Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update.

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.

The Role of GLP1-RAs in Direct Modulation of Lipid Metabolism in Hepatic Tissue as Determined Using In Vitro Models of NAFLD.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the progression of NAFLD to severe hepatic conditions. In this review article, we discuss the role of GLP-1 and GLP-1RA in the treatment of NAFLD using human hepatocyte models.

THE IMPACT OF TOTAL PHYSICAL ACTIVITY ON MICROVASCULAR COMPLICATIONS IN TYPE 1 DIABETES MELLITUS PATIENTS.

The incidence of diabetes is increasing worldwide, emphasizing an emerging need for blood glucose control optimization to prevent the development of chronic complications and improve the quality of life. This retrospective cohort study aimed to investigate the effects of total physical activity on microvascular diabetic complication development in patients with type 1 diabetes mellitus (T1DM). The study included 71 T1DM patients, average age 41 years and HbA1c 7.78%. Most patients (82.1%) reported having hypoglycemia, while the minority of patients developed microvascular complications, mostly nonproliferative retinopathy (17.7%). All subjects included in the study were moderately or vigorously physically active. No association was observed between total physical activity and regulation of glycemia, hypoglycemic incidents, or development of microvascular complications. Until sufficient data from prospective studies become available, our data support the findings of no negative effect of higher intensity physical activity on the development of microvascular complications in T1DM patients.

Renoprotective Effect of Liraglutide Is Mediated via the Inhibition of TGF-Beta 1 in an LLC-PK1 Cell Model of Diabetic Nephropathy.

Background: Recently published research demonstrated direct renoprotective effects of the glucagon-like peptide-1 receptor agonist GLP 1 RA, but the relevant molecular mechanisms are still not clear. The aim of this research was to assess the effects of Liraglutide in a cell culture model of diabetic nephropathy on cell viability, antioxidant (GSH) and transforming growth factor beta 1 (TGF- ß1) levels and extracellular matrix (ECM) expression. The metabolic activity in hyperglycemic conditions and the effect of Liraglutide treatment were assessed by measuring Akt, pAkt, GSK3ß, pGSK3ß, pSTAT3, SOCS3, iNOS and NOX4 protein expression with Western blot. F actin distribution was used to assess the structural changes of the cells upon treatment. Materials and methods: The cells were exposed to high glucose (HG30 mM) followed by 0.5 mM H2O2 and a combination of glucose and H2O2 during 24 h. Subsequently, the cells were treated with different combinations of HG30, H2O2 and Liraglutide. Cell viability was determined by an MTT colorimetric test, and the GSH, TGF-ß1 concentration and ECM expression were measured using a spectrophotometric/microplate reader assay and an ELISA kit, respectively. Western blotting was used to detect the protein level of Akt, pAkt, GSK3ß, pGSK3ß, pSTAT3, SOCS3, iNOS and NOX4. The F-actin cytoskeleton was visualized with Phalloidin stain and subsequently quantified. Results: Cell viability was decreased as well as GSH levels in cells treated with a combination of HG30/H2O2, and HG30 alone (p < 0.001). The addition of Liraglutide improved the viability in cells treated with HG30, but it did not affect the cell viability in the cell treated with the addition of H2O2. GSH increased with the addition of Liraglutide in HG30/H2O2 (p < 0.001) treated cells, with no effect in cells treated only with HG30. TGF-ß1 levels (p < 0.001) were significantly increased in HG30 and HG30/H2O2. The addition of Liraglutide significantly decreased the TGF-ß1 levels (p < 0.01; p < 0.05) in all treated cells. The synthesis of collagen was significantly increased in HG30/H2O2 (p < 0.001), while the addition of Liraglutide in HG30/H2O2 significantly decreased collagen (p < 0.001). Akt signaling was not significantly affected by treatment. The GSK3b and NOX4 levels were significantly reduced (p < 0.01) after the peroxide and glucose treatment, with the observable restoration upon the addition of Liraglutide suggesting an important role of Liraglutide in oxidative status regulation and mitochondrial activity. The treatment with Liraglutide significantly upregulated STAT3 (p < 0.01) activity, with no change in SOCS3 indicating a selective regulation of the STAT 3 signaling pathway in glucose and the oxidative overloaded environment. A significant reduction in the distribution of F-actin was observed in cells treated with HG30/H2O2 (p < 0.01). The addition of Liraglutide to HG30-treated cells led to a significant decrease of distribution of F-actin (p < 0.001). Conclusion: The protective effect of Liraglutide is mediated through the inhibition of TGF beta, but this effect is dependent on the extent of cellular damage and the type of toxic environment. Based on the WB analysis we have revealed the signaling pathways involved in cytoprotective and cytotoxic effects of the drug itself, and further molecular studies in vitro and vivo are required to elucidate the complexity of the pathophysiological mechanisms of Liraglutide under conditions of hyperglycemia and oxidative stress.

Liraglutide Exerts Protective Effects by Downregulation of PPARγ, ACSL1 and SREBP-1c in Huh7 Cell Culture Models of Non-Alcoholic Steatosis and Drug-Induced Steatosis.

(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The aim of our study was to study cell culture models of NAS and DIS and determine the effects of liraglutide (LIRA) in those models. (2) Methods: Huh7 cells were treated with oleic acid (OA), or amiodarone (AMD) to establish models of NAS and DIS, respectively. Cells were treated with LIRA and cell viability was assessed by MTT, lipid accumulation by Oil-Red-O staining and triglyceride assay, and intracellular signals involved in hepatosteatosis were quantitated by RT-PCR. (3) Results: After exposure to various OA and AMD concentrations, those that achieved 80% of cells viabilities were used in further experiments to establish NAS and DIS models using 0.5 mM OA and 20 µM AMD, respectively. In both models, LIRA increased cell viability (p < 0.01). Lipid accumulation was increased in both models, with microsteatotic pattern in DIS, and macrosteatotic pattern in NAS which corresponds to greater triglyceride accumulation in latter. LIRA ameliorated these changes (p < 0.001), and downregulated expression of lipogenic ACSL1, PPARγ, and SREBP-1c pathways in the liver (p < 0.01) (4) Conclusions: LIRA ameliorates hepatocyte steatosis in Huh7 cell culture models of NAS and DIS.

The role of direct oral anticoagulants in the era of COVID-19: are antiviral therapy and pharmacogenetics limiting factors?

In patients with COVID-19, thromboinflammation is one of the main causes of morbidity and mortality, which makes anticoagulation an integral part of treatment. However, pharmacodynamic and pharmacokinetic properties of direct oral anticoagulants (DOACs) limit the use of this class of anticoagulants in COVID-19 patients due to a significant interference with antiviral agents. DOACs use in COVID-19 hospitalized patients is currently not recommended. Furthermore, patients already on oral anticoagulant drugs should be switched to heparin at hospital admission. Nevertheless, outpatients with a confirmed diagnosis of COVID-19 are recommended to continue prior DOAC therapy. More studies are required to clarify the pathogenesis of COVID-19-induced derangement of the coagulation system in order to recommend an appropriate anticoagulant treatment.

Pretreatment of Garlic Oil Extracts Hampers Epithelial Damage in Cell Culture Model of Peptic Ulcer Disease.

Background and Objectives: Peptic ulcer disease is a chronic disease affecting up to 10% of the world's population. Proton pump inhibitors, such as lansoprazole are the gold standard in the treatment of ulcer disease. However, various studies have shown the effectiveness of garlic oil extracts in the treatment of ulcer disease. A cellular model can be established in the human gastric cell line by sodium taurocholate. The aim of this study was to explore the effects of garlic oil extracts pretreatment and LPZ addition in the cell culture model of peptic ulcer disease by examining oxidative stress and F-actin distribution. Materials and Methods: Evaluation was performed by determination of glutathione and prostaglandin E2 concentrations by ELISA; human gastric cell line proliferation by cell counting; expression of ATP-binding cassette, sub-family G, member 2; nuclear factor kappa B subunit 2 by RT PCR; and F-actin cytoskeleton visualization by semi-quantification of Rhodamine Phalloidin stain. Results: Our results showed significant reduction of cell damage after sodium taurocholate incubation when the gastric cells were pretreated with lansoprazole (p < 0.001) and increasing concentrations of garlic oil extracts (p < 0.001). Pretreatment with lansoprazole and different concentrations of garlic oil extracts increased prostaglandin E2 and glutathione concentrations in the cell culture model of peptic ulcer disease (p < 0.001). Positive correlation of nuclear factor kappa B subunit 2 (p < 0.01) with lansoprazole and garlic oil extracts pretreatment was seen, while ATP-binding cassette, sub-family G, member 2 expression was not changed. Treatment with sodium taurocholate as oxidative stress on F actin structure was less pronounced, although the highest concentration of garlic oil extracts led to a statistically significant increase of total amount of F-actin (p < 0.001). Conclusions: Hence, pretreatment with garlic oil extracts had gastroprotective effect in the cell model of peptic ulcer disease. However, further experiments are needed to fully elucidate the mechanism of this protective role.

Management of Glycemia during Acute Aerobic and Resistance Training in Patients with Diabetes Type 1: A Croatian Pilot Study.

(1) Background: The increased risk of developing hypoglycemia and worsening of glycemic stability during exercise is a major cause of concern for patients with type 1 diabetes mellitus (T1DM). (2) Aim: This pilot study aimed to assess glycemic stability and hypoglycemic episodes during and after aerobic versus resistance exercises using a flash glucose monitoring system in patients with T1DM. (3) Participants and Methods: We conducted a randomized crossover prospective study including 14 adult patients with T1DM. Patients were randomized according to the type of exercise (aerobic vs. resistance) with a recovery period of three days between a change of groups. Glucose stability and hypoglycemic episodes were evaluated during and 24 h after the exercise. Growth hormone (GH), cortisol, and lactate levels were determined at rest, 0, 30, and 60 min post-exercise period. (4) Results: The median age of patients was 53 years, with a median HbA1c of 7.1% and a duration of diabetes of 30 years. During both training sessions, there was a drop in glucose levels immediately after the exercise (0'), followed by an increase at 30' and 60', although the difference was not statistically significant. However, glucose levels significantly decreased from 60' to 24 h in the post-exercise period (p = 0.001) for both types of exercise. Glycemic stability was comparable prior to and after exercise for both training sessions. No differences in the number of hypoglycemic episodes, duration of hypoglycemia, and average glucose level in 24 h post-exercise period were observed between groups. Time to hypoglycemia onset was prolonged after the resistance as opposed to aerobic training (13 vs. 8 h, p = NS). There were no nocturnal hypoglycemic episodes (between 0 and 6 a.m.) after the resistance compared to aerobic exercise (4 vs. 0, p = NS). GH and cortisol responses were similar between the two sessions, while lactate levels were significantly more increased after resistance training. (5) Conclusion: Both exercise regimes induced similar blood glucose responses during and immediately following acute exercise.

Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, pharmaceutical, or natural inhibitors. However, their varying mechanisms may suggest a more realistic classification system. Herein, we present a new mechanistic-based classification of endocytosis inhibitors, in which they are segregated among four distinct classes including: (i) inhibitors that disrupt endocytosis-related protein-protein interactions, and assembly or dissociation of complexes; (ii) inhibitors of large dynamin GTPase and/or kinase/phosphatase activities associated with endocytosis; (iii) inhibitors that modulate the structure of subcellular components, especially the plasma membrane, and actin; and (iv) inhibitors that cause physiological or metabolic alterations in the endocytosis niche. Excluding antiviral drugs designed to halt SARS-CoV-2 replication, other drugs, either FDA-approved or suggested through basic research, could be systematically assigned to one of these classes. We observed that many anti-SARS-CoV-2 drugs could be included either in class III or IV as they interfere with the structural or physiological integrity of subcellular components, respectively. This perspective may contribute to our understanding of the relative efficacy of endocytosis-related inhibitors and support the optimization of their individual or combined antiviral potential against SARS-CoV-2. However, their selectivity, combined effects, and possible interactions with non-endocytic cellular targets need more clarification.

Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer.

Although we are lately witnessing major improvements in breast cancer treatment and patient outcomes, there is still a significant proportion of patients not receiving efficient therapy. More precisely, patients with triple-negative breast cancer or any type of metastatic disease. Currently available prognostic and therapeutic biomarkers are not always applicable and oftentimes lack precision. The science of glycans is a relatively new scientific approach to better characterize malignant transformation and tumor progression. In this review, we summarize the most important information about glycosylation characteristics in breast cancer cells and how different glycoproteins and enzymes involved in glycosylation could serve as more precise biomarkers, as well as new therapeutic targets.

Molecular Mechanisms Linking Empagliflozin to Renal Protection in the LLC-PK1 Model of Diabetic Nephropathy.

Aims: Chronic diabetes complications, including diabetic nephropathy (DN), frequently result in end-stage renal failure. This study investigated empagliflozin (SGLT2i) effects on collagen synthesis, oxidative stress, cell survival, and protein expression in an LLC-PK1 model of DN. Methods: Combinations of high glucose (HG) and increasing empagliflozin concentrations (100 nM and 500 nM), as well as combinations of HG, H2O2, and empagliflozin, were used for cell culture treatment. The cell viability, glutathione (tGSH), ECM expression, and TGF-ß1 concentration were measured. In addition, the protein expression of Akt, pAkt, GSK3, pGSK3, pSTAT3, and SMAD7 was determined. Results: The addition of both concentrations of empagliflozin to cells previously exposed to glucose and oxidative stress generally improved cell viability and increased GSH levels (p < 0.001, p < 0.05). In HG30/H2O2/Empa500-treated cells, significant increase in pSTAT3, pGSK3ß, GSK3ß, SMAD7, and pAKT levels (p < 0.001, p < 0.001, p < 0.05) was observed except for AKT. Lower drug concentrations did not affect the protein expression levels. Furthermore, empagliflozin treatment (100 nM and 500 nM) of HG30/H2O2-injured cells led to a decrease in TGF-ß1 levels (p < 0.001). In cells exposed to oxidative stress and hyperglycemia, collagen production remained unchanged. Conclusion: Renoprotective effects of empagliflozin, in this LLC-PK1 cell model of DN, are mediated via activation of the Akt/GSK-3 signalling pathway, thus reducing oxidative stress-induced damage, as well as enhanced SMAD7 expression leading to downregulation of TGF-ß1, one of the key mediators of inflammation and fibrosis.

Impact of DAA Treatment on Cardiovascular Disease Risk in Chronic HCV Infection: An Update.

Hepatitis C virus (HCV) infection is a systemic disease associated with multiple significant extrahepatic manifestations. Emerging studies indicate association between the HCV infection and a higher incidence of major adverse cardiovascular events such as: coronary artery disease, heart failure, stroke and peripheral artery disease, when compared to general population. Atherosclerosis is a common pathophysiologic mechanism of cardiovascular disease (CVD) development which is the leading cause of mortality in the Western world. Proposed mechanisms of HCV-induced atherosclerosis includes systemic inflammation due to the chronic infection with increased levels of pro-atherogenic cytokines and chemokines. Furthermore, it has been demonstrated that HCV exists and replicates within atheroschlerotic plaques, supporting the theory of direct pro-atherogenic effect of the virus. Direct acting antiviral agents (DAAs) represent a safe and highly effective treatment of HCV infection. Beside the improvement in liver-related outcomes, DAAs exhibit a beneficial effect on extra-hepatic manifestations of chronic HCV infection. Recently, it has been shown that patients with chronic HCV infection treated with DAA-based therapeutic regimes had a 43% reduction of CVD events incidence risk. Moreover, eradication of HCV with DAAs results in a significant positive effect on risk factors for cardiovascular disease, despite a general worsening of the lipid profile. This positive effects is mainly due to an improvement of endothelial function and glucose metabolism. Although DAA treatment is associated with a beneficial impact on cardiovascular events, further studies are needed to fully elucidate the mechanisms responsible.

Drug-induced Fatty Liver Disease: Pathogenesis and Treatment.

Metabolic dysfunction-associated fatty liver disease (commonly known as MAFLD) impacts global health in epidemic proportions, and the resulting morbidity, mortality and economic burden is enormous. While much attention has been given to metabolic syndrome and obesity as offending factors, a growing incidence of polypharmacy, especially in the elderly, has greatly increased the risk of drug-induced liver injury (DILI) in general, and drug-induced fatty liver disease (DIFLD) in particular. This review focuses on the contribution of DIFLD to DILI in terms of epidemiology, pathophysiology, the most common drugs associated with DIFLD, and treatment strategies.

Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update.

Liver fibrosis is a life-threatening disease, with challenging morbidity and mortality for healthcare systems worldwide. It imparts an enormous economic burden to societies, making continuous research and informational updates about its pathogenesis and treatment crucial. This review's focus is on the current knowledge about the Wnt signaling pathway, serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells (HSCs). Two types of Wnt pathways are distinguished, namely the ß-catenin-dependent canonical and non-canonical Ca2+ or planar cell polarity (PCP)-dependent pathway. The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries. Activation of the ß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix (ECM), leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes, lacking the original function of healthy hepatocytes. Therefore, liver function is reduced due to the severely advanced disease. Selective inhibition of ß-catenin inhibits inflammatory processes (since chemokines and pro-inflammatory cytokines are produced during Wnt activation), reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis, thereby reducing the progression of liver fibrosis in vivo. While the canonical Wnt pathway is usually inactive in a physiologically healthy liver, it shows activity during cell regeneration or renewal and in certain pathophysiological conditions, such as liver diseases and cancer. Targeted blocking of some of the basic components of the Wnt pathway is a therapeutic approach. These include the frizzled transmembrane receptor (Fz) receptors using the secreted frizzled-related protein family (sFRP), Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1 (DKK1) or niclosamide, glycogen kinase-3 beta (GSK-3ß) using SB-216763, cyclic-AMP response element-binding protein (CBP) using PRI-724 and ICG-001, the lymphoid enhancer binding factor (LEF)/T cell-specific transcription factor (TCF) system as well as Wnt inhibitory factor 1 (WIF1) and miR-17-5p using pinostilbene hydrate (PSH). Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action. Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies' development.

Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients' Population.

Single nucleotide polymorphism (SNP) in genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 SNPs in 126 Croatian breast cancer (BC) patients and possible association with anastrozole-induced undesirable side effects were analyzed. Eighty-two postmenopausal patients with estrogen receptor (ER)-positive BC treated with anastrozole and 44 postmenopausal ER-positive BC patients before hormonal adjuvant therapy were included in the study. Genomic DNA was genotyped by TaqMan Real-Time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The homozygotes for the variant G allele of CYP3A5*3 were predominant (88%), and the homozygotes for the reference A allele were not detected. While homozygotes for the variant G allele of CYP3A4*1B were not detected, predominantly wild type homozygotes for A allele (94%) were present. CYP3A4*1B and CYP3A5*3 SNPs were in 84.3% linkage disequilibrium (D' = 0.843) and 95.1% (D' = 0.951) in group treated with anastrozole and w/o treatment, respectively. Homozygotes for the A allele of UGT1A4*2 were not detected in our study groups. Although the variant CYP3A5*3 allele, which might result in poor metabolizer phenotype and more pronounced side effects, was predominant, significant association with BMD changes induced by anastrozole were not confirmed.

Peptic Ulcer Disease: A Brief Review of Conventional Therapy and Herbal Treatment Options.

Peptic ulcer is a chronic disease affecting up to 10% of the world's population. The formation of peptic ulcers depends on the presence of gastric juice pH and the decrease in mucosal defenses. Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) infection are the two major factors disrupting the mucosal resistance to injury. Conventional treatments of peptic ulcers, such as proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists, have demonstrated adverse effects, relapses, and various drug interactions. On the other hand, medicinal plants and their chemical compounds are useful in the prevention and treatment of numerous diseases. Hence, this review presents common medicinal plants that may be used for the treatment or prevention of peptic ulcers.

HCV Extrahepatic Manifestations.

Hepatitis C virus (HCV) has been shown to affect many tissues other than liver. However, of the many extrahepatic manifestations (EMs) that have been associated with HCV, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes and neurological disorders, only a few have been shown to be directly related to HCV infection of extrahepatic tissues. HCV-triggered immune-mediated mechanisms account for most of the EMs. It is estimated that up to 74% of patients with chronic hepatitis C can develop at least one EM. All HCV patients with EMs should be considered for antiviral therapy, although not all will resolve with sustained virological response.

Obesity Paradox in Chronic Liver Diseases: Product of Bias or a Real Thing?

In recent years, evidence supporting the theory of obesity paradox has increased, showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal weight. So far, evidence is most comprehensive in cardiovascular and chronic renal diseases; however, published studies are prone to many biases, enabling us to reach a definite conclusion. Available data in chronic liver disease is scarce and ambiguous. Obesity is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver disease. Yet, there seem to be new data indicating the opposite - the obesity paradox exists in severe and end-stage liver cirrhosis, which could be attributed to a better lean mass in patients with higher body mass index, meaning that sarcopenia, as one of the most important prognostic factors of survival, is less likely to be present. Nonetheless, the problem of various methodological problems addressing the association between body weight and mortality, which is present both in liver disease and other chronic diseases, are preventing us from attaining an unanimous conclusion. Still, we should be aware that the obesity paradox might be true, especially in severe and end-stage illness. This suggests focusing our efforts toward preserving or building up fat-free mass and decreasing inflammatory activity responsible for catabolism and sarcopenia, and implying that the underlaying cause should be treated.

Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives.

BACKGROUND: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases. METHODS: A structured search of bibliographic databases - Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described. RESULTS: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described. CONCLUSION: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.

Association of Wnt Inhibitors, Bone Mineral Density and Lifestyle Parameters in Women with Breast Cancer Treated with Anastrozole Therapy.

AIM: To determine the levels of Wnt inhibitors in patients treated with aromatase inhibitors (AIs) prior to therapy and to investigate their association with bone mineral density (BMD) and lifestyle parameters. METHODS: 137 breast cancer patients were divided into a group treated with 1 mg of anastrozole and a group w/o anastrozole therapy. Serum concentrations of sclerostin and dickkopf1 (DKK1) were measured by ELISA. BMD was measured by dual-energy X-ray absorptiometry (DXA). Lifestyle factors were investigated by a self-reported questionnaire. RESULTS: Sclerostin was significantly higher in the AI-treated group (31.8 pmol/L vs. 24.1 pmol/L; p < 0.001), whereas DKK1 was significantly lower in the AI-treated group (24.3 pmol/L vs. 26.02 pmol/L; p < 0.001). Total hip and femoral neck BMD were significantly lower in the AI-treated group. CONCLUSION: AI treatment was associated with increased levels of sclerostin and decreased levels of DKK1.