Inducible nitric oxide synthase activity mediates TNF-α-induced endothelial cell dysfunction.

Inducible nitric oxide synthase (iNOS) and vascular endothelial dysfunction have been implicated in the development and progression of atherosclerosis. This study aimed to elucidate the role of iNOS in vascular endothelial dysfunction. Ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry combined with multivariate data analysis was used to characterize the metabolic changes in human umbilical vein endothelial cells (HUVECs) in response to different treatment conditions. In addition, molecular biology techniques were employed to explain the molecular mechanisms underlying the role of iNOS in vascular endothelial dysfunction. Tumor necrosis factor-α (TNF-α) enhances the expression of iNOS, TXNIP, and the level of reactive oxygen species (ROS) facilitates the entry of nuclear factor-κB (NF-κB) into the nucleus and promotes injury in HUVECs. iNOS deficiency reversed the TNF-α-mediated pathological changes in HUVECs. Moreover, TNF-α increased the expression of tumor necrosis factor receptor-2 (TNFR-2) and the levels of p-IκBα and IL-6 proteins and CD31, ICAM-1, and VCAM-1 protein expression, which was significantly reduced in HUVECs with iNOS deficiency. In addition, treating HUVECs in the absence or presence of TNF-α or iNOS, respectively, enabled the identification of putative endogenous biomarkers associated with endothelial dysfunction. These biomarkers were involved in critical metabolic pathways, including glycosylphosphatidylinositol-anchor biosynthesis, amino acid metabolism, sphingolipid metabolism, and fatty acid metabolism. iNOS deficiency during vascular endothelial dysfunction may affect the expression of TNFR-2, vascular adhesion factors, and the level of ROS via cellular metabolic changes, thereby attenuating vascular endothelial dysfunction.NEW & NOTEWORTHY Inducible nitric oxide synthase (iNOS) deficiency during vascular endothelial dysfunction may affect the expression of tumor necrosis factor receptor-2 and vascular adhesion factors via cellular metabolic changes, thereby attenuating vascular endothelial dysfunction.

Risk factors for hypercoagulability after laparoscopic hepatic haemangioma resection.

Background: Laparoscopic hepatectomy with a small incision, light abdominal wall trauma and rapid postoperative recovery has been widely used in the surgical treatment of benign liver diseases. However, the occurrence of complications, such as deep-vein thrombosis, associated with laparoscopic techniques has raised concerns. This study aimed to investigate the factors influencing the development of a hypercoagulable state in patients following laparoscopic hepatic haemangioma resection. Materials and Methods: Between 2017 and 2019, 78 patients to be treated by laparoscopic hepatic haemangioma resection were selected prospectively for the study. The differences in relevant clinical factors between patients with and without blood hypercoagulability at 24 h after surgery were compared, and the factors influencing the development of blood hypercoagulability after surgery were analysed. Results: The study included 78 patients, split into the hypercoagulable group (n = 27) and nonhypercoagulable group (n = 51). Compared with patients who did not develop blood hypercoagulability, patients who did had significantly higher preoperative levels of fibrinogen (Fib), D-dimer (D-Di), fibrinogen degradation products (FDP), platelet count (PLT), low-density lipoprotein cholesterol (LDL-C) and history of hyperlipidaemia whereas high-density lipoprotein cholesterol (HDL-C) levels were significantly lower (P < 0.05.) in hypercoagulable group. Univariate and multifactorial logistic regression analyses showed that a history of hyperlipidaemia, Fib ≥3.83 g/L, D-Di ≥9.12 µg/ml, FDP ≥14.64 µg/ml, PLT ≥292 × 109/L, HDL-C ≥1.25 mmol/L and LDL-C ≥2.03 mmol/L was the most common independent risk factors for the development of a hypercoagulable state of blood in patients after laparoscopic hepatic haemangioma resection (P < 0.05). Conclusion: For patients undergoing laparoscopic hepatic haemangioma resection, attention should be paid to the development of a hypercoagulable state in those with the risk factors described in this study.

Dihydroartemisinin alleviates steatosis and inflammation in nonalcoholic steatohepatitis by decreasing endoplasmic reticulum stress and oxidative stress.

Nonalcoholic steatohepatitis (NASH) is a severely inflammatory subtype of nonalcoholic fatty liver. Endoplasmic reticulum stress (ERS) and oxidative stress (OS) cause metabolic abnormalities, promote liver steatosis and inflammation, and are central to the development of NASH. Dihydroartemisinin (DHA) is a compound extracted from Artemisia annua that is often used in the treatment of malaria. Recent studies have shown that DHA also has a wide range of pharmacological effects, acting on various organs throughout the body to exert anti-inflammatory, antioxidant, and anti-fibrotic effects. In this study, we demonstrated in vitro that the anti-inflammatory effect of DHA is effective against NASH and reduces liver steatosis. DHA treatment decreased the synthesis of lipids, such as cholesterol and free fatty acids, and the expression of nuclear factor kappa-B. This is accomplished by inhibiting the unfolded protein response and reducing the production of reactive oxygen species, thereby inhibiting OS and ERS. This study reveals DHA's therapeutic effect and potential mechanism in NASH, implying that DHA could be a new and promising candidate for NASH therapy.

Sinapic acid inhibits pancreatic cancer proliferation, migration, and invasion via downregulation of the AKT/Gsk-3ß signal pathway.

Among digestive system cancers, the extremely poor prognosis of pancreatic cancer (PC) is a pressing concern. Nonoperative treatments such as targeted and immunotherapy, have improved the current situation, however, the accompanying side effects of these chemicals should not be ignored. Here, we discovered a novel hydroxycinnamic acid named sinapic acid (SA) derived from fruits, vegetables, cereals, and oil crops as an effective anti-PC molecule. Both the in vitro and in vivo models we designed showed that SA exhibited anticancer activities but not apoptosis induction. Research on the underlying mechanisms illustrated that AKT phosphorylation was blocked by SA, and the downstream Gsk-3ß was downregulated subsequently. Our study revealed the inhibitory activity and underlying mechanisms of SA, providing evidence that SA is a potential strategy for cancer research and can be a promising option of PC chemotherapy.

Prognostic value of the modified Glasgow prognostic score in biliary tract cancer patients: a systematic review and meta-analysis.

BACKGROUND: Biliary tract cancer (BTC) is an invasive adenocarcinoma affecting the hepatobiliary system, but high recurrence rates highlight the need for more effective adjuvant approaches. The modified Glasgow prognostic score (mGPS) has been explored as an independent prognostic indicator in patients with BTC. However, consensus on its prognostic value is lacking. This meta-analysis aimed to comprehensively assess the association between mGPS and diverse clinical outcomes in BTC by systematically analyzing relevant studies. METHODS: A systematic search approach was used to look for eligible papers published until June 2023 in PubMed, Web of Science, and Embase, with a focus on overall survival (OS) and disease-free/recurrence-free survival (DFS/RFS). The prognostic potential of mGPS was assessed using hazard ratios (HRs) with corresponding 95% CIs. RESULTS: A total of 15 papers comprising 2447 patients were included in this meta-analysis. The results demonstrated that, in patients with BTC, the high mGPS was associated with poorer OS (HR=1.49, 95% CI=1.35-1.65, P<0.001) and DFS/RFS (HR=3.23, 95%CI=1.98-5.26, P=0.193). CONCLUSION: According to this meta-analysis, our study found that high mGPS was associated with poorer OS and DFS/RFS in patients with BTC.

Postbiotics Prepared Using Lactobacillus reuteri Ameliorates Ethanol-Induced Liver Injury by Regulating the FXR/SHP/SREBP-1c Axis.

SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.

Prognostic impact of the Controlling Nutritional Status Score in patients with biliary tract cancer: a systematic review and meta-analysis.

Background: Biliary tract cancer (BTC) is a malignancy associated with unfavorable outcomes. Advanced BTC patients have a propensity to experience compromised immune and nutritional status as a result of obstructive jaundice and biliary inflammation. Currently, there is a lack of consensus on the impact of the Controlling Nutritional Status (CONUT) score in the context of BTC prognosis. The purpose of this study is to conduct a meta-analysis on the association between CONUT and the prognosis of patients suffering from BTC. Methods: A defined search strategy was implemented to search the PubMed, Embase, and Web of Science databases for eligible studies published until March 2023, with a focus on overall survival (OS), relapse-free survival/recurrence-free survival(RFS), and relevant clinical characteristics. The prognostic potential of the CONUT score was evaluated using hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: In this meta-analysis, a total of 1409 patients from China and Japan were involved in 9 studies. The results indicated that the CONUT score was significantly correlated with worse OS (HR=2.13, 95% CI 1.61-2.82, P<0.0001) and RFS (HR=1.83, 95% CI 1.44-2.31, P<0.0001) in patients with BTC. And, the analysis showed that a high CONUT score was significantly associated with clinical characteristics such as jaundice (OR=1.60, 95% CI=1.14-2.25, P=0.006), poorly differentiated tumor (OR=1.43, 95% CI=1.03-1.99, P=0.03), pT3 and 4 stage of the tumor (OR=1.87, 95% CI=1.30-2.68, P=0.0007), and complications of Clavien-Dindo classification grade IIIa or higher (OR=1.79, 95% CI=1.03-3.12, P=0.04). Conclusion: This meta-analysis indicates that a high CONUT score can serve as a significant prognostic indicator for survival outcomes among patients diagnosed with BTC.

Efficacy and safety of surufatinib in the treatment of advanced solid tumors: a systematic evaluation and meta­analysis.

Previous retrospective studies have suggested that surufatinib is effective for treating advanced solid tumors; however, the efficacy and safety of this drug needs to be investigated further via high-quality evidence or randomized controlled trials. In the present study, a meta-analysis was carried out to evaluate the safety and effectiveness of surufatinib for patients with advanced solid tumors. Systematic, electronic literature searches were conducted using PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov. The disease control rate (DCR) of surufatinib in solid tumors was 86% [effect size (ES), 0.86; 95% confidence interval (CI), 0.82-0.90; I2=34%; P=0.208] and the objective response rate was 16% (ES, 0.16; 95% CI, 0.12-0.21; I2=48%; P=0.103), while the progressive disease rate was only 9% (ES, 0.09; 95% CI, 0.05-0.15; I2=68%, P=0.014). Surufatinib showed different degrees of adverse reactions during the treatment of solid tumors. Among these adverse events, the incidence of increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 24% (ES, 0.24; 95% CI, 0.18-0.30; I2=45.1%; P=0.141) and 33% (ES, 0.33; 95%CI, 0.28-0.38; I2=63.9%; P=0.040), respectively. In the placebo-controlled trial, the relative risks (RRs) of elevated AST and ALT were 1.04 (95% CI, 0.54-2.02; I2=73.3%; P=0.053) and 0.84 (95% CI, 0.57-1.23; I2=0%; P=0.886), respectively. Overall, surufatinib was characterized by a high DCR and a low disease progression rate, thus indicating that it could exert a good therapeutic effect on solid tumors. Additionally, surufatinib showed a lower RR for adverse effects compared with other treatment modalities.

Aloin Attenuates Oxidative Stress, Inflammation, and CCl4-Induced Liver Fibrosis in Mice: Possible Role of TGF-ß/Smad Signaling.

Liver fibrosis refers to the excessive buildup of extracellular matrix (ECM) components in liver tissue. It is considered a pathological response to liver damage for which there is no effective treatment. Aloin, an anthraquinone compound isolated from the aloe plant, has shown good pharmacological effects in the treatment of gastric cancer, ulcerative colitis, myocardial hypertrophy, traumatic brain injury, and other diseases; however, its specific impact on liver fibrosis remains unclear. To address this gap, we conducted a study to explore the mechanisms underlying the potential antifibrotic effect of aloin. We constructed a mouse liver fibrosis model using carbon tetrachloride (CCl4) dissolved in olive oil as a modeling drug. Additionally, a cellular model was developed by using transforming growth factor ß1 (TGF-ß1) as a stimulus applied to hepatic stellate cells. After aloin intervention, serum alanine aminotransferase, hepatic hydroxyproline, and serum aspartate aminotransferase were reduced in mice after aloin intervention compared to CCl4-mediated liver injury without aloin intervention. Aloin relieved the oxidative stress caused by CCl4 via reducing hepatic malondialdehyde in liver tissue and increasing the level of superoxide dismutase. Aloin treatment decreased interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α and increased the expression of IL-10, which inhibited the inflammatory response in liver injury. In addition, aloin inhibited the activation of hepatic stellate cells and reduced the level of α-smooth muscle actin (α-SMA) and collagen type I. In cell and animal experiments, aloin attenuated liver fibrosis, acting through the TGF-ß/Smad2/3 signaling pathway, and mitigated CCl4- and TGF-ß1-induced inflammation. Thus, the findings of this study provided theoretical data support and a new possible treatment strategy for liver fibrosis.

Zyxin promotes hepatocellular carcinoma progression via the activation of AKT/mTOR signaling pathway.

Hepatocellular carcinoma (HCC) is a common malignancy that is driven by multiple genes and pathways. The aim of this study was to investigate the role and specific mechanism of the actin-interacting protein zyxin (ZYX) in HCC. We found that the expression of ZYX was significantly higher in HCC tissues compared to that in normal liver tissues. In addition, overexpression of ZYX in hepatoma cell lines (PLC/PRF/5, HCCLM3) enhanced their proliferation, migration and invasion, whereas ZYX knockdown had the opposite effects (SK HEP-1, Huh-7). Furthermore, the change in the expression levels of ZYX also altered that of proteins related to cell cycle, migration and invasion. Similar results were obtained with xenograft models. The AKT/mTOR signaling pathway is one of the key mediators of cancer development. While ZYX overexpression upregulated the levels of phosphorylated AKT/mTOR proteins, its knockdown had the opposite effect. In addition, the AKT inhibitor MK2206 neutralized the pro-oncogenic effects of ZYX on the HCC cells, whereas the AKT activator SC79 restored the proliferation, migration and invasion of HCC cells with ZYX knockdown. Taken together, ZYX promotes the malignant progression of HCC by activating AKT/mTOR signaling pathway, and is a potential therapeutic target in HCC.

Kaempferol From Penthorum chinense Pursh Attenuates Hepatic Ischemia/Reperfusion Injury by Suppressing Oxidative Stress and Inflammation Through Activation of the Nrf2/HO-1 Signaling Pathway.

The purpose of this study is to investigate the protective effect of kaempferol (KAE), the main active monomer from Penthorum chinense Pursh, on hepatic ischemia/reperfusion injury (HI/RI) and its specific mechanism. HI/RI is a common complication closely related to the prognosis of liver surgery, and effective prevention and treatment methods are still unavailable. Ischemia/reperfusion (I/R) injury is caused by tissue damage during ischemia and sustained oxidative stress and inflammation during reperfusion. Penthorum chinense Pursh is a traditional Chinese medicine widely used to treat liver disease since ancient times. Kaempferol (KAE), a highly purified flavonoid active monomer isolated and extracted from Penthorum chinense Pursh, was investigated for its protective effect on HI/RI. Our study indicates that KAE pretreatment alleviated I/R-induced transaminase elevation and pathological changes. Further analysis revealed that KAE pretreatment attenuates I/R-induced oxidative stress (as measured by the content of MDA, SOD and GSH) in vivo and reduces hypoxia/reoxygenation (H/R) -induced reactive oxygen species (ROS) generation in vitro. Meanwhile, KAE inhibits activation of NF-κB/p65 and reduces the release of pro-inflammatory factors (TNF-α and IL-6) to protect the liver from I/R-induced inflammation. Nuclear erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotection regulator because it induces anti-inflammatory, antioxidant, and cytoprotective genes. Therefore, we analyzed the protein levels of Nrf2 and its downstream heme oxygenase-1 (HO-1) in the liver of mice and hepatocytes of humankind, respectively, and discovered that KAE pretreatment activates the Nrf2/HO-1 signaling pathway. In summary, this study confirmed the hepatoprotective effect of KAE on HI/RI, which inhibits oxidative stress and inflammation by activating the Nrf2/HO-1 signaling pathway.

Thiamine pretreatment improves endotoxemia-related liver injury and cholestatic complications by regulating galactose metabolism and inhibiting macrophage activation.

BACKGROUND: As a major metabolic site, the liver is an important target organ of endotoxemia. High serum lipopolysaccharide (LPS) levels can cause hepatocyte necrosis and produce cholestasis, which results in severe liver injury. Contrastingly, thiamine (THA) has shown anti-inflammatory effects against severe infections and may be indicated for systemic endotoxemia treatment. Therefore, the present study was conducted to investigate the effective treatment of endotoxemia-induced liver injury with THA and the possible molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: in vivo, We established two models of endotoxemia-induced liver injury at the in vivo level using LPS and bile duct ligation (BDL) + LPS, administering prophylactic THA intraperitoneally to mice. In vitro, the effects of THA on RAW264.7 and THP-1 administration of LPS-induced inflammatory macrophage activation were observed. Metabolomic analysis screening and subsequent validation experiments were also performed. THA has different degrees of preventive therapeutic effects on different causes of endotoxemia-induced liver injury, as evidenced by a decreased alanine aminotransferase (ALT) and decreased inflammatory factors. This study aimed to clarify the specific mechanism. We subsequently found that THA reduced the inflammatory macrophages produced by RAW264.7 and THP-1 in response to LPS. Additionally, THA reduced galactose liver accumulation and improved glucose metabolism. Moreover, Galectin-3 (Gal-3), as a point of interaction between macrophage activation and galactose metabolism mechanisms, was observed to inhibit Gal-3 expression by THA at both in vivo and in vitro levels. CONCLUSIONS: This study revealed that THA may be a viable prophylactic treatment option for the prevention of liver injury occurring in endotoxemia, which is associated with its effects on the modulation of Gal-3 to improve the inflammatory response and the inhibition of galactose metabolism. Additional evidence is provided for its clinical application.

Efficacy and safety of the apolipoprotein C-III inhibitor Volanesorsen: a systematic evaluation and meta-analysis.

PURPOSE: Familial celiac disease syndrome (FCS) is a form of hypertriglyceridemia (HTG) caused by the accumulation of celiac particles. Currently, volanesorsen is considered to be used to treat patients with FCS and HTG to improve symptoms. To evaluate the effect of volanesorsen on lipid metabolism in patients with FCS, we performed a systematic evaluation and meta-analysis. METHODS: A systematic search of PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library was conducted, and the bibliographies of original articles were checked manually. The quality of the studies was assessed using the Cochrane Risk of Bias tool. RESULTS: Four randomized, controlled trials involving 246 patients were analyzed in this study. Patients treated with volanesorsen showed (MD = -78.85%; 95% CI = -96.04 to -61.65, P = 0.67, I2 = 0%) decrease in TG and (MD = -80.08%; 95% CI = -90.02 to -71.54, P = 0.25, I2 = 29%) decrease in ApoC-III levels compared to patients in the placebo group showing a significant decrease. In addition, HDL-C increased (MD = 46.01% 95% CI = 41.03 to 50.99, P = 0.41, I2 = 0%), NHDL-C decreased (MD = -32.12%; 95% CI = -44.39 to -19.85, P = 0.11, I2 = 55%), VLDL-C decreased (MD = -65.88%; 95% CI = -83.97 to -47.79, P = 0.71, I2 = 0%), apo A1 increased (MD = 13.12%; 95% CI = 7.83 to 18.40, P = 0.72, I2 = 0%), and apoB increased (MD = 7.94 %; 95% CI = -1.90 to 17.78, P = 0.54, I2 = 0%) all suggest that volanesorsen has an overall FCS with a therapeutic effect. However, LDL-C increased (MD = 99.59%; 95% CI = 69.19 to 130.00, P = 0.61, I2 = 0%) and apo B48 decreased (MD = 82.89%; 95% CI = -100.88 to -64.91, P = 0.42, I2 = 0%), showing an inverse effect, suggesting that volanesorsen's did not target all proteins of lipid metabolism.

Transcriptomic Analysis Reveals Lactobacillus reuteri Alleviating Alcohol-Induced Liver Injury in Mice by Enhancing the Farnesoid X Receptor Signaling Pathway.

Alcoholic liver disease (ALD) is caused by alcohol abuse and can progress to hepatitis, cirrhosis, and even hepatocellular carcinoma. Previous studies suggested that Lactobacillus reuteri (L. reuteri) ameliorates ALD, but the exact mechanisms are not fully known. This study created an ALD model in mice, and the results showed L. reuteri significantly alleviating lipid accumulation in the mice. Transcriptome sequencing showed the L. reuteri treatment group had the most enriched metabolic pathway genes. We then studied the farnesoid X receptor (FXR) metabolic pathway in the mice liver tissue. Western blot analysis showed that FXR and carbohydrate response element binding protein (ChREBP) were upregulated and sterol regulatory element binding transcription factor 1 (Srebf1) and Cluster of differentiation (CD36) were downregulated in the L. reuteri-treated group. Subsequently, we administered FXR inhibitor glycine-ß-muricholic acid (Gly-ß-MCA) to mice, and the results show that Gly-ß-MCA could reduce the therapeutic effect of L. ruteri. In conclusion, our study shows L. reuteri improved liver lipid accumulation in mice via the FXR signaling regulatory axis and may be a viable treatment option for ALD.

Sinapic Acid Alleviates Acute Pancreatitis in Association with Attenuation of Inflammation, Pyroptosis, and the AMPK/NF-[Formula: see text]B Signaling Pathway.

Among the diseases of the digestive system, the incidence of acute pancreatitis (AP) has increased. Although the AP is primarily self-limited, mortality remains high when it progressed to severe acute pancreatitis (SAP). Despite significant advances in new drug development, treatments for AP are not ideal. Here, we discovered a novel hydroxycinnamic acid, sinapic acid (SA), which is widely distributed in plants and is an effective treatment for AP. Using in vitro and in vivo models, we demonstrated that pretreatment with SA ameliorated cerulein-induced pancreatic damage and inflammation and inhibited the activation of Caspase-1 and Caspase-11, which mediate pyroptosis of pancreatic acinar cells during AP. These effects may occur through the inhibition of AMPK phosphorylation and downregulation of NF-[Formula: see text]B. Our findings demonstrate the therapeutic effects and reveal the underlying mechanisms of SA, which warrants its further study as an effective treatment for AP.