ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia-reperfusion injury.

There is increasing need to expand availability of donor liver grafts, including steatotic livers. However, the current use of steatotic grafts in liver transplantation is less acceptable due to their higher susceptibility to ischemia-reperfusion (I/R) injury. To investigate the mechanism underlying the susceptibility of steatotic liver to I/R injury, we detected cell death markers and inflammation in clinical donor livers and animal models. We found that caspase-8-mediated hepatic apoptosis is activated in steatotic liver I/R. However, ablation of caspase-8 only slightly mitigated steatotic liver I/R injury without affecting inflammation. We further demonstrated that RIPK1 kinase induces both caspase-8-mediated apoptosis and cell death-independent inflammation. Inhibition of RIPK1 kinase significantly protects against steatotic liver I/R injury by alleviating both hepatic apoptosis and inflammation. Additionally, we found that RIPK1 activation is induced by Z-DNA binding protein 1 (ZBP1) but not the canonical TNFα pathway during steatotic liver I/R. Deletion of ZBP1 substantially decreases the steatotic liver I/R injury. Mechanistically, ZBP1 is amplified by palmitic acid-activated JNK pathway in steatotic livers. Upon I/R, excessive reactive oxygen species trigger ZBP1 activation by inducing its aggregation independent of the Z-nucleic acids sensing action in steatotic livers, leading to the kinase activation of RIPK1 and the subsequent aggravation of liver injury. Thus, ZBP1-mediated RIPK1-driven apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be targeted to protect steatotic donor livers during transplantation.

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.

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.

Protective effect of pinocembrin from Penthorum chinense Pursh on hepatic ischemia reperfusion injury via regulating HMGB1/TLR4 signal pathway.

Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and transplantation. Pinocembrin (PIN) is a kind of flavonoid monomer extracted from the local traditional Chinese medicine Penthorum chinense Pursh (P. chinense). However, the effect of PIN on HIRI has not determined. We investigated the protective effect and potential mechanism of PIN against HIRI. Model mice were subjected to partial liver ischemia for 60 min, experimental mice were pretreated with PIN orally for 7 days, and H2 O2 -induced oxidative damage model in AML12 hepatic cells was established in vitro. Histopathologic analysis and serum biochemical levels revealed that PIN had hepatoprotective activities against HIRI. The variation of GSH, SOD, MDA, and ROS levels indicated that PIN treatments attenuated oxidative stress in tissue. PIN pretreatment obviously ameliorated apoptosis, and restrained the expression of HMGB1 and TLR4 in vivo. In vitro, compared with H2 O2 group, the contents of ROS, mitochondrial membrane potential, apoptotic cells, and Bcl-2 protein were decreased, while the Bax protein expression was increased. Moreover, HMGB-1 small interfering RNA test and western blotting showed that PIN pretreatment reduced HMGB1 and TLR4 protein levels. In conclusion, PIN pretreatment effectively protected hepatocytes from HIRI and inhibited the HMGB1/TLR4 signaling pathway.

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.

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.

Glycolysis-Related LINC02432/Hsa-miR-98-5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a malignant cancer with high incidence and mortality. Glycometabolic rearrangements (aerobic glycolysis) is a hallmark of PAAD and contributes to tumorigenesis and progression through numerous mechanisms. This study aimed to identify a novel glycolysis-related lncRNA-miRNA-mRNA ceRNA signature in PAAD and explore its potential molecular function. We first calculated the glycolysis score for each PAAD patient by the ssGSEA algorithm and found that patients with higher hallmark glycolysis scores had poorer prognosis. Subsequently, we obtained a novel glycolysis-related LINC02432/hsa-miR-98-5p/HK2 axis from the TCGA and GEO databases using comprehensive bioinformatics analysis and developed a nomogram to predict overall survival. Furthermore, functional characterization analysis revealed that LINC02432/hsa-miR-98-5p/HK2 axis risk score was negatively correlated with ferroptosis. The tumor immune infiltration analysis suggested positive correlations between ceRNA risk score and infiltrated M0 macrophage levels in PAAD. Correlation analysis found that ceRNA risk scores were positively correlated with four chemokines (CXCL3, CXCL5, CXCL8 and CCL20) and one immune checkpoint gene (SIGLEC15). Meanwhile, tumor mutation burden (TMB), an indicator for predicting response to immunotherapy, was positively correlated with ceRNA risk score. Finally, the drug sensitivity analysis showed that the high-risk score patients might be more sensitive to EGFR, MEK and ERK inhibitors than low-risk score patients. In conclusion, our study suggested that LINC02432/hsa-miR-98-5p/HK2 axis may serve as a novel diagnostic, prognostic, and therapeutic target in PAAD treatment.

N-Acetyl-l-tryptophan inhibits CCl4-induced hepatic fibrogenesis via regulating TGF-ß1/SMAD and Hippo/YAP1 signal.

BACKGROUND: Although liver fibrosis is a key pathologic process in many liver diseases, therapeutic approaches for inhibiting liver fibrosis are still very limited. N-Acetyl-l-tryptophan (l-NAT) has a hepatoprotective effect via inhibiting the destruction of liver cells, enhancing cell viability and reducing the inflammation. However, the effect of l-NAT on liver fibrosis is not determined. PURPOSE: The present study investigated the effect of l-NAT on liver fibrosis and explored it potential molecular mechanism. METHODS: To address this concern, this study was carried out via fibrotic mice model induced by CCl4 and many approaches such as various histological staining methods, western blot assay, etc. RESULT: l-NAT decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in fibrotic mice model induced by carbon tetrachloride (CCl4). Histological staining showed that l-NAT ameliorated liver injury and fibrosis, and reduced the expression of α-smooth muscle actin (α-SMA) and Collagen I protein. l-NAT also attenuated apoptosis by down-regulating the level of pro-apoptotic protein Bax and up-regulating that of anti-apoptotic protein Bcl-2. Moreover, l-NAT inhibited the expressions of TGF-ß1/SMAD and matrix metalloproteinase 9 (MMP9) proteins, and reversed the expression of YAP1 protein in CCl4-induced liver fibrosis. CONCLUSION: These results clearly demonstrated that l-NAT attenuated CCl4-induced liver fibrosis in mice, and this protective mechanism might relate to TGF-ß1/SMAD and Hippo/YAP1 signaling pathway. Thus, this study provided data basis for the prevention and treatment of liver fibrosis.

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.

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.

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.

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.

Fault Critical Point Prediction Method of Nuclear Gate Valve with Small Samples Based on Characteristic Analysis of Operation.

The number of fault samples for the new nuclear valve is commonly rare; thus, the machine learning algorithm is not suitable for the fault prediction of this kind of equipment. In order to overcome this difficulty, this paper proposes a novel method for the fault critical point prediction of the gate valve based on the characteristic analysis of the operation process variables. The operation process of gate valve switch often contains various fault characteristics and information, and this method first adopts the Shannon entropy to describe the power spectrum of vibration signal relevant to the operation process of gate valve switch, and then employs the mean value of the power spectrum entropy as an indirect process variable and further investigates the differences between the indirect process variable under the healthy state and the fault state with a different fault degree. In addition, the power signal of the gate valve is also employed as the direct process variable and the features of the direct process variable under the healthy state and the fault state with different fault degrees are also investigated. Based on the previous indirect process variable and direct process variable, the prediction approach for the critical point of the gate valve fault is established by analyzing the change in the indirect process variable and direct process variable before and after faults. Finally, the data of a nuclear gate valve experiment are employed to demonstrate the feasibility of the proposed method and the results show that the proposed method can effectively predict the fault critical point of the mentioned nuclear gate valve. If the diagnostic threshold is set properly, the critical point prediction of a nuclear gate valve fault can be realized as 100% or close to 100%. Furthermore, the proposed method can be directly applied to the nuclear gate valve in a nuclear power plant to improve the operation reliability of the valve. At the same time, the method can be applied to the fault diagnosis and prediction of valves in other fields, such as the chemical industry.

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.

MMP25-AS1/hsa-miR-10a-5p/SERPINE1 axis as a novel prognostic biomarker associated with immune cell infiltration in KIRC.

Long non-coding RNAs (lncRNAs) play a significant role in multiple human cancers as competing endogenous RNAs (ceRNAs). However, a systematic mRNA-microRNA (miRNA)-lncRNA network linked to kidney renal clear cell carcinoma (KIRC) prognosis has not been described. In this study, we aimed to identify the prognosis-related ceRNA regulatory network and analyzed its relationship with immune cell infiltration to predict KIRC patient survival. The MMP25-AS1/hsa-miR-10a-5p/SERPINE1 ceRNA network related to the prognosis of KIRC was obtained through bioinformatics analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Meanwhile, we constructed a three-gene-based survival predictor model, which could be referential for future clinical research. Methylation analyses suggested that the abnormal upregulation of the SERPINE1 likely resulted from hypomethylation. Furthermore, the immune infiltration analysis showed that the MMP25-AS1/hsa-miR-10a-5p/SERPINE1 axis could affect the changes in the tumor immune microenvironment and the development of KIRC by affecting the expression of chemokines (CCL4, CCL5, CXCL13, and XCL2). Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that the high expression of SERPINE1 might be related to tumor immune evasion in KIRC. In summary, the current study constructing the MMP25-AS1/hsa-miR-10a-5p/SERPINE1 ceRNA network might be a novel significant prognostic factor associated with the diagnosis and prognosis of KIRC.

The Dietary Supplement γ-Oryzanol Attenuates Hepatic Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress and HMGB1/NLRP3 Inflammasome.

The purpose of this study is to investigate the protective effect of γ-oryzanol (ORY) against hepatic ischemia reperfusion (HIR) injury and the potential protective mechanisms of ORY. ORY is an important biologically active ingredient isolated from rice bran oil, which has anti-inflammatory and antiapoptotic effects. However, it is still unknown whether ORY can protect the liver from the HIR damage. In this study, ORY was administered orally for seven days, after which the animals were subjected to liver ischemia for 60 minutes and reperfused for 6 hours. Related indicators were analyzed. The results showed that ORY pretreatment significantly reduced the levels of AST and ALT, relieved hepatocellular damage and apoptosis, and attenuated the exhaustion of SOD and GSH and accumulation of MDA and MPO. Interestingly, ORY treatment could significantly decreased ER stress. Furthermore, ORY pretreatment remarkably reduced the protein expressions of HMGB1, NLRP3, caspase-1 (p20), and IL-1ß to protect the liver from I/R-induced inflammasome activation and apoptosis. In conclusion, we demonstrated the potential effect of ORY in modulating oxidative stress, endoplasmic reticulum stress, and inflammasome activation during HIR.

The predictive value of systemic immune inflammation index for postoperative survival of gallbladder carcinoma patients.

BACKGROUND: Growing evidence indicates that systemic immune inflammation index (SII) can predict the prognosis of various solid tumors. The objective of this study aimed to investigate the efficacy of SII in predicting the prognosis of gallbladder carcinoma (GBC) patients after radical surgery. METHODS: A consecutive series of 93 patients with GBC who underwent radical resection were enrolled in the retrospective study. The cutoff value for the SII was calculated using the time-dependent receiver operating characteristic (ROC) curve analysis by overall survival (OS) prediction. The associations between the SII and the clinicopathologic characteristics were analyzed using Pearson's χ2 test and Fisher's exact test. Survival curves were calculated using the Kaplan-Meier method. Univariate analysis was performed to evaluate the prognostic relevance of preoperative parameters. The multivariate Cox regression proportional hazard model was used to assess variables significant on univariate analysis. RESULTS: The Kaplan-Meier survival analysis and the multivariate analysis of patients with GBC who received radical resection showed SII independently predicted OS. The univariate analysis showed that the TNM stage, SII, CA19-9, ALP, prealbumin, NLR, MLR, lymph node metastasis, and histopathological type were all associated with overall survival. In time-dependent ROC analysis, the area of the SII-CA19-9 under the ROC curve (AUC) was higher than that of the preoperative SII or CA19-9 levels for the prediction of OS. CONCLUSION: Our results demonstrate that high SII was a predictor of poor long-term outcomes among patients with GBC undergoing curative surgery. SII-CA19-9 classification may be more effective in predicting the postoperative prognosis of GBC patients.