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The relationship between cardiac deformation by 2D speckle tracking, hypertrophy, and the extent of late gadolinium enhancement (LGE) in patients with hypertrophic cardiomyopathy remains uncertain. Our study aims to compare left ventricular global longitudinal strain (GLS) with the extent of LGE and to determine a relationship between GLS and hypertrophy.

Background and objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.

Abstract Background Intervertebral disc cell fibrosis has been established as a contributing factor to intervertebral disc degeneration (IDD). This study aimed to identify fibrosis-related diagnostic genes for patients with IDD. Methods RNA-sequencing data was downloaded from Gene Expression Omnibus (GEO) database. The diagnostic genes was identified using Random forest based on the differentially expressed fibrosis-related genes (DE-FIGs) between IDD and control samples. The immune infiltration states in IDD and the regulatory network as well as potential drugs targeted diagnostic genes were investigated. Quantitative Real-Time PCR was conducted for gene expression valifation. Results CEP120 and SPDL1 merged as diagnostic genes. Substantial variations were observed in the proportions of natural killer cells, neutrophils, and myeloid-derived suppressor cells between IDD and control samples. Further experiments indicated that AC144548.1 could regulate the expressions of SPDL1 and CEP120 by combininghsa-miR-5195-3p and hsa-miR-455-3p, respectively. Additionally, transcription factors FOXM1, PPARG, and ATF3 were identified as regulators of SPDL1 and CEP120 transcription. Notably, 56 drugs were predicted to target these genes. The down-regulation of SPDL1 and CEP120 was also validated. Conclusion This study identified two diagnostic genes associated with fibrosis in patients with IDD. Additionally, we elucidated their potential regulatory networks and identified target drugs, which offer a theoretical basis and reference for further study into fibrosis-related genes involved in IDD.

Introduction: NAFLD is strongly associated with metabolic syndrome, and for many years, fatty liver was an exclusive feature of obese patients. The study tries to assess whether the body mass index (BMI) and body circumference is correlated to steatosis, fibrosis, or inflammatory activity of the liver.

Introduction. High-resolution contrast-enhanced cardiac magnetic resonance imaging reveals left atrial fibrosis, the severity of which may be related to the effectiveness of catheter ablation.Aim. To study the structural changes of the left atrium myocardium according to magnetic resonance imaging with contrast in patients with persistent atrial fibrillation before balloon cryoablation and compare the results with the effectiveness of the intervention.Materials and methods. The study included 89 patients with persistent form of atrial fibrillation. The patients were randomized into two groups: in the 1st, the pulmonary veins cryoablation was performed (n = 39 (53.4%)); in the 2nd, the pulmonary veins and posterior wall of the left atrium cryoablation was performed (n = 34 (46.6%)). All patients before cryoablation underwent cardiac magnetic resonance imaging with delayed contrast using a high-resolution MR pulse sequence. The clinical efficacy of the intervention was evaluated after 12 months after the cryoablation.Results. The severity of fibrotic myocardial lesion of the left atrium before balloon cryoablation was 0.7% [0; 3,07]. Overall efficiency of the intervention rate was 57.1%. Cryoablation was most effective (59.5%) in patients severity of fibrosis less than 20% and least effective (50%) severity of fibrosis more than 20%. Risk factors for atrial fibrillation recurrence after cryoablation were: early atrial fibrillation recurrence, female sex, the maximum atrial fibrillation duration more than 3 months, stroke/TIA.Conclusion. The severity of left atrial fibrosis more than 20%, early recurrence of atrial fibrillation in the first 3 months after the cryoablation, female sex, the duration of the maximum atrial fibrillation episode more than 3 months, and a history of stroke/transient ischemic attack may be associated with recurrence of AF during the period observation 3–12 months.

Objective: The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) accumulate with overnutrition and have been implicated in non-alcoholic steatohepatitis (NASH) development. ORMDL3, a negative regulator of the rate-limiting step in ceramide biosynthesis, has been identified as an obesity-related gene. Therefore, we assessed the role of ORMDL3 in diet-induced obesity and development of NASH. Methods: Globally overexpressing Ormdl3-Flag transgenic mice (ORMDL3TG) were fed a western high-fat, carbohydrate and cholesterol enriched diet, with high fructose-glucose drinking water. Physiological, biochemical and sphingolipidomic analyses were employed to measure the effect of ORMDL3 overexpression on NASH development. Results: ORMDL3TG male but not female mice fed a western high-fat diet and sugar water had exacerbated adipocyte hypertrophy together with increased severity of white adipose inflammation and fibrosis. Hepatic steatosis, dyslipidemia, impaired glucose homeostasis, hyperinsulinemia, and insulin resistance were significantly more severe only in obese ORMDL3TG male mice that accompanied dramatic liver fibrosis, inflammation, and formation of hepatic crown-like structures, which are unique features of human and murine NASH. Obesogenic diet induces ORMDL expression in male mice but reduces it in females. Mechanistically, overexpression of Ormdl3 lowered the levels of S1P and ceramides only in obese female mice and antithetically increased them in tissues of obese males. ORMDL3TG male mice exhibited a much greater induction of the UPR, propagating ER stress that contributed to their early development of NASH. Conclusions: This study uncovered a previously unrecognized role for ORMDL3 in sexual dimorphism important for the development and progression of NASH.

Retinal fibrosis was a key characteristic of diabetes retinopathy (DR). Apelin was found to be a candidate for tissue fibrosis. Nevertheless, the role of Apelin in the Müller cells in DR remains unclear. This study identified the function and mechanism of Apelin in Müller cells and the fibrosis of retinal tissue. Western blot was carried out to detect the Apelin, GFAP, Collagen I, α-SMA, JAK2 and STAT3 protein levels. Masson staining was performed to display the histopathological changes in retinal tissue of diabetic mellitus (DM) rats. The immunofluorescence staining was conducted to evaluate the Apelin levels in the retinal tissue. The levels of GFAP, Collagen I and α-SMA in the retinal tissue of DM rats was visualised by the immunohistochemistry staining. The results showed that Apelin, GFAP, Collagen I andα-SMA expression was prominently elevated in the retinal tissue of DM rats and high glucose (HG)-exposed Müller cells. The results of Masson staining showed that the epiretinal fibrotic membrane was observed in DM rats. Apelin knockdown declined the GFAP, Collagen I andα-SMA levels. Besides, the protein levels of p-JAK2 and p-STAT3 were elevated in the HG-treated Müller cells, while Apelin knockdown declined them. FLLL32 treatment neutralised the role of Apelin. In conclusion, Apelin facilitated the fibrogenic activity of Müller cells through activating the JAK2/STAT3 signalling pathway, and thus inducing the retinal fibrosis in DR.

Objective: FAS-mediated apoptosis of hepatocytes and aberrant TGF-β signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis. Methods: Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-β1 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis. Results: Let-7 decreased TGF-β1 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models. Conclusions: Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis.

The problem of the formation of irreversible residual changes after suffering viral lung damage with COVID-19 (COronaVIrus Disease 2019) after two years of the pandemic remains important and discussed. This is due to a large number of patients who have had a coronavirus infection (including those with a large amount of lung damage) and a possible unfavorable prognosis with a decrease in the quality and life expectancy. Given the fact that antifibrotic therapy has recently been actively used for a number of interstitial lung diseases (with idiopathic pulmonary fibrosis and systemic diseases), the question of the possible use of these drugs in case of an unfavorable outcome of COVID-19 is being considered. However, it is still not known exactly how often fibrosis develops in the outcome of a new coronavirus infection, and groups of patients who may have a poor prognosis in the form of an outcome in fibrosis have not been clearly identified.The review considers the pathogenetic aspects of the possible development of irreversible changes in patients with COVID-19, predisposing factors, as well as diagnostic features with an emphasis on CT scan with the authors’ own observations.

Objective: Fibroblastic rheumatism (FR) is a rare disease first described by Chaouat in 1980 which is characterized by a combination of rheumatologic and dermatological manifestations. Rheumatologic features are symmetrical polyarthralgia with joint stiffness, associated with cutaneous nodules and sclerodactyly. Histology shows an increased number of fibroblasts and marked dermal fibrosis. In this report, we described a rare cutaneous disease-fibroblastic rheumatism, in which the patient had an excellent response to methotrexate associated with colchicine. Case Presentation: A 13 years old boy who was previously healthy started in 2013 deformities over his fingers without pain or any inflammatory signs associated with joint stiffness. This is the second Brazilian case of FR treated with methotrexate and colchicine. Conclusions: The patient observed a slight improvement in cutaneous nodules and joint stiffness. Though FR is a rare disease, early diagnosis is mandatory. This case reinforces that MTX associated with colchicine may be an additional therapeutic tool for these patients.

Aim: The aim of this study was to investigate the role and mechanism of long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3)-205 in renal inflammation and fibrosis in diabetic nephropathy (DN). Materials and Methods: lncRNA microarray profiling was used to examine differentially expressed lncRNAs of kidney tissues in db/db mice compared to db/m mice. Mouse mesangial cells (mMCs) were cultured in vitro with advanced glycation end products (AGEs) via transfection with lncRNA MEG3-205 siRNAs or plasmids. The role of lncRNA MEG3-205 in vivo was examined in db/db mice treated with long-acting lncRNA MEG3-205 siRNA. The interaction between lncRNA MEG3-205 and let-7a was investigated using luciferase assay and RNA immunoprecipitation assay. Results: lncRNA MEG3-205 was markedly upregulated in renal tissues of db/db mice, DN patients, and AGEs-treated mesangial cells. Overexpression of lncRNA MEG3-205 promoted the secretion of pro-inflammatory cytokines and synthesis of extracellular matrix proteins in mesangial cells. Both lncRNA MEG3-205 and myeloid differentiation primary-response protein 88 (MyD88) could bind to let-7a, and lncRNA MEG3-205 overexpression can significantly rescue the silencing effect of let-7a on MyD88 protein expression in mMCs. Mechanistically, we identified that lncRNA MEG3-205 could act as a competing endogenous RNA by binding with let-7a and thus regulate MyD88. Knockdown of lncRNA MEG3-205 alleviated albuminuria and attenuated renal inflammation and fibrosis in db/db mice. Conclusion: These findings indicated an important role of the lncRNA MEG3-205/let-7a/MyD88 axis in regulating renal inflammation and fibrosis in DN. Targeting lncRNA MEG3-205 might present a promising therapeutic strategy for DN.

Abstract Background Direct-acting antivirals (DAAs) have revolutionized the therapy of HCV infection with higher sustained virological response (SVR) rates. Fibrosis regression after achieving SVR to DAA remains to be evaluated in chronic hepatitis C patients. One of the main inquiries here is what occurs with liver fibrosis after achieving a SVR, albeit the current DAA was not intended to be antifibrotic. Liver biopsy was replaced by various non-invasive methods, like FIB4 score and fibroscan. The aim of the study was to evaluate the impact of SVR following DAAs on liver fibrosis in chronic HCV patients. Results Five hundred of 1170 F4 treated patients (42.7%) improved and became 190 F3, 90 F2, and 220 F1. Also, 40 of 60 F3 patients improved and became 10 F2 and 30 F1. Also, 350 of 1230 treated patients (28.4%) transited from significant fibrosis (≥F3) to non-significant fibrosis (≤F2). There was a significant improvement of FIB-4 (p

Abstract Background The aim of this study was to propose a simple predictive score to differentiate NASH from simple steatosis. Results This study included 64 patients who had biopsy-proven NAFLD, of which 34 patients had steatohepatitis and 30 had simple steatosis. Clinical, anthropometric, and biochemical variables of the study population were analyzed. Univariate analysis showed platelet count, ferritin, and transaminases (ALT&AST) were predictors of NASH. This led to the proposal of a new diagnostic tool, FAT score (F signifies Ferritin, A indicates AST&ALT, T denotes t in Platelet) with AUROC of 0.95. The ROC curves for the significant variables were plotted and cutoff values were identified. Each component is awarded a score of 0 or 1, based on this cutoff value. The component is awarded a score of 1 if the component score is above the cutoff value and 0, if the score is below cutoff. The maximum score which can be obtained is 4. A score of ≥ 3 was able to predict NASH from simple steatosis with a sensitivity of 76.5% and a specificity of 100%. The score was validated with a cohort of 84 liver biopsy patients wherein a cutoff ≥ 3 was found to give a specificity of 100% in the validation cohort. Conclusions FAT score is a simple predictive model to differentiate NASH from simple steatosis (cutoff of more than or equal to 3) without performing a liver biopsy. A FAT score less than 3 rules out the need for biopsy.

Diabetic kidney disease (DKD) is now a pandemic worldwide, and novel therapeutic options are urgently required. Adenosine, an adenosine triphosphate metabolite, plays a role in kidney homeostasis through interacting with four types of adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR. Increasing evidence highlights the role of adenosine and ARs in the development and progression of DKD: 1) increased adenosine in the plasma and urine of diabetics with kidney injury, 2) increased expression of each of the ARs in diabetic kidneys, 3) the protective effect of coffee, a commonly ingested nonselective AR antagonist, on DKD, and 4) the protective effect of AR modulators in experimental DKD models. We propose AR modulators as a new therapeutic option to treat DKD. Detailed mechanistic studies on the pharmacology of AR modulators will help us to develop effective first-in-class AR modulators against DKD.

Background Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. Results Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. Conclusion These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Background. Few data with adequate evidence exists as regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment.

Objective: Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P), were protected from development of NASH. The aim of this study was to elucidate the role of hepatocyte-specific SphK1 in development of NASH and to compare its contribution to hepatosteatosis in male and female mice. Methods: We assessed mouse livers in early-stage fibrosis induced by high fat feeding, using single harmonic generation microscopy, LC-MS/MS analysis of hydroxyproline levels, and expression of fibrosis markers. We identified an antifibrotic intercellular signaling mechanism by culturing primary mouse hepatocytes alongside, and in co-culture with, LX2 hepatic stellate cells. Results: We generated hepatocyte-specific SphK1 knockout mice (SphK1-hKO). Unlike the global knockout, SphK1-hKO male mice were not protected from diet-induced steatosis, inflammation, or fibrogenesis. In contrast, female SphK1-hKO mice were protected from inflammation. Surprisingly, however, in these female mice, there was a ∼10-fold increase in the fibrosis markers Col1α1 and 2–3 fold induction of alpha smooth muscle actin and the pro-fibrotic chemokine CCL5. Because increased fibrosis in female SphK1-hKO mice occurred despite an attenuated inflammatory response, we investigated the crosstalk between hepatocytes and hepatic stellate cells, central players in fibrosis. We found that estrogen stimulated release of S1P from female hepatocytes preventing TGFβ-induced expression of Col1α1 in HSCs via S1PR3. Conclusions: The results revealed a novel pathway of estrogen-mediated cross-talk between hepatocytes and HSCs that may contribute to sex differences in NAFLD through an anti-fibrogenic function of the S1P/S1PR3 axis. This pathway is susceptible to pharmacologic manipulation, which may lead to novel therapeutic strategies.

Background: Liver cirrhosis causes over one million deaths annually worldwide, but its prognosis varies depending on the presence of complications and decompensating events. Reduction of portal pressure is associated with a reduced risk of mortality in cirrhotic patients. Statin therapy has successfully reduced portal pressure in previous studies, but its effects on overall mortality are unclear. This report aims to determine whether statin therapy significantly affects mortality in patients with liver cirrhosis. Methods: A comprehensive literature search was conducted using five electronic databases: PubMed, Scopus, Embase, Ovid MEDLINE, and Web of Science. Meta-analyses, randomized controlled trials (RCTs), and cohort studies were selected based on pre-set inclusion and exclusion criteria. The quality of selected studies was evaluated using critical appraisal tools developed by the Center for Evidence-Based Medicine. Results: One meta-analysis, one RCT, and one retrospective cohort study were included in this report. The meta-analysis and cohort study were of good quality and reported significantly reduced mortality with statin therapy in cirrhosis patients. However, the RCT had poor validity and did not report a statistically significant difference in mortality between the intervention and control groups. The survival benefits of statins may be limited to Child–Pugh A and B patients only, but this requires confirmation in a larger population of Child–Pugh C patients. Conclusion: Statins potentially reduce mortality in patients with liver cirrhosis, but more evidence is required before they can be widely recommended in clinical practice for this indication.

Background/Purpose: Adipose tissue contains progenitor cells that contribute to beneficial tissue expansion when needed by de novo adipocyte formation (classical white or beige fat cells with thermogenic potential). However, in chronic obesity, they can exhibit an activated pro-fibrotic, extracellular matrix (ECM)-depositing phenotype that highly aggravates obesity-related adipose tissue dysfunction. Methods: Given that progenitors' fibrotic activation and fat cell browning appear to be antagonistic cell fates, we have examined the anti-fibrotic potential of pro-browning agents in an obesogenic condition. Results: In obese mice fed a high fat diet, thermoneutral housing, which induces brown fat cell dormancy, increases the expression of ECM gene programs compared to conventionally raised animals, indicating aggravation of obesity-related tissue fibrosis at thermoneutrality. In a model of primary cultured murine adipose progenitors, we found that exposure to β-hydroxybutyrate selectively reduced Tgfβ-dependent profibrotic responses of ECM genes like Ctgf, Loxl2 and Fn1. This effect is observed in both subcutaneous and visceral-derived adipose progenitors, as well as in 3T3-L1 fibroblasts. In 30 patients with obesity eligible for bariatric surgery, those with higher circulating β-hydroxybutyrate levels have lower subcutaneous adipose tissue fibrotic scores. Mechanistically, β-hydroxybutyrate limits Tgfβ-dependent collagen accumulation and reduces Smad2-3 protein expression and phosphorylation in visceral progenitors. Moreover, β-hydroxybutyrate induces the expression of the ZFP36 gene, encoding a post-transcriptional regulator that promotes the degradation of mRNA by binding to AU-rich sites within 3′UTRs. Importantly, complete ZFP36 deficiency in a mouse embryonic fibroblast line from null mice, or siRNA knock-down in primary progenitors, indicate that ZFP36 is required for β-hydroxybutyrate anti-fibrotic effects. Conclusion: These data unravel the potential of β-hydroxybutyrate to limit adipose tissue matrix deposition, a finding that might exploited in an obesogenic context.

Objective: Fibrotic organ responses have recently been identified as long-term complications in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. Methods: Based on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single-nuclei RNA sequencing. Results: Hepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice fed a lipogenic MCD diet. Single-nuclei RNA sequencing revealed a distinct TSC22D4-dependent gene signature identifying an upregulation of mitochondrial-related processes in hepatocytes upon loss of TSC22D4. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models of hepatocyte-selective TSC22D4 loss-of-function. Conclusions: Together, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Hepatocyte-specific reduction of TSC22D4 improves hepatic steatosis and promotes hepatocyte survival via mitochondrial-related mechanisms thus paving the way for targeted therapies.

Fibrotic lesions accompany several pathological conditions, including tumors. We show that expression of a dominant-active form of the Ras oncogene in Drosophila salivary glands (SGs) leads to redistribution of components of the basement membrane (BM) and fibrotic lesions. Similar to several types of mammalian fibrosis, the disturbed BM attracts clot components, including insect transglutaminase and phenoloxidase. SG epithelial cells show reduced apicobasal polarity accompanied by a loss of secretory activity. Both the fibrotic lesions and the reduced cell polarity are alleviated by ectopic expression of the antimicrobial peptide drosomycin (Drs), which also restores the secretory activity of the SGs. In addition to extracellular matrix components, both Drs and F-actin localize to fibrotic lesions.

Chronic mitral regurgitation (MR) is the second valvular heart disease for incidence, which worsening severity gradually affects all cardiac chambers and leads to poor outcome if untreated. The recent development of minimally invasive surgical techniques and percutaneous intervention has reduced the operative risk, allowing a more confident referral of these patients for intervention. Therefore, there is a growing need of reliable markers to select the best therapeutic strategies and to identify the optimal timing for intervention. Myocardial fibrosis (MF) gradually occurs as a result of left atrial and ventricular (LA and LV) remodeling due to MR pressure and volume overload. It has been identified as an index of clinical outcome and arrhythmic risk in patients with MR. Particularly, the assessment of LA fibrosis not only allows to define different MR etiology, but also was associated with prognosis and atrial fibrillation (AF) burden. Nowadays, noninvasive estimation of MF is possible through the use of advanced imaging modalities, particularly cardiac magnetic resonance and speckle tracking echocardiography. This review discusses the role of LA fibrosis as a diagnostic and prognostic marker in patients with MR and its quantification by noninvasive multimodality cardiac imaging.

Left ventricular non-compaction (LVNC) is an increasingly recognized phenotype. The current definition of the LVNC does not mention LV dysfunction as an absolute criterion in addition to morphological criteria. LV dilatation and decreased LV ejection fraction (LVEF) are often late manifestations of the disease and correlate with the occurrence of cardiovascular complications. However, to define LVNC as a cardiomyopathy, functional criteria must be fulfilled, in addition to the morphological ones. Multimodality imaging, such as myocardial deformation and myocardial work analysis derived from speckle tracking echocardiography (STE), in combination with cardiac magnetic resonance (CMR) might improve diagnosis and characterization of non-compaction, exposing earlier signs of LV systolic dysfunction. We present two comparative cases of LVNC in order to highlight the idea of subclinical dysfunction even in apparently benign forms with preserved LVEF, and also the importance of multimodality imaging approach.

Both acute and chronic kidney disease have a strong underlying inflammatory component. This review focuses primarily on T helper 17 (Th17) cells as mediators of inflammation and their potential to modulate acute and chronic kidney disease. We provide updated information on factors and signaling pathways that promote Th17 cell differentiation with specific reference to kidney disease. We highlight numerous clinical studies that have investigated Th17 cells in the setting of human kidney disease and provide updated summaries from various experimental animal models of kidney disease indicating an important role for Th17 cells in renal fibrosis and hypertension. We focus on the pleiotropic effects of Th17 cells in different renal cell types as potentially relevant to the pathogenesis of kidney disease. Finally, we highlight studies that present contrasting roles for Th17 cells in kidney disease progression.

What is new? Serum IL-12 level is associated with NAFLD severity. Elevation in serum IL-12 level is in line with more severe NAFLD based on BARD score and NAFLD fibrosis score. Positive correlation is observed between serum IL-12 level and BARD score.

aiman,1 Rino Alvani Gani11Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia; 2Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia; 3Department of Internal Medicine, Haematology and Oncology Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, IndonesiaCorrespondence: Cosmas Rinaldi Adithya LesmanaDepartment of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jalan Diponegoro No. 71, Jakarta, IndonesiaEmail [email protected] Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease with excessive fat accumulation in the liver. Transient elastography (TE) with controlled attenuation parameter (CAP) is a device and method to examine the degree of fibrosis and steatosis. However, this device is not widely available across Indonesia. Neutrophil and lymphocyte ratio (NLR) is a simple marker for inflammation, which has a potency to predict disease outcome. This study aims to know the diagnostic value of NLR as the indicator of steatosis and fibrosis severity. Methods: This was a cross-sectional study with consecutive sample collection. We used secondary data from medical records, starting from 2016 to 2018. A descriptive and data analysis, including correlation test, multivariate linear regression, t-test, receiver operating curve (ROC) and area under the curve (AUC) were done to find out the outcome of the study. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) Version 20.0 (SPSS Inc, Chicago, Illinois). A P value < 0.05 was considered as statistically significant. Results: Out of 106 subjects, 62.3% patients were women with the mean of age 57.29 years old and 77.4% had metabolic syndrome. Most patients had moderate to severe steatosis degree (66%) with the mean of TE mean 6.14 (2.8– 18.2) kPa. There was a positive correlation between CAP and TE compared with NLR with r = 0.648 (p < 0.001) and r = 0.621 (p < 0.001), respectively. The use of RNL to assess moderate-severe steatosis has a cutoff point of 1.775 with sensitivity, specificity, PPV and NPV, respectively, at 81.5%, 80.6%, 89.1%, and 69.1%; cutoff point 2.150 to assess significant fibrosis with sensitivity, specificity, PPV and NPV of 92.3%, 87.5%, 70.6%, and 97.2%, respectively. Conclusion: NLR has a positive and significant correlation with the degree of steatosis and fibrosis with high sensitivity and specificity as evaluated by TE/CAP. [ABSTRACT FROM AUTHOR]

Modern concepts about the role of connective tissue growth factor in various physiological and pathological processes are described in the review. Connective tissue growth factor regulates a variety of cellular functions, including proliferation, migration, adhesion, differentiation and synthesis of extracellular matrix proteins in cells of different types. This factor is also involved in more complex biological processes of angiogenesis, chondrogenesis, wound healing, fibrosis and oncogenesis. Increased expression of connective tissue growth factor is observed in different cardiovascular and oncological diseases. Potential role of this growth factor in regulation of cellular senescence and aging processes is also discussed.

Background: The present study aimed to investigate and compare the effect of starved fibroblast culture supernatant (SFS), DMEM and normal saline alone or along with LA7 on dexamethasone-treated immunosuppressed Wistar rats. Methods: After the isolation of fibroblasts from the fresh foreskin of children, it was cultured in serum-free DMEM, and the supernatant collected after 16 hours (16h-SFS). This solution and the other treatments were injected subcutaneously into the rats from each group once daily for 14 days. The liver, intestine and lung histology along with blood cellular and biochemical characteristics were studied. Results: The results showed that dexamethasone as immunosuppressant reduced the body weight. The histological change in the liver was mild fibrosis induced by LA7+16h-SFS. Also, among the different blood cellular and biochemical indices measured, the eosinophil percentage in the 16h-SFS treated rats , glucose levels in the 16h-SFS+LA7 group and triglyceride concentrations in the 16h-SFS group were changed (p

Fibrosis is characterised by excessive deposition of the extracellular matrix (ECM) and develops because of fibroblast differentiation during the process of inflammation. There are few effective treatment options for this diseases due to the aetiology of fibrosis is not completely clarified. Long non-coding RNAs (lncRNAs), a type of ncRNA with a length of greater than 200 nucleotides without evident protein coding function, are important regulators of most biological and pathological processes, including participation, regulation or mediation of disease development. Among them, H19 is recently discovered as a class of lncRNAs which is related to fibrotic disease and inflammation. These observations implied a potential role for H19 as a promising therapeutic targets for treatment of fibrotic diseases. In this review, we will describe the characteristics of H19 and summarise recent advances in the mechanisms of H19 in the process of fibrosis. Finally, we will succinctly discuss the recent progress of the involvement of H19 in the development and pathogenesis of fibrosis diseases.

Background : We investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs).Methods : We performed in vitro studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with in vivo studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats were divided into three groups: control (C) group (peritoneal dialysis [PD] catheter but not infused with dialysate), PD group (4.25% glucose-containing dialysate), and PD + tranilast group (4.25% glucose-containing dialysate along with tranilast).Results : In in vitro experiments, transforming growth factor-beta 1 (TGF-β1) increased α-smooth muscle actin and Snail expression and reduced E-cadherin expression in HPMCs. TGF-β1 also reduced cell contact, induced a fibroblastoid morphology, and increased phosphorylation of Akt, Smad2, and Smad3 in HPMCs. Tranilast significantly inhibited TGF-β1-induced EMT and attenuated these morphological changes in HPMCs. In in vivo studies, after 6 weeks of experimental PD, the peritoneal membrane was significantly thicker in the PD group than in the C group. Tranilast protected against PD-induced glucose mass transfer change and histopathological changes in rats.Conclusion : Tranilast prevented EMT both in HPMCs triggered with TGF-β1 and in rats with PD-induced peritoneal fibrosis. Thus, tranilast may be considered a therapeutic intervention that enables long-term PD by regulating TGF-β1 signaling pathways.

Background: Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics. Scope of review: This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials. Major conclusions: Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.

MicroRNAs (miRNAs) are well-known candidates for modulating the dysregulated signaling pathways during fibrosis. In this study, we investigated the expression pattern of 16 miRNAs, which have previously been confirmed or predicted to target genes involved in extracellular matrix (ECM) homeostasis. Primary culture of dermal fibroblasts was obtained from skin biopsies of diffused cutaneous SSc (dcSSc) patients and healthy controls. Expression of let-7a, miR-1, miR-15a, miR-17, miR-19a, miR-20a, miR-21, miR-27b, miR-26a, miR-29a, miR-29b, miR29c, miR-141, miR-125a-5p, miR-193a-3p, and miR-200a were quantified by Real-time PCR. Functional analysis of microRNAs was performed using synthetic oligonucleotides. To further confirm the pro- or anti-fibrotic effects of miRNAs, normal fibroblasts were treated with 10 ng/mL of transforming growth factor (TGF)-β to generate an in vitro model of dermal fibrosis. miR-21 and miR-29a were upregulated and downregulated, respectively, in both dcSSc and TGF-β-treated fibroblasts. We observed that restoration of miR-29a expression or blockade of miR-21 function negatively affected collagen production. COL1A1 expression in SSc fibroblasts is more sensitive to changes of miR-29a and miR-21 expression in compare to normal fibroblasts. miR-29a alone was effective to decrease TGF-β-induced collagen production in dermal fibroblasts. miR-21 and TGF-β had synergistic effects on induction of collagen production. However, neither miR-21 nor miR-29a affected alpha smooth muscle actin (α-SMA) expression in the presence or absence of TGF-β in dermal fibroblasts. miR-21 and miR-29a as pro- and anti-fibrotic miRNAs modulate collagen production in an opposing manner. Focusing on miR-21 and miR-29s as therapeutic targets would be effective in patients with SSc or other fibrotic diseases which show aberrant expression of collagen expression.

Chronic kidney disease (CKD) is increasing worldwide without an effective therapeutic strategy. Sympathetic nerve activation is implicated in CKD progression, as well as cardiovascular dysfunction. Renal denervation is beneficial for controlling blood pressure (BP) and improving renal function through reduction of sympathetic nerve activity in patients with resistant hypertension and CKD. Sympathetic neurotransmitter norepinephrine (NE) via adrenergic receptor (AR) signaling has been implicated in tissue homeostasis and various disease progressions, including CKD. Increased plasma NE level is a predictor of survival and the incidence of cardiovascular events in patients with end-stage renal disease, as well as future renal injury in subjects with normal BP and renal function. Our recent data demonstrate that NE derived from renal nerves causes renal inflammation and fibrosis progression through alpha-2 adrenergic receptors (α2-AR) in renal fibrosis models independent of BP. Sympathetic nerve activation-associated molecular mechanisms and signals seem to be critical for the development and progression of CKD, but the exact role of sympathetic nerve activation in CKD progression remains undefined. This review explores the current knowledge of NE-α2-AR signaling in renal diseases and offers prospective views on developing therapeutic strategies targeting NE-AR signaling in CKD progression.

Objective: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. Methods: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue.To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. Results: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. Conclusions: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

Objective: Discoidin domain receptor 1 (DDR1) is a collagen binding receptor tyrosine kinase implicated in atherosclerosis, fibrosis, and cancer. Our previous research showed that DDR1 could regulate smooth muscle cell trans-differentiation, fibrosis and calcification in the vascular system in cardiometabolic disease. This spectrum of activity led us to question whether DDR1 might also regulate adipose tissue fibrosis and remodeling. Methods: We have used a diet-induced mouse model of cardiometabolic disease to determine whether DDR1 deletion impacts upon adipose tissue remodeling and metabolic dysfunction. Mice were fed a high fat diet (HFD) for 12 weeks, followed by assessment of glucose and insulin tolerance, respiration via indirect calorimetry, and brown fat activity by FDG-PET. Results: Feeding HFD induced DDR1 expression in white adipose tissue, which correlated with adipose tissue expansion and fibrosis. Ddr1−/− mice fed an HFD had improved glucose tolerance, reduced body fat, and increased brown fat activity and energy expenditure compared to Ddr1+/+ littermate controls. HFD-fed DDR1−/− mice also had reduced fibrosis, smaller adipocytes with multilocular lipid droplets, and increased UCP-1 expression characteristic of beige fat formation in subcutaneous adipose tissue. In vitro, studying C3H10T1/2 cells stimulated to differentiate, DDR1 inhibition caused a shift from white to beige adipocyte differentiation, whereas DDR1 expression was increased with TGFβ-mediated pro-fibrotic differentiation. Conclusion: This study is the first to identify a role for DDR1 as a driver of adipose tissue fibrosis and suppressor of beneficial beige fat formation.

The article describes the clinical and morphological dynamics of systemic scleroderma diffuse form on the background of autologous bone marrow mesenchymal stem cells transplantation. The basis for the mesenchymal stem cells transplantation was the presence of a high activity index of the autoimmune process (EScSG), expressed diffuse skin changes (dense edema, induration) and resistance to immunosuppressive therapy. Transplantation of autologous bone marrow cells at systemic scleroderma contributes clinically to a significant reduction or cupping of skin induration, Raynaud’s syndrome, improvement of patient’s quality of life; morphological decrease of excessive fibrous tissue, stimulation of angiogenesis, and restoration of skin epithelium.

Background : Acute kidney injury (AKI) is a risk factor for progression to chronic kidney disease, with even subclinical AKI episodes progressing to chronic kidney disease. Several risk factors such as preexisting kidney disease, hyperglycemia, and hypertension may aggravate renal disease after AKI. However, mechanisms underlying the progression of AKI are still unclear. This study identified the effect of human cluster of differentiation 36 (CD36) overexpression on the progression of folic acid-induced AKI. Methods : Pax8-rtTA/tetracycline response element-human CD36 transgenic mice were used to elucidate the effect of human CD36 overexpression in the proximal tubules on folic acid-induced AKI. Results : Results of histological analysis showed severely dilated tubules with casts and albuminuria in folic acid-treated transgenic mice overexpressing human CD36 compared with folic acid-treated wild-type mice. In addition, analysis of mRNA expression showed a significant increase in the collagen 3a1 gene in folic acid-treated transgenic mice overexpressing human CD 36 compared with folic acid-treated wild type mice. Conclusion : Human CD36-overexpressing transgenic mice showed severe pathological changes and albuminuria compared with wild-type mice. Moreover, mRNA expression of the collagen 3a1 gene increased in folic acid-treated transgenic mice. These results suggest that human CD36 overexpression is a risk factor of AKI and its progression to chronic kidney disease.

Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-β, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17 A, IL-21, and IL-22) and the future prospects in the current disease.

Objective: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. Methods: OCA and IP118 alone and in combination were sub-chronically administered to Lepob/Lepob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lepob/Lepob mice was graded using a customized integrated scoring system. Results: OCA reduced liver weight and lipid in NASH mice (both by −17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (−21%), liver lipid (−15%), ALT (−29%), and AST (−27%). The combination of OCA + IP118 further reduced liver weight (−29%), liver lipid (−22%), ALT (−39%), and AST (−36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (−4.3% and −3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (−25.3%) to a greater degree than IP118 alone (−12.5%) and further improved glucose tolerance and reduced hepatic lipid. Conclusion: Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.

Objective: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. Method: We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. Results: Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. Conclusions: By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.