Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH.

BACKGROUND: MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear. METHODS: Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH. RESULTS: We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis. CONCLUSIONS: These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.

BTLA deficiency promotes HSC activation and protects against hepatic ischemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. APPROACH AND RESULT: A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. "Loss-of-function" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-ß1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. CONCLUSIONS: These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.

Diatomite-incorporated hierarchical scaffolds for osteochondral regeneration.

Osteochondral regeneration involves the highly challenging and complex reconstruction of cartilage and subchondral bone. Silicon (Si) ions play a crucial role in bone development. Current research on Si ions mainly focuses on bone repair, by using silicate bioceramics with complex ion compositions. However, it is unclear whether the Si ions have important effect on cartilage regeneration. Developing a scaffold that solely releases Si ions to simultaneously promote subchondral bone repair and stimulate cartilage regeneration is critically important. Diatomite (DE) is a natural diatomaceous sediment that can stably release Si ions, known for its abundant availability, low cost, and environmental friendliness. Herein, a hierarchical osteochondral repair scaffold is uniquely designed by incorporating gradient DE into GelMA hydrogel. The adding DE microparticles provides a specific Si source for controlled Si ions release, which not only promotes osteogenic differentiation of rBMSCs (rabbit bone marrow mesenchymal stem cells) but also enhances proliferation and maturation of chondrocytes. Moreover, DE-incorporated hierarchical scaffolds significantly promoted the regeneration of cartilage and subchondral bone. The study suggests the significant role of Si ions in promoting cartilage regeneration and solidifies their foundational role in enhancing bone repair. Furthermore, it offers an economic and eco-friendly strategy for developing high value-added osteochondral regenerative bioscaffolds from low-value ocean natural materials.

Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 supports formation of the pro-metastatic microenvironment in HCC.

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvß3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA.

Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Sophisticated Magneto-Mechanical Actuation Promotes In Situ Stem Cell Assembly and Chondrogenesis for Treating Osteoarthritis.

Abnormal mechanical loading often leads to the progressive degradation of cartilage and causes osteoarthritis (OA). Although multiple mechanoresponsive strategies based on biomaterials have been designed to restore healthy cartilage microenvironments, methods to remotely control the on-demand mechanical forces for cartilage repair pose significant challenges. Here, a magneto-mechanically controlled mesenchymal stem cell (MSC) platform, based on the integration of intercellular mechanical communication and intracellular mechanosignaling processes, is developed for OA treatment. MSCs loaded with antioxidative melanin@Fe3O4 magnetic nanoparticles (Magcells) rapidly assemble into highly ordered cell clusters with enhanced cell-cell communication under a time-varying magnetic field, which enables long-term retention and differentiation of Magcells in the articular cavity. Subsequently, via mimicking the gait cycle, chondrogenesis can be further enhanced by the dynamic activation of mechanical signaling processes in Magcells. This sophisticated magneto-mechanical actuation strategy provides a paradigm for developing mechano-therapeutics to repair cartilage in OA treatment.

A Clinic-Radiomics Model for Predicting the Incidence of Persistent Organ Failure in Patients with Acute Necrotizing Pancreatitis.

Background: Persistent organ failure (POF) is the leading cause of death in patients with acute necrotizing pancreatitis (ANP). Although several risk factors have been identified, there remains a lack of efficient instruments to accurately predict the incidence of POF in ANP. Methods: Retrospectively, the clinical and imaging data of 178 patients with ANP were collected from our database, and the patients were divided into training (n = 125) and validation (n = 53) cohorts. Through computed tomography image acquisition, the volume of interest segmentation, and feature extraction and selection, a pure radiomics model in terms of POF prediction was established. Then, a clinic-radiomics model integrating the pure radiomics model and clinical risk factors was constructed. Both primary and secondary endpoints were compared between the high- and low-risk groups stratified by the clinic-radiomics model. Results: According to the 547 selected radiomics features, four models were derived from features. A clinic-radiomics model in the training and validation sets showed better predictive performance than pure radiomics and clinical models. The clinic-radiomics model was evaluated by the ratios of intervention and mechanical ventilation, intensive care unit (ICU) stays, and hospital stays. The results showed that the high-risk group had significantly higher intervention rates, ICU stays, and hospital stays than the low-risk group, with the confidence interval of 90% (p < 0.1 for all). Conclusions: This clinic-radiomics model is a useful instrument for clinicians to evaluate the incidence of POF, facilitating patients' and their families' understanding of the ANP prognosis.

A deep learning model for prediction of post hepatectomy liver failure after hemihepatectomy using preoperative contrast-enhanced computed tomography: a retrospective study.

Objective: Post-hepatectomy liver failure (PHLF) remains clinical challenges after major hepatectomy. The aim of this study was to establish and validate a deep learning model to predict PHLF after hemihepatectomy using preoperative contrast-enhancedcomputed tomography with three phases (Non-contrast, arterial phase and venous phase). Methods: 265 patients undergoing hemihepatectomy in Sir Run Run Shaw Hospital were enrolled in this study. The primary endpoint was PHLF, according to the International Study Group of Liver Surgery's definition. In this study, to evaluate the proposed method, 5-fold cross-validation technique was used. The dataset was split into 5 folds of equal size, and each fold was used as a test set once, while the other folds were temporarily combined to form a training set. Performance metrics on the test set were then calculated and stored. At the end of the 5-fold cross-validation run, the accuracy, precision, sensitivity and specificity for predicting PHLF with the deep learning model and the area under receiver operating characteristic curve (AUC) were calculated. Results: Of the 265 patients, 170 patients with left liver resection and 95 patients with right liver resection. The diagnosis had 6 types: hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver metastases, benign tumor, hepatolithiasis, and other liver diseases. Laparoscopic liver resection was performed in 187 patients. The accuracy of prediction was 84.15%. The AUC was 0.7927. In 170 left hemihepatectomy cases, the accuracy was 89.41% (152/170), and the AUC was 82.72%. The accuracy was 77.47% (141/182) with liver mass, 78.33% (47/60) with liver cirrhosis and 80.46% (70/87) with viral hepatitis. Conclusion: The deep learning model showed excellent performance in prediction of PHLF and could be useful for identifying high-risk patients to modify the treatment planning.

The occurrence, speciation, and ecological effect of plastic pollution in the bay ecosystems.

Bay is a unique part of the ecosystem, acting as the intersection for marine and terrestrial systems and hosting diverse biological organisms. The ubiquitous application of plastics has resulted in a massive amount of plastic waste released and accumulated in the bay ecosystem, posing significant ecological effects. Thus, thoroughly understanding plastic pollution's occurrence, speciation, and ecological effect in the bay ecosystems is of vital importance. We conducted a comprehensive review on the sources and distribution of plastics in the bay ecosystem, and the associate ecological effects, from individual toxicity to trophic transfer in ecosystems. Among bay areas around the world, the concentrations of microplastics vary from 0.01 to 3.62 × 105 item/m3 in seawater and 0 to 6.75 × 105 item/kg in sediment. Small-sized plastic particles (mostly <2 mm) were widely reported in bay organisms with the concentration range of 0 to 22.5 item/ind. Besides, the toxicity of plastics on marine organisms has been documented in terms of mortality, growth, development, reproduction, enzyme activity and transcription. Since abundance of small plastic particles (e.g., micro- and nano-scale) is far greater than large plastic debris in the bay ecosystems, in-depth risk assessment of small-sized plastics needs to be conducted under environmentally realistic conditions. Our review could provide a better understanding on the occurrence, speciation, and ecological effect of plastic pollution in the bay ecosystems.

Photomagnetically Powered Spiky Nanomachines with Thermal Control of Viscosity for Enhanced Cancer Mechanotherapy.

Nanomachines with active propulsion have emerged as an intelligent platform for targeted cancer therapy. Achieving an efficient locomotion performance using an external energy conversion is a key requirement in the design of nanomachines. In this study, inspired by diverse spiky structures in nature, a photomagnetically powered nanomachine (PMN) with a spiky surface and thermally dependent viscosity tunability is proposed to facilitate mechanical motion in lysosomes for cancer mechanotherapy. The hybrid nanomachine is integrated with magnetic nanoparticles as the core and covered with gold nanotips. Physical simulations and experimental results prove that the spiky structure endows nanomachines with an obvious photomagnetic coupling effect in the NIR-II region through the alignment and orienting movement of plasmons on the gold tips. Using a coupling-enhanced magnetic field, PMNs are efficiently assembled into chain-like structures to further elevate energy conversion efficiency. Notably, PMNs with the thermal control of viscosity are efficiently propelled under simultaneously applied dual external energy sources in cell lysosomes. Enhanced mechanical destruction of cancer cells via PMNs is confirmed both in vitro and in vivo under photomagnetic treatment. This study provides a new direction for designing integrated nanomachines with active adaptability to physiological environments for cancer treatment.

Influence of Metabolic Risk Factors on the Risk of Bacterial Infections in Hepatitis B-Related Cirrhosis: A 10-Year Cohort Study.

Aim: The effect of metabolic factors on the risk of bacterial infections (BIs) in patients with hepatitis B virus (HBV)-related cirrhosis has not been demonstrated. This study aimed to explore specific metabolic factors associated with the BIs in these patients. Methods: A population-based cohort of 471 patients with HBV-related cirrhosis was retrospectively enrolled between 2009 and 2019. The primary end point was the incidence of BIs during hospitalization, which were compared according to the metabolism-related indicators, namely, presence of diabetes, level of high-density lipoprotein cholesterol (HDLC) and triglyceride, and body mass index (BMI). The propensity score matching (PSM) was adopted to eliminate baseline discrepancies. Results: Compared with the non-diabetic group, the incidences of BIs were higher in the diabetic group before and after PSM (p = 0.029 and p = 0.027). Similar results were found in the low HDLC group as compared with the normal HDLC group before and after PSM (p < 0.001 and p = 0.025). Further analysis showed that the incidences of BIs in patients with low HDLC alone were lower than patients with both low HDLC and diabetes before and after PSM (p = 0.003 and p = 0.022). Similarly, the incidence of BIs in patients with diabetes alone was lower than those in patients with both low HDLC and diabetes both before and after PSM (p = 0.002 and p = 0.018). However, neither triglyceride nor BMI level was related to BIs in our cohort. Conclusion: In patients with HBV-related cirrhosis, the presence of diabetes and low level of HDLC were risk factors of BIs, showing a synergistic effect.

Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. METHODS: The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. RESULTS: High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. CONCLUSION: WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract.

A stent-based diverting technique after low anterior resection of rectal cancer: our preliminary experience.

BACKGROUND: Anastomotic leakage (AL) is a severe complication of rectal cancer low anterior resection (LAR). Ileostomy, the most common method to reduce the severity of AL, is associated with the risk of permanent stoma and an additional operation for stoma reversal. This purpose of this study is to develop a novel protective technique called the stent-based diverting technique (SDT) to protect the anastomosis following LAR. METHODS: From March 2020 to December 2020, thirty-four patients treated with LAR followed by SDT were enrolled prospectively at Sir Run Run Shaw Hospital. Demographic characteristics, laboratory test results, surgical outcomes, and oncological features were recorded. RESULTS: Overall, the median period of stent degradation was 21 (18-24) days. One patient (2.9%) had anastomotic leakage, and another patient (2.9%) had intestinal obstruction, while no other complications (e.g., intestinal volvulus, perforation, fistula) were observed in this study. CONCLUSIONS: The unique SDT may be a novel approach to prevent anastomotic leakage following low anterior resection of rectal cancer.

Rechargeable Sodium-Ion Battery Based on Polyazaacene Analogue Anode.

The high theoretical specific capacity, strong structural designability and relatively inexpensive manufacturing cost make the exploration of organic electrode materials more attractive in recent years. In this article, owing to the large π-conjugated structure, plenty of nitrogen heteroatoms and multiring aromatic system, polyazaacene analogue poly(1,6-dihydropyrazino[2,3 g]quinoxaline-2,3,8-triyl-7-(2H)-ylidene-7,8-dimethylidene) (PQL) was applied as the anode in sodium-ion batteries (SIBs). PQL was almost insoluble in conventional liquid organic electrolyte (1 M NaClO4 in ethylene carbonate (EC)/dimethyl carbonate (DMC) (v:v=1 : 1) with 5 % fluoroethylene carbonate (FEC)), which strongly improved its cycle stability. The initial discharge capacity was obtained to be 1825 mAh g-1 at the current density of 100 mA g-1 and stabilized at 317 mAh g-1 after 400 cycles with the coulombic efficiency as high as 97 %. It not only showed good rate capability at high current densities (202, 183 mAh g-1 at 1 A g-1 and 1.5 A g-1 ) but also had a superior energy density around 290 Wh kg-1 .

Immune-related cholangitis induced by immune checkpoint inhibitors: a systematic review of clinical features and management.

BACKGROUND AIMS: Immune checkpoint inhibitors (ICIs) improve the survival of patients with advanced tumors. However, immune-related adverse events limit the use of ICIs. Although liver toxicity has been concerned gradually, little is known about bile duct injury associated with ICIs. Hence, this review aims to describe clinicopathological features, imaging, and management of immune-mediated cholangitis (IMC) induced by ICIs. METHODS: We retrieved the literature from the PubMed database for case reports and series of IMC induced by ICIs. IMC was then classified as small-ducts type, large-ducts type and mixed type. Biochemical parameters, pathological characteristics, imaging features, treatment and response were evaluated and compared among three patterns. RESULTS: Fifty-three cases of IMC were enrolled. The median values of alkaline phosphatase and alanine transaminase of IMC were 1328 and 156 IU/L. The ALP level of the large-ducts type was higher than that of the small-ducts type (P = 0.021). The main pathological characteristics of small-ducts cholangitis were portal inflammation, bile duct injury and ductular reaction. The imaging features of large-duct cholangitis were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Forty-eight (90%) cases received immunosuppression therapy. Biliary enzymes reduced in 79% of cases receiving immunosuppression therapy, but only 8.5% of cases returned to normal. It took a long time for biliary enzymes to recover. CONCLUSIONS: The clinicians should be aware of the possibility of IMC if the biliary enzymes increase significantly after the use of ICIs. The liver function can be improved partially by immunosuppressive therapy in the majority of IMC.

A positive feedback loop between Periostin and TGFß1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.

BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma.

Ferroptosis is a newly identified cell death mechanism and potential biomarker for hepatocellular carcinoma (HCC) therapy; however, its clinical relevance and underlying mechanism remain unclear. In this study, transcriptome and methylome data from 374 HCC cases were investigated for 41 ferroptosis-related genes to identify ferroptosis activity-associated subtypes. These subtypes were further investigated for associations with clinical and pathological variables, gene mutation landscapes, deregulated pathways and tumour microenvironmental immunity. A gene expression signature and predictive model were developed and validated using an additional 232 HCC cases from another independent cohort. Two distinct ferroptosis phenotypes (Ferroptosis-H and Ferroptosis-L) were identified according to ferroptosis gene expression and methylation in the patients with HCC. Patients with the Ferroptosis-H had worse overall and disease-specific survival, and the molecular subtypes were significantly associated with different clinical characteristics, mRNA expression patterns, tumour mutation profiles and microenvironmental immune status. Furthermore, a 15-gene ferroptosis-related prognostic model (FPM) for HCC was developed and validated which demonstrated accurate risk stratification ability. A nomogram included the FPM risk score, ECOG PS and hepatitis B status was developed for eventual clinical translation. Our results suggest that HCC subtypes defined by ferroptosis gene expression and methylation may be used to stratify patients for clinical decision-making.

Aggravation of hepatic ischemia­reperfusion injury with increased inflammatory cell infiltration is associated with the TGF­ß/Smad3 signaling pathway.

Ischemia­reperfusion (IR) injury is a major challenge influencing the outcomes of hepatic transplantation. Transforming growth factor­ß (TGF­ß) and its downstream gene, SMAD family member 3 (Smad3), have been implicated in the pathogenesis of chronic hepatic injuries, such as hepatic fibrosis. Thus, the present study aimed to investigate the role of the TGF­ß/Smad3 signaling pathway on hepatic injury induced by IR in vivo. In total, 20 129S2/SvPasCrl wild­type (WT) mice were randomized into two groups; 10 mice underwent IR injury surgery and 10 mice were sham­operated. Histopathological changes in liver tissues and serum levels of alanine aminotransferase (ALT) were examined to confirm hepatic injury caused by IR surgery. The expression levels of TGF­ß1, Smad3 and phosphorylated­Smad3 (p­Smad3) were detected via western blotting. Furthermore, a total of five Smad3­/­ 129S2/SvPasCrl mice (Smad3­/­ mice) and 10 Smad3+/+ littermates received IR surgery, while another five Smad3­/­ mice and 10 Smad3+/+ littermates received the sham operation. Histopathological changes in liver tissues and serum levels of ALT were then compared between the groups. Furthermore, hepatic apoptosis and inflammatory cell infiltration after IR were evaluated in the liver tissues of Smad3­/­ mice and Smad3+/+ mice. The results demonstrated that the expression levels of TGF­ß1, Smad3 and p­Smad3 were elevated in hepatic tissue from WT mice after IR injury. Aggravated hepatic injury, increased apoptosis and enhanced inflammatory cell infiltration induced by hepatic IR injury were observed in the Smad3­/­ mice compared with in Smad3+/+ mice. Collectively, the current findings suggested that activation of the TGF­ß/Smad3 signaling pathway was present alongside the hepatic injury induced by IR. However, the TGF­ß/Smad3 signaling pathway may have an effect on protecting against liver tissue damage caused by IR injury in vivo.

Mitochondrial dysfunction attenuates rapid regeneration in livers with toxin-induced fibrosis.

BACKGROUND: The mechanism of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-induced rapid liver regeneration remains poorly documented, especially in patients with fibrosis. Therefore, this study aims to investigate the underlying mechanism of ALPPS-induced accelerated regeneration in toxin-induced fibrosis models. METHODS: The ALPPS-induced regeneration model was established in livers with thioacetamide (TAA)-induced fibrosis to determine the regenerative pathways involved in rapid regeneration. Confirmatory experiments were performed in transforming growth factor beta 1 (TGFß1)-treated AML12 cells and mice with carbon tetrachloride (CCl4)-induced fibrosis. Finally, mitochondrial dysfunction was validated in fibrotic/non-fibrotic patients. RESULTS: In TAA-induced fibrotic mice, ALPPS-induced regeneration was significantly inferior to that of the control group (P=0.027 at day 2 and P<0.001 at day 7). Furthermore, mitochondria-associated genes were significantly downregulated in TAA-challenged mice. Accordingly, the reduced production of ATP and elevated levels of malondialdehyde indicated disturbances in intracellular energy metabolism during the ALPPS-induced regenerative process after TAA treatment. Further investigations were performed in TGF-ß1-treated AML12 cells and CCl4-treated mice, which indicated that mitochondrial dysfunction attenuated the capacity for rapid regeneration after ALPPS. CONCLUSIONS: In summary, this study revealed that mitochondrial dysfunction led to inferior regeneration in livers with toxin-induced fibrosis and identified new therapeutic targets to improve the feasibility and safety of the ALPPS procedure. Further studies in human patients are required in the future.

Assessment of non-vitamin K antagonist oral anticoagulants for the management of left ventricular thrombus.

Although several studies have assessed the effect of non-vitamin K antagonist oral anticoagulants (NOACs) relative to that of vitamin K antagonists (VKAs) in patients with left ventricular thrombus, the results remain controversial. Herein, a meta-analysis was performed to compare the effectiveness and safety of NOACs versus VKAs for the treatment of left ventricular thrombus. We systematically searched the Cochrane Library, PubMed and Embase databases until November 2020 for studies that compared the effects of NOACs versus VKAs in patients with left ventricular thrombus. The treatment effects were expressed as odds ratios (ORs) with 95% confidence intervals (CIs) and pooled by a random-effects model. Seven retrospective studies involving 865 patients with left ventricular thrombus (266 NOAC and 599 VKA users) were included. The pooled analysis suggested no difference in the rate of thrombus resolution between the NOAC and VKA groups (OR = 0.83, 95% CI 0.61-1.13). There were also no differences in the rates of stroke or systemic embolism (OR = 0.62, 95% CI 0.20-1.97), bleeding events (OR = 0.73, 95% CI 0.37-1.45), or all-cause death (OR = 0.92, 95% CI 0.50-1.69) between patients treated with NOACs and those treated with VKAs. In addition, the rates of thrombus resolution, stroke or systemic embolism, bleeding events, and all-cause death between NOAC- and warfarin-treated patients were also similar. Our current evidence suggested that NOAC and VKA users had similar rates of thrombus resolution and clinical outcomes among patients with left ventricular thrombus. Further large-scale prospective studies should confirm our results.