Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum) is a herbaceous perennial plant in the Polygonaceae family that produces biofunctional stilbenes and quinones. The dried rhizome and root of P. cuspidatum in traditional oriental medicine have been used for ameliorating inflammatory illnesses, diabetes, gout, cancer, and other ailments.This work aimed to investigate the protective effects of P. cuspidatum extracts (PCE) on sepsis-associated acute kidney injury (SA-AKI) and its underlying mechanism.The potential mechanisms by which PCE improved SA-AKI were preliminarily predicted by network pharmacology. The dry powders of PCE were obtained using the freeze-drying method. A mouse model of SA-AKI was established by intraperitoneal injection of lipopolysaccharide (LPS). The protective effects of PCE on SA-AKI in vivo were studied using pathological and biochemical methods. LPS-stimulated HK-2 cells were prepared for in vitro evaluation. The qPCR and immunoblotting assays were performed to confirm the mechanism involved.The network pharmacology results indicate that emodin (Emo) and polydatin (PD) are potential active components of P. cuspidatum ameliorating SA-AKI. The experimental results showed that PCE improved renal function indices (creatinine, urea nitrogen, and urinary protein) in SA-AKI mice. Mechanistically, PCE mitigated oxidative stress, regulated the expression levels of pyroptosis-related proteins, and repressed the production of inflammatory cytokines by inactivating nuclear factor-kappa B (NF-κB) signaling in vivo. Similar results were observed in LPS-stimulated HK-2 cells in the presence of Emo or PD.Our results demonstrated that PCE and active ingredients (Emo and PD) in PCE ameliorated SA-AKI by suppressing oxidative stress, inflammation, and pyroptosis. 

Polygonum cuspidatum Sieb. et Zucc. Extracts improve sepsis-associated acute kidney injury by inhibiting NF-κB-mediated inflammation and pyroptosis.

CREB3 subfamily belongs to the bZIP transcription factor family and comprises five members. Normally they are located on the endoplasmic reticulum (ER) membranes and proteolytically activated through RIP (regulated intramembrane proteolysis) on Golgi apparatus to liberate the N-terminus to serve as transcription factors. CREB3L1 acting as one of them transcriptionally regulates the expressions of target genes and exhibits distinct functions from the other members of CREB3 family in eukaryotes. Physiologically, CREB3L1 involves in the regulation of bone morphogenesis, neurogenesis, neuroendocrine, secretory cell differentiation, and angiogenesis. Pathologically, CREB3L1 implicates in the modulation of osteogenesis imperfecta, low grade fibro myxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), glioma, breast cancer, thyroid cancer, and tissue fibrosis. This review summarizes the upstream and downstream regulatory network of CREB3L1 and thoroughly presents our current understanding of CREB3L1 research progress in both physiological and pathological conditions with special focus on the novel findings of CREB3L1 in cancers.

The Regulatory Network of CREB3L1 and Its Roles in Physiological and Pathological Conditions

The development of acute lung injury (ALI), a common respiratory condition with multiple causes, is significantly influenced by the pro-inflammatory environment of signal transducer and activator of transcription 3 (STAT3) in macrophages. Our study aimed to evaluate the anti-inflammatory effects of B9 (N-(4-hydroxyphenyl)-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonamide), a novel inhibitor targeting the STAT3 SH2 domain, in macrophages and to assess its therapeutic potential for ALI using a mouse model of lipopolysaccharide (LPS)-induced ALI. We found that B9 (30 mg/kg) significantly reduced lung pathological damage and neutrophil infiltration caused by the intratracheal administration of LPS. Additionally, the high expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in alveolar lavage fluid was also inhibited by B9 treatment. The decreased expression of CD86 and increased CD206 in lung tissue demonstrated the anti-inflammatory effect of B9, which was due to its inhibition of the STAT3 signaling pathway in macrophages of ALI mice. Furthermore, B9 suppressed the activation of RAW264.7 cells induced by LPS, characterized by its ability to inhibit the activation of iNOS and STAT3 in a dose-dependent manner, as well as reduce the secretion of IL-6 and IL-1β. The in vivo preliminary safety evaluation indicated that B9 had a favorable safety profile at the administered doses. These results suggest that B9 exerts a therapeutic effect on LPS-induced ALI, potentially by preventing the phosphorylation of STAT3 Y705 and S727 without affecting the STAT3 protein level. Taken together, these findings provide a foundation for developing B9 as a novel anti-inflammatory agent for ameliorating LPS-induced ALI. 

The STAT3 inhibitor B9 alleviates lipopolysaccharide-induced acute lung injury through its anti-inflammatory effects.

Contrast-induced acute kidney injury (CI-AKI) refers to acute kidney injury that occurs after intravascular contrast media is applied. It is the third most common cause for acute renal failure in hospitalized patients and can cause severe renal impairment and adverse cardiovascular outcomes. In severe cases, it can even lead to the death of the patient. Due to its complicated pathogenesis, the pathogenesis of CI-AKI has not yet been elucidated. Therefore, it is of great significance to further study the pathogenesis for the prevention of CI-AKI. Moreover, a good animal model of CI-AKI is an important tool for in-depth research on the pathogenesis of acute kidney injury induced by contrast agents.

Research progress on animal models of contrast-induced acute kidney injury.

Protective Mechanism of Alpinia Officinarum Hance Against Cisplatin-Induced Acute Kidney Injury Based on Ultra-High Performance Liquid Chromatography with Quadrupole Time-of-Flight Mass Spectrometry Combined with Network Pharmacology

Lyn attenuates sepsis-associated acute kidney injury by inhibition of phospho-STAT3 and apoptosis.

Abstract Background While transcription factor (TF) regulation is known to play an important role in osteoblast development, differentiation, and bone metabolism, the molecular features of TFs in human osteoblasts at the single-cell resolution level have not yet been characterized. Here, we identified modules (regulons) of co-regulated genes by applying single-cell regulatory network inference and clustering to the single-cell RNA sequencing profiles of human osteoblasts. We also performed cell-specific network (CSN) analysis, reconstructed regulon activity-based osteoblast development trajectories, and validated the functions of important regulons both in vivo and in vitro. Results We identified four cell clusters: preosteoblast-S1, preosteoblast-S2, intermediate osteoblasts, and mature osteoblasts. CSN analysis results and regulon activity-based osteoblast development trajectories revealed cell development and functional state changes of osteoblasts. CREM and FOSL2 regulons were mainly active in preosteoblast-S1, FOXC2 regulons were mainly active in intermediate osteoblast, and RUNX2 and CREB3L1 regulons were most active in mature osteoblasts. Conclusions This is the first study to describe the unique features of human osteoblasts in vivo based on cellular regulon active landscapes. Functional state changes of CREM, FOSL2, FOXC2, RUNX2 , and CREB3L1 regulons regarding immunity, cell proliferation, and differentiation identified the important cell stages or subtypes that may be predominantly affected by bone metabolism disorders. These findings may lead to a deeper understanding of the mechanisms underlying bone metabolism and associated diseases. 

/pdf/regulon-active-landscape-reveals-cell-development-and-1pnyn3j0.pdf

Regulon active landscape reveals cell development and functional state changes of human primary osteoblasts in vivo

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Lyn attenuates sepsis-associated acute kidney injury by inhibition of phospho-STAT3 and apoptosis.

Regulon active landscape reveals cell development and functional state changes of human primary osteoblasts in vivo