Septic acute kidney injury (AKI) is a frequent and serious complication of sepsis in critically ill patients associated with high morbidity and mortality. However, the treatment of septic AKI has still been beyond satisfaction. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and is proposed as a potential agent for treating cancer and inflammatory diseases. In the present study, we aimed to investigate the effect of DHA on lipopolysaccharide (LPS)-induced AKI and the underlying mechanism. Male C57BL/6 mice were pretreated with or without DHA (20 mg/kg/d) for two days, and then were treated with one dose LPS (10 mg/kg) intraperitoneal injection to induce septic AKI. Twenty-four hours after LPS injection, blood samples and kidneys were collected for evaluation. The results indicated that DHA significantly ameliorated LPS-induced AKI as evidenced by improvement of renal function (serum creatinine and blood urea nitrogen), amelioration of renal pathological injury, and inhibition of tubular cell apoptosis. Meanwhile, DHA also strikingly attenuated inflammatory response, suppressed NF-κB signaling pathway activation, and inhibited oxidative stress in LPS-challenged mice. In conclusion, DHA could protect against LPS-induced AKI possibly by anti-inflammatory and antioxidant activities.

Background: Acute kidney injury (AKI) is a common clinical condition resulting in a rapid decline in renal function, and requires improvement in effective preventive measures. Ferroptosis, a novel form of cell death, is closely related to AKI. Shenshuaifu granule (SSF) has been demonstrated to prevent AKI through suppressing inflammation and apoptosis. Objective: This study aimed to explore whether SSF can inhibit ferroptosis in AKI. Methods: Active ingredients in SSF were detected through HPLC-MS/MS, and their binding abilities with ferroptosis were evaluated by molecular docking. Then, male C57/BL/6J mice were randomly divided into control, cisplatin, and cisplatin+SSF groups. In the latter two groups, mice were intraperitoneally injected with 20 mg/kg of cisplatin. For five consecutive days prior to cisplatin injection, mice in the cisplatin+SSF group were gavaged with 5.2 g/kg of SSF per day. 72 h after cisplatin injection, the mice were sacrificed. Serum creatinine (SCr) and blood urea nitrogen (BUN) were measured to evaluate renal function. H&E and PAS staining were used to observe pathological damage of kidney. Cell death was observed by TUNEL staining, and iron accumulation in kidneys of mice was detected by Prussian blue staining. Western blotting, immunohistochemistry, and immunofluorescence were used to investigate the presence of inflammation, oxidative stress, mitochondrial dysfunction, iron deposition, and lipid peroxidation in mouse kidneys. Results: Active ingredients in SSF had strong affinities with ferroptosis. SSF reduced SCr (p< 0.01) and BUN (p< 0.0001) levels, pathological damage (p< 0.0001), dead cells in the tubular epithelium (p< 0.0001) and iron deposition (p< 0.01) in mice with cisplatin induced AKI. And SSF downregulated macrophage infiltration (p< 0.01), the expressions of high mobility group box 1 (HMGB1, p< 0.05) and interleukin (IL)-17 (p< 0.05), upregulated superoxide dismutase (SOD) 1 and 2 (p< 0.01), and catalase (CAT, p< 0.05), and alleviated mitochondrial dysfunction (p< 0.05). More importantly, SSF regulated iron transport and intracellular iron overload and reduced the expression of ferritin (p< 0.05). Moreover, it downregulated the expressions of cyclo-oxygenase-2 (Cox-2, p< 0.001), acid CoA ligase 4 (ACSL4, p< 0.05), and solute carrier family 7, member 11 (SLC7A11, p< 001), upregulated glutathione peroxidase 4 (GPX4, p< 0.01) and p53 (p< 0.01), and decreased 4-hydroxynonenal (4-HNE) level (p< 0.001). Conclusion: SSF attenuates AKI by inhibiting ferroptosis mediated by p53/SLC7A11/GPX4 pathway.

Chronic kidney disease (CKD) is a significant global public health issue. However, the burden of CKD by etiology and trends over time remains inadequately studied. Data from the Global Burden of Disease Study 2021 (GBD 2021) were analyzed, including cases by region, etiology, age, and sex. Metrics included age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), age-standardized prevalence rate (ASPR), disability-adjusted life years (DALYs), and age-standardized DALYs rate (ASDR) between 1990 and 2021. The Joinpoint regression analysis was used to calculate the average annual percentage change (AAPC), and age-period-cohort (APC) analysis was performed to assess trends. In 2021, CKD posed a substantial global burden, with 673,722,703 cases and 19,935,038 new cases. The incidence rate was 233.6 with an AAPC of 0.634. CKD caused 1,527,639 deaths, corresponding to a mortality rate of 18.5 and an AAPC of 0.745. DALYs associated with CKD totaled 44,453,684, with an AAPC of 0.322. CKD burden was primarily attributed to diabetes mellitus type 2 (DMT2), hypertension, and unspecified causes, affecting individuals aged 50 years and older. ASIR and ASPR were higher among females, while males had higher ASMR and ASDR. At regional and national levels, the incidence of CKD was positively correlated with the socio-demographic index (SDI), while mortality, DALYs, and prevalence negatively correlated with SDI. APC analysis revealed an elevated mortality risk (Net Drift = 0.3), increasing with age and over successive periods. Birth cohort analysis indicated higher mortality risks among individuals born after 1992. The global burden of CKD continued to rise due to aging populations, increasing risk factors, and improved detection. While some regions showed success in reducing CKD mortality, widening disparities demanded urgent attention. Early-stage disease and modifiable risks offered prevention opportunities, but realizing this required sustained healthcare investment, especially in resource-limited settings. Therefore, coordinated efforts addressing both risk factors and disease management would be essential to reduce its growing burden.

To investigate whether dihydroartemisinin (DHA) attenuates ischaemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) in mice by inhibiting oxidative stress and inflammation and to explore its potential molecular mechanisms. Network pharmacology analysis was used to screen relevant targets, and molecular docking of DHA with core targets was performed. Molecular dynamics simulation of the target with the lowest binding free energy, NQO1-DHA.The renal protective effect of DHA on the IRI-induced AKI mouse model was evaluated. The expression levels of NQO1, Nrf2 and other proteins were detected by Western blotting. The expression levels of Nrf2 and others were detected by immunohistochemistry (IHC) and immunofluorescence (IF). Through network pharmacological analysis, we obtained that PI3K/AKT and MAPK signaling pathway may be related to DHA in the treatment of AKI.Molecular dynamics simulation indicated that NQO1 is an important target protein for DHA to exert nephroprotective effects.Moreover, the potential molecular mechanisms were verified by experiments.DHA reduced the serum creatinine (Scr) and urea nitrogen (BUN) levels in AKI mice, significantly improved AKI pathology, alleviated oxidative stress and inflammatory injury, which may be related to its activation of the Nrf2 pathway and regulation of macrophage polarization. Through network pharmacology, molecular dynamics simulation and experimental validation, we initially investigated that DHA alleviate AKI by ameliorating oxidative stress and inflammatory damage, which may be related to its activation of the Nrf2 pathway and the regulation of macrophage polarisation, which lays the foundation for subsequent in-depth study of the specific mechanism of action.

Shenshuaifu Granule (SSF) is an in-hospital preparation approved by the Guangdong Food and Drug Administration of China. It has been clinically used against kidney diseases for more than 20 years with a definite curative effect. Cisplatin (CDDP) is a first-line chemotherapeutic drug in clinical practice, primarily excreted by the kidney with nephrotoxicity as a common side effect. Approximately 5-20% of cancer patients develop acute kidney injury (AKI) after chemotherapy; however, prevention and control strategies are currently unavailable. Therefore, it is important to identify safe and effective drugs that can prevent the nephrotoxicity of CDDP. SSF is an herbal formulation with 8 herbs, and has been used to protect the kidney in China. Nonetheless, its mechanism in relieving CDDP nephrotoxicity remains unclear. Therefore, this work attempt to prove that SSF can alleviate CDDP nephrotoxicity. We also explore its mechanism. First, Thin Layer Chromatography (TLC) of a few herbs in SSF were performed for quality control. Several open-access databases were used to identify the active ingredients of SSF, their corresponding targets, and CDDP-induced nephrotoxicity targets. We performed Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Next, the results of network pharmacology were validated using CDDP-induced nephrotoxicity mouse models. Renal function in the mice was assessed by analyzing the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). On the other hand, renal damage was assessed by determining the level of tubular injury and apoptotic cells using Periodic acid-Schiff (PAS) staining and Terminal Dutp Nick End-Labeling (TUNEL) staining, respectively. The expression of inflammatory and apoptotic-related targets including IL-1β, IL-6, TNF-α, Cox-2, Bax, Bcl-2, Cleaved-caspase 3, and Cleaved-caspase 9 was determined using Western Blot (WB) and Immunohistochemistry (IHC). Furthermore, WB was used to analyze the expression of proteins associated with the TLR4/MyD88/NF-κB pathway in the kidneys of mice with CDDP-induced nephrotoxicity. Finally, molecular docking simulations were performed to evaluate the binding abilities between major active ingredients of SSF and core targets. Through network pharmacology, we identified 127 active ingredients of SSF and their corresponding 134 targets. Additional screening identified 14 active ingredients and 17 targets for further analysis. In biological process (BP), the targets were enriched in inflammation and apoptosis, among others. In KEGG terms, they were enriched in apoptosis and NF-κB pathways. Animal experiments revealed that SSF significantly reduced the levels of Scr and BUN and prevented renal tubular damage in mice treated with CDDP. In addition, SSF inhibited inflammation and apoptosis by targeting the TLR4/MyD88/NF-κB pathway. Molecular docking revealed good binding capacities of active ingredients and core targets. In summary, the experimental findings were consistent with the network pharmacological predictions. SSF can inhibit inflammation and apoptosis by targeting the TLR4/MyD88/NF-κB pathway. Taken together, our data suggest that SSF is an alternative agent for the treatment of CDDP-induced nephrotoxicity.

Background: Cisplatin is an effective anti-tumor drug. However, its usage is constrained by side effects such as nephron toxicity. Cisplatin-induced acute kidney injury (AKI) appears in approximately 20%–30% of cases. Hence, finding an effective protective strategy is necessary. San-Huang decoction (SHD) is a Chinese herbal decoction with good efficacy in treating chronic kidney disease (CKD). Nevertheless, the mechanism of SHD on AKI remains unclear. Consequently, we proposed to explore the potential mechanism of SHD against cisplatin-induced AKI.Methods: Active compounds, core target proteins, and associated signaling pathways of SHD were predicted through network pharmacology. Then confirmed by molecular docking. In vivo experiment, Cisplatin + SHD group was treated with SHD (6.5 g/kg/day) for 6 days before building the model. An AKI model was established with a single intraperitoneal injection of cisplatin at 20 mg/kg. After 72 h of cisplatin injection, all mice were sacrificed to collect blood and kidney tissues for verification of network pharmacology analysis.Results: We found that calycosin, rhein, and ginsenoside Rh2 may be SHD’s primary active compounds in treating cisplatin-induced AKI, and AKT, TNF-α, IL-6, IL-1β, caspase-3, and MMP9 are the core target proteins. The relationship between the compound and target protein was further confirmed by molecular docking. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses predicted that SHD has an anti-inflammatory role through the TNF and IL-17 signaling pathway. Moreover, Western blot and immunohistochemistry validated the potential molecular mechanisms of SHD, predicted from network pharmacology analysis. The mechanism of cisplatin-induced AKI involves apoptosis and inflammation. In apoptosis, Caspase-3, caspase-8, caspase-9, and Bax proteins were down-regulated, while Bcl-2 was up-regulated by SHD. The differential expression of MMP protein is involved in the pathological process of AKI. MMP9 protects from glomerular tubule damage. MMP9 and PI3K/AKT anti-apoptosis pathway were up-regulated by SHD. In addition, we discovered that SHD alleviated AKI by inhibiting the NF-κB signaling pathway.Conclusion: SHD plays a critical role in anti-inflammation and anti-apoptosis via inhibiting the NF-κB signaling pathway and activating PI3K/AKT anti-apoptosis pathway, indicating that SHD is a candidate herbal drug for further investigation in treating cisplatin-induced AKI.