One of the most common diseases affecting people and leading to high morbidity is kidney injury. The alleviation of inflammation and apoptosis is considered a potential therapeutic approach for kidney injury. Sophocarpine (SOP), a tetracyclic quinolizidine alkaloid, exhibits various beneficial biological properties. To investigate the effects of SOP on isoproterenol (ISO)-induced kidney injury, we randomly divided mice into four groups: Control, ISO, ISO+SOP (20 mg/kg) and ISO+SOP (40 mg/kg). SOP was administered intraperitoneally to the mice over two weeks, accompanied by intraperitoneal stimulation of ISO (10 mg/kg) for another four weeks. After the mice were sacrificed, several methods such as ELISA, staining (H&E, TUNEL, DHE and Masson) and Western blotting were applied to detect the corresponding indicators. The kidney injury serum biomarkers SCr and BUN increased after the ISO challenge, while this effect was reversed by treatment with SOP. Pathological changes induced by ISO were also reversed by treatment with SOP in the staining. The inflammatory cytokines IL-β, IL-6, TNF-α, MCP-1 and NLRP3 increased after the challenge with ISO, while they were decreased by treatment with SOP. The apoptotic proteins cleaved-caspase-3 and Bax increased, while Bcl-2 decreased, after the challenge with ISO, and these effects were reversed by treatment with SOP. The antioxidant proteins SOD-1 and SOD-2 decreased after being stimulated by ISO, while they increased after the treatment with SOP. The fibrotic proteins collagen I, collagen III, α-SMA, fibronectin, MMP-2 and MMP-9 increased after the challenge with ISO, while they decreased after the treatment with SOP. We further discovered that the TLR-4/NF-κB and TGF-β1/Smad3 signaling pathways were suppressed, while the Nrf2/HO-1 signaling pathway was activated. In summary, SOP could alleviate ISO-induced kidney injury by inhibiting inflammation, apoptosis, oxidative stress and fibrosis. The molecular mechanisms were suppression of the TLR-4/NF-κB and TGF-β1/Smad3 signaling pathways and activation of the Nrf2/HO-1 signaling pathway, indicating that SOP might serve as a novel therapeutic strategy for kidney injury.

Glycemic variability (GV) and systolic blood pressure variability (SBPV) have been reported to be associated with all-cause mortality. However, it remains unclear whether the combination of these parameters further stratifies mortality risk in septic patients admitted to the intensive care unit (ICU). The aim of this study was to investigate the combined association of GV and SBPV with mortality in patients with sepsis. The study utilized data from MIMIC-IV database. Patients with sepsis were stratified into four groups. The endpoint indicators of this study include ICU mortality, in-hospital mortality, 30-day mortality, 90-day mortality, 180-day mortality, and 1-year mortality. Kaplan-Meier method was used to estimate the survival curves. The risks of ICU mortality, in-hospital mortality, and mortality at 30 days, 90 days, 180 days, and 1 year were assessed using Cox regression analyses. The study also performed subgroup analysis to evaluate the robustness of the findings. In addition, we evaluated the predictive value of GV and SBPV for mortality by calculating the Harrell C-index, IDI and NRI for each parameter separately and in combination. Among 15,454 patients with sepsis, 1,576 patients died in ICU, and 5,189 patients died 1-year follow-up. High GV and high SBPV were associated with an increased risk of mortality. Patients with high GV and high SBPV have higher risk of ICU mortality (HR 1.56, 95% CI 1.32–1.85), in-hospital mortality (HR 1.46, 95% CI 1.26–1.69), 30-day mortality (HR 1.42, 95% CI 1.24–1.63), 90-day mortality (HR 1.32, 95% CI 1.17–1.49), 180-day mortality (HR 1.31, 95% CI 1.17–1.47), and 1-year mortality (HR 1.29, 95% CI 1.16–1.44) than those with low GV and low SBPV. Across all endpoints, the combination of GV and SBPV significantly improved predictive accuracy compared to GV or SBPV alone. Furthermore, the increased risk of mortality associated with high GV and high SBPV was more significant in patients with age < 60 (P for interaction < 0.001). GV and SBPV were each independently associated with an increased risk of mortality in septic patients admitted to the ICU, and their combination demonstrated an additive association with mortality risk in this population. Monitoring and potentially managing these hemodynamic parameters may be important for risk stratification in severe sepsis.

Previous studies have demonstrated that targeting inflammation is a promising strategy for treating lipopolysaccharide (LPS)-induced sepsis and related heart injury. Interleukin-35 (IL-35), which consists of two subunits, Epstein–Barr virus-induced gene 3 (EBI3) and p35, is an immunosuppressive cytokine of the IL-12 family and exhibits strong anti-inflammatory activity. However, the role of IL-35 in LPS-induced heart injury remains obscure. In this study, we explored the role of IL-35 in heart injury induced by LPS and its potential mechanisms. Mice were treated with a plasmid encoding IL-35 (pIL-35) and then injected intraperitoneally (ip) with LPS (10 mg/kg). Cardiac function was assessed by echocardiography 12 h later. LPS apparently decreased the expression of EBI3 and p35 and caused cardiac dysfunction and pathological changes, which were significantly improved by pIL-35 pretreatment. Moreover, pIL-35 pretreatment significantly decreased the levels of cardiac proinflammatory cytokines including TNF-α, IL-6, and IL-1β, and the NLRP3 inflammasome. Furthermore, increased BCL-2 levels and decreased BAX levels inhibited apoptosis, and LPS-induced upregulation of the expression of pro-fibrotic genes (MMP2 and MMP9) was inhibited. Further investigation indicated that pIL-35 pretreatment suppressed the activation of the cardiac NF-κBp65 and TGF-β1/Smad2/3 signaling pathways in LPS-treated mice. Similar cardioprotective effects of IL-35 pretreatment were observed in mouse myocardial fibroblasts challenged with LPS in vitro. In summary, IL-35 pretreatment can attenuate cardiac inflammation, apoptosis, and fibrosis induced by LPS, implicating IL-35 as a promising therapeutic target in sepsis-related cardiac injury.