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Objective: As the main active ingredient of Tibetan medicine Hongjingtian (Rhodiolae Crenulatae Radix et Rhizoma), salidroside (Sal) has a good anti-apoptotic potential. Currently, there are some conflicting results on the anti-apoptotic mechanisms of Sal. Here we conducted a systematic review and meta-analysis to provide the preclinical evidence of its anti-apoptotic properties in preventing and treating hypoxic-ischemic cerebral damage (HICD). Methods: The literature on the anti-apoptotic potential of Sal in the treatment of HICD from January 1, 1980 to November 9, 2021 was searched online using Chinese databases including Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Database, and English databases including PubMed and Web of Science. The quality of the included articles was evaluated by the Cochrane Collaboration network bias risk assessment criteria, and meta-analysis was performed using RevMan 5.3 software. Results: A total of 40 articles were finally included. Among the 40 articles, 30 were about in vivo animal experiments and 17 about in vitro cell experiments, and 7 of them included both animal and cell experiments. After analysis, it was found that Sal had significant effects on disease-related indicators of HICD (P < 0.05), such as cerebral infarctsize and brain water content. As to in vivo studies, Sal mainly affects the expressions of apoptotic factors through anti-inflammation, anti-oxidation, activation of complement pathway, and regulation of signal transduction and autophagy, thus exerting anti-apoptotic potential in treating HICD. While for in vitro studies, Sal plays the anti-apoptotic role in HICD models mainly through anti-oxidation, anti-inflammation, reduction of Ca2+ overload, regulation of mitochondrial function, signal transduction, and C3 complement. Conclusion: Sal can take anti-apoptotic effects to prevent and treat HICD through mechanisms such as anti-inflammation, anti-oxidation, enhanced autophagy, complement and signal transduction, regulation of mitochondrial membrane potential, and reduction of Ca2+ overload.

Cadmium (Cd) is one of the most polluting heavy metal in the environment. Cd exposure has been elucidated to cause dysfunction of the glomerular filtration barrier (GFB). However, the underlying mechanism remains unclear. C57BL/6J male mice were administered with 2.28 mg/kg cadmium chloride (CdCl2) dissolved in distilled water by oral gavage for 14 days. The expression of SDC4 in the kidney tissues was detected. Human renal glomerular endothelial cells (HRGECs) were exposed to varying concentrations of CdCl2 for 24 h. The mRNA levels of SDC4, along with matrix metalloproteinase (MMP)‐2 and 9, were analyzed by quantitative PCR. Additionally, the protein expression levels of SDC4, MMP‐2/9, and both total and phosphorylated forms of Smad2/3 (P‐Smad2/3) were detected by western blot. The extravasation rate of fluorescein isothiocyanate–dextran through the Transwell was used to evaluate the permeability of HRGECs. SB431542 was used as an inhibitor of transforming growth factor (TGF)‐β signaling pathway to further investigate the role of TGF‐β. Cd reduced SDC4 expression in both mouse kidney tissues and HRGECs. In addition, Cd exposure increased permeability and upregulated P‐Smad2/3 levels in HRGECs. SB431542 treatment inhibited the phosphorylation of Smad2/3, Cd‐induced SDC4 downregulation, and hyperpermeability. MMP‐2/9 levels increased by Cd exposure was also blocked by SB431542, demonstrating the involvement of TGF‐β/Smad pathway in low‐dose Cd‐induced SDC4 reduction in HRGECs. Given that SDC4 is an essential component of glycocalyx, protection or repair of endothelial glycocalyx is a potential strategy for preventing or treating kidney diseases associated with environmental Cd exposure. This study aims to explore the effects of low‐dose cadmium on syndecan‐4 expression. The results revealed that Cd exposure decreases SDC4 expression in both mice kidney tissues and human renal glomerular endothelial cells (HRGECs). Cd exposure induces hyperpermeability in HRGECs and increases the levels P‐Smad2/3 and MMP‐2/9. TGF‐β signaling inhibitor SB431542 blocks Cd‐induced SDC4 reduction and MMP‐2/9 upregulation. The study revealed that low‐dose Cd reduces expression of SDC4 through activation of the TGF‐β signaling. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron‐dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti‐ferroptotic activity of scutellarein was investigated through CCK8, real‐time quantitative polymerase chain reaction (RT‐qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA‐sequencing (RNA‐seq), electrospray ionization mass spectra (ESI‐MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras‐selective lethal small molecule (RSL)‐3‐induced ferroptosis and mitochondria injury in BEAS‐2B cells, and ameliorated LPS/CS‐induced COPD in mice. Furthermore, scutellarein also repressed RSL‐3‐ or LPS/CS‐induced lipid peroxidation, GPX4 down‐regulation, and overactivation of Nrf2/HO‐1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL‐3‐ or LPS/CS‐induced Fe2+ elevation through directly chelating Fe2+. Moreover, scutellarein bound to the lipid peroxidizing enzyme arachidonate 15‐lipoxygenase (ALOX15), which resulted in an unstable state of the catalysis‐related Fe2+ chelating cluster. Additionally, ALOX15 overexpression partially abolished scutellarein‐mediated anti‐ferroptotic activity. Our findings revealed that scutellarein alleviated COPD by inhibiting ferroptosis via directly chelating Fe2+ and interacting with ALOX15, and also highlighted scutellarein as a candidate for the treatment of COPD and other ferroptosis‐related diseases. [ABSTRACT FROM AUTHOR]