Effect of Ursodeoxycholic Acid on Preventing SARS-CoV-2 Infection in Patients With Liver Transplantation: a multicenter retrospective cohort study.

BACKGROUND: Immunosuppressed recipients of liver transplantation (LT) are more likely to develop coronavirus disease 2019 (COVID-19) and may have an increased risk of developing worse outcomes. AIM: To assess the effect of ursodeoxycholic acid (UDCA) on preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. DESIGN: Adult patients (aged ≥ 18 years) who underwent LT between January 1st, 2015, and December 31st, 2022, were included and categorized into two groups according to their use of UDCA. METHODS: The prevalence and severity of COVID-19 among transplantation patients between the UDCA and non-UDCA groups were estimated and compared. RESULTS: Among the 897 LT patients who met the inclusion criteria, infection rate of SARS-CoV-2 was 78.4%, and the rate of severe illness was 5.1% from January 2022 to January 2023 in China. In the multivariate analysis, only UDCA treatment (P = 0.006) was found to be a protective factor against SARS-CoV-2 infection. After propensity score matching, the SARS-CoV-2 infection rate in the UDCA group was lower than that in the non-UDCA group (74.1% vs. 84.6%, P = 0.002). This rate was further reduced to 62.1% (P = 0.002) when the oral administration dose was greater than 15 mg/kg/d. There was no difference in the rates of severe COVID-19 illness, ICU admission, or ventilation rate or length of hospital stay with or without UDCA treatment (all P > 0.05). CONCLUSIONS: The use of UDCA in LT patients significantly reduced the SARS-CoV-2 infection rate and showed a dose-dependent protective effect.

A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62.

Quinazoline and its derivatives have drawn much attention in the development of potential antitumor agents. Here, we synthesized a series of 1,2,3-triazole derivatives of quinazoline at the C6 position and evaluated for their cytotoxic activity in various human cancer cell lines. We found that compound 5a was the most cytotoxic to HCT-116 cells (IC50, 0.36 µM). Target profiling found that 5a directly binds to both the autophagy-associated protein SQSTM1/P62 and the E3 ligase RNF168, promoting their interaction. Consistently, 5a treatment induces a decrease in RNF168-mediated H2A ubiquitination and compromises homologous recombination-mediated DNA repair, thus increasing the sensitivity of HCT-116 to X-ray radiation. Moreover, 5a suppressed xenografted tumor growth in mice in a dose-dependent manner. Taken together, the 1,2,3-triazole derivative of quinazoline 5a may serve as a novel compound for tumor therapy based on its role in promoting a P62/RNF168 interaction.

Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury.

Background: Hepatic ischemia-reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage migration inhibitory factor (MIF) in hepatic I/R injury is unclear. Methods: We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia-reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored in vivo and in vitro. Results: MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress in vivo and in vitro, whereas MIF overexpression significantly aggravated liver injury. Via RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice. Conclusion: Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.

Interaction analysis of FADS2 gene variants with chronic hepatitis B infection in Chinese patients.

The risk of chronic hepatitis B (CHB) infection is often affected by polyunsaturated fatty acids (PUFAs) metabolism which is strongly influenced by single nucleotide polymorphisms (SNPs) within the PUFA metabolic pathway. Given this, we designed this study to determine the relationship between specific polymorphisms within fatty acid desaturase 2 (FADS2), a key enzyme in PUFA metabolism, and CHB infection. We completed this evaluation using a case-control study comprising 230 CHB patients and 234 unrelated healthy controls in which the genetic relationships between three previously identified SNPs, isolated via mass spectrometry, and CHB infection. Our data revealed that none of these three SNPs (rs174568, rs174601, and rs2727270) were significantly associated with susceptibility to CHB infection when compared to healthy controls. However, when we stratified our cohort by sex, male subjects with the TC genotype for FADS2 exhibited a decreased risk for CHB infection (OR = 0.62, 95%CI = 0.39-0.96; OR = 0.64, 95%CI = 0.41-1.00; OR = 0.57, 95%CI = 0.36-0.90). Furthermore, age stratification revealed that both the T allele and the TC genotypes for each of the three target SNPs were less common in Chinese CHB cases in people younger than 50 years old. Correlation analysis also revealed that there was no statistically significant relationship between these three SNPs and HBV-DNA replication or hepatitis B surface antigen (HBsAg) levels. Thus, our data suggests that rs174568, rs174601, and rs2727270 may affect the CHB outcomes in various age or sex subgroups, suggesting that they may be useful predictive or diagnostic biomarkers of CHB infection in some populations.

Multi-species hydrocarbon measurement using TDLAS with a wide scanning range DFG laser.

Tunable diode laser absorption spectroscopy (TDLAS) is a widely used diagnostic technique due to its high sensitivity, fast response, low cost, and other merits. Hydrocarbon detection is a field of great interest in the application of tunable diode lasers as hydrocarbons are fundamental molecules in many industrial processes. Many tunable diode lasers are only suitable for single species detection due to the short scanning range and in real situations. However, different hydrocarbon species tend to exist simultaneously. Here we present a laser system based on the difference-frequency generation (DFG) method for simultaneous hydrocarbon mixtures detection. The direct absorption spectra of different hydrocarbons covering various groups (e.g., alkane, olefin, and aromatic) were measured. The measurements of the concentration dependence of absorbance for each molecule were carried out. The R2 values were larger than 0.997, which demonstrated the system can measure hydrocarbons covering different molecular classes accurately. The mixture components were identified using the independent component analysis and quantitative analysis was performed using the classical least-squares method. Future studies will focus on the validation of the system in actual processes.

E3 ubiquitin ligase ring finger protein 5 protects against hepatic ischemia reperfusion injury by mediating phosphoglycerate mutase family member 5 ubiquitination.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear. APPROACH AND RESULTS: RNF5 expression was significantly down-regulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression of cell lines were subjected to hypoxia-reoxygenation challenge. Results showed that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, whereas RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of apoptosis-regulating kinase 1 (ASK1) and its downstream c-Jun N-terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR. CONCLUSIONS: We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.

Caspase-1 Inhibitor Reduces Pyroptosis Induced by Brain Death in Kidney.

Brain death (BD) induces an organ-level inflammatory response. However, the underlying mechanisms have not been fully elucidated. Here, we investigated the role of caspase-1-mediated pyroptosis in BD-induced kidney injury in rats. A BD model was established in Sprague-Dawley rats. The rats were intravenously injected with Z-YVAD-FMK 1 h before BD, and sham-operated rats served as controls. After 0, 1, 2, 4, and 6 h of BD, renal injury, and renal expression of the nod-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, caspase-11, gasdermin D (GSDMD), IL-1ß, and IL-18 were assessed using quantitative reverse transcriptase-polymerase chain reaction, western blotting, and immunohistochemistry. Blood urea nitrogen and serum creatinine levels were measured. Additionally, renal tubular epithelial cells (NRK-52E) were subjected to 3 h of hypoxia followed by 6 h of reoxygenation and incubated with Z-YVAD-FMK before hypoxia and reoxygenation. Caspase-11 was knocked-down using small interfering RNA technology. Cell viability and levels of pyroptosis-associated proteins were assessed thereafter. NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18 expression levels were upregulated in BD rats. Treatment with Z-YVAD-FMK reduced mRNA and protein levels of caspase-1, GSDMD, IL-1ß, and IL-18, improved renal function, and alleviated renal injury. Z-YVAD-FMK efficaciously reduced pyroptosis effects in kidneys in BD rats. Thus, it could be considered as a therapeutic target for BD-induced kidney injury.

High expression of DHX9 promotes the growth and metastasis of hepatocellular carcinoma.

BACKGROUND: DHX9, an NTP-dependent RNA helicase, is closely associated with the proliferation and metastasis of some tumor cells and the prognosis of patients, but its role in hepatocellular carcinoma (HCC) is not well-known. This study was performed to explore the expression and role of DHX9 in HCC. METHODS: The expression of DHX9 in HCC tissues and cell lines was detected by TCGA database, qPCR, western blotting, and immunohistochemistry. The relationship between the DHX9 expression level and the prognosis of patients with HCC was accessed. Then, the function of DHX9 knockdown in HCC cells was examined by CCK-8, scratch, Transwell, and apoptosis assays. Epithelial-mesenchymal transition (EMT) was detected by western blotting. RESULTS: DHX9 was highly expressed in HCC tissues by analyzing both TCGA database and clinical samples. High DHX9 expression level was associated with TNM stage, vascular invasion and metastasis of HCC patients, and was an independent adverse prognostic factor. DHX9 knockdown significantly inhibited cell proliferation, migration, invasion and EMT and increased cell apoptosis in HCC cells. CONCLUSION: Our findings suggest that DHX9 participates in the progression of HCC as an oncogene and may be a potential target for the clinical diagnosis and therapy of HCC.

Dopamine and dopamine receptor D1 as a novel favourable biomarker for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common malignant tumours worldwide. Therefore, the identification and development of sensitivity- genes as novel diagnostic markers and effective therapeutic targets is urgently needed. Dopamine and dopamine receptor D1 (DRD1) are reported to be involved in the progression of various cancers. However, the crucial role of DRD1 in HCC malignant activities remains unclear. METHODS: We enrolled 371 patients with liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) to detect the expression and functions of DRD1. The Tumour Immune Estimation Resource (TIMER), UALCAN database, Kaplan-Meier plotter, cBioPortal database, and LinkedOmics database were utilized for the systematic investigation of DRD1 expression and related clinical features, coexpressed genes, functional pathways, mutations, and immune infiltrates in HCC. RESULTS: In this study, we determined that DRD1 expression was decreased in HCC tumour tissues versus normal tissues and that low DRD1 expression indicated a poor prognosis. The significance of DRD1 expression varied among different tumour samples. The somatic mutation frequency of DRD1 in the LIHC cohort was 0.3%. The biological functions of DRD1 were detected and validated, and DRD1 was shown to be involved in various functional activities, including metabolism, oxidation, mitochondrial matrix-related processes and other related signaling pathways. In addition, out study indicated that DRD1 had significant correlations with the infiltration of macrophages, B cells and CD+ T cells in HCC. CONCLUSIONS: These findings demonstrated the rationality of the potential application of DRD1 function as a novel biomarker for HCC diagnosis and a therapeutic target for HCC treatment.

Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability.

DNA double-strand break (DSB) repair by homologous recombination (HR) is essential for ensuring genome stability. Abnormal spindle-like microcephaly-associated (ASPM) gene encodes a spindle protein that is commonly implicated in primary microcephaly. We found that ASPM is recruited to sites of DNA damage in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ligase HERC2, preventing HERC2 from accessing to BRCA1 and ensuring BRCA1 stability. Inhibition of ASPM expression promotes HERC2-mediated BRCA1 degradation, compromises HR repair efficiency and chromosome stability, and sensitizes cancer cells to ionizing radiation. Moreover, we observed a synergistic effect between ASPM and PARP inhibition in killing cancer cells. This research has uncovered a novel function for ASPM in facilitating HR-mediated repair of DSBs by ensuring BRCA1 stability. ASPM might constitute a promising target for synthetic lethality-based cancer therapy.

Small-world effects in a modified epidemiological model with mutation and permanent immune mechanism.

Pandemic with mutation and permanent immune spreading in a small-world network described is studied by a modified SIR model, with consideration of mutation-immune mechanism. First, a novel mutation-immune model is proposed to modify the classical SIR model to simulate the transmission of mutable viruses that can be permanently immunized in small-world networks. Then, the influences of the size, coordination number and disorder parameter of the small-world network on the spread of the epidemic are analyzed in detail. Finally, the influences of mutation cycle and infection rate on epidemic transmission in small-world network are investigated further. The results show that the structure of the small-world network and the virus mutation cycle have an important impact on the spread of the epidemic. For viruses that can be permanently immunized, virus mutation is equivalent to making the immune cycle of human beings from infinite to finite. The dynamical behavior of the modified SIR epidemic model changes from an irregular, low-amplitude evolution at small disorder parameter to a spontaneous state of wide amplitude oscillations at large disorder parameter. Moreover, similar transition can also be found in increasing mutation cycle parameter. The maximum valid variation mutation decreases with the increase of disorder parameter and coordination number, but increase with respect to system size. In addition above, as the infection rate increases, the fraction of the infected increases and then decreases. As the mutation cycle increases, the time-average fraction of the infected and the infection rate corresponding to the maximum time-average fraction of the infected also decrease. As one conclusion, the results could give a deep understanding Pandemic with mutation and permanent immune spreading, from viewpoint of small-world network.

Interaction analysis of gene variants related to one-carbon metabolism with chronic hepatitis B infection in Chinese patients.

BACKGROUND: The risk of chronic hepatitis B (CHB) infection is influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by polymorphic variants in one-carbon metabolism genes. In the present study, we investigated the relationship between polymorphisms belonging to the one-carbon metabolic pathway and CHB infection. METHODS: A case-control study using 230 CHB patients and 234 unrelated healthy controls was carried out to assess the genetic association of 24 single nucleotide polymorphisins (SNPs) determined by mass spectrometry. RESULTS: Three SNPs, comprising rs10717122 and rs2229717 in serine hydroxymethyltransferase1/2 (SHMT2) and rs585800 in betaine-homocysteine S-methyltransferase (BHMT), were associated with the risk of CHB. Patients with DEL allele, DEL.DEL and DEL.T genotypes of rs10717122 had a 1.40-, 2.00- and 1.83-fold increased risk for CHB, respectively. Cases inheriting TA genotype of rs585800 had a 2.19-fold risk for CHB infection. The T allele of rs2229717 was less represented in the CHB cases (odds ratio = 0.66, 95% confidence interval = 0.48-0.92). The T allele of rs2229717 was less in patients with a low hepatitis B virus-DNA level compared to the control group (odds ratio = 0.49, 95% confidence interval = 0.25-0.97) and TT genotype of rs2229717 had a significant correlation with hepatitis B surface antigen level (p = 0.0195). Further gene-gene interaction analysis showed that subjects carrying the rs10717122 DEL.DEL/DEL.T and rs585800 TT/TA genotypes had a 2.74-fold increased risk of CHB. CONCLUSIONS: The results of the present study suggest that rs10717122, rs585800 and rs2229717 and gene-gene interactions of rs10717122 and rs585800 affect the outcome of CHB infection, at the same time as indicating their usefulness as a predictive and diagnostic biomarker of CHB infection.

Alpinetin protects against hepatic ischemia/reperfusion injury in mice by inhibiting the NF-κB/MAPK signaling pathways.

Liver damage induced by ischemia/reperfusion (I/R) remains a primary issue in liver transplantation and resection. Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, is widely used to treat various inflammatory diseases. However, the effects of alpinetin on hepatic I/R injury remain unclear. The present study investigated the protective effects of alpinetin pretreatment on hepatic I/R injury in mice. C57BL/6 mice were subjected to 1 h of partial hepatic ischemia followed by 6 h of reperfusion. Alpinetin (50 mg/kg) was given by intraperitoneal injection 1 h before liver ischemia. The blood and liver tissues were collected to assess biochemical indicators, hepatocyte damage, and levels of proteins related to signaling pathways. Furthermore, a hepatocytes hypoxia/reoxygenation (H/R) model was established for in vitro experiments. In vivo, we observed that alpinetin significantly attenuated the increases in alanine aminotransferase, aspartate transaminase, proinflammatory cytokines, hepatocyte damage, and apoptosis caused by hepatic I/R. Moreover, the hepatic I/R-induced nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinase (MAPK) pathways were suppressed by alpinetin. In vitro, we also observed that alpinetin inhibited the inflammatory response, apoptosis, and activation of the NF-κB/MAPK pathways in hepatocytes after H/R treatment. Our data indicate that alpinetin ameliorated the inflammatory response and apoptosis induced by hepatic I/R injury in mice. The protective effects of alpinetin on hepatic I/R injury may be due to its ability to inhibit the NF-κB/MAPK signaling pathways. These results suggest that alpinetin is a promising potential therapeutic reagent for hepatic I/R injury.

Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy.

Ischemia-reperfusion injury (IRI) is inevitable during liver surgery, and it is an important factor affecting the prognosis of patients. IL-6 rs1800796 single nucleotide polymorphisms (SNPs) can promote synthesis and secretion of IL-6 and protect hepatocytes from IRI. In this study, we investigated the mechanisms by which IL-6 alleviates hepatic IRI. We transfected lentivirus which carries IL-6 rs1800796 to L02 cells and constructed the cell line (L02-IL6) with a high expression of IL-6. The biological function of IL-6 SNPs was explored through a cell model of hypoxia-reoxygenation (H/R). Cell viability was evaluated by CCK8 and Real-Time Cell Analysis (RTCA), and found that the viability of the L02-IL6 cells was higher than that of the control group (P < 0.01). Flow cytometry assay showed that the rate of apoptosis was significantly decreased in L02-IL6 cells. Furthermore, in comparison with the control group, the level of cleaved-caspase3, which is an important marker of apoptosis, was dramatically decreased. These differences showed that the sequence variants at rs1800796 of the IL-6 gene could improve the resistance against H/R. Moreover, the levels of autophagy-related proteins, such as LC3 and Beclin-1, were upregulated in L02-IL6 group on H/R injury, which means IL-6 could alleviate apoptosis via activating the autophagy pathway. And we also found that the STAT3 signal pathway was activated. Next, we investigated whether the exogenous treatment with IL-6 affect hepatocytes and thus play a protective role. We pre-treated the L02 cells with recombinant human IL-6 for 12 h and then made H/R treatment. We found the treatment with 100 ng/ml IL-6 alleviated the damage of L02 cells and inhibited the apoptosis. And the further study revealed the pre-treatment with IL-6 activated the STAT3 signaling pathway in the L02 cells and then caused the activation of autophagy and apoptosis inhibition. IL-6 might play a critical role in alleviating hepatic IRI, through its modulation of the STAT3 signaling pathway, and activation of autophagy. Recombinant human IL-6 might be a potential therapeutic target in hepatic IRI.

The Impact of Social Value Orientation, Game Context and Trust on Cooperative Behavior After Cooperative Video Game Play.

This study explores the effects of the cooperative video game context, social value orientation (SVO) and trust on cooperative behavior. The main finding is that collaborative game play significantly increases cooperative behavior, especially in prosocial individuals. In addition, a mediation model is established in which trust partially mediates the association between the game mode and cooperative behavior. The results indicate that playing collaborative games increases cooperation in prosocial people partially by facilitating the trust they have in their gaming partners. The theoretical and practical implications of these findings are discussed.

[Study on the epidemic development of COVID-19 in Hubei province by a modified SEIR model].

OBJECTIVE: To establish a SEIR epidemic dynamics model that can be used to evaluate the COVID-19 epidemic, and to predict and evaluate the COVID-19 epidemic in Hubei province using the proposed model. METHODS: COVID-19 SEIR transmission dynamics model was established, which took transmission ability in latent period and tracking quarantine interventions into consideration. Based on the epidemic data of Hubei province from January 23, 2020 to February 24, 2020, the parameters of the newly established modified SEIR model were fitted. By using Euler integral algorithm to solve the modified SEIR dynamics model, the epidemic situation in Hubei province was analyzed, and the impact of prevention and control measures such as quarantine and centralized treatment on the epidemic development was discussed. RESULTS: The theoretical estimation of the epidemic situation by the modified SEIR epidemic dynamics model is in good agreement with the actual situation in Hubei province. Theoretical analysis showed that prevention and control quarantine and medical follow-up quarantine played an important inhibitory effect on the outbreak of the epidemic.The centralized treatment played a key role in the rapid decline in the number of infected people. In addition, it is suggested that individuals should improve their prevention awareness and take strict self-protection measures to curb the increase in infected people. CONCLUSIONS: The modified SEIR model is reliable in the evaluation of COVID-19 epidemic in Hubei province, which provides a theoretical reference for the decision-making of epidemic interventions.

Donor Brain Death Leads to a Worse Ischemia-Reperfusion Injury and Biliary Injury After Liver Transplantation in Rats.

BACKGROUND: Brain-dead (BD) donor is the main source for liver transplantation (LT). We aim to investigate the effect of brain death on donor liver inflammatory activity and its association with ischemia-reperfusion (I/R) injury and biliary tract injury after LT. MATERIAL AND METHOD: A brain death model using male Lewis rats was established, in both BD and non-BD groups; livers were harvested for transplantation using a 2-cuff technique. The rats were sacrificed 12 hours (n = 10) or 4 weeks (n = 10) after transplantation. I/R injury and long-term biliary tract injury were observed after transplantation. RESULTS: All rats survived for 4 weeks after transplantation. At 12 hours after BD-donor LT (BDDLT), liver injury worsened; serum transaminases, bilirubin, oxidative stress, inflammatory responses and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining level substantially increased (P < .05). At 4 weeks after BDDLT, serum bilirubin and bile lactate dehydrogenase and γ-glutamyl transpeptidase levels were elevated (P < .05). Biliary fibrosis and epithelial-mesenchymal transition (EMT) were detectable and NDRG1 gene expression was decreased. CONCLUSIONS: These results suggested that brain death-induced inflammatory response in donor organs and resulted in a worse I/R injury and biliary tract injury after LT in rats. The brain death-related biliary tract injury may be associated with the regulation of EMT through NDRG1.

Six-Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia-Reperfusion Injury by Suppressing Transforming Growth Factor-ß-Activated Kinase 1.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS: In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-ß-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS: Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

Synthesis and cytotoxic activity of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group as the A-ring or B-ring.

Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC50 value of 2.65 µM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway.