Fenfen Peng

Background: Anisomeles indica (Lamiaceae) is a traditional medicinal plant widely used in the treatment of inflammatory and systemic disorders. Increasing evidence suggests that it represents a rich source of bioactive natural products with broad pharmacological potential. Aims: This review aims to systematically summarize the phytochemistry, pharmacological activities, safety profiles, and recent advances in drug discovery of Anisomeles indica , with a particular focus on its major diterpenoid constituent, ovatodiolide (OVA). Materials and Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Web of Science, Scopus, and CNKI, covering studies related to ethnopharmacology, phytochemistry, pharmacology, toxicology, and pharmacokinetics of Anisomeles indica and its constituents. Results: Phytochemical studies have identified diverse constituents, particularly macrocyclic diterpenoids such as OVA, which exhibit extensive biological activities including anti‐inflammatory, anti‐cancer, antiviral, antibacterial, antioxidant, and immunomodulatory effects. Mechanistically, these effects involve key signaling pathways such as NF‐κB, STAT3, PI3K/Akt/mTOR, β‐catenin, and TGF‐β signaling. Despite promising bioactivities, OVA is limited by rapid clearance and poor oral bioavailability. To overcome these limitations, medicinal chemistry efforts have led to the development of optimized derivatives, such as NMP‐diepoxyovatodiolide and ACT004, which demonstrate improved pharmacokinetics, enhanced safety, and robust efficacy in preclinical models. Discussion: The pharmacological diversity of Anisomeles indica arises from its complex chemical composition and multi‐target mechanisms. However, challenges remain, including variability in extract composition, insufficient clinical validation, and suboptimal pharmacokinetic properties of key compounds. Conclusion: Anisomeles indica represents a promising source of multifunctional therapeutic agents. Continued efforts in standardization, mechanistic validation, and clinical translation, together with the development of pharmacokinetically optimized derivatives, are essential to fully realize its potential as a platform for next‐generation drug discovery.

Key Points: Upregulation and colocalization of EGF receptor and SOX9 were exhibited in injured renal proximal tubule epithelial cells (RPTCs). Genetic or pharmacologic inhibition of EGF receptor activation in mice blocked SOX9 upregulation in the ischemic injured RPTCs. Inhibition of yes-associated protein/transcriptional coactivator with PDZ-binding motif–transcriptional enhanced associate domain in mice or cultured RPTCs blocked SOX9 upregulation in response to ischemic AKI or EGF treatment. Background: In surviving renal proximal tubule cells (RPTCs) after AKI, the induction of SOX9 expression plays a crucial role in promoting kidney repair. However, persistent upregulation of SOX9 in RPTCs contributes to the development of CKD. The molecular mechanisms underlying SOX9 induction in response to kidney injury are not completely understood. We and others have previously reported that the activation of EGF receptor (EGFR) in RPTCs can accelerate kidney recovery from ischemic injury, but persistent EGFR activation leads to tubulointerstitial fibrosis. Methods: We examined SOX9 and EGFR expression in renal tubular epithelial cells of patients with acute tubular injury or early stages of chronic allograft nephropathy. We investigated the role of EGFR activation in regulating SOX9 upregulation in injured RPTCs using different mouse models. We further confirmed the underlying mechanism by which EGFR activation upregulates SOX9 expression in cultured human RPTCs. Results: Elevation and colocalization of SOX9 and EGFR expression were detected in renal tubular epithelial cells of patients with acute tubular injury or early stages of chronic allograft nephropathy. Overexpression of human heparin-binding EGF in RPTC of mice led to increased SOX9 expression, which was abolished when these mice were crossed with EGFR tyrosine kinase–deficient waved2 mice. Genetic or pharmacologic inhibition of EGFR resulted in decreased SOX9 expression in renal tubular cells in response to ischemic AKI. Mechanistically, ischemic AKI activates proximal tubule EGFR, leading to the activation of Akt–yes-associated protein/transcriptional coactivator with PDZ-binding motif–transcriptional enhanced associate domain pathway and the subsequent induction of SOX9. Conclusions: EGFR activation is crucial for SOX9 expression in RPTCs after AKI.

Salidroside (2- (4-Hydroxyphenyl) ethyl β-D-glucopyranoside, SAL) is a bioactive compound present in Rhodiola rosea L., exhibiting diverse pharmacological properties such as anti-inflammatory and anti-fibrotic effects. Despite its known benefits, the therapeutic potential of SAL in peritoneal dialysis (PD) -induced peritoneal fibrosis remains unexplored. This study aims to investigate the protective effects of SAL in PD-related peritoneal fibrosis and its underlying mechanisms through the integration of single-cell RNA-seq, bulk RNA-seq, and network pharmacology analyses. A total of 249 disease targets were identified through single-cell RNA-seq and bulk RNA-seq analyses. Functional enrichment analysis highlighted the involvement of extracellular matrix organization, neutrophil degranulation, and the vitamin D receptor (VDR) pathway in peritoneal fibrosis. By intersecting 148 drug targets with the 249 disease targets, four therapeutic targets for SAL treatment against peritoneal fibrosis were pinpointed: cathepsin S, VDR, plasminogen activator urokinase, and galectin 3. In a murine model of peritoneal fibrosis induced by intraperitoneal injection of 4.25% PD fluid, SAL treatment significantly mitigated peritoneal fibrosis, as evidenced by reduced collagen deposition, decreased protein expression of α-smooth muscle actin and Collagen I, and a thinner peritoneum. In vitro experiments demonstrated that SAL treatment inhibited extracellular matrix deposition, potentially through upregulation of VDR expression. In conclusion, SAL may target VDR domains as a therapeutic agent for PD-related peritoneal fibrosis. These findings comprehensively identify potential therapeutic targets for SAL in combating peritoneal fibrosis, providing a theoretical basis for the clinical application of SAL in the treatment of peritoneal fibrosis.

Key Points: Non- DNMT3A clonal hematopoiesis of indeterminate potential was associated with CKD progression in a meta-analysis of 5654 individuals with CKD. In an adenine-induced CKD mouse model, Tet2 -clonal hematopoiesis of indeterminate potential was linked to lower GFR, increased kidney inflammation, tubular injury, and fibrosis. Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. CHIP has been associated with incident AKI and kidney function decline in the general population, particularly mutations in CHIP genes other than DNMT3A (termed non- DNMT3A CHIP). Previous studies of CHIP in individuals with CKD had limited sample sizes and conflicting findings. Methods: We examined CHIP and CKD progression in four CKD cohorts ( N =5654): the Chronic Renal Insufficiency Cohort, the African American Study of Kidney Disease, individuals with CKD from the BioVU biorepository, and the Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events. Primary outcomes were incident CKD progression (50% eGFR decline or kidney failure) and eGFR slope over time. In addition, kidney function and pathology were assessed in a Tet2 -CHIP mouse model of CKD induced by dietary adenine. Results: Across all cohorts, the average age was 66±11 years, with an average baseline eGFR of 43±15 ml/min per 1.73 m ² , and 24% had CHIP. After meta-analysis, non- DNMT3A CHIP was associated with a 64% higher relative risk of incident CKD progression (hazard ratio, 1.64; 95% confidence interval, 1.00 to 2.68), with the strongest effect observed in individuals with baseline eGFR 30–60 ml/min per 1.73 m ² (hazard ratio, 1.85; 95% confidence interval, 1.18 to 2.90). Non- DNMT3A CHIP carriers also exhibited a faster eGFR decline ( β , −0.62±0.28 ml/min per 1.73 m ² per year; P = 0.03). In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusions: Non- DNMT3A CHIP was associated with CKD progression among individuals with CKD. Furthermore, Tet2 -CHIP mouse models support a causal role in kidney injury.

Background: Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. Methods: The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. Results: BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway. Conclusion: Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1β and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL’s anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.