Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease.

BACKGROUND: Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood. METHODS: To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks. RESULTS: Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice. CONCLUSIONS: These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.

Current Evidence and Perspectives of Cluster of Differentiation 44 in the Liver's Physiology and Pathology.

Cluster of differentiation 44 (CD44), a multi-functional cell surface receptor, has several variants and is ubiquitously expressed in various cells and tissues. CD44 is well known for its function in cell adhesion and is also involved in diverse cellular responses, such as proliferation, migration, differentiation, and activation. To date, CD44 has been extensively studied in the field of cancer biology and has been proposed as a marker for cancer stem cells. Recently, growing evidence suggests that CD44 is also relevant in non-cancer diseases. In liver disease, it has been shown that CD44 expression is significantly elevated and associated with pathogenesis by impacting cellular responses, such as metabolism, proliferation, differentiation, and activation, in different cells. However, the mechanisms underlying CD44's function in liver diseases other than liver cancer are still poorly understood. Hence, to help to expand our knowledge of the role of CD44 in liver disease and highlight the need for further research, this review provides evidence of CD44's effects on liver physiology and its involvement in the pathogenesis of liver disease, excluding cancer. In addition, we discuss the potential role of CD44 as a key regulator of cell physiology.

Depolymerized Chitosan-g-[Poly(MMA-co-HEMA-cl-EGDMA)] Based Nanogels for Controlled Local Release of Bupivacaine.

This study is designed to formulate and characterize chitosan-based nanogels that provide the controlled delivery of anesthetic drugs, such as bupivacaine (BPV), for effective postoperative pain management over prolonged periods of time. Drug carriers of chitosan/poly (MMA-co-HEMA-cl-EGDMA) (CsPMH) nanogels were prepared by varying the composition of comonomers such as MMA, HEMA, and redox initiator CAN. The nanogels were then characterized using FTIR, TGA, SEM, and TEM. The CsPMH nanogels showed greater encapsulation efficiencies from 43.20-91.77%. Computational studies were also conducted to evaluate the interaction between the drug and CsPMH nanoparticles. Finally, BPV-loaded nanoparticles were used to examine their in vitro release behavior. At pH 7.4, all the drug carriers displayed the "n" value around 0.7, thus the BPV release follows anomalous diffusion. Drug carrier 7 demonstrated a steady and sustained release of BPV for approximately 24 h and released about 91% of BPV, following the K-P mechanism of drug release. On the other hand, drug carrier 6 exhibited controlled release for approximately 12 h and released only 62% of BPV.

sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p.

Mesenchymal stromal cells (MSCs) are considered as a promising therapeutic tool for liver fibrosis, a main feature of chronic liver disease. Because small extracellular vesicles (sEVs) harboring a variety of proteins and RNAs are known to have similar functions with their derived cells, MSC-derived sEVs carry out the regenerative capacities of MSCs. Human tonsil-derived MSCs (T-MSCs) are reported as a novel source of MSCs, but their effects on liver fibrosis remain unclear. In the present study, we investigated the effects of T-MSC-derived sEVs on liver fibrosis. The expression of profibrotic genes decreased in human primary hepatic stellate cells (pHSCs) co-cultured with T-MSCs. Treatment of T-MSC-sEVs inactivated human and mouse pHSCs. Administration of T-MSC-sEVs ameliorated hepatic injuries and fibrosis in chronically damaged liver induced by carbon tetrachloride (CCl4). miR-486-5p highly enriched in T-MSC-sEVs targeting the hedgehog receptor, smoothened (Smo), was upregulated, whereas Smo and Gli2, the hedgehog target gene, were downregulated in pHSCs and liver tissues treated with T-MSC-sEVs or miR-486-5p mimic, indicating that sEV-miR-486 inactivates HSCs by suppressing hedgehog signaling. Our results showed that T-MSCs attenuate HSC activation and liver fibrosis by delivering sEVs, and miR-486 in the sEVs inactivates hedgehog signaling, suggesting that T-MSCs and their sEVs are novel anti-fibrotic therapeutics for treating chronic liver disease.

Development and testing of the career decision-making self-efficacy scale for nursing students: a methodological study.

BACKGROUND: The conventional Career Decision-Making Self-Efficacy Scale does not reflect the situation in Korea due to different sociocultural attributes and fails to account for the unique nursing profession and changes in healthcare. We aimed to develop and psychometrically test the Career Decision-Making Self-Efficacy Scale for Nursing Students. METHODS: A methodological study using a newly developed questionnaire tool and investigation of the validity and reliability of the preliminary instrument. Data were collected from 400 nursing students through an online survey conducted in May 2021. We identified 56 preliminary items through a literature review and focus group interviews. Of them, 40 were completed with a content validity index > .80. Content, construct, and criterion-related validity; internal consistency reliability; and test-retest reliability were used in the analysis. RESULTS: Exploratory factor analysis revealed three factors including 21 items: adapting to work (20.5%), understanding the major (20.2%), and goal setting (16.4%), explaining 57.1% of the total variance. As a result of confirmatory factor analysis, 17 items in the three-factor structure were validated. Reliability, as verified by the test-retest interclass correlation coefficient, was .86 and Cronbach's α was .92. The final Career Decision-Making Self-Efficacy Scale for Nursing Students consists of 17 items: adapting to work (7 items); understanding the major (4 items); and goal setting (6 items). CONCLUSION: The scale developed to measure the career decision-making self-efficacy of nursing students showed sufficient validity and reliability.

Pathophysiological Aspects of Alcohol Metabolism in the Liver.

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.

DNA Methylation in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a widespread hepatic disorder in the United States and other Westernized countries. Nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD, can progress to end-stage liver disease, including cirrhosis and liver cancer. Poor understanding of mechanisms underlying NAFLD progression from simple steatosis to NASH has limited the development of effective therapies and biomarkers. An accumulating body of studies has suggested the importance of DNA methylation, which plays pivotal roles in NAFLD pathogenesis. DNA methylation signatures that can affect gene expression are influenced by environmental and lifestyle experiences such as diet, obesity, and physical activity and are reversible. Hence, DNA methylation signatures and modifiers in NAFLD may provide the basis for developing biomarkers indicating the onset and progression of NAFLD and therapeutics for NAFLD. Herein, we review an update on the recent findings in DNA methylation signatures and their roles in the pathogenesis of NAFLD and broaden people's perspectives on potential DNA methylation-related treatments and biomarkers for NAFLD.

Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells.

BACKGROUND & AIMS: Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP. METHODS: Primary HSCs were isolated from C57BL/6 or Smoflox/flox mice; we also performed studies with rat and human myofibroblastic HSCs. We measured changes of glutaminolytic genes during culture-induced primary HSC transdifferentiation. Glutaminolysis was disrupted in cells by glutamine deprivation or pathway inhibitors (bis-2-[5-phenylacetamido-1,2,4-thiadiazol-2-yl] ethyl sulfide, CB-839, epigallocatechin gallate, and aminooxyacetic acid), and effects on mitochondrial respiration, cell growth and migration, and fibrogenesis were measured. Hedgehog signaling to YAP was disrupted in cells by adenovirus expression of Cre-recombinase or by small hairpin RNA knockdown of YAP. Hedgehog and YAP activity were inhibited by incubation of cells with cyclopamine or verteporfin, and effects on glutaminolysis were measured. Acute and chronic liver fibrosis were induced in mice by intraperitoneal injection of CCl4 or methionine choline-deficient diet. Some mice were then given injections of bis-2-[5-phenylacetamido-1,2,4-thiadiazol-2-yl] ethyl sulfide to inhibit glutaminolysis, and myofibroblast accumulation was measured. We also performed messenger RNA and immunohistochemical analyses of percutaneous liver biopsies from healthy human and 4 patients with no fibrosis, 6 patients with mild fibrosis, and 3 patients with severe fibrosis. RESULTS: Expression of genes that regulate glutaminolysis increased during transdifferentiation of primary Q-HSCs into myofibroblastic HSCs, and inhibition of glutaminolysis disrupted transdifferentiation. Blocking glutaminolysis in myofibroblastic HSCs suppressed mitochondrial respiration, cell growth and migration, and fibrogenesis; replenishing glutaminolysis metabolites to these cells restored these activities. Knockout of the hedgehog signaling intermediate smoothened or knockdown of YAP inhibited expression of glutaminase, the rate-limiting enzyme in glutaminolysis. Hedgehog and YAP inhibitors blocked glutaminolysis and suppressed myofibroblastic activities in HSCs. In livers of patients and of mice with acute or chronic fibrosis, glutaminolysis was induced in myofibroblastic HSCs. In mice with liver fibrosis, inhibition of glutaminase blocked accumulation of myofibroblasts and fibrosis progression. CONCLUSIONS: Glutaminolysis controls accumulation of myofibroblast HSCs in mice and might be a therapeutic target for cirrhosis.

The role of depression in the relationship between cognitive decline and quality of life among breast cancer patients.

PURPOSE: Cancer patients who underwent chemotherapy experience cognitive decline, which, in turn, negatively impacts quality of life (QoL). Depression is considered a psychological factor that is negatively associated with the QoL of cancer patients. However, the relationships among cognitive functioning, depression, and QoL in breast cancer patients are under-researched in the literature. The aim of this cross-sectional study was to identify the role of depression in the relationship between cognitive functioning and QoL among breast cancer patients. METHODS: One hundred thirty breast cancer patients who underwent primary treatment participated. Participants completed the Functional Assessment of Cancer Therapy-Cognitive Function version 3, the Montreal Cognitive Assessment, the Beck Depression Inventory-II, and the Functional Assessment of Cancer Therapy-Breast Scale. The data were analyzed using multiple regression according to Baron and Kenny's strategies and the Sobel test. RESULTS: Subjective and objective cognitive functioning and depression were statistically significant predictors of QoL in breast cancer patients. Depression played a partial mediating role in the relationship between objective cognitive functioning and QoL and between subjective cognitive functioning and QoL. Additionally, the Sobel test demonstrated that depression had a significant partial mediating effect between subjective cognitive functioning and QoL (Z = 4.91, p < 0.001) and between objective cognitive functioning and QoL (Z = 2.62, p = 0.009). CONCLUSIONS: The findings indicated that depression could influence the association between cognitive functioning and QoL in breast cancer patients. Healthcare providers should develop an intervention focused on decreasing depression to evaluate the effectiveness of improving quality of life for breast cancer patients with cognitive dysfunction.

Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis.

Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice.

BACKGROUND/AIMS: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver's response to malarial infection. METHODS: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. RESULTS: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1ß, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-ß, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin ß4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. CONCLUSION: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts.

BACKGROUND/AIMS: Myofibroblasts (MF) derived from quiescent nonfibrogenic hepatic stellate cells (HSC) are the major sources of fibrous matrix in cirrhosis. Because many factors interact to regulate expansion and regression of MF-HSC populations, efforts to prevent cirrhosis by targeting any one factor have had limited success, motivating research to identify mechanisms that integrate these diverse inputs. As key components of RNA regulons, RNA binding proteins (RBPs) may fulfill this function by orchestrating changes in the expression of multiple genes that must be coordinately regulated to affect the complex phenotypic modifications required for HSC transdifferentiation. METHODS: We profiled the transcriptomes of quiescent and MF-HSC to identify RBPs that were differentially-expressed during HSC transdifferentiation, manipulated the expression of the most significantly induced RBP, insulin like growth factor 2 binding protein 3 (Igf2bp3), and evaluated transcriptomic and phenotypic effects. RESULTS: Depleting Igf2bp3 changed the expression of thousands of HSC genes, including multiple targets of TGF-ß signaling, and caused HSCs to reacquire a less proliferative, less myofibroblastic phenotype. RNA immunoprecipitation assays demonstrated that some of these effects were mediated by direct physical interactions between Igf2bp3 and mRNAs that control proliferative activity and mesenchymal traits. Inhibiting TGF-ß receptor-1 signaling revealed a microRNA-dependent mechanism that induces Igf2bp3. CONCLUSIONS: The aggregate results indicate that HSC transdifferentiation is ultimately dictated by Igf2bp3-dependent RNA regulons and thus, can be controlled simply by manipulating Igf2bp3.

Liver-Derived Exosomes and Their Implications in Liver Pathobiology.

The liver has a wide range of physiological functions in the body, and its health is maintained by complex cross-talk among hepatic cells, including parenchymal hepatocytes and nonparenchymal cells. Exosomes, which are one method of cellular communication, are endosomal-derived small vesicles that are released by donor cells and delivered to the target cells at both short and long distances. Because exosomes carry a variety of cargoes, including proteins, mRNAs, microRNAs and other noncoding RNAs originating from donor cells, exosomes convey cellular information that enables them to potentially serve as biomarkers and therapeutics in liver diseases. Hepatocytes release exosomes to neighboring hepatocytes or nonparenchymal cells to regulate liver regeneration and repair. Nonparenchymal cells, including hepatic stellate cells, liver sinusoidal endothelial cells, and cholangiocytes, also secrete exosomes to regulate liver remodeling upon liver injury. Exosomes that are released from liver cancer cells create a favorable microenvironment for cancer growth and progression. In this review, we summarize and discuss the current findings and understanding of exosome-mediated intercellular communication in the liver, with a particular focus on the function of exosomes in both health and disease. Based on the current findings, we suggest the potential applications of exosomes as biomarkers and therapeutics for liver diseases.

Hedgehog Signaling is Associated with Liver Response to Fractionated Irradiation in Mice.

BACKGROUND/AIMS: Radiation-induced liver disease (RILD) is a major obstacle in treating liver cancer; however, the mechanisms underlying RILD development remain unclear. Hedgehog (Hh) orchestrates liver response to injury. Herein, we investigated the liver response with Hh to fractionated irradiation (FI) using a small murine model for RILD. METHODS: Male mice exposed to liver-targeted FI with 6Gy in 5 consecutive weekly fractions were sacrificed at one day after weekly irradiation and 6 or 10 weeks post 5th FI for the acute and late response model, respectively. RESULTS: The levels of ALT/AST and apoptosis were elevated in all radiation groups. The expression of Hh ligand, Sonic and Indian Hh, and Hh activator, smoothened and gli2, was higher in the acute groups than the control group. Pro-fibrogenic markers were also up-regulated in this model compared with the control group. Histomorphological changes and ballooned hepatocytes were observed in the late response model. Both the expression of Hh and profibrotic genes and the fibrosis level increased in this model compared with the control groups. CONCLUSION: Enhanced Hedgehog signaling and liver injury with fibrosis in RILD murine model suggests hedgehog as the potential regulator in RILD progression and the suitability of this model for studying RILD.

MicroRNA Expression Profiling in CCl4-Induced Liver Fibrosis of Mus musculus.

Liver fibrosis is a major pathological feature of chronic liver diseases, including liver cancer. MicroRNAs (miRNAs), small noncoding RNAs, regulate gene expression posttranscriptionally and play important roles in various kinds of diseases; however, miRNA-associated hepatic fibrogenesis and its acting mechanisms are poorly investigated. Therefore, we performed an miRNA microarray in the fibrotic livers of Mus musculus treated with carbon-tetrachloride (CCl4) and analyzed the biological functions engaged by the target genes of differentially-expressed miRNAs through gene ontology (GO) and in-depth pathway enrichment analysis. Herein, we found that four miRNAs were upregulated and four miRNAs were downregulated more than two-fold in CCl4-treated livers compared to a control liver. Eight miRNAs were predicted to target a total of 4079 genes. GO analysis revealed that those target genes were located in various cellular compartments, including cytoplasm, nucleolus and cell surface, and they were involved in protein-protein or protein-DNA bindings, which influence the signal transductions and gene transcription. Furthermore, pathway enrichment analysis demonstrated that the 72 subspecialized signaling pathways were associated with CCl4-induced liver fibrosis and were mostly classified into metabolic function-related pathways. These results suggest that CCl4 induces liver fibrosis by disrupting the metabolic pathways. In conclusion, we presented several miRNAs and their biological processes that might be important in the progression of liver fibrosis; these findings help increase the understanding of liver fibrogenesis and provide novel ideas for further studies of the role of miRNAs in liver fibrosis.

Inhibition of hedgehog signalling attenuates UVB-induced skin photoageing.

The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of UV-induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh-regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that UVB induced Hh signalling by the expression of Hh ligands and Hh-mediated transcription factors, respectively. Moreover, UVB-induced Hh activation relied on mitogen-activated protein kinase (p38, ERK and JNK) activity and inflammatory responses (upregulation of COX-2, IL-1ß, IL-6 and TNF-α), resulting in premature senescence and photoageing in vitro and in vivo. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with UVB-induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.

The psychometric properties of the Korean version of the functional assessment of cancer therapy-cognitive (FACT-Cog) in Korean patients with breast cancer.

PURPOSE: The aim of this study was to evaluate the psychometric properties of the Korean version of the Functional Assessment of Cancer Therapy-Cognitive scale (FACT-Cog) in patients with breast cancer in Korea. METHODS: The FACT-Cog was translated into Korean using forward and back translation. Patients with breast cancer who had undergone chemotherapy were enrolled from the university hospital and assessed using the Korean version of the FACT-Cog, the cognitive functioning scale of the EORTC-QLQ-C30 (EORTC-CF), and the Beck Depression Inventory-Second Edition (BDI-II). Analyses of internal consistency, construct validity, concurrent validity, and convergent validity were performed to evaluate the psychometric characteristics. RESULTS: A total of 250 patients completed the questionnaire. There were no missing data and patients completed the scale within 10 min. The Korean version of the FACT-Cog had acceptable internal consistency, with Cronbach's alpha coefficients of 0.94 for the total scores and 0.87-0.95 for the four subscales. The item-total correlation coefficients ranged from 0.36 to 0.95. Moderate correlations were found (r = 0.33 to 0.53) between the Korean version of the FACT-Cog and the EORTC-CF. There was acceptable convergent validity, with weak and moderately significant correlations (r = -0.41 to -0.22) between the Korean version of the FACT-Cog and the BDI-II. Confirmatory factory analysis supported a four-factor structure of the Korean version of the FACT-Cog with a good model fit. CONCLUSIONS: The Korean version of the FACT-Cog is a valid and reliable scale to measure self-reporting of cognitive impairment in patients with breast cancer who are undergoing chemotherapy.

Potential role of thymosin Beta 4 in liver fibrosis.

Liver fibrosis, the main characteristic of chronic liver diseases, is strongly associated with the activation of hepatic stellate cells (HSCs), which are responsible for extracellular matrix production. As such, investigating the effective regulators controlling HSC activation provides important clues for developing therapeutics to inhibit liver fibrosis. Thymosin beta 4 (Tß4), a major actin-sequestering protein, is known to be involved in various cellular responses. A growing body of evidence suggests that Tß4 has a potential role in the pathogenesis of liver fibrosis and that it is especially associated with the activation of HSCs. However, it remains unclear whether Tß4 promotes or suppresses the activation of HSCs. Herein, we review the potential role of Tß4 in liver fibrosis by describing the effects of exogenous and endogenous Tß4, and we discuss the possible signaling pathway regulated by Tß4. Exogenous Tß4 reduces liver fibrosis by inhibiting the proliferation and migration of HSCs. Tß4 is expressed endogenously in the activated HSCs, but this endogenous Tß4 displays opposite effects in HSC activation, either as an activator or an inhibitor. Although the role of Tß4 has not been established, it is apparent that Tß4 influences HSC activation, suggesting that Tß4 is a potential therapeutic target for treating liver diseases.

Morroniside Protects C2C12 Myoblasts from Oxidative Damage Caused by ROS-Mediated Mitochondrial Damage and Induction of Endoplasmic Reticulum Stress.

Oxidative stress contributes to the onset of chronic diseases in various organs, including muscles. Morroniside, a type of iridoid glycoside contained in Cornus officinalis, is reported to have advantages as a natural compound that prevents various diseases. However, the question of whether this phytochemical exerts any inhibitory effect against oxidative stress in muscle cells has not been well reported. Therefore, the current study aimed to evaluate whether morroniside can protect against oxidative damage induced by hydrogen peroxide (H2O2) in murine C2C12 myoblasts. Our results demonstrate that morroniside pretreatment was able to inhibit cytotoxicity while suppressing H2O2-induced DNA damage and apoptosis. Morroniside also significantly improved the antioxidant capacity in H2O2-challenged C2C12 cells by blocking the production of cellular reactive oxygen species and mitochondrial superoxide and increasing glutathione production. In addition, H2O2-induced mitochondrial damage and endoplasmic reticulum (ER) stress were effectively attenuated by morroniside pretreatment, inhibiting cytoplasmic leakage of cytochrome c and expression of ER stress-related proteins. Furthermore, morroniside neutralized H2O2-mediated calcium (Ca2+) overload in mitochondria and mitigated the expression of calpains, cytosolic Ca2+-dependent proteases. Collectively, these findings demonstrate that morroniside protected against mitochondrial impairment and Ca2+-mediated ER stress by minimizing oxidative stress, thereby inhibiting H2O2-induced cytotoxicity in C2C12 myoblasts.

Low molecular weight fucoidan improves endoplasmic reticulum stress-reduced insulin sensitivity through AMP-activated protein kinase activation in L6 myotubes and restores lipid homeostasis in a mouse model of type 2 diabetes.

Low molecular weight fucoidan (LMWF) is widely used to treat metabolic disorders, but its physiologic effects have not been well determined. In the present study, we investigated the metabolic effects of LMWF in obese diabetic mice (leptin receptor-deficient db/db mice) and the underlying molecular mechanisms involved in endoplasmic reticulum (ER) stress-responsive L6 myotubes. The effect of LMWF-mediated AMP-activated protein kinase (AMPK) activation on insulin resistance via regulation of the ER stress-dependent pathway was examined in vitro and in vivo. In db/db mice, LMWF markedly reduced serum glucose, triglyceride, cholesterol, and low-density lipoprotein levels, and gradually reduced body weights by reducing lipid parameters. Furthermore, it effectively ameliorated glucose homeostasis by elevating glucose tolerance. In addition, the phosphorylation levels of AMPK and Akt were markedly reduced by ER stressor, and subsequently, glucose uptake and fatty acid oxidation were also reduced. However, these adverse effects of ER stress were significantly ameliorated by LMWF. Finally, in L6 myotubes, LMWF markedly reduced the ER stress-induced upregulation of the mammalian target of rapamycin-p70S61 kinase network and subsequently improved the action of insulin via AMPK stimulation. Our findings suggest that AMPK activation by LMWF could prevent metabolic diseases by controlling the ER stress-dependent pathway and that this beneficial effect of LMWF provides a potential therapeutic strategy for ameliorating ER stress-mediated metabolic dysfunctions.