Piperine attenuates hepatic ischemia/reperfusion injury via suppressing the TLR4 signaling cascade in mice.

Piperine, the major active substance in black pepper, has been shown to have anti-inflammatory and antioxidant effects in several ischemic diseases. However, the role of piperine in hepatic ischemia/reperfusion injury (HIRI) and its underlying mechanisms remain unclear. In this study, the mice were administered piperine (30 mg/kg) intragastric administration before surgery. After 24 h of hepatic ischemia-reperfusion, liver histopathological evaluation, serum transaminase measurements, and TUNEL analysis were performed. The infiltration of inflammatory cells and production of inflammatory mediators in the liver tissue were determined by immunofluorescence and immunohistochemical staining. The protein levels of toll-like receptor 4 (TLR4) and related proteins such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin-1 receptor-associated kinase 1 (IRAK1), p65, and p38 were detected by western blotting. The results showed that plasma aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte apoptosis, oxidative stress, and inflammatory cell infiltration significantly increased in HIRI mice. Piperine pretreatment notably repaired liver function, improved the histopathology and apoptosis of liver cells, alleviated oxidative stress injury, and reduced inflammatory cell infiltration. Further analysis showed that piperine attenuated tumor necrosis factor-a (TNF-α) and interleukin 6 (IL-6) production and reduced TLR4 activation and phosphorylation of IRAK1, p38, and NF-κB in HIRI. Piperine has a protective effect against HIRI through the TLR4/IRAK1/NF-κB signaling pathway and may be a safer option for future clinical treatment and prevention of ischemia-related diseases.

LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways.

Excessive inflammatory response and increased oxidative stress play an essential role in the pathophysiology of ischemia/reperfusion (I/R)-induced acute kidney injury (IRI-AKI). Emerging evidence suggests that lipoxin A4 (LXA4), as an endogenous negative regulator in inflammation, can ameliorate several I/R injuries. However, the mechanisms and effects of LXA4 on IRI-AKI remain unknown. In this study, A bilateral renal I/R mouse model was used to evaluate the role of LXA4 in wild-type, IRG1 knockout, and IRAK-M knockout mice. Our results showed that LXA4, as well as 5-LOX and ALXR, were quickly induced, and subsequently decreased by renal I/R. LXA4 pretreatment improved renal I/R-induced renal function impairment and renal damage and inhibited inflammatory responses and oxidative stresses in mice kidneys. Notably, LXA4 inhibited I/R-induced the activation of TLR4 signal pathway including decreased phosphorylation of TAK1, p36, and p65, but did not affect TLR4 and p-IRAK-1. The analysis of transcriptomic sequencing data and immunoblotting suggested that innate immune signal molecules interleukin-1 receptor-associated kinase-M (IRAK-M) and immunoresponsive gene 1 (IRG1) might be the key targets of LXA4. Further, the knockout of IRG1 or IRAK-M abolished the beneficial effects of LXA4 on IRI-AKI. In addition, IRG1 deficiency reversed the up-regulation of IRAK-M by LXA4, while IRAK-M knockout had no impact on the IRG1 expression, indicating that IRAK-M is a downstream molecule of IRG1. Mechanistically, we found that LXA4-promoted IRG1-itaconate not only enhanced Nrf2 activation and increased HO-1 and NQO1, but also upregulated IRAK-M, which interacted with TRAF6 by competing with IRAK-1, resulting in deactivation of TLR4 downstream signal in IRI-AKI. These data suggested that LXA4 protected against IRI-AKI via promoting IRG1/Itaconate-Nrf2 and IRAK-M-TRAF6 signaling pathways, providing the rationale for a novel strategy for preventing and treating IRI-AKI.

Pulse pressure variation guided goal-direct fluid therapy decreases postoperative complications in elderly patients undergoing laparoscopic radical resection of colorectal cancer: a randomized controlled trial.

OBJECTIVE: The use of goal-directed fluid therapy (GDFT) has been shown to reduce complications and improve prognosis in high-risk abdominal surgery patients. However, the utilization of pulse pressure variation (PPV) guided GDFT in laparoscopic surgery remains a subject of debate. We hypothesized that utilizing PPV guidance for GDFT would optimize short-term prognosis in elderly patients undergoing laparoscopic radical resection for colorectal cancer compared to conventional fluid therapy. METHODS: Elderly patients undergoing laparoscopic radical resection of colorectal cancer were randomized to receive either PPV guided GDFT or conventional fluid therapy and explore whether PPV guided GDFT can optimize the short-term prognosis of elderly patients undergoing laparoscopic radical resection of colorectal cancer compared with conventional fluid therapy. RESULTS: The incidence of complications was significantly lower in the PPV group compared to the control group (32.8% vs. 57.1%, P = .009). Additionally, the PPV group had a lower occurrence of gastrointestinal dysfunction (19.0% vs. 39.3%, P = .017) and postoperative pneumonia (8.6% vs. 23.2%, P = .033) than the control group. CONCLUSION: Utilizing PPV as a monitoring index for GDFT can improve short-term prognosis in elderly patients undergoing laparoscopic radical resection of colorectal cancer. REGISTRATION NUMBER: ChiCTR2300067361; date of registration: January 5, 2023.

Elucidating Cuproptosis-Associated Genes in the Progression from Nash to HCC Using Bulk and Single-Cell RNA Sequencing Analyses and Experimental Validation.

Background and Objectives: Non-alcoholic steatohepatitis (NASH) is a significant risk factor for hepatocellular carcinoma (HCC) development. Timely treatment during the NASH stage is essential to minimize the possibility of disease progression to HCC. Cuproptosis is a newly identified form of cellular death that could impact the progression of various diseases and cancers. Materials and Methods: Transcriptome and single-cell sequencing datasets were utilized to investigate the role of cuproptosis-related genes (CRGs) in NASH progression to HCC. FDX1, LIPT1, and PDHP were identified as CRGs in NASH patients, and FDX1, DBT, GCSH, SLC31A1, and DLAT were identified as CRGs in patients with NASH progressing to HCC. FDX1 was found to play a significant role in both NASH patients and patients with NASH progressing to HCC. This study constructed cuproptosis-related clusters (CRCs) using the Nonnegative Matrix Factorization algorithm, and they were linked to fatty acid metabolism and the PPAR signaling pathway in both NASH CRCs and HCC CRCs. The Weighted Correlation Network Analysis algorithm identified CRP, CRC, TAT, CXCL10, and ACTA1 as highly relevant genes in NASH CRCs and HCC CRCs. The expression of FDX1 was validated in both mouse models and human NASH samples. Results: The investigation highlights FDX1 as a pivotal CRG in both NASH and NASH progression to HCC. The comprehensive characterization of CRGs sheds light on their potential biofunctional importance in the context of NASH and HCC. Our experimental results show that FDX1 expression was significantly increased in NASH patients. Conclusions: The present study identified key CRGs, revealing their potential impact on NASH and HCC. Meanwhile, targeting FDX1 may prevent the progression of NASH to HCC.

Allicin attenuated hepatic ischemia/reperfusion injury in mice by regulating PPARγ-IRAK-M-TLR4 signal pathway.

Background: Hepatic ischemia/reperfusion (I/R) injury to the liver is a significant cause of morbidity and mortality following liver surgery, trauma, and hemorrhagic shock. It was reported that allicin, a type of garlic compound, had a protective effect against other hepatic diseases. Allicin's ability to protect against liver injury caused by ischemic reperfusion remains unknown. As a result, we conducted this study to determine allicin's effects and mechanism of action in hepatic I/R injury. Method: The liver I/R injury model was established by clamping the blood supply to the left and middle liver lobes. Three days prior to the hepatic I/R injury, different concentrations of allicin were gavaged. Then, hepatic function, histological changes, apoptosis markers, oxidative stress, and inflammatory cytokines were measured, and the molecular mechanisms were evaluated using western blot. Another separation experiment used IRAK-M knockout mice and peroxisome proliferator-activated receptor-gamma (PPARγ) inhibitor to deduce the molecular mechanisms. Results: Pretreatment with allicin prior to hepatic I/R injury reduced liver damage by inhibiting aminotransferase activity and alleviating liver injury. It significantly decreased cell apoptosis, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) production, and hepatic oxidative stress. Furthermore, this study demonstrated that GW9662 (inhibitor of PPARγ) abrogated allicin's positive effect by inhibiting PPARγ expression while suppressing IRAK-M expression. Thus, the depletion of IRAK-M cannot influence the expression of PPARγ. The down-regulation of PPARγ-IRAK-M disabled the protection of allicin in I/R injury. Conclusion: Allicin protects against hepatic I/R injury via dose-dependent regulation of the PPARγ-IRAK-M-TLR4 signaling pathway, and it may be a potential drug in future clinical treatment.

Liposomal chrysin attenuates hepatic ischaemia-reperfusion injury: possible mechanism via inhibiting NLRP3 inflammasome.

OBJECTIVES: The chrysin has properties of low aqueous solubility, bioavailability and absorption, and its effect on hepatic ischaemia-reperfusion (HIR) remains unclear. Thus, we prepared a liposomal chrysin (LC) and explored its effect and potential mechanism on HIR. METHODS: A thin-film dispersion method was used to prepare LC, and a mouse HIR model was used. Mice were pre-treated with LC (100 mg/kg) or placebo by gavage feeding at 16.5 h, 8.5 h, 0.5 h before modelling. RESULTS: The average particle sizes, polydispersity index, zeta potential, encapsulation efficiency and drug loading of LC were 129 ± 13.53 nm, 0.265 ± 0.021, -34.46 ± 4.14 mV, 95.03 ± 2.17%, 16.4 ± 0.8%. The concentration of chrysin in plasma and liver tissue by LC administration increased 2.54 times and 1.45 times. LC pre-treatment reduced HIR-induced liver injury and inhibited cell apoptosis. Besides, LC pre-treatment decreased reactive oxygen species and malondialdehyde and inhibited the inflammation response indicated by lower IL-6, TNF-α, infiltration of neutrophils. Further, LC pre-treatment significantly decreased NLRP3 activation, evidenced by reduced cleaved caspase-3, NLRP3, ASC, cleaved caspase-1 and IL-1ß expression. CONCLUSIONS: LC has good biocompatibility, and it could attenuate HIR-induced injury. Its mechanism was associated with NLRP3 inflammasome inhibition, and LC might be an effective drug for treating and preventing HIR-induced injury.

The effect of programmed intermittent epidural bolus compared with continuous epidural infusion in labor analgesia with ropivacaine: a meta-analysis of randomized controlled trials.

BACKGROUND: Programmed intermittent epidural bolus (PIEB) as a new technique for labor analgesia has aroused extensive attention. The character of separation of the motor block to sensory block makes ropivacaine becoming an important local anesthetic for labor analgesia. In this meta-analysis, we aimed to assess the efficiency and safety of PIEB regime compared to continuous epidural infusion (CEI) regime on labor analgesia with ropivacaine following the evidence emerged newly. METHODS: PubMed, EMBASE and the Cochrane library were searched for potential articles. Eligible studies should meet these criterions: (I) healthy women; (II) it should compare PIEB and CEI; (III) ropivacaine should be use as local anesthetic for the maintenance of analgesia; (IV) the study should report the any of the outcomes we need. Maternal satisfaction, consumption of ropivacaine and duration of labor as well as the adverse effect were used to measure the efficacy and safety of those two regimes. Mean difference (MD), relative risk (RR), 95% confidence intervals (CI) were used to present the final results. RESULTS: Ten articles of randomized controlled trials and 3,790 subjects were eventually included in study. The pooled results showed that PIEB with ropivacaine significantly improved satisfaction (MD, 7.87; 95% CI: 6.02 to 9.72; I2 =0%; P<0.001), reduced the local anesthetic (milligram) in total (MD, -10.37 milligrams; 95% CI: -17.70 to -3.03; I2 =94%; P<0.001) and hourly (MD, -1.80 milligrams; 95% CI: -2.62 to -0.98; I 2 =56%; P<0.001). PIEB shortened the second stage of labor but has similar total duration of labor and it also decrease the incidence of motor block compare to CEI. There were no differences in mode of delivery and rescue bolus between two groups. CONCLUSIONS: This study shows that PIEB regime was associated with higher satisfaction, lower consumption of ropivacaine in hours and totally, and shorter duration of second stage of labor compared to CEI in analgesia with ropivacaine during childbirth. PIEB regime has greater safety on fetus and maternity than CEI regime and it decreased the incidence of motor block without increasing other side effects compared to CEI.

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells.

Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.