Inhibitory role of remifentanil in hepatic ischemia-reperfusion injury through activation of Fmol/Parkin signaling pathway: A study based on network pharmacology analysis and high-throughput sequencing.

BACKGROUND: This study was conducted to elucidate the critical molecular pathways underlying the protective effects of remifentanil against hepatic ischemia-reperfusion injury in rats. Our approach integrated network pharmacology analysis with high-throughput sequencing to achieve a comprehensive understanding of the mechanisms involved. STUDY DESIGN/METHODS: The study utilized GSE24430 gene expression data from GEO to investigate remifentanil's impact on Hepatic Ischemia-Reperfusion Injury in rats. Weighted Correlation Network Analysis (WGCNA) was employed to pinpoint crucial genes and identify modules of co-expressed genes. Differential analysis with the "Limma" package revealed genes differentially expressed in IRI vs. control groups. PubChem and PharmMapper provided target genes affected by remifentanil. Protein-protein interaction networks were constructed via GeneCards and STRING. Functional analysis pinpointed core genes involved in remifentanil's IRI alleviation. IRI rat models were established, and hepatic injury indicators, liver structure via H&E staining, autophagosome counts via electron microscopy, and gene/protein expression via RT-qPCR and Western blot were assessed. High-throughput sequencing analyzed molecular pathways affected by varying remifentanil doses in IRI rats. RESULTS: In the study, we discovered four primary co-expression modules associated with hepatic IRI, and the grey module exhibited the highest correlation with hepatic IRI.A total of sixty-eight genes that were differentially expressed were found to have a connection with hepatic IRI.Network pharmacology analysis found that remifentanil may alleviate hepatic IRI through Fmol.found that the Fmol/Parkin signaling pathway may alleviate hepatic IRI via Additionally, the database autophagy. The established hepatic IRI rat models further confirmed the above findings. CONCLUSION: Our study established that remifentanil triggers the Fmol/Parkin signaling cascade, amplifying the expression levels of Fmol and Parkin. This process culminates in the activation of autophagy within hepatic cells, ultimately alleviating hepatic ischemia-reperfusion injury (IRI).

Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space. In this study, the structure-based scaffold hopping strategy was performed by hybrid FXR agonist 1 and T0901317, which resulted in the discovery of sulfonamide FXR agonist 19. Molecular docking study reasonably explained the SAR in this series, and compound 19 fitted well with the binding pocket in a similar mode to the co-crystal ligand. In addition, compound 19 exhibited considerable selectivity against other nuclear receptors. In NASH model, compound 19 alleviated the typical histological features of fatty liver, including steatosis, lobular inflammation, ballooning, and fibrosis. Moreover, compound 19 exhibited acceptable safety profiles with no acute toxicity to major organ. These results suggested that the novel sulfonamide FXR agonist 19 might be a promising agent for the treatment of NASH.

Activation of α-7 Nicotinic Acetylcholine Receptor Attenuates Cardiac Inflammation Through NLRP3/Caspase-1/IL-18 Pathway.

Activation of α-7 nicotinic acetylcholine receptor (α7nAChR) receptor might induce cardiac inflammation, cardiac remodeling, and dysfunction. In this regard, this study aims to clarify the role and mechanism of α7nAChR in the process of cardiac inflammation and damage. Normal male C57BL/6J and NLRP3-knockout mice were used to evaluate the effect of PHA-543613, a selective agonist of α7nAChR, on cardiac inflammation and possible involvement of NLRP3/Caspase-1/IL-18 using western blotting and ELISA. Activation of α7nAChR using PHA-543613 (NE), at the doses of 0.5 mg/kg and 1 mg/kg, induced cardiac inflammation. In addition, both in vivo and in vitro studies showed higher expression of NLRP3 and higher activation of Caspase-1 and IL-18 after treating animals with NE. On the other hand, we did not observe any significant changes in inflammatory cytokines and cardiac inflammation after administration of NE in NLRP3-knockout mice. It could be concluded that blocking the NLRP3/Caspase-1/IL-18 pathway can simultaneously inhibit the inflammatory response mediated by α7nAChR and it would a novel target for inhibiting cardiac inflammation and remodeling.

Studies on the degradation of trace phenol and indole odorants by chlorine and permanganate in drinking water treatment.

The frequent detection of phenols and indoles in source water gives rise to concern about the taste and odor problems mainly caused by some chemicals. Exploration for the efficient removal of trace amounts of phenols and indoles in source water is imperative. This study investigated the removals and oxidation kinetics of 3-methylphenol (3-MP), 2,6-dichlorophenol (2,6-DCP), indole and 3-methylindole (3-MI) by NaClO and KMnO4. The results showed that the selected chemical odorants could be removed by NaClO and KMnO4. Meanwhile, the oxidation processes could be well described by the second-order kinetics model, in which kinetics constants of chemical odorants were from 1.44 × 104 to 1.45 × 106 L·mol-1·min-1 and followed the order 3-MI > indole> 3-MP> 2,6-DCP by NaClO. However, the kinetics constants for the selected chemical odorants were also determined from 1.10 × 103 to 2.25 × 104 L·mol-1·min-1 and in the order 2,6-DCP> 3-MI> 3-MP > indole by KMnO4. The phenols degradation mechanisms by NaClO are chlorine substitution, and the products generated are 3,4,6-trichloro-2-methylphenol, 2,4,6-trichlorophenol, etc. And that of indoles are chlorine substitution and hydroxylation by NaClO, which generated 6-chloroindole, 2,6-dichloroaniline, etc. The phenols degradation pathways are oxidative coupling reactions by KMnO4, and that of indoles are hydroxylation reactions by KMnO4. This study provides a further basis for NaClO and KMnO4 oxidation to remove trace phenols and indoles in drinking water pre-treatments.

Atg7 Knockout Alleviated the Axonal Injury of Neuro-2a Cells Induced by Tri-Ortho-Cresyl Phosphate.

Autophagy is believed to be essential for the maintenance of axonal homeostasis in neurons. However, whether autophagy is causally related to the axon degeneration in organophosphorus-induced delayed neuropathy (OPIDN) still remains unclear. This research was designed to investigate the role of autophagy in axon degeneration following tri-ortho-cresyl phosphate (TOCP) in an in vitro model. Differentiated wild-type and Atg7-/- neuro-2a (N2a) cells were treated with TOCP for 24 h. Axonal degeneration in N2a cells was quantitatively analyzed; the key molecules responsible for axon degeneration and its upstream signaling pathway were determined by Western blotting and real-time PCR. The results found that Atg7-/- cells exhibited a higher resistance to TOCP insult than wild-type cells. Further study revealed that TOCP caused a significant decrease in pro-survival factors NMNATs and SCG10 and a significant increase in pro-degenerative factor SARM1 in both cells. Notably, Atg7-/- cells presented a higher level of pro-survival factors and a lower level of pro-degenerative factors than wild-type cells in the same setting of TOCP administration. Moreover, DLK-MAPK pathway was activated following TOCP. Altogether, our results suggest that autophagy is able to affect TOCP-induced axonal injury via regulating the balance between pro-survival and pro-degenerative factors, providing a promising avenue for the potential therapy for OPIDN patients.

Optimizing the Microstructure and Mechanical Properties of Vacuum Counter-Pressure Casting ZL114A Aluminum Alloy via Ultrasonic Treatment.

The effect of ultrasonic temperature on density, microstructure and mechanical properties of vacuum counter-pressure casting ZL114A alloy during solidification was investigated by optical microscopy (OM), scanning electron microscope (SEM) and a tensile test. The results show that compared with the traditional vacuum counter-pressure casting aluminum alloy, the primary phase and eutectic silicon of the alloy with ultrasonic treatment has been greatly refined due to the dendrites broken by ultrasonic vibration. However, the refining effect of ultrasonic treatment on vacuum counter-pressure casting aluminum alloy will be significantly affected by ultrasonic temperature. When the ultrasonic temperature increases from 680 °C to 720 °C, the primary phase is gradually refined, and the morphology of eutectic silicon also changes from coarse needle-like flakes to fine short rods. With a further increase in the ultrasonic temperature, the microstructure will coarse again. The tensile strength and elongation of vacuum counter-pressure casting ZL114A alloy increases first and then decreases with the increase of ultrasonic temperature. The optimal mechanical properties were achieved with tensile strength of 327 MPa and the elongation of 5.57% at ultrasonic temperature of 720 °C, which is 6.3% and 8.2%, respectively, higher than that of alloy without ultrasonic treatment.

Effects of Continuous and Pulsed Ultrasonic Treatment on Microstructure and Microhardness in Different Vertical Depth of ZL205A Castings.

In this paper, in order to improve the performance of the ZL205A castings, continuous ultrasonic and pulsed ultrasonic treatments were applied to the melted alloy to study the effect of ultrasound propagation distance on microstructure and microhardness. The results indicated that ZL205A grains were significantly refined by ultrasonic vibration, but the refinement effect became weak gradually with the increase of sampling depth. The minimum grain sizes were 103.2 µm and 122.5 µm respectively in continuous and pulsed ultrasonic treatment. Grain boundary segregation also became more serious and coarser with the increase of vertical depth. In addition, microhardness and vertical depth are not positively correlated linearly. As the vertical depth increased, microhardness first decreased and then increased, the maximum hardnesses were 73.9 HV and 72.84 HV, respectively, in the two process modes. According to the experiment results and available studies, the mechanism of ultrasonic treatment maybe that: the cooling rate of solidification interface front increased by cavitation and streaming, thus changing the solute redistribution behavior of the ZL205A melt.

Carbon disulfide activates p62-Nrf2-keap1 pathway in rat nerve tissues.

Oxidative stress is associated with the pathogenesis of carbon disulfide (CS2) induced polyneuropathy. The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting cells against oxidative stress. However, whether there exists a Nrf2-mediated antioxidative machinery in CS2-induced neuropathy has not been elucidated. In the present study, male wistar rats were randomly divided into three experimental groups and one control group. The rats in experimental groups were treated with CS2 by gavage at dosages of 200, 400 and 600mg/kg/day respectively, six times per week for 6 weeks. Nrf2-keap1 antioxidative pathway and p62-related kinase signaling in rat nerve tissues was examined by western blotting and real-time PCR. The results demonstrated that CS2 treatment resulted in Nrf2 translocation from the cytosol to the nucleus in rat spinal cords. In the meantime, the expression of antioxidative enzymes such as NAD(P)H quinone oxidoreductase-1, heme oxygenase-1, and glutamate-cysteine ligase was significantly increased. Furthermore, CS2 treatment increased the level of p62 and its phosphorylation status, while decreased the level of keap1. In addition, CS2 also lead to the activation of CAMKK2 and ULK1 kinase signaling in rat spinal cords and sciatic nerves. Taken together, our results indicated that CS2 intoxication was associated with the activation of Nrf2-ARE antioxidative machinery, which might play a protective role against CS2-induced neuronal damage.

[Effects of antiviral nucleotide/nucleoside analogues and interferon on hepatitis B virus-related liver cirrhosis: a meta-analysis].

OBJECTIVE: To evaluate the effects of antiviral nucleotide/nucleoside analogues (NUCs) and interferon (IFN) on liver fibrosis and progression to cirrhosis in patients with hepatitis B virus (HBV) infection. METHODS: The literature databases of PubMed (1966 to 2011), Embase (1966 to 2011), Wanfang database (1998 to 2011), Chinese National Knowledge Infrastructure (CNKI; 1997 to 2010), and Chinese Biomedical (CBMdisc; 1860 to 2011) were searched for studies that met the following criteria: (1) case-control phase III clinical trails that used only one kind of antiviral drug (NUCs or IFN), with the controls receiving placebo or no treatment; (2) analysis of biopsy specimens collected before and after treatment for both the cases and controls; (3) assessment of fibrosis as an outcome measure of the treatment's effect. The data from all 11 studies included in the meta-analysis were extracted and analyzed by the RevMan5.1 software. RESULTS: NUC treatment significantly regressed liver fibrosis, as compared with placebo treatment (33.7% vs. 19.2%, relative risk (RR): 1.82, 95% confidence interval (CI): [1.47, 2.25], P less than 0.01). NUC treatment significantly reduced the progression of fibrosis, as compared with placebo treatment (9.1% vs. 24.8%, RR: 0.33, 95% CI: [0.19, 0.58], P less than 0.01). IFN treatment significantly reduced progression of fibrosis, as compared with no treatment (23.8% vs. 30.7%, RR: 0.48, 95% CI: [0.34, 0.69], P less than 0.01). IFN significantly reduced progression to cirrhosis, as compared with no treatment (10.6% vs. 18.0%, RR: 0.62, 95% CI: [0.44, 0.88], P less than 0.01). CONCLUSION: One year of NUC treatment could partly regress liver fibrosis and partly reduce the progression of fibrosis, while one year of IFN treatment could reduce the progression of fibrosis and cirrhosis.