-induced renal tubular epithelial cell oxidative stress and apoptosis. METHODS: In vivo, the kidneys of db/db mice, which are a type 2 diabetes model, were infected with adeno-associated virus to induce NQO1 overexpression. In vitro, human renal tubular epithelial cells (HK-2 cells) were transfected with NQO1 pcDNA3.1(+) and cultured in high glucose (HG). Gene and protein expression was assessed by quantitative real-time PCR, western blotting, immunofluorescence analysis, and immunohistochemical staining. Reactive oxygen species (ROS) were examined by MitoSox red and flow cytometry. TUNEL assays were used to measure apoptosis. RESULT: In vivo, NQO1 overexpression reduced the urinary albumin/creatinine ratio (UACR) and blood urea nitrogen (BUN) level in db/db mice. Our results revealed that NQO1 overexpression could significantly increase the ratio of NAD+/NADH and silencing information regulator 1 (Sirt1) expression and block tubular oxidative stress and apoptosis in diabetic kidneys. In vitro, NQO1 overexpression reduced the generation of ROS, NADPH oxidase 1 (Nox1) and Nox4, the Bax/Bcl-2 ratio and the expression of Cleaved Caspase-3 and increased NAD+/NADH levels and Sirt1 expression in HK-2 cells under HG conditions. However, these effects were reversed by the Sirt1 inhibitor EX527. CONCLUSIONS: All these data suggest that NQO1 has a protective effect against oxidative stress and apoptosis in DN, which may be mediated by the regulation of Sirt1 through increasing intracellular NAD+/NADH levels. Therefore, NQO1 may be a new therapeutic target for DN.

TXNIP deficiency mitigates podocyte apoptosis via restraining the activation of mTOR or p38 MAPK signaling in diabetic nephropathy.

Thioredoxin-interacting protein (TXNIP), is identified as an inhibitor of the thiol oxidoreductase thioredoxin that acts endogenously, and is increased by high glucose (HG). In this study, we investigated the potential function of TXNIP on apoptosis of podocytes and its potential mechanism in vivo and in vitro in diabetic nephropathy (DN). TXNIP silencing attenuated HG-induced apoptosis and obliterated the activation of signaling pathways of mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) in conditionally immortalized mouse podocytes. Furthermore, the Raptor and Rictor shRNAs, mTOR specific inhibitor KU-0063794 and p38 MAPK inhibitor SB203580 were used to assess the role of mTOR or p38 MAPK pathway on podocyte apoptosis induced by HG. The Rictor and Raptor shRNAs and KU-0063794 appeared to reduce HG-induced apoptosis in podocytes. Simultaneously, SB203580 could also restrain HG-induced apoptosis in podocytes. Streptozotocin rendered equivalent diabetes in TXNIP-/- (TKO) and wild-type (WT) control mice. TXNIP deficiency mitigated renal injury in diabetic mice. Additionally, TXNIP deficiency also descended the apoptosis-related protein and Nox4 levels, the mTOR signaling activation and the p38 MAPK phosphorylation in podocytes of diabetic mice. All these data indicate that TXNIP deficiency may mitigate apoptosis of podocytes by inhibiting p38 MAPK or mTOR signaling pathway in DN, underlining TXNIP as a putative target for therapy.

Thioredoxin-interacting protein deficiency alleviates phenotypic alterations of podocytes via inhibition of mTOR activation in diabetic nephropathy.

Thioredoxin-interacting protein (TXNIP) is induced by high glucose (HG), whereupon it acts to inhibit thioredoxin, thereby promoting oxidative stress. We have found that TXNIP knockdown in human renal tubular cells helped prevent the epithelial-to-mesenchymal transition (EMT). Here, we studied the potential effect of TXNIP on podocyte phenotypic alterations in diabetic nephropathy (DN) in vivo and in vitro. In conditionally immortalized mouse podocytes under HG conditions, knocking down TXNIP disrupted EMT, reactive oxygen species (ROS) production, and mammalian target of rapamycin (mTOR) pathway activation. Further, Raptor short hairpin RNA (shRNA), Rictor shRNA, and mTOR specific inhibitor KU-0063794 were used to assess if the mTOR signal pathway is involved in HG-induced EMT in podocytes. We found that Raptor shRNA, Rictor shRNA, and KU-0063794 could all restrain HG-induced EMT and ROS production in podocytes. In addition, antioxidant Tempol or N-acetylcysteine presented a prohibitive effect on HG-induced EMT in podocytes. Streptozotocin was utilized to render equally diabetic in wild-type (WT) control and TXNIP -/- (TKO) mice. Diabetes did not increase levels of 24-hr urinary protein, serum creatinine, blood urea nitrogen, and triglyceride in TXNIP -/- mice. Podocyte phenotypic alterations and podocyte loss were detected in WT but not in TKO diabetic mice. Oxidative stress was also suppressed in diabetic TKO mice relative to WT controls. Also, TXNIP deficiency suppresses the activation of mTOR in glomeruli of streptozotocin-induced diabetic mice. Moreover, TXNIP expression, mTOR activation, Nox1, and Nox4 could be detected in renal biopsy tissues of patients with DN. This suggests that decreased TXNIP could ameliorate phenotypic alterations of podocytes via inhibition of mTOR in DN, highlighting TXNIP as a promising therapeutic target.

Brachytherapy in the treatment of breast cancer.

Brachytherapy is an important radio-therapeutic modality for a variety of malignancies, including prostate cancer, cervix cancer, breast cancer, vagina cancer, endometrium cancer, head and neck cancer, and many more. This technique has been shown to be an effective and safe non-pharmaceutical treatment with fewer serious complications and better outcome than other treatments for breast cancer. Every year, hundreds of thousands of patients around the world benefit from brachytherapy, which reliably delivers a relatively higher radiation dose to the intended target. However, the follow-up time, patient eligibility criteria, treatment strategy, and radiation doses used in published studies are somewhat inconsistent, making it difficult to strictly compare and evaluate the performance of the treatment. More rigorous studies are required to confirm the safety of this technique and to make outcome data more comparable. In this review, we focus on recent advances in breast brachytherapy techniques and provide an overview of outcomes, cosmetic outcome, toxicity, complications, and limitations of brachytherapy for the treatment of breast cancer. We also summarize the clinical outcomes and toxicity results in patients receiving or not receiving brachytherapy.

Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy.

Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-ß1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-ß1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.

CD36 is involved in high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells.

The epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of diabetic nephropathy. Our recent study showed that ROS mediated high glucose (HG)-induced EMT in renal tubular epithelial cells. CD36, a class-B scavenger receptor, has been reported to mediate the production of ROS in chronic kidney disease. In the present study, we examined the effect of inhibition of CD36 with CD36 siRNA or sulfosuccinimidyl-oleate (SSO), a CD36 antagonist, on HG-induced EMT in HK-2 cells. HG induced CD36 expression in a time-dependent manner in HK-2 cells. HG was shown to induce EMT at 72 h. This was blocked by knockdown of CD36 or treatment with SSO. Meanwhile, we also found that knockdown of CD36 or treatment with SSO inhibited HG-induced ROS generation, activation of ERK1/2 and Smad2, expression of TGF-ß1 and synthesis of fibronectin. These data suggest that inhibition of CD36 prevented HG-induced EMT in HK-2 cells, highlighting CD36 as a potential therapeutic target for diabetic nephropathy.

Irisin ameliorates UUO-induced renal interstitial fibrosis through TGF-ß1/periostin/MMP-2 signaling pathway.

Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-ß1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-ß1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-ß1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.

Global research trends in unilateral ureteral obstruction-induced renal fibrosis: A bibliometric and visualized study.

BACKGROUND: Renal fibrosis is considered the pathway from almost all chronic kidney diseases (CKD) to end-stage renal diseases. The unilateral ureteral obstruction (UUO) model is a well-established experimental animal model to simulate renal fibrosis associated with obstructive nephropathy in an accelerated manner. In this study, in order to understand the development trends of research on UUO-induced renal fibrosis between 2005 and 2022 and predict prospects, we conducted a comprehensive bibliometric and visualized study using Web of Science (WoS). METHODS: The articles regarding UUO-induced renal fibrosis were culled from the "Core Collection" of the WoS database. VOSviewer software and the R-Bibliometrix Package were used in visual analysis of countries/regions, journals, authors, keywords, institutions, and highly cited articles in this field. RESULTS: The number of articles regarding UUO-induced renal fibrosis has obviously increased annually. China had the largest number of publications in this field. The most frequently used keywords were "inflammation," "transforming growth factor-beta1," "oxigative stress," "smad3," "beta-catenin," and "autophagy." Am J Physiol-Renal was the leading journal. The most highly influential documents were published by Higgins DF and his colleagues, with 46 local citations and 749 global citations. The leading institution was Nanjing Medical University. Furthermore, Zhang Y. was the author who contributed most to this field. CONCLUSION: Our results suggest that the molecular mechanism of UUO-induced renal fibrosis remains a research hot topic, especially on the inflammatory response and oxidative stress, and international cooperation is expected to expand and deepen in the future.

Pan-Cancer Analysis and Experimental Validation of SOX4 as a Potential Diagnosis, Prognosis, and Immunotherapy Biomarker.

INTRODUCTION: SOX4 plays an important role in tumorigenesis and cancer progression. The role of SOX4 in pan-cancer and its underlying molecular mechanism in liver hepatocellular carcinoma (LIHC) are not fully understood. In this study, a comprehensive analysis and experimental validation were performed to explore the function of SOX4 across tumor types. METHODS: Raw data in regard to SOX4 expression in malignant tumors were downloaded from the TCGA and GTEx databases. The expression levels, prognostic values, genetic mutation, and DNA promoter methylation of SOX4 across tumor types were explored via systematic bioinformatics analysis. The ceRNA regulatory network, immune characteristics, and prognostic models were analyzed in LIHC. Finally, we conducted in vitro experiments including Western blotting, cell proliferative assay, trypan blue staining, and fluorescence microscopy to further explore the function of SOX4 in LIHC. RESULTS: SOX4 expression was significantly upregulated in 24 tumor types. SOX4 expression level was strongly associated with unfavorable prognoses, genetic mutations, and DNA methylation levels across different tumor types. Especially in LIHC, LINC00152/hsa-miR-139-3p/SOX4 was identified as a crucial ceRNA network. Moreover, this study also provides insight into the roles of SOX4 expression in immune cell infiltration, macrophage polarization, immune subtype, molecular subtype, and immunomodulators, as well as the tumor immune microenvironment (TIME)-related prognosis, in LIHC. The study established six favorable prognostic models to predict LIHC prognosis based on the SOX4-associated genes. Finally, lenvatinib treatment can increase the expression of SOX4 in hepatocellular carcinoma cells and lead to drug resistance. Silencing SOX4 can effectively eliminate the drug resistance caused by lenvatinib treatment and inhibit the proliferation of cancer cells. CONCLUSIONS: This study highlights that SOX4 may serve as a promising therapeutic target for tumor treatment.

Facile Tailoring of Surface Terminations of MXenes by Doping Nb Element: Toward Extraordinary Pseudocapacitance Performance.

MXenes show promising potential in supercapacitors due to their unique two-dimensional (2D) structure and abundant surface functional groups. However, most studies about MXenes have focused on tailoring surface structures by alternating synthesis methods or post-etch treatments, and little is known about the inherent relationship between surface groups and M elements. Herein, we propose a simple and novel strategy to adjust the surface structure of few-layered MXene flakes by adding a small amount of Nb element. Because of the strong affinity between Nb and O elements, the as-received V1.8Nb0.2CTx and Ti2.7Nb0.3C2Tx MXenes have much fewer -F functional groups and a higher O content than V2CTx and Ti3C2Tx MXenes, respectively. Thus, both V1.8Nb0.2CTx and Ti2.7Nb0.3C2Tx MXenes show enhanced pseudocapacitance performance. Especially, V1.8Nb0.2CTx delivers an ultrahigh volumetric capacitance of 1698 F/cm3 at a scan rate of 2 mV/s. Moreover, benefiting from the high activity of MAX precursors obtained through a fast self-propagating high-temperature synthesis, the etching time to produce V-based MXenes is much shorter than that in previous reports. Therefore, the results presented here are applicable to the surface engineering and rational design of 2D MXene materials and develop them into promising, cost-effective electrode materials for supercapacitors or other energy-storage equipment.

Irisin Ameliorates Renal Tubulointerstitial Fibrosis by Regulating the Smad4/ß-Catenin Pathway in Diabetic Mice.

Background: The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. Methods: The purpose of this article is to examine irisin's function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-ß1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. Results: In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and ß-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/ß-catenin signaling pathway. Conclusion: The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/ß-catenin pathway.

Evaluation of the impacts of human activities on propagation from meteorological drought to hydrological drought in the Weihe River Basin, China.

Understanding the relationship among different types of drought is crucial for drought mitigation and early warnings. Much attention has been recently focused on the propagation from meteorological drought (MD) to hydrological drought (HD); however, the influences of human activities on drought propagation have rarely been explored. The novelty of the study was to propose an effective framework to quantify the impacts of human activities on MD-HD propagation. We adopted the framework to comprehensively evaluate the anthropic impacts on hydrological drought variations and time, thresholds, and probabilities of MD-HD propagation in the Weihe River Basin (WRB) during different periods. The results showed that human activities did significantly disturb HD variations and MD-HD propagation characteristics. Specifically, human activities increased the frequency and extremes of HD and weakened its correlation with MD. The MD-HD propagation characteristics showed spatiotemporal differences across three subbasins because of the different levels of human activities. The thresholds of MD triggering different levels of HD generally became larger with change rates from 1% to 143% and 3% to more than 189% during two periods, respectively. Meanwhile, we also found that the thresholds became distinctly smaller, which could only be observed in spring and winter. Moreover, the relationship between natural and human-induced probabilities of HD occurrence showed three patterns with the increase of MD severity. The quantitative results of this study can provide guide information on adaptation strategies to promote drought preparedness in the WRB. The proposed framework can be also applied in other regions to improve the understanding of hydrological drought mechanisms.

Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-ß1/Smad3 axis in diabetic kidney disease.

Sestrin2 is identified as a stress-induced protein and could functionate in many aspects. In our study, we investigated the latent impact of Sestrin2 on podocyte injury and its molecular mechanism in vivo and in vitro in diabetic kidney disease (DKD). Sestrin2 was low-expressed in renal biopsies from individuals with DKD, the glomeruli from diabetic mice, and mouse podocytes exposed to high glucose (HG). Sestrin2 overexpression ameliorated HG-induced phenotypic alterations, apoptosis, and oxidative stress in conditionally immortalized mouse podocytes and modulated the activity of Thrombospondin-1 (TSP-1)/transforming growth factor (TGF-ß1)/Smad3 pathway in podocytes. Moreover, TSP-1 inhibitor LSKL or TGF-ß blocker Pirfenidone arrested podocyte injury induced by HG. Streptozotocin (STZ) was employed to render equivalent diabetes in B6-TgN (CMV-Sestrin2) (TgN) and wild-type (WT) control mice. Sestrin2 alleviated increased levels of 24-h urinary protein, blood urea nitrogen, serum creatinine and triglyceride, and urine 8-OHdG in diabetic mice. Podocyte phenotypic alterations, increased expression of apoptosis-associated proteins and podocyte loss were observed in WT but not in diabetic TgN mice, as well as oxidative stress. Additionally, TSP-1/TGF-ß1/Smad3 signaling pathway was also suppressed in glomeruli of diabetic TgN mice. Thus, Sestrin2 mitigates podocyte injury in DKD via orchestrating TSP-1/TGF-ß1/Smad3 pathway, underlining Sestrin2 as a promising therapeutic target for DKD.

C1q/tumour necrosis factor-related protein-3 alleviates high-glucose-induced lipid accumulation and necroinflammation in renal tubular cells by activating the adenosine monophosphate-activated protein kinase pathway.

Lipid accumulation and progressive necroinflammation play pivotal roles in the development of diabetic nephropathy. C1q tumour necrosis factor-related protein-3 (CTRP3) is an adipokine with pleiotropic functions in cell proliferation, glucose and lipid metabolism, and inflammation. However, the mechanism and involvement of CTRP3 in lipid metabolism and the necroinflammation of renal tubular cells remain unclear. Here, we report that CTRP3 expression decreased in a time- and concentration-dependent manner in high glucose-stimulated HK-2 cells. We noted that the overexpression of CTRP3 or recombinant CTRP3 (rCTRP3) treatment prevented high glucose-induced lipid accumulation by inhibiting the expression of sterol regulatory element-binding protein-1 and increasing the expression of peroxisome proliferator-activated receptor-α and ATP-binding cassette A1. Moreover, the nucleotide-binding oligomerisation domain-like receptor protein 3-mediated inflammatory response and mixed lineage kinase domain-like protein-dependent necroinflammation were inhibited by CTRP3 overexpression or rCTRP3 treatment in HK-2 cells cultured in high glucose. Furthermore, lipotoxicity-induced by palmitic acid was found to be involved in necroinflammation in HK-2 cells, and CTRP3 displayed the same protective effect. CTRP3 also activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, whereas adenine 9-ß-D-arabinofuranoside, an AMPK inhibitor, replicated the protective effects of CTRP3. Besides, using kidney biopsies from patients with diabetes, we found that decreased CTRP3 expression was accompanied by increased lipid deposition, as well as the structural and functional injury of renal tubular cells. Our findings demonstrate that CTRP3 affects lipid metabolism and necroinflammation in renal tubular cells via the AMPK signalling pathway. Thus, CTRP3 may be a potential therapeutic target in diabetic renal injury.

Development and validation of a nomogram to better predict hypertension based on a 10-year retrospective cohort study in China.

Background: Hypertension is a highly prevalent disorder. A nomogram to estimate the risk of hypertension in Chinese individuals is not available. Methods: 6201 subjects were enrolled in the study and randomly divided into training set and validation set at a ratio of 2:1. The LASSO regression technique was used to select the optimal predictive features, and multivariate logistic regression to construct the nomograms. The performance of the nomograms was assessed and validated by AUC, C-index, calibration curves, DCA, clinical impact curves, NRI, and IDI. Results: The nomogram140/90 was developed with the parameters of family history of hypertension, age, SBP, DBP, BMI, MCHC, MPV, TBIL, and TG. AUCs of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. C-index of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. The nomogram130/80 was developed with the parameters of family history of hypertension, age, SBP, DBP, RDWSD, and TBIL. AUCs of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. C-index of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. Both nomograms demonstrated favorable clinical consistency. NRI and IDI showed that the nomogram140/90 exhibited superior performance than the nomogram130/80. Therefore, the web-based calculator of nomogram140/90 was built online. Conclusions: We have constructed a nomogram that can be effectively used in the preliminary and in-depth risk prediction of hypertension in a Chinese population based on a 10-year retrospective cohort study. Funding: This study was supported by the Hebei Science and Technology Department Program (no. H2018206110).

Intercalation and delamination of Ti2SnC with high lithium ion storage capacity.

Li-ion batteries attract great attention due to the rapidly increasing and urgent demand for high energy storage devices. MAX phase compounds, layered ternary transition metal carbides and/or nitrides show promise as candidate materials of electrodes for Li-ion batteries. However, the highest specific capacity reported up to now is relatively low (180 mA h g-1), preventing them from use in real applications. Exploring more MAX phase compounds with delaminated two-dimensional structure is an effective solution to increase the specific capacity. Herein, we report the reversible electrochemical intercalation of Li+ into Ti2SnC (MAX phase) nanosheets. Owing to the synergistic effects of intercalation and dimethyl sulfoxide (DMSO)-assisted exfoliation, Ti2SnC nanosheets are successfully obtained via sonication in DMSO. Moreover, when using as an anode of a Li-ion battery, Ti2SnC nanosheets exhibited an increasing specific capacity with cycling due to the exfoliation of Ti2SnC nanosheets via reversible Li-ion intercalation. After 1000 charge-discharge cycles, Ti2SnC nanosheets delivered a high specific capacity of 735 mA h g-1 at a current density of 50 mA g-1, which is far better than other MAX phases, such as Ti2SC, Ti3SiC2 and Nb2SnC. The current work demonstrates the Li-ion storage potential and indicates a novel strategy for further intercalation and delamination of MAX phases.

PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice.

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been reported in diabetic kidney, yet the potential role of NLRP3 inflammasome in DN is not well known. In this study, we explored the role of NLRP3 inflammasome on inflammation and fibrosis in diabetic kidney using NLRP3 knockout mice. Renal expression of NLRP3, caspase-1 p10, interleukin-18 (IL-18) and cleaved IL-1ß was increased in diabetic wild-type (WT) mice at 24 weeks. NLRP3 knockout (KO) improved renal function, attenuated glomerular hypertrophy, glomerulosclerosis, mesangial expansion, interstitial fibrosis, inflammation and expression of TGF-ß1 and connective tissue growth factor (CTGF), as well as the activation of Smad3 in kidneys of STZ-induced diabetic mice. In addition, NLRP3 KO inhibited expression of thioredoxin-interacting protein (TXNIP) and NADPH oxidase 4 (Nox4) and superoxide production in diabetic kidneys. The diabetes-induced increase in urinary level of 8-hydroxydeoxyguanosine (8-OHdG) was attenuated in NLRP3 KO mice. In vitro experiments, using HK-2 cells, revealed that high glucose (HG)-mediated expression of TXNIP and Nox4 was inhibited by transfection with NLRP3 shRNA plasmid or antioxidant tempol treatment. Silencing of the NLRP3 resulted in reduced generation of reactive oxygen species (ROS) in HK-2 cells under HG conditions. Furthermore, we also found exposure of IL-1ß to HK-2 cells induced ROS generation and expression of TXNIP and Nox4. Taken together, inhibition of NLRP3 inflammasome activation inhibits renal inflammation and fibrosis at least in part via suppression of oxidative stress in diabetic nephropathy.