Weijun Huang

Chronic inflammation contributes to the onset and progression of diabetic kidney disease (DKD), yet a model centered solely on soluble cytokines does not fully explain the cellular origin, spatially directed delivery, or sustained amplification of local signals. Extracellular vesicles (EVs) couple vesicular signaling with cytokine regulation through EV-associated cytokine or ligand signals and through RNA or protein cargo that reprograms cytokine production in recipient cells. This review examines how metabolic stress alters EV release and cargo composition, summarizes evidence for unidirectional and bidirectional communication between resident kidney cells and immune cells, and evaluates the EV specificity and evidential completeness of each donor–recipient axis. Evidence is strongest for communication between tubular epithelial cells and macrophages; findings involving podocytes, mesangial cells, and glomerular endothelial cells are largely unidirectional or inferred across studies. Under the in vitro polarization conditions used in the source studies, EVs from macrophages polarized toward a pro-inflammatory phenotype generally promote injury, whereas some EVs from macrophages polarized toward a reparative phenotype limit cell damage or improve autophagy. On this basis, we propose an EV-associated inflammatory communication network linked by shared inflammatory endpoints and inferred return signals. Within this network, we propose that injury-promoting and protective signals compete dynamically and thereby influence persistent inflammation and fibrosis-related disease progression. This hypothesis integrates existing evidence and offers a framework for understanding persistent inflammation in DKD and for testing therapies that target intercellular communication.

Background: Diabetic nephropathy (DN) is one of the common complications of diabetes, which is the leading cause of end-stage renal disease worldwide. Ginkgo biloba extract (GBE) has shown effectiveness in DN animal models and represents a promising therapeutic candidate. However, a comprehensive preclinical meta-analysis remains to be conducted, and the dose-time effect of GBE in the treatment of DN has not been evaluated. Objective: To evaluate the therapeutic effectiveness, mechanism and dose-time effect of GBE for DN by systematic review and meta-analysis. Methods: Seven databases (PubMed, Web of science, Embase, CBM, CNKI, Wanfang and VIP databases) were searched in this systematic review up to July 2025. Study quality was assessed using SYRCLE bias risk tool. STATA 14.0 software was employed to evaluate fasting blood glucose serum creatinine (SCr), blood urea nitrogen 24-h urine protein (24 h Upro), kidney index and indicators related to inflammatory response, oxidative stress, fibrosis, and glycolipid metabolism. The dose-time effect of Ginkgo biloba extract was evaluated by three-dimensional dose-time-effect analysis. Results: 30 pertinent articles were included in the meta-analysis. Comparative analysis revealed that GBE exhibited statistically significant effect in reducing FBG, SCr, BUN, 24 h Upro, and KI. Furthermore, it also improved inflammatory indicators such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as oxidative stress indicators like superoxide dismutase (SOD), malondialdehyde (MDA), antioxidation capability (AOC) and glutathione peroxidases (GSH-Px). Additionally, GBE showed positive effect in alleviating fibrosis and reducing serum total cholesterol (TC) and advanced glycation end products (AGEs). The dose-time-effect diagram showed that the rational dose of GBE for DN treatment was 36–200 mg/kg/d for 8–12 weeks. Conclusion: GBE may delay the progression of DN through multimodal mechanisms, including inhibition of inflammatory responses, attenuation of oxidative stress, suppression of fibrotic pathways, and modulation of glycolipid metabolism. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420250652386 .

Purpose: The objective of this study is to investigate the efficacy of the Shenlian (SL) decoction on regulating cellular pyroptosis and macrophage M1 polarization in the treatment of diabetic nephropathy (DN), and to elucidate its mechanism of action through the use of animal and cellular experiments. Methods: The potential targets for SL decoction were predicted using the TCMSP and Swiss Target databases. The differential genes for DN were obtained using the GeneCards database, and potential mechanisms for the treatment of DN with SL decoction were explored through enrichment analysis. The efficacy of SL decoction in the treatment of DN and its regulation of macrophage polarization and pyroptosis were evaluated in vivo using db/db mice. The RAW264.7 cell line and the TCMK‐1 cell line were cultured in vitro. The objective was to investigate the effect of SL decoction on the inhibition of M1 macrophage polarization and scorched death of renal tubular epithelial cells (TECs). Results: The results of the enrichment analysis indicated that the Toll‐like signaling pathway was a principal pathway in the treatment of DN with SL decoction. The results of animal and cellular experiments demonstrated that SL decoction has the potential to enhance renal function in patients with DN, while simultaneously reducing the concentration of serum inflammatory factors. Additionally, it was observed that SL decoction could inhibit the infiltration of macrophages and the polarization of macrophages into the M1 phenotype. Furthermore, the activation of the TLR4 signaling pathway and the pyroptosis of renal tubular cells were also inhibited by SL decoction. Conclusion: This study employed network pharmacology and in vivo and in vitro experiments to confirm that SL decoction can improve renal function in patients with DN. The results demonstrated that the mechanism of action of SL decoction is related to regulating the M1 polarization of macrophages in the DN kidney and inhibiting the pyroptosis of renal TECs.

Background: Diabetic nephropathy is a leading complication of diabetes mellitus and poses a significant public health challenge. Ferroptosis has emerged as a critical pathological factor that exacerbates the progression of diabetic nephropathy. While previous studies have demonstrated the antiferroptotic effects of curcumol (Cur), its therapeutic potential in treating diabetic nephropathy, along with the underlying mechanisms, remains to be fully elucidated. Methods: To investigate this, we established a high glucose‐induced MPC‐5 cell injury model. Initially, we identified the safe concentration range of curcumol. Using Western blot (WB) analysis and transcriptomic profiling, we assessed target proteins and regulatory pathways, and systematically measured ferroptosis‐related biomarkers. To further explore Cur′s effect on ferroptosis, we cotreated the in vitro model with the ferroptosis inhibitor Fer‐1 and activator RLS3, analyzing the key pathways involved using WB and transcriptomic approaches. Additionally, we established a diabetic kidney disease (DKD) mouse model to assess the effects of Cur on renal function indicators, including serum creatinine, urea nitrogen, and 24‐h urinary protein levels. Renal pathological changes and molecular markers were evaluated, and the core pathway mechanisms were validated by WB analysis. Results: In in vitro experiments, Cur reduced iron deposition and total iron content by downregulating TRF and NCOA4. It also inhibited ACSL4‐mediated lipid peroxidation, resulting in lower levels of ROS, MDA, and 4‐HNE. Additionally, Cur upregulated the expression of SLC3A2, SLC7A11, and GPX4, thereby restoring the GSH‐GPX4 antioxidant system. In vivo, Cur improved renal function and alleviated renal injury in DKD mice through the xCT/GPX4 signaling pathway. These findings suggest that Cur mitigates ferroptosis via the xCT/GPX4 pathway, ultimately slowing the progression of diabetic kidney disease. Conclusion: Our in vitro and in vivo experiments demonstrate that Cur has therapeutic potential for DKD. Mechanistically, Cur protects against podocyte ferroptosis by modulating the xCT/GPX4 pathway.

Background: Shenlian (SL) decoction, a renowned traditional Chinese formula for diabetes mellitus, has also been employed to treat intestinal disorders. Previous studies have demonstrated the efficacy of SL decoction in regulating blood glucose and intestinal bacteria. Nevertheless, further analysis is required to elucidate the mechanistic link between SL decoction–mediated improvement of intestinal function and treatment of Type 2 diabetes mellitus (T2DM). Methods: Firstly, the active ingredients of SL decoction were sourced from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, with putative targets of active ingredients being predicted using the same database. Secondly, the Online Mendelian Inheritance in Man (OMIM) and GeneCards databases were employed to screen the aforementioned targets that act on T2DM, and protein–protein interaction (PPI) networks were constructed in accordance with the results. Thirdly, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), which resulted in a comprehensive analysis of the association between SL decoction for the treatment of T2DM and the modulation of intestinal functions. Finally, the effect of the SL decoction on predicted lipopolysaccharide (LPS)‐related targets, as well as intestinal function markers, was validated through in vivo experimentation. Results: A total of 36 active ingredients and 145 potential targets of SL decoction were predicted. GO enrichment analysis indicated that the principal biological processes by which the SL decoction acted against T2DM were responses to LPSs, while KEGG enrichment analysis identified the nuclear factor kappa B (NF‐ κ B) signaling pathway and toll‐like receptor signaling pathway as the key pathways involved. The in vivo experiments showed that SL decoction improved glycolipid metabolism indexes, inflammatory factor levels, and LPS levels in db/db mice. The immunohistochemical results demonstrated that the SL decoction restored the expression of Occludin, Claudin‐1, and ZO‐1 in the intestine and inhibited the expression of toll‐like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MYD88), and NF‐ κ B in both the intestine and pancreas. Furthermore, it may influence the levels of short‐chain fatty acids (SCFAs) in feces. Conclusions: This research investigated the multigene pharmacological mechanism of SL decoction against T2DM using network pharmacology and in vivo experiments. SL decoction treatment of T2DM may reverse inflammation by inhibiting LPS‐related pathway activation and improving intestinal function.

Background: Diabetic kidney disease (DKD) is a major global cause of end‐stage renal disease. Emerging evidence suggests that hypoxia is a critical factor in the advancement of DKD. Traditional Chinese medicine (TCM) is an effective alternative therapy for DKD. The Qi‐Gui‐Sheng‐Jiang‐San (QGSJS) decoction is an effective formula for treating DKD clinically, and its mechanism may be related to regulating hypoxia response, necessitating further investigation and a thorough analysis of the underlying biological mechanisms. Methods: Initially, we employed network pharmacology methods to collect and screen the active constituents of the QGSJS decoction from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and relevant chemical databases. Subsequently, the targets of these active components were predicted via the PubChem and TCMSP databases, while relevant targets associated with DKD were sourced from GeneCards, OMIM, and DrugBank. In the second phase, we built a protein–protein interaction (PPI) network via the STRING database to identify core targets. This was followed by GO and KEGG enrichment analyses to assess if the QGSJS decoction′s mechanisms of action are linked to hypoxic response regulation. Finally, in vivo experiments were performed to confirm the findings from the network pharmacology analysis and to comprehensively elucidate the QGSJS decoction′s mechanisms of action. Results: The network pharmacology analysis revealed 57 active components in the QGSJS decoction, capable of influencing 72 targets associated with DKD. Quercetin, kaempferol, and isorhamnetin are likely to be the key constituents of the QGSJS decoction. The PPI network suggests that HIF1A serves as a hub gene, closely associated with IL6, NFKBIA, and VEGFA. Enrichment analysis indicates that the QGSJS decoction modulates the HIF‐1 signaling pathway and impacts biological processes and molecular functions linked to HIF‐1 α . In vivo studies demonstrate the QGSJS decoction′s renal protective properties, suppressing the expression of HIF‐1 α , p‐STAT3, p‐Akt, VEGF, VEGFR, p‐NF‐ κ B, and NOTCH1 in the kidneys without affecting PHD2. Conclusion: The QGSJS decoction primarily inhibits HIF‐1 α through non–oxygen‐dependent pathways, mitigating damage related to abnormal hypoxic responses, which may be the main mechanism through which it protects the kidneys.

Background: Diabetic kidney disease is a significant complication of diabetes. Previous studies have confirmed that Qufeng Tongluo (QFTL) decoction can alleviate podocyte injury in a diabetic rat model, but its mechanism remains unclear. The present in vitro study investigated QFTL’s mechanism in protecting podocytes. Methods: The mouse podocyte clone 5 (MPC-5) cell line stimulated by high glucose and hydrogen peroxide was used as a model for podocyte injury. The cells were treated with QFTL, QFTL + SC79 (activator of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and C2 ceramide (inhibitor of the PI3K/Akt). Immunofluorescence, western blot and polymerase chain reaction (PCR) were employed to detect the expression of microtubule-associated protein 1 light chain 3 (LC3), sequestosome 1 (SQSTM1/p62), PI3K, Akt, and phosphatase and tensin homolog (PTEN) proteins and their messenger RNA (mRNA) levels. Results: High glucose and hydrogen peroxide stimulation may disrupt podocytes’ cytoskeletal structure, while QFTL may mitigate these structural changes. After the SC79 intervention, QFTL’s alleviation of the cytoskeletal structure damage disappeared. High glucose and hydrogen peroxide stimulation decreased the expression of LC3 in MPC-5 cells, whereas QFTL upregulated its expression, but this effect was reversed by the SC79 intervention. Interestingly, P62 decreased after high glucose + hydrogen peroxide stimulation, and QFTL failed to upregulate P62. The expression levels of PI3K, Akt, and PTEN in the model group decreased, which were improved by QFTL. Conclusion: These results suggest that QFTL can maintain the stability of autophagic flux in injured podocytes, which may be related to its ability to improve P62 expression but not to regulating the PI3K/Akt signaling pathway.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM). Radix Astragali (RA), a frequently used Chinese herbal medicine in the Leguminosae family, Astragalus genus, with its extracts, has been proven to be effective in DN treatment both in clinical practice and experimental studies. RA and its extracts can reduce proteinuria and improve renal function. They can improve histopathology changes including thickening of the glomerular basement membrane, mesangial cell proliferation, and injury of endothelial cells, podocytes, and renal tubule cells. The mechanisms mainly benefited from antioxidative stress which involves Nrf2/ARE signaling and the PPARγ‐Klotho‐FoxO1 axis; antiendoplasmic reticulum stress which involves PERK‐ATF4‐CHOP, PERK/eIF2α, and IRE1/XBP1 pathways; regulating autophagy which involves SIRT1/NF‐κB signaling and AMPK signaling; anti‐inflammation which involves IL33/ST2 and NF‐κB signaling; and antifibrosis which involves TGF‐β1/Smads, MAPK (ERK), p38/MAPK, JNK/MAPK, Wnt/β‐catenin, and PI3K/AKT/mTOR signaling pathways. This review focuses on the clinical efficacy and the pharmacological mechanism of RA and its representative extracts on DN, and we further document the traditional uses of RA and probe into the TCM theoretical basis for its application in DN.