Effectiveness of edoxaban in portal vein thrombosis associated with liver cirrhosis.

Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child-Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Current Trends on the Involvement of Zinc, Copper, and Selenium in the Process of Hepatocarcinogenesis.

Numerous nutritional factors increase the risk of hepatocellular carcinoma (HCC) development. The dysregulation of zinc, copper, and selenium homeostasis is associated with the occurrence of HCC. The impairment of the homeostasis of these essential trace elements results in oxidative stress, DNA damage, cell cycle progression, and angiogenesis, finally leading to hepatocarcinogenesis. These essential trace elements can affect the microenvironment in HCC. The carrier proteins for zinc and copper and selenium-containing enzymes play important roles in the prevention or progression of HCC. These trace elements enhance or alleviate the chemosensitivity of anticancer agents in patients with HCC. The zinc, copper, or selenium may affect the homeostasis of other trace elements with each other. Novel types of cell death including ferropotosis and cupropotosis are also associated with hepatocarcinogenesis. Therapeutic strategies for HCC that target these carrier proteins for zinc and copper or selenium-containing enzymes have been developed in in vitro and in vivo studies. The use of zinc-, copper- or selenium-nanoparticles has been considered as novel therapeutic agents for HCC. These results indicate that zinc, copper, and selenium may become promising therapeutic targets in patients with HCC. The clinical application of these agents is an urgent unmet requirement. This review article highlights the correlation between the dysregulation of the homeostasis of these essential trace elements and the development of HCC and summarizes the current trends on the roles of these essential trace elements in the pathogenesis of hepatocarcinogenesis.

Alcohol-related cancer morbidity and mortality are stratified using modified albumin platelet product.

Alcohol abuse is associated with several diseases, such as hepatocellular carcinoma, cirrhosis, and extrahepatic malignancies. Recently, we reported albumin platelet product (APP) and modified APP (mAPP) as novel indices of liver fibrosis staging and prognosis in patients without alcoholic liver diseases. This retrospective cohort study aimed to extend application of APP and mAPP in prognosis prediction of patients with alcoholic liver diseases. We enrolled 222 patients with alcoholic liver diseases based on their medical records. Cut-off values of APP = 4.349 and mAPP = 2.484 were adopted based on a past report. Hazard ratios of APP and mAPP were compared to those of albumin-bilirubin score and fibrosis-4 index. The primary and secondary endpoints were carcinogenesis and death, respectively. Thus, APP = 4.349 and mAPP = 2.484 significantly differentiated cancer-free survival and overall survival in univariate analysis. Hazard ratios of mAPP = 2.484 were greater than those of the albumin-bilirubin score of -2.270 and fibrosis-4 index of 3.25. Multivariate analysis revealed mAPP = 2.484 as an independent risk factor for carcinogenesis and overall death. In conclusion, mAPP is a simple index to stratify patient's risk for carcinogenesis and death.

Involvement of essential trace elements in the pathogenesis of hepatitis C virus­related chronic liver disease and nonalcoholic steatohepatitis.

Essential trace elements are involved in the pathogenesis of chronic liver disease (CLD), which causes hepatic inflammation, steatosis and fibrosis. The present study investigated the roles of essential trace elements in the pathogenesis of hepatitis C virus-related CLD (CLD-C) and nonalcoholic steatohepatitis (NASH), and compared the levels of these trace elements between the two groups. Serum zinc (Zn), selenium (Se), copper (Cu) and ferritin levels were measured in patients with CLD-C (n=66) and NASH (n=26). Subsequently, the correlations between the levels of these essential trace elements in patient sera and the biochemical or pathological parameters of patients with CLD-C and NASH were determined. The results demonstrated that the serum ferritin levels were significantly correlated with serum alanine aminotransferase levels in both the CLD-C and NASH groups. In both groups, the serum Zn and Se levels were significantly associated with serum albumin levels, and inversely associated with the stages of hepatic fibrosis. Furthermore, serum ferritin levels were positively associated, and serum Zn levels were inversely correlated with the grades of hepatic steatosis in patients with CLD-C, whereas serum Se levels were closely associated with the grades of hepatic steatosis only in patients with NASH. In both groups, serum ferritin levels were positively correlated, and serum Zn levels were inversely correlated with homeostasis model for the assessment of insulin resistance (HOMA-IR) values, and serum Se was negatively correlated with the HOMA-IR values in patients with CLD-C only. In conclusion, these results indicated that the involvement of essential trace elements in insulin resistance and hepatic steatosis may differ slightly between patients with CLD-C and those with NASH.

Higher Indocyanine Green Retention Is Associated with Improved Prognosis in Patients with Hepatocellular Carcinoma Treated with Transcatheter Arterial Chemoembolization.

PURPOSE: To test indocyanine green retention rate at 15 minutes (ICG-R15) as a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization (TACE) therapy. MATERIALS AND METHODS: This retrospective cohort study was performed on the data of 278 consecutive patients with HCC treated with TACE after ICG-R15 testing at a single university hospital. Cox proportional hazard model analysis was performed to identify independent prognostic factors. After adjusting for age, sex, stage of HCC, albumin-bilirubin score, etiologies, and baseline year by propensity score matching, the prognostic impact of higher ICG-R15 was evaluated using the Kaplan-Meier curve. RESULTS: Univariate and multivariate analyses identified higher ICG-R15 as a positive prognostic factor for overall survival. Propensity score matching generated two 77-patient cohorts: ICG-R15 <20% group and ICG-R15 >20% group. The overall survival of the ICG-R15 >20% group was significantly better than that of the ICG-R15 <20% group. CONCLUSIONS: Higher ICG-R15 acted as a positive long-term prognostic factor in patients with HCC treated with TACE.

Efficacy and outcome of molecular targeted therapies in elderly patients with hepatocellular carcinoma: Relative dose intensity associated with overall survival.

AIM: Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting. METHODS: In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old). RESULTS: Overall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI. CONCLUSIONS: MTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.

Predictors of therapeutic response to peginterferon α­2a and nucleos(t)ide analog combination therapy for HBeAg­negative chronic hepatitis B: 1­year follow­up after treatment.

Chronic hepatitis B (CHB) is a major global health concern. Guidelines for the management of hepatitis B virus (HBV) indicate that the loss of hepatitis B surface antigen (HBsAg) is a key endpoint of interest. The present study aimed to examine long-term changes in HBsAg levels in HBV-DNA-negative, hepatitis B e-antigen (HBeAg)-negative patients treated with peginterferon (Peg-IFN) α-2a and nucleos(t)ide analog (NA), and to examine the conditions that make them susceptible to HBsAg decline. A total of 17 patients with CHB treated with NA and Peg-IFN were observed for 96 weeks (48 weeks of Peg-IFN therapy and 48 weeks of post-treatment follow-up). In this study, responders were defined as those with a 50% or greater decrease in HBsAg levels from baseline at week 96. Beginning at week 16 of Peg-IFN therapy, there was a significant difference in the decrease in HBsAg levels from baseline between the responders and non-responders. In responders, HBsAg levels tended to be >60% lower 16 weeks after Peg-IFN initiation than before initiation. Age at the start of NA use and the duration of NA use before Peg-IFN treatment initiation were significant pretreatment factors associated with HBsAg response. In conclusion, Peg-IFN was revealed to be more effective in HBeAg-negative patients with CHB who started NA at a young age and have been on long-term treatment, particularly if the HBsAg levels decreased to less than 60% of the starting level at week 16 after starting Peg-IFN treatment.

MicroRNAs and Nonalcoholic Steatohepatitis: A Review.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.

Relationship between Accurate Diagnosis of Sarcopenia and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab Combination Therapy.

Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4-26.4) and 10.6 (1.1-24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4-27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (p < 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia.

Nutritional Support for Alcoholic Liver Disease.

Malnutrition is a common finding in alcohol use disorders and is associated with the prognosis of patients with alcoholic liver disease (ALD). These patients also frequently show deficiencies in vitamins and trace elements, increasing the likelihood of anemia and altered cognitive status. The etiology of malnutrition in ALD patients is multifactorial and complex and includes inadequate dietary intake, abnormal absorption and digestion, increased skeletal and visceral protein catabolism, and abnormal interactions between ethanol and lipid metabolism. Most nutritional measures derive from general chronic liver disease recommendations. Recently, many patients with ALD have been diagnosed with metabolic syndrome, which requires individualized treatment via nutritional therapy to avoid overnutrition. As ALD progresses to cirrhosis, it is frequently complicated by protein-energy malnutrition and sarcopenia. Nutritional therapy is also important in the management of ascites and hepatic encephalopathy as liver failure progresses. The purpose of the review is to summarize important nutritional therapies for the treatment of ALD.

Phase Lag Analysis Scalp Electroencephalography May Predict Seizure Frequencies in Patients with Childhood Epilepsy with Centrotemporal Spikes.

Background: Childhood epilepsy with centrotemporal spikes (CECTS) is the most common epilepsy syndrome in school-aged children. However, predictors for seizure frequency are yet to be clarified using the phase lag index (PLI) analyses. We investigated PLI of scalp electroencephalography data at onset to identify potential predictive markers for seizure times. Methods: We compared the PLIs of 13 patients with CECTS and 13 age- and sex-matched healthy controls. For the PLI analysis, we used resting-state electroencephalography data (excluding paroxysmal discharges), and analyzed the mean PLIs among all electrodes and between interest electrodes (C3, C4, P3, P4, T3, and T4) and other electrodes. Furthermore, we compared PLIs between CECTS and control data and analyzed the associations between PLIs and total seizure times in CECTS patients. Results: No differences were detected in clinical profiles or visual electroencephalography examinations between patients with CECTS and control participants. In patients with CECTS, the mean PLIs among all electrodes and toward interest electrodes were higher at the theta and alpha bands and lower at the delta and gamma bands than those in control participants. Additionally, the mean PLIs toward interest electrodes in the beta frequency band were negatively associated with seizure times (P = 0.02). Conclusion: The resting-state delta, theta, alpha, and gamma band PLIs might reflect an aberrant brain network in patients with CECTS. The resting-state PLI among the selected electrodes of interest in the beta frequency band may be a predictive marker of seizure times in patients with CECTS.

Pegylated interferon therapy-related microRNA-6126 downregulates sodium taurocholate cotransporting polypeptide expression in hepatocytes.

Hepatitis B virus (HBV) infection is one of the most serious global health problems. Our previous data using an in vitro assay revealed that miR-6126 suppressed the extracellular HBs antigen level, suggesting that miR-6126 had potential to suppress viral activity of HBV. In the current study, we aimed to clarify whether miR-6126 downregulated the expression level of sodium taurocholate cotransporting polypeptide (NTCP), a host cell receptor required for HBV entry. In brief, HepG2-NTCP cells were utilized to evaluate the expression level of NTCP and the PreS1 attachment to NTCP after transfection with miR-6126. The protein expression level of NTCP was evaluated using Western blot analysis and immunostaining. In addition to HepG2-NTCP cells, PXB cells were also utilized to validate inhibitory effect of miR-6126 on PreS1 attachment. The HBs antigen level in the culture supernatant was measured to evaluate reduction of HBV entry into hepatocytes. The stability of NTCP mRNA was evaluated to ascertain the cause of the downregulation of NTCP mRNA. The expression profile of messenger RNAs was evaluated using next-generation sequencing to search for direct targets of miR-6126. Consequently, transfection of miR-6126 decreased the NTCP expression level in HepG2-NTCP cells. Attachment of the PreS1 probe on the cell surface decreased in HepG2-NTCP cells and PXB cells, primary human hepatocytes. HBs antigen level in the culture supernatant also declined in PXB cells. Stability of NTCP mRNA was reduced by miR-6126 transfection in HepG2 cells. In conclusion, miR-6126 downregulated the expression of NTCP mRNA, which contributed to the inhibition of HBV entry into hepatocytes exerted by miR-6126.

Pemafibrate improves liver dysfunction and non-invasive surrogates for liver fibrosis in patients with non-alcoholic fatty liver disease with hypertriglyceridemia: a multicenter study.

BACKGROUND: This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia. METHODS: A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used. RESULTS: Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (p = 0.003). The levels of AST (p = 0.038), alanine aminotransferase (ALT) (p = 0.003), and gamma-glutamyl transferase (GGT) (p = 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (p < 0.05). However, serum HDL-cholesterol (p = 0.193), LDL-cholesterol (p = 0.967), and eGFR (p = 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers' Type IV collagen (p = 0.753) and FIB-4 index (p = 0.333) did not significantly differ, while Autotaxin (p = 0.006) and the AST-to-platelet ratio index (APRI) (p = 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (p = 0.959) and CAP (p = 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (p = 0.0475). CONCLUSION: Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.

HbA1c of 5.8% or higher as the most useful indicator for recommendation of ultrasonography to detect nonalcoholic fatty liver disease.

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. This study was performed to examine the association between NAFLD and each factor of metabolic syndrome and to identify the factors that are most strongly associated with NAFLD in participants undergoing health checkups. Methods: We studied 6538 participants who underwent a health checkup from 2017 to 2018 in our institution. Participants with alcohol intake exceeding 20 g/day or with other chronic liver diseases were excluded. Fatty liver was detected by ultrasonography. Results: In total, 4310 participants were enrolled, and 28.4% had fatty liver (NAFLD). The prevalence of NAFLD was highest in the diabetes mellitus (DM)-only group than in the dyslipidemia-only or hypertension-only group. The DM-only group was the only group whose prevalence of NAFLD was >50% in the overall study and in males. The prevalence of NAFLD was higher in males than in females in the DM-only, hypertension-only, and dyslipidemia-only groups. The prevalence of NAFLD was >70% in the dyslipidemia and DM combined group. Multivariate analysis showed that gender and HbA1c were the independent factors most strongly associated with NAFLD. The cutoff value for HbA1c by receiver operating characteristic curve analysis was 5.8% (sensitivity, 57.9%; specificity, 72.6%; area under the curve, 0.70). Conclusion: NAFLD was most strongly associated with DM, among the various components of metabolic syndrome. We strongly recommend abdominal ultrasonography to detect NAFLD in patients with an HbA1c of ≥5.8% in general practice and during health checkups.

Antitumor Effect of Zinc Acetate in Hepatocellular Carcinoma Cell Lines via the Induction of Apoptosis.

We aimed to verify antitumor effects of zinc acetate on hepatocellular carcinoma (HCC) in vitro. Five HCC cell lines (HepG2, Hep3B, Huh7, HLE and Alex) were used to evaluate the antitumor effects of zinc acetate. Cell viability was determined by the Cell Counting Kit-8 assay. The cell-cycle alteration was evaluated by a flow cytometric analysis and the detection of cell cycle-related proteins. Apoptosis was determined based on the caspase-cleaved cytokeratin 18 (cCK18) levels. The microRNAs (miRNAs) related to an antitumor effect of zinc acetate were identified using microarrays. Zinc acetate significantly inhibited the proliferation of HCC cells in a dose-dependent manner. The treatment with zinc acetate resulted in significantly increased cCK18 levels in the supernatant and enhanced the expression of heme oxygenase-1 (HO-1) in HCC cells. The flow cytometric analysis revealed an increase of HCC cells in the S and G2/M phases by the administration of zinc acetate, and the expressions of Cdk2 and cyclin E were increased. The miRNA expression profile of the HCC cells treated with zinc acetate was extremely different from that of the untreated HCC cells. These results suggest that the zinc acetate supplementation induces the apoptosis of HCC cells, but does not affect the cell cycle progression. Upregulation of HO-1 and the alteration of miRNAs' profile may be involved in antitumor effects of zinc acetate in HCC cells.

Effect of Lenvatinib treatment on the cell cycle and microRNA profile in hepatocellular carcinoma cells.

Lenvatinib is a tyrosine kinase receptor inhibitor used to treat unresectable hepatocellular carcinoma (HCC). In this study, we investigated the antitumor effects of Lenvatinib treatment on HCC cell lines. Proliferation was examined in four HCC cell lines (HuH-7, Hep3B, Li-7, and PLC/PRF/5) using Cell Counting Kit-8 assays. Xenograft mouse models were used to assess the effects of Lenvatinib in vivo. Cell cycle, western blotting, and microRNA (miRNA) expression analyses were performed to identify the antitumor inhibitory potential of Lenvatinib on HCC cells. Lenvatinib treatment suppressed proliferation of HuH-7 and Hep3B, but not Li-7 and PLC/PRF/5 cells and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in Lenvatinib-sensitive cells. Lenvatinib treatment also reduced tumor growth in HuH-7 xenograft mouse models. miRNA microarrays revealed that Lenvatinib treatment altered the expression of miRNAs in HuH7 cells and exosomes. Our results demonstrated the therapeutic potential of Lenvatinib and provide molecular mechanistic insights into its antitumor effects for treating HCC.

Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 µg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.

Influence of gender on diaphragm thickness using a method for determining intima media thickness in healthy young adults.

BACKGROUND: To clarify the differences in diaphragm thickness between male and female participants in healthy young adults with ultrasonography using the mean intima media thickness (IMT) method and to investigate the relationship between diaphragm thickness and respiratory pressure. METHODS: Twenty-nine healthy individuals (16 females and 13 males) participated in the study. Diaphragm thickness was measured at total lung capacity (TLC) and at functional residual capacity (FRC) in each participant. We measured the diaphragm thickness using a method for mean intima media thickness. Moreover, change ratio of diaphragm thickness was calculated with the diaphragm thickness at TLC and FRC. RESULTS: Mean diaphragm thicknesses at FRC in males were significantly narrower than those in females (p < 0.001). The change ratio of diaphragm thickness was significantly augmented in males compared with that in females (p < 0.001). There was a positive correlation between the change ratio of diaphragm thickness and pulmonary function data and respiratory muscle strength in healthy young adults. CONCLUSIONS: The change ratio of diaphragm thickness using the IMT method can be accurately performed with a high degree of reproducibility by clinical laboratory technicians and may be a useful indicator for evaluating diaphragm muscle strength.

Characterization of Cisplatin Effects in Lenvatinib-resistant Hepatocellular Carcinoma Cells.

BACKGROUND/AIM: Drug resistance to molecular targeted agents, such as lenvatinib, is an important issue. The aim of this study was to explore the mechanism of lenvatinib resistance and to investigate potential drugs that may improve the treatment of lenvatinib-resistant (LR) hepatocellular carcinoma (HCC). MATERIALS AND METHODS: LR cells were developed by long-term culture under lenvatinib exposure. We analyzed the biological characteristics of LR cells in vitro, and investigated the antitumor effects and endogenous mechanisms of cisplatin in LR cells. RESULTS: The proliferative potential of LR cells was enhanced by activation of ERK signaling and changes in several miRNAs. Cisplatin inhibited cell proliferation of LR cells and induced G2/M cell cycle arrest. Furthermore, cisplatin triggered the DNA damage response, via the ATM/ATR-Chk1/Chk2 signaling pathway. CONCLUSION: Proliferation of LR cells was induced upon ERK signaling activation. Cisplatin exerted antitumor effects in LR cells and was involved in the regulation of miRNAs associated with drug resistance.

Antitumor Effect of Regorafenib on MicroRNA Expression in Hepatocellular Carcinoma Cell Lines.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.