Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the SERPINA1 gene encoding AAT and the common mutant Z allele of SERPINA1 encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR‐34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser574. Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.

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Mast cells distribution in human liver disease and experimental rat liver fibrosis. Indications for mast cell participation in development of liver fibrosis

Journal of Hepatology ◽

10.1016/s0168-8278(97)80113-4 ◽

1997 ◽

Vol 26 (5) ◽

pp. 1042-1054 ◽

Cited By ~ 84

Author(s):

Thomas Armbrust ◽

Danko Batusic ◽

Burkhardt Ringe ◽

Giuliano Ramadori

Keyword(s):

Mast Cell ◽

Liver Disease ◽

Mast Cells ◽

Liver Fibrosis ◽

Rat Liver ◽

Human Liver ◽

Rat Liver Fibrosis ◽

Human Liver Disease

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Endoglin in human liver disease and murine models of liver fibrosis-A protective factor against liver fibrosis

Liver International ◽

10.1111/liv.13595 ◽

2017 ◽

Vol 38 (5) ◽

pp. 858-867 ◽

Cited By ~ 6

Author(s):

Muhammad Alsamman ◽

Viktor Sterzer ◽

Steffen K. Meurer ◽

Hacer Sahin ◽

Ute Schaeper ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Human Liver ◽

Protective Factor ◽

Murine Models ◽

Human Liver Disease

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Keratins 8/18 represent type II acute-phase proteins which are differentially regulated in human liver disease

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1331972 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

N Güldiken ◽

V Usachov ◽

K Levada ◽

M Ziol ◽

P Nahon ◽

...

Keyword(s):

Liver Disease ◽

Acute Phase ◽

Human Liver ◽

Acute Phase Proteins ◽

Type Ii ◽

Human Liver Disease

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FINANCIAL CONTROLLING IN THE SYSTEM OF FINANCIAL MANAGEMENT

Knowledge International Journal ◽

10.35120/kij2801137y ◽

2018 ◽

Vol 28 (1) ◽

pp. 137-141

Author(s):

Petya Yordanova – Dinova

Keyword(s):

Comparative Analysis ◽

Financial Management ◽

Financial Stability ◽

Business Environment ◽

Innovative Approach ◽

Financial Sustainability ◽

The Common ◽

The Difference ◽

Effective Use ◽

And Control

This paper explores the comparative analysis of the financial controlling, who is a result from the common controlling concept and the financial management. In the specialized literature, financial controlling is seen as an innovative approach to financial management. It is often presented as the most promising instrument of financial diagnostics. Generally speaking, financial controlling is seen as a process of managing the company`s assets which are valued in monetary measures. The difference between the financial management and the financial controlling is that the second covers all functions of management, analysis and control of finances, aiming at maximizing their effective use and increasing the value of the enterprise. Financial controlling is often seen as a function of the common practice of financial management. Its objective is to preserve the financial stability and financial sustainability of enterprises operating in a highly aggressive business environment.

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Inhibition of IL-13: A New Pathway for Atopic Dermatitis

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475420982553 ◽

2020 ◽

pp. 120347542098255

Author(s):

Kayadri Ratnarajah ◽

Michelle Le ◽

Anastasiya Muntyanu ◽

Steve Mathieu ◽

Simon Nigen ◽

...

Keyword(s):

Monoclonal Antibody ◽

Atopic Dermatitis ◽

Severity Index ◽

Severe Atopic Dermatitis ◽

Treatment Alternative ◽

Control Groups ◽

Rapid Improvement ◽

Common Receptor ◽

The Common ◽

And Control

Dupilumab, a monoclonal antibody against the common receptor of interleukin (IL)-4 and IL-13, was the first biologic therapy approved in Canada for treatment of moderate-to-severe atopic dermatitis (AD). While it is considered safe and effective, dupilumab is not universally effective and 8%-38% of patients develop conjunctivitis, while some patients develop head and neck dermatitis. Thus, new therapeutic options are warranted. While both IL-4 and IL-13 play important roles in the pathogenesis of AD, it has been recently demonstrated that IL-13 is the primary upregulated cytokine in AD skin biopsy samples. A placebo-controlled phase 2b clinical trial evaluating the efficacy and safety of lebrikizumab, an IL-13 inhibitor, in AD demonstrated that, at 16 weeks, Eczema Area and Severity Index (EASI) 75 and Investigator’s Global Assessment (IGA) 0/1 were achieved by 60.6% and 44.6% of patients taking lebrikizumab at its highest dose (vs 24.3% and 15.3% of patients taking placebo, respectively). Moreover, treatment with lebrikizumab was associated with rapid improvement of pruritus and low rates of conjunctivitis (1.4%-3.8%). Another IL-13 monoclonal antibody, tralokinumab, was evaluated for safety and efficacy in moderate-to-severe AD. By week 12, among adults receiving 300 mg tralokinumab, 42.5% achieved EASI-75 and 26.7% achieved IGA 0/1 score (vs 15.5% and 11.8% in the placebo group, respectively). Both lebrikizumab and tralokinumab demonstrated acceptable safety profiles in AD (and non-AD) trials with adverse events often being comparable between treatment and control groups. Thus, IL-13 inhibitors may provide a safe and effective treatment alternative for patients with moderate-to-severe AD.

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Diagnosis and Therapeutic Management of Liver Fibrosis by microRNA

International Journal of Molecular Sciences ◽

10.3390/ijms22158139 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8139

Author(s):

Tomoko Tadokoro ◽

Asahiro Morishita ◽

Tsutomu Masaki

Keyword(s):

Liver Fibrosis ◽

Viral Infections ◽

Primary Biliary Cholangitis ◽

Medical Need ◽

Key Factor ◽

Complications Of Cirrhosis ◽

And Control ◽

Functional Rnas ◽

Remarkable Progress ◽

Made In

Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called “exosomes” have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent.

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Prevalent Pathogenic Variants of ATP7B in Chinese Patients with Wilson’s Disease: Geographical Distribution and Founder Effect

Genes ◽

10.3390/genes12030336 ◽

2021 ◽

Vol 12 (3) ◽

pp. 336

Author(s):

Guo-Min Yang ◽

Rou-Min Wang ◽

Nan Xia ◽

Zi-Wei Zheng ◽

Yi Dong ◽

...

Keyword(s):

Geographical Distribution ◽

Founder Effect ◽

Wilson’S Disease ◽

Autosomal Recessive Disorder ◽

Wilson's Disease ◽

Chinese Patients ◽

Mainland Chinese ◽

Pathogenic Variants ◽

Specific Distribution ◽

The Common

Wilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes (p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.

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Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants

Journal of Clinical Medicine ◽

10.3390/jcm9020545 ◽

2020 ◽

Vol 9 (2) ◽

pp. 545 ◽

Cited By ~ 3

Author(s):

Rob W. Roudijk ◽

Laurens P. Bosman ◽

Jeroen F. van der Heijden ◽

Jacques M. T. de Bakker ◽

Richard N. W. Hauer ◽

...

Keyword(s):

Early Stage ◽

Pathogenic Variant ◽

Observer Agreement ◽

Arrhythmogenic Cardiomyopathy ◽

Fragmented Qrs ◽

Early Disease Detection ◽

Pathogenic Variants ◽

Disease Penetrance ◽

Ecg Leads ◽

And Control

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.

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Association between EFHD2 gene polymorphisms and schizophrenia among the Han population in northern China

Journal of International Medical Research ◽

10.1177/0300060520932801 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006052093280

Author(s):

Meng Gao ◽

Kuo Zeng ◽

Ya Li ◽

Yong-ping Liu ◽

Xi Xia ◽

...

Keyword(s):

Allele Frequency ◽

Neurodevelopmental Disorder ◽

Haplotype Frequency ◽

Northern China ◽

Polymorphism Analysis ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Gene Encoding ◽

Frequency Distributions ◽

And Control

Objective Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. The gene encoding EF-hand domain-containing protein D2 ( EFHD2) may be a genetic risk locus for schizophrenia. Methods We genotyped four EFHD2 single-nucleotide polymorphisms (281 schizophrenia cases [SCZ], 321 controls) from northern Chinese Han individuals using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. Differences existed in genotype, allele, and haplotype frequency distributions between SCZ and control groups. Results The rs2473357 genotype and allele frequency distributions differed between SCZ and controls; however, this difference disappeared after Bonferroni correction. Differences in rs2473357 genotype and allele frequency distributions between SCZ and controls were more pronounced in men than in women. The G allele increased schizophrenia risk (odds ratio = 1.807, 95% confidence interval = 1.164–2.803). Among six haplotypes (G–, A–, G-insC, A-C, G-C, and G-T), the G– haplotype frequency distribution differed between SCZ and controls in women; the A-C and G-C haplotype frequency distributions differed between SCZ and controls in men. Conclusions EFHD2 may be involved in schizophrenia. Sex differences in EFHD2 genotype and allele frequency distributions existed among schizophrenia patients. Further research is needed to determine the role of EFHD2 in schizophrenia.

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