Xiao-Cong Zuo

Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of AKI, but there are no effective preventive or therapeutic measures in clinical practice. Glycyrrhizin, a bioactive compound isolated from the Glycyrrhiza glabra L., exhibits anti-inflammatory effects; however, the effects and mechanisms of glycyrrhizin on CI-AKI remain unknown. In present study, the effects of glycyrrhizin on renal dysfunction and tissue damage were evaluated in CI-AKI rats and mice. And the mechanisms were further investigated in iohexol treated renal tubular epithelial cells. Molecular docking and network pharmacology were used to discover the binding targets of glycyrrhizin and identify potential pathogenic pathway. Gene knockout mice and gene silencing cells were used to detect whether glycyrrhizin alleviated CI-AKI through target proteins mediated pathway. Results showed that both pretreatment and co-treatment with glycyrrhizin could alleviate iohexol-induced renal dysfunction and pathological damage in vivo. Similarly, glycyrrhizin could improve iohexol-induced decrease in cell viability of both HK-2 cells and primary mice renal tubular epithelial cells. Mechanistically, glycyrrhizin could directly bind to the active site of HMGB1, then blocking iohexol-induced ferroptosis of renal tubular epithelial cells. HMGB1 silencing was able to inhibit overactivation of AMPK/Beclin-1 axis during CI-AKI, and iohexol-downregulated protein expressions of GPX4 and SLC7A11 were reversed in kidneys of AMPK knockout mice. Comparable results were obtained in vitro with AICAR treatment. Our study is the first to demonstrate that glycyrrhizin exerts both protective and therapeutic effect on CI-AKI by inhibiting tubular epithelial cell ferroptosis via HMGB1/AMPK/Beclin-1 axis, providing a potential choice for treating CI-AKI.

The mitochondrial enzyme arginase‐2 (Arg‐2) is implicated in the pathophysiology of contrast‐induced acute kidney injury (CI‐AKI). Therefore, Arg‐2 represents a candid target for CI‐AKI prevention. Here, layer‐by‐layer (LbL) assembled renal‐targeting polymeric nanoparticles are developed to efficiently deliver small interfering RNA (siRNA), knockdown Arg‐2 expression in renal tubules, and prevention of CI‐AKI is evaluated. First, near‐infrared dye‐loaded poly(lactic‐co‐glycolic acid) (PLGA) anionic cores are electrostatically coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg‐2 siRNA. Next, nanoparticles are coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential electrostatic layering of CS and HA improves loading capacity of Arg‐2 siRNA and yields LbL‐assembled nanoparticles. Renal targeting and accumulation is enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA‐KTP). The resultant kidney‐targeting and siRNA loaded nanoparticles (PLGA/CS/HA‐KTP siRNA) exhibit proprietary accumulation in kidneys and proximal tubular cells at 24 h post‐tail vein injection. In iohexol‐induced in vitro and in vivo CI‐AKI models, PLGA/CS/HA‐KTP siRNA delivery alleviates oxidative and nitrification stress, and rescues mitochondrial dysfunction while reducing apoptosis, thereby demonstrating a robust and satisfactory therapeutic effect. Thus, PLGA/CS/HA‐KTP siRNA nanoparticles offer a promising candidate therapy to protect against CI‐AKI.

Background: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited.Methods: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN.Results: Our analysis identified 88 co-DEGs through the “limma” and “WGCNA” R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model.Conclusion: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.

Background: Overweight and obesity are well-known risk factors for developing type 2 diabetes (T2DM). However, details on the evolution of the T2DM burden attributed to China’s high body mass index (BMI) in China have not been thoroughly studied. This study aimed to investigate the temporal trends of the T2DM burden attributable to a high BMI in China from 1990 to 2019 and to evaluate the independent effects of age, period, and cohort on the burden of T2DM attributed to a high BMI.Methods: Data on T2DM burden attributable to a high BMI from 1990 to 2019 were obtained from the Global Burden of Disease Study 2019. Deaths, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) of T2DM attributable to a high BMI were estimated by age and sex. The joinpoint regression model was performed to calculate the annual percentage change (APC) and the average annual percentage change (AAPC) in the burden of T2DM attributed to a high BMI. The age–period–cohort analysis was applied to estimate the independent effects of age, period, and cohort on the temporal trends of mortality and the DALY rate.Results: In 2019, deaths and DALYs from T2DM attributable to a high BMI in China were 47.53 thousand and 3.74 million, respectively, five times higher than in 1990. Among those under 60 years of age, men had higher deaths and DALYs than women, while the gender differences reversed in those over 60 years of age. Furthermore, the ASMR and ASDR in 2019 were 2.39 per 100,000 (95%UI 1.12–3.90) and 181.54 per 100,000 (95%UI 93.71–286.33), respectively, representing a 91% and 126% increase since 1990. In China, women previously had a higher ASMR and ASDR than men, while the differences in the ASMR and ASDR between the sexes were reversed in recent years. From 1990 to 2019, the ASMR in women increased before 2004 and then decreased from 2004 to 2015, and increased again after, with an overall AAPC value of 1.6%. In contrast, the ASMR in men continued to increase, with an overall AAPC value of 3.2%. The ASDR continued to increase in men and women, with AAPCs of 2.2% and 3.5%, respectively. The age effect showed that the relative risk of mortality increased with age in both men and women, except for the 75–84 age group. The impact of the age on the DALY rate revealed a trend of first rising and then decreasing, peaking at 65–69 years. The effect of the period on the burden of T2DM attributable to a high BMI increased from 1990 to 2019. The cohort effect generally showed a downward trend.Conclusion: The burden of T2DM attributed to a high BMI in China increased substantially from 1990 to 2019, particularly in men. Therefore, there is an urgent need for gender- and age-based public health guidelines on prevention strategies, early diagnosis, and effective management of T2DM, overweight, and obesity in China.

Background: Drug-induced acute kidney damage (DI-AKI) is a clinical phenomenon of rapid loss of kidney function over a brief period of time as a consequence of the using of medicines. The lack of a specialized treatment and the instability of traditional kidney injury markers to detect DI-AKI frequently result in the development of chronic kidney disease. Thus, it is crucial to continue screening for DI-AKI hub genes and specific biomarkers.Methods: Differentially expressed genes (DEGs) of group iohexol, cisplatin, and vancomycin’s were analyzed using Limma package, and the intersection was calculated. DEGs were then put into String database to create a network of protein-protein interactions (PPI). Ten algorithms are used in the Cytohubba plugin to find the common hub genes. Three DI-AKI models’ hub gene expression was verified in vivo and in vitro using PCR and western blot. To investigate the hub gene’s potential as a biomarker, protein levels of mouse serum and urine were measured by ELISA kits. The UUO, IRI and aristolochic acid I-induced nephrotoxicity (AAN) datasets in the GEO database were utilized for external data verification by WGCNA and Limma package. Finally, the Elisa kit was used to identify DI-AKI patient samples.Results: 95 up-regulated common DEGs and 32 down-regulated common DEGs were obtained using Limma package. A PPI network with 84 nodes and 24 edges was built with confidence >0.4. Four hub genes were obtained by Algorithms of Cytohubba plugin, including TLR4, AOC3, IRF4 and TNFAIP6. Then, we discovered that the protein and mRNA levels of four hub genes were significantly changed in the DI-AKI model in vivo and in vitro. External data validation revealed that only the AAN model, which also belonged to DI-AKI model, had significant difference in these hub genes, whereas IRI and UUO did not. Finally, we found that plasma TLR4 levels were higher in patients with DI-AKI, especially in vancomycin-induced AKI.Conclusion: The immune system and inflammation are key factors in DI-AKI. We discovered the immunological and inflammatory-related genes TLR4, AOC3, IRF4, and TNFAIP6, which may be promising specific biomarkers and essential hub genes for the prevention and identification of DI-AKI.

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

Contrast‐induced nephropathy (CIN) is an acute kidney injury (AKI) observed after the administration of contrast media. Calcium channel blockers (CCBs) have been reported to exert a renal protective effect. This study aims to investigate the role of cilnidipine, a novel CCBs, on CIN by regulating the calcium/calmodulin‐dependent protein kinase Ⅱ(CaMKⅡ)/mitochondrial permeability transition pore (mPTP) pathway. Here, iohexol, a representative contrast media, was used to establish CIN model. KN‐93 (CaMKⅡ inhibitor) and atractyloside (mPTP opener) were administered in rats, and CaMKⅡ overexpression was used in Human proximal tubular epithelial cells. Markers of renal injury (serum creatinine, blood urea nitrogen, and urinary NAGL), hematoxylin‐eosin stain, oxidative stress (ROS, superoxide dismutase [SOD], and malondialdehyde [MDA] levels), cell death (MTT and terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labeling [TUNEL]), mitochondrial function (mPTP, mitochondrial membrane potential [MMP], and ATP) were assessed. Western blots were used to measure the expression levels of Bax/Bcl‐2, caspase‐3, CaMKⅡ/mPTP signaling pathways. Results showed that cilnidipine markedly improved kidney function, and alleviated tubular cell apoptosis, oxidative stress and mitochondrial damage induced by iohexol in vitro and in vivo. The underlying mechanism may be that cilnidipine relieved CaMKⅡ activation and mPTP opening induced by iohexol. All of these protective effects of cilnidipine were attenuated by CaMKⅡ overexpression and atractyloside (mPTP opener) pretreatment. Moreover, KN‐93 (CaMKⅡ inhibitor) treatment showed a similar renal protective effect with cilnidipine, while the protective effect of cilnidipine on kidney in CIN rats was not further suppressed by KN‐93 cotreatment. These in vitro and in vivo results point toward the fact that cilnidipine might be a novel therapeutic drug against contrast‐induced nephrotoxicity in a CaMKⅡ‐dependent manner.