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-1β, 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-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, 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

Pathological Contribution of Extracellular Vesicles and Their MicroRNAs to Progression of Chronic Liver Disease

Extracellular vesicles (EVs) are membrane-bound endogenous nanoparticles released by the majority of cells into the extracellular space. Because EVs carry various cargo (protein, lipid, and nucleic acids), they transfer bioinformation that reflects the state of donor cells to recipient cells both in healthy and pathologic conditions, such as liver disease. Chronic liver disease (CLD) affects numerous people worldwide and has a high mortality rate. EVs released from damaged hepatic cells are involved in CLD progression by impacting intercellular communication between EV-producing and EV-receiving cells, thereby inducing a disease-favorable microenvironment. In patients with CLD, as well as in the animal models of CLD, the levels of released EVs are elevated. Furthermore, these EVs contain high levels of factors that accelerate disease progression. Therefore, it is important to understand the diverse roles of EVs and their cargoes to treat CLD. Herein, we briefly explain the biogenesis and types of EVs and summarize current findings presenting the role of EVs in the pathogenesis of CLD. As the role of microRNAs (miRNAs) within EVs in liver disease is well documented, the effects of miRNAs detected in EVs on CLD are reviewed. In addition, we discuss the therapeutic potential of EVs to treat CLD

Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD

Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis

Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis

Influence of CO2 save-cost-framed emission labelling on consumer behaviour

We investigated how the principles of save-cost-framing, a variation of gain-loss framing, affected the shopping choices of UBC students. We examined whether the save-cost-framing of CO2 emission from transportation impacts the choice between local or non-local food items. Knowing that loss-framed climate protection messages are more effective in increasing willingness to comply compared to gain-framed messages8, we predicted that given a choice between local and non-local foods, students would be more likely to choose the local option under a carbon-cost-frame compared to a carbon-saving frame. Additionally, we predicted that students would be more likely to choose local options under a carbon-saving frame compared to a neutral frame. Using Qualtrics, participants were allocated to 1 of 3 survey conditions: neutral, carbon-save-frame, or carbon-cost-frame, and given a choice between local and non-local options across 7 paired food items. Data was collected from 155 students through online recruitment, with 124 valid responses. Results of a one-way between-subjects ANOVA revealed no significant differences, but a chi-square test indicated a significant difference between the conditions and our hypothesis was partially supported. We found participants chose the local options in the save-frame and cost-frame conditions more than in the neutral frame. Disclaimer: “UBC SEEDS provides students with the opportunity to share the findings of their studies, as well as their opinions, conclusions and recommendations with the UBC community. The reader should bear in mind that this is a student project/report and is not an official document of UBC. Furthermore readers should bear in mind that these reports may not reflect the current status of activities at UBC. We urge you to contact the research persons mentioned in a report or the SEEDS Coordinator about the current status of the subject matter of a project/report.”Arts, Faculty ofPsychology, Department ofUnreviewedUndergraduat

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

Abstract 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

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

Targeted Deletion of Thymosin Beta 4 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in a Transgenic Mouse Model

Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin β4 (Tβ4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated Tβ4 conditional knockout (Tβ4-flox) mice to investigate in vivo functions of Tβ4 in liver fibrosis. To selectively delete Tβ4 in activated HSCs, double-transgenic (DTG) mice were generated by mating Tβ4-flox mice with α-smooth muscle actin (α-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. Tβ4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of Tβ4 by an adeno-associated virus reversed the effect of HSC-specific Tβ4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that Tβ4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis