Salidroside alleviates LPS-induced liver injury and inflammation through SIRT1- NF-κB pathway and NLRP3 inflammasome.

Objectives: Salidroside (SAL), an active ingredient purified from the medicinal plant Rhodiola rosea, has anti-inflammatory, anti-oxidant, anticancer, and neuroprotective properties. The study aims to examine SAL's protective role in liver damage brought on by lipopolysaccharide (LPS). Materials and Methods: Six to eight-week-old male C57BL/6 wild-type mice were intraperitoneally treated with 10 mg/kg LPS for 24 hr and 50 mg/kg SAL two hours before LPS administration. Mice were categorized into control, LPS, and LPS + SAL groups. To evaluate liver injury, biochemical and TUNNEL staining test studies were performed. The Elisa assay analyzed interleukin- 1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) pro-inflammatory cytokine expression levels. RT-qPCR and western blotting measured mRNA and protein expression of SIRT1, NF-кB, NLRP3, cleaved caspase-1, and GSDMD, respectively. Results: Analysis of the serum alanine/aspartate aminotransferases (ALT/AST), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) revealed that SAL protected against hepatotoxicity induced by LPS. The pathological evaluation of the liver supported the protection provided by SAL. SAL treatment reversed IL-1ß, TNF-α, and IL-6 pro-inflammatory cytokines after being induced by LPS (all, P<0.001). The western blotting examination results demonstrated that SAL increased the levels of Sirtuin 1 (SIRT1) expression but markedly reduced the phosphorylation of Nuclear Factor Kappa B (NF-B) and the expressions of NLRP3, cleaved caspase-1, and gasdermin D (GSDMD) induced by LPS (all, P<0.001). Conclusion: Our results speculated that by inhibiting the SIRT1- NF-κB pathway and NLRP3 inflammasome, SAL defends against LPS-induced liver injury and inflammation.

Astragaloside IV attenuates lipopolysaccharide induced liver injury by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

Aims and objectives: Sepsis-associated liver injury is a common public health problem in intensive care units. Astragaloside IV (AS-IV) is an active component extracted from the Chinese herb Astragalus membranaceus, and has been shown to have anti-oxidation, anti-inflammation, and anti-apoptosis properties. The research aimed to investigate the protective effect of AS-IV in lipopolysaccharide (LPS)-induced liver injury. Methods: Male C57BL/6 wild-type mice (6-8 week-old) were intraperitoneally injected with 10 mg/kg LPS for 24 h and AS-IV (80 mg/kg) 2 h before the LPS injection. Biochemical and histopathological analyses were carried out to assess liver injury. The RT-qPCR analyzed the mRNA expression of IL-1ß, TNF-α, and IL-6. The mRNA and protein expression of SIRT1, nuclear Nrf2, Nrf2, and HO-1 were measured by Western blotting. Results: Serum alanine/aspartate aminotransferases (ALT/AST) analysis, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were showed that AS-IV protected against LPS-induced hepatotoxicity. The protection afforded by AS-IV was confirmed by pathological examination of the liver. Pro-inflammatory cytokines, including interleukin- 1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were observed to be reversed by AS-IV after exposure to LPS. Western blot analysis demonstrated that AS-IV enhanced the expression levels of Sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). Conclusions: AS-IV protects against LPS-induced Liver Injury and Inflammation by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

Hsa_circ_0001550 facilitates colorectal cancer progression through mediating microRNA-4262/nuclear casein kinase and cyclin-dependent kinase substrate 1 cascade.

BACKGROUND: Circular RNAs (circRNAs) play important roles in various malignancies, such as colorectal cancer (CRC). However, the function of hsa_circ_0001550 in CRC remains to be elucidated. METHODS: The expression levels of hsa_circ_0001550, microRNA (miR)-4262, and nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) were determined by real-time qPCR. Cell biological behaviors were evaluated via colony formation assay, transwell assay, flow cytometry, and sphere formation assays. The target relationship was validated via dual-luciferase reporter and RNA pull-down assays. Protein expression was analyzed by western blot. Xenograft tumor model was adopted to evaluate hsa_circ_0001550 function in vivo. RESULTS: Hsa_circ_0001550 enrichment was enhanced in CRC tissue specimens and cell lines. Hsa_circ_0001550 absence hindered CRC cell proliferation, metastasis, stemness, and caused apoptosis. Hsa_circ_0001550 targeted miR-4262, and hsa_circ_0001550 absence-caused impacts were diminished by anti-miR-4262. MiR-4262 targeted NUCKS1. Hsa_circ_0001550 had positive regulation on NUCKS1 expression. NUCKS1 overexpression overturned the influences of hsa_circ_0001550 silencingon CRC cell progression. Hsa_circ_0001550 interference notably blocked in vivo xenograft tumor growth. CONCLUSION: Hsa_circ_0001550 facilitated CRC progression by binding to miR-4262 to positively regulate NUCKS1 abundance.

Exosomes derived from the blood of patients with sepsis regulate apoptosis and aerobic glycolysis in human myocardial cells via the hsa­miR­1262/SLC2A1 signaling pathway.

Myocardial injury occurs in the majority of patients with sepsis and is associated with early mortality. MicroRNAs (miRs) transported by exosomes have been implicated in numerous diseases, such as tumors, acute myocardial infarction and cardiovascular disease. Human serum albumin (hsa)­miR­1262 has been shown to serve a role in sepsis; however, its role in exosomes isolated from patients with sepsis and septic myocardial injury remains unclear. In the present study, serum exosomes were isolated via ultracentrifugation. Solute carrier family 2 member 1 (SLC2A1), an essential mediator in energy metabolism, was silenced and overexpressed in the human myocardial AC16 cell line using lentiviral plasmids containing either SLC2A1­targeting short interfering RNAs or SLC2A1 cDNA, respectively. Cell apoptosis was analyzed using flow cytometry, and the extracellular acidification rate and oxygen consumption rate of AC16 cells were determined using an XFe24 Extracellular Flux Analyzer. Furthermore, the dual­luciferase reporter assay was used to evaluate the interaction between hsa­miR­1262 and SLC2A1. Finally, reverse transcription­quantitative PCR and western blotting were used to evaluate gene and protein expression levels, respectively. Exosomes isolated from the blood of patients with sepsis (Sepsis­exo) markedly reduced aerobic glycolysis activity, but significantly promoted the apoptosis of human AC16 cells in a time­dependent manner. Moreover, Sepsis­exo significantly increased hsa­miR­1262 expression levels, but significantly decreased SLC2A1 mRNA expression levels in a time­dependent manner. Bioinformatics analysis indicated that hsa­miR­1262 bound to the 3' untranslated region of SLC2A1 to negatively regulate its expression. The silencing of SLC2A1 promoted apoptosis and suppressed glycolysis in AC16 cells, whereas SLC2A1 overexpression resulted in the opposite effects. Therefore, the present study demonstrated that exosomes derived from patients with sepsis may inhibit glycolysis and promote the apoptosis of human myocardial cells through exosomal hsa­miR­1262 via its target SLC2A1. These findings highlighted the importance of the hsa­miR­1262/SLC2A1 signaling pathway in septic myocardial injury and provided novel insights into therapeutic strategies for septic myocardial depression.

Herbal therapy for ameliorating nonalcoholic fatty liver disease via rebuilding the intestinal microecology.

The worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, and this metabolic disorder has been recognized as a severe threat to human health. A variety of chemical drugs have been approved for treating NAFLD, however, they always has serious side effects. Chinese herbal medicines (CHMs) have been widely used for preventing and treating a range of metabolic diseases with satisfactory safety and effective performance in clinical treatment of NAFLD. Recent studies indicated that imbanlance of the intestinal microbiota was closely associated with the occurrence and development of NAFLD, thus, the intestinal microbiota has been recognized as a promising target for treatment of NAFLD. In recent decades, a variety of CHMs have been reported to effectively prevent or treat NAFLD by modulating intestinal microbiota to further interfer the gut-liver axis. In this review, recent advances in CHMs for the treatment of NAFLD via rebuilding the intestinal microecology were systematically reviewed. The key roles of CHMs in the regulation of gut microbiota and the gut-liver axis along with their mechanisms (such as modulating intestinal permeability, reducing the inflammatory response, protecting liver cells, improving lipid metabolism, and modulating nuclear receptors), were well summarized. All the knowledge and information presented here will be very helpful for researchers to better understand the applications and mechanisms of CHMs for treatment of NAFLD.

TRIM31 promotes apoptosis via TAK1-mediated activation of NF-κB signaling in sepsis-induced myocardial dysfunction.

Sepsis is a major condition caused by an overwhelming inflammatory response to an infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in septic patients and a major predictor of morbidity and mortality. Here, we investigated the role of tripartite motif 31 (TRIM31) protein in sepsis progression in vitro and in vivo. Quantitative real-time PCR and western blot were used to detect the expression levels of relative genes and proteins. Cell proliferation and apoptosis were evaluated to determine cell viability. H&E and IHC staining were performed to examine morphological and pathological changes in mice. ELISA assay was used to detect inflammatory factors. TRIM31 was upregulated in septic patients compared with normal people. TRIM31 depletion reduced LPS-induced apoptosis whereas TRIM31 overexpression-elevated LPS-induced apoptosis. Furthermore, TRIM31 interacted with and ubiquitinated transforming growth factor-ß-activated kinase-1 (TAK1), resulting in TAK1 activation and subsequent induction of NF-κB signaling. Of note, Trim31 depletion or blockade by PDTC treatment inhibited LPS-induced apoptosis in vivo. In conclusion, TRIM31 played an important role in SIMD by activating TAK1-mediated NF-κB signaling pathway.

Upregulation of miR-552 Predicts Unfavorable Prognosis of Gastric Cancer and Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells.

BACKGROUND: Accumulating evidence indicates that micro-RNAs play a key role in tumor progression and prognosis. However, the overall biological role and clinical significance of microRNA-552 (miR-552) in the pathogenesis of gastric cancer (GC) remain unclear. METHODS: miR-552 expression was measured in 122 pairs of cancerous and noncancerous tissues and cell lines by quantitative real-time polymerase chain reaction. The relationship between miR-552 and the clinical parameters of patients was analyzed by the χ2 test; Kaplan-Meier analysis and multivariate Cox regression analysis were used to predict the overall survival time and prognosis of patients with different expression of miR-552. Finally, CCK-8 and Transwell were used to detect the changes in cell proliferation, migration, and invasion ability. RESULTS: miR-552 was expressed at markedly high levels in GC tissues compared to normal tissues and in some GC cell lines (p < 0.001). The upregulation of miR-552 was significantly associated with tumors with advanced TNM stage (p = 0.026), lymph node metastasis (p = 0.018), intestinal metaplasia (p = 0.044), and genomically stable subtype (p = 0.035). Moreover, GC patients with high miR-552 expression showed shorter overall survival (log-rank test, p = 0.011) than those with low expression. Meanwhile, miR-552 was an independent prognostic factor for GC patients (HR 5.657, 95% CI 1.619-19.761, p = 0.007). Finally, miR-552 overexpression promoted the proliferation, migration, and invasion of GC cells (p < 0.01). CONCLUSION: Taken together, our results indicate that miR-552, as an oncogene of GC, can promote cell proliferation, migration, and invasion, and miR-552 may be a novel prognostic biomarker for GC.