Therapeutic targets in liver fibrosis

2011 ◽  
Vol 300 (5) ◽  
pp. G709-G715 ◽  
Author(s):  
Jonathan A. Fallowfield
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Market Potential ◽  
Therapeutic Approaches ◽  
The Us ◽  
Exciting Potential ◽  
Definition Of ◽  
And Function ◽  
Near Future

Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

scholarly journals Current Treatment Options for Cystic Fibrosis-Related Liver Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8586 ◽  
Author(s):  
Katharina Staufer
Keyword(s):  
Cystic Fibrosis ◽  
Liver Disease ◽  
Current Knowledge ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Transmembrane Conductance Regulator ◽  
Definition Of ◽  
Related Liver Disease ◽  
Near Future

Cystic Fibrosis-related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF), and affects children and adults. The understanding of the pathogenesis of CFLD is key in order to develop efficacious treatments. However, it remains complex, and has not been clarified to the last. The search for a drug might be additionally complicated due to the diverse clinical picture and lack of a unified definition of CFLD. Although ursodeoxycholic acid has been used for decades, its efficacy in CFLD is controversial, and the potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators and targeted gene therapy in CFLD needs to be defined in the near future. This review focuses on the current knowledge on treatment strategies for CFLD based on pathomechanistic viewpoints.

Phytotherapy for Cardiovascular Disease: A Bench-to-Bedside Approach

2020 ◽  
Vol 26 (35) ◽  
pp. 4410-4429
Author(s):  
Mervin Chávez-Castillo ◽  
Ángel Ortega ◽  
Pablo Duran ◽  
Daniela Pirela ◽  
María Marquina ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Treatment Strategies ◽  
Mechanisms Of Action ◽  
Global Trends ◽  
Anti Oxidant ◽  
Therapeutic Alternatives ◽  
Near Future

At present, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and global trends suggest that this panorama will persist or worsen in the near future. Thus, optimization of treatment strategies and the introduction of novel therapeutic alternatives for CVD represent key objectives in contemporary biomedical research. In recent years, phytotherapy-defined as the therapeutic use of whole or minimally modified plant components-has ignited large scientific interest, with a resurgence of abundant investigation on a wide array of medicinal herbs (MH) for CVD and other conditions. Numerous MH have been observed to intervene in the pathophysiology of CVD via a myriad of molecular mechanisms, including antiinflammatory, anti-oxidant, and other beneficial properties, which translate into the amelioration of three essential aspects of the pathogenesis of CVD: Dyslipidemia, atherosclerosis, and hypertension. Although the preclinical data in this scenario is very rich, the true clinical impact of MH and their purported mechanisms of action is less clear, as large-scale robust research in this regard is in relatively early stages and faces important methodological challenges. This review offers a comprehensive look at the most prominent preclinical and clinical evidence currently available concerning the use of MH in the treatment of CVD from a bench-to-bedside approach.

scholarly journals Th17 and Treg Cells in Bone Related Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Min Wang ◽  
Tian Tian ◽  
Shuang Yu ◽  
Na He ◽  
Daoxin Ma
Keyword(s):  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Treg Cells ◽  
Bone Diseases ◽  
Reciprocal Relationship ◽  
T Helper ◽  
Therapeutic Approaches ◽  
T Helper 17 ◽  
And Function

Bone-related diseases share the process of immune response that targets bone tissue and bone marrow and then induce adverse effects on structure and function. In recent years, reciprocal relationship between immune cells and bone systems has been uncovered gradually. Regulatory T (Treg) and T helper 17 (Th17) cells are newly identified subsets of CD4+ T cells, and the balance between them is particularly essential for maintaining immune homeostasis. Accumulated data have demonstrated quantitative or functional imbalance between Th17 and Treg in bone related diseases, suggesting that Th17 and Treg cells are involved in these bone diseases. Understanding the molecular mechanisms regulating Th17 and Treg cells will create opportunities for the development of therapeutic approaches. This review will present the role of Th17 and Treg cells in the inflammatory bone diseases and bone marrow malignancies and find the potential therapeutic target for immunotherapy.

scholarly journals Intestinal congestion and reperfusion injury: Damage caused to the intestinal tract and distal organs

2021 ◽  
Author(s):  
Yajing Chen ◽  
WeiGao Pu ◽  
Ewetse Maswikiti Paul ◽  
Pengxian Tao ◽  
Xuemei Li ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Intestinal Tract ◽  
Treatment Strategies ◽  
Intestinal Wall ◽  
Structure And Function ◽  
Common Complication ◽  
Therapeutic Approaches ◽  
New Ideas ◽  
And Function ◽  
Organ Dysfunctions

In clinical practice, intestinal autologous diseases, ailments and organ transplants can cause severe congestive damage to the intestinal tract. However, after the etiological factor is  gotten rid of and blood flow is free without any hinderance, further damage to the intestinal wall often occurs, causing other related organ dysfunctions. This ultimately results in intestinal congestion reperfusion injury (ICRI). When the structure and function of the intestine are destroyed, bacteria, metabolites and endotoxins in the intestinal tract perfuse and enter the portal vein through the already compromised intestinal mucosa, to the other organs via the liver. Nevertheless, this gives rise to further aggravation of the injury, and reperfusion injury syndrome  occurs. ICRI is a very common complication encountered by clinicians, and its harm is more severe and serious as compared to that caused by  ischemic-reperfusion. Quite a a few number of studies on ICRI have been reported to date. The exact mechanism of the injury is still idiopathic, and effective treatment strategies are still limited. Based on   recent studies, this article is aimed at  reviewing the destruction, damage mechanisms resulting from intestinal congestion reperfusion injury to the intestinal anatomical sites and distant organs. It is geared towards providing new ideas for the prevention and therapeutic approaches of intestinal congestion reperfusion injury.

scholarly journals Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1249 ◽  
Author(s):  
Mousumi Khatun ◽  
Ratna B. Ray
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Cytokines And Chemokines ◽  
Chronic Hcv

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.

scholarly journals Technologies for Monitoring Lifestyle Habits Related to Brain Health: A Systematic Review

Sensors ◽  
2019 ◽  
Vol 19 (19) ◽  
pp. 4183 ◽  
Author(s):  
Moreno-Blanco ◽  
Solana-Sánchez ◽  
Sánchez-González ◽  
Oropesa ◽  
Cáceres ◽  
...  
Keyword(s):  
Continuous Monitoring ◽  
Mobile Technologies ◽  
Data Driven ◽  
Mental Wellbeing ◽  
Objective Data ◽  
Brain Health ◽  
Definition Of ◽  
And Function ◽  
Near Future ◽  
Fine Tune

Brain health refers to the preservation of brain integrity and function optimized for an individual’s biological age. Several studies have demonstrated that our lifestyles habits impact our brain health and our cognitive and mental wellbeing. Monitoring such lifestyles is thus critical and mobile technologies are essential to enable such a goal. Three databases were selected to carry out the search. Then, a PRISMA and PICOTS based criteria for a more detailed review on the basis of monitoring lifestyle aspects were used to filter the publications. We identified 133 publications after removing duplicates. Fifteen were finally selected from our criteria. Many studies still use questionnaires as the only tool for monitoring and do not apply advanced analytic or AI approaches to fine-tune results. We anticipate a transformative boom in the near future developing and implementing solutions that are able to integrate, in a flexible and adaptable way, data from technologies and devices that users might already use. This will enable continuous monitoring of objective data to guide the personalized definition of lifestyle goals and data-driven coaching to offer the necessary support to ensure adherence and satisfaction.

scholarly journals SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line

2020 ◽  
Vol 21 (20) ◽  
pp. 7627
Author(s):  
Sabine Stöckl ◽  
Georg Lindner ◽  
Shushan Li ◽  
Philipp Schuster ◽  
Sebastian Haferkamp ◽  
...  
Keyword(s):  
Cell Line ◽  
Treatment Strategies ◽  
Tumor Treatment ◽  
Therapeutic Approaches ◽  
Normal Cartilage ◽  
Chondrosarcoma Cell ◽  
And Migration ◽  
And Function ◽  
Chondrosarcoma Cell Line

As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options.

scholarly journals ATRIAL FIBRILLATION IN PATIENT WITH DIABETES MELLITUS 2 TYPE: CO-EXISTANCE AND THERAPEUTIC APROCHES

2018 ◽  
Keyword(s):  
Diabetes Mellitus ◽  
Atrial Fibrillation ◽  
Diabetes Mellitus Type 2 ◽  
Molecular Mechanisms ◽  
Lifestyle Modification ◽  
Treatment Strategies ◽  
Therapeutic Approaches ◽  
Anticoagulation Treatment ◽  
Diabetes Mellitus 2

On the example of the clinical case of atrial fibrillation in patient with diabetes mellitus type 2, were discussed molecular mechanisms and therapeutic perspectives, anticoagulation treatment and anti-arrhythmic treatment strategies benefit. Recommendations on lifestyle modification and medicament treatment tactics are described. Atrial fibrillation and diabetes mellitus are very common comorbidities and with high expectance they will co-exist together in the future because of the both conditions prevalence especially in older patients group. Therefore, establishing of the most effective and safe treatment it is very important to the subpopulation of patients with AF and DM. New studies with larger numbers of patients from different age and rage groups with diabetes and AF are needed to investigate the mechanisms of thisrelationship and all possible therapeutic approaches in order to determine the best possible individual management of both conditions.

scholarly journals Ubiquitin-Like Post-Translational Modifications (Ubl-PTMs): Small Peptides with Huge Impact in Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1575 ◽  
Author(s):  
Sofia Lachiondo-Ortega ◽  
Maria Mercado-Gómez ◽  
Marina Serrano-Maciá ◽  
Fernando Lopitz-Otsoa ◽  
Tanya B Salas-Villalobos ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
In Vitro Models ◽  
Therapeutic Approaches ◽  
Small Peptides ◽  
Post Translational Modifications ◽  
Huge Impact

Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, therapeutic approaches for liver fibrosis remain limited. Profiling and characterization of the post-translational modifications (PTMs) of proteins, and more specifically NEDDylation and SUMOylation ubiquitin-like (Ubls) modifications, can provide a better understanding of the liver fibrosis pathology as well as novel and more effective therapeutic approaches. On this basis, in the last years, several studies have described how changes in the intermediates of the Ubl cascades are altered during liver fibrosis and how specific targeting of particular enzymes mediating these ubiquitin-like modifications can improve liver fibrosis, mainly in in vitro models of hepatic stellate cells, the main fibrogenic cell type, and in pre-clinical mouse models of liver fibrosis. The development of novel inhibitors of the Ubl modifications as well as novel strategies to assess the modified proteome can provide new insights into the overall role of Ubl modifications in liver fibrosis.

Melatonin: Protection of the Intervertebral Disc

2019 ◽  
Vol 2 (3) ◽  
pp. 1-9
Author(s):  
Russel J Reiter ◽  
Sergio Rosales-Corral ◽  
Ramaswamy Sharma
Keyword(s):  
Intervertebral Disc ◽  
Molecular Mechanisms ◽  
Intervertebral Discs ◽  
Lumbar Pain ◽  
Low Back ◽  
Work Time ◽  
Protective Actions ◽  
Aging Populations ◽  
Definition Of ◽  
Endogenous Melatonin

     Low back pain (lumbar pain) due to injury of or damage to intervertebral discs is common in all societies.  The loss of work time as a result of this problem is massive.  Recent research suggests that melatonin may prevent or counteract intervertebral disc damage. This may be especially relevant in aging populations given that endogenous melatonin, in most individuals, dwindles with increasing age. The publications related to melatonin and its protection of the intervertebral disc are reviewed herein, including definition of some molecular mechanisms that account for melatonin’s protective actions. 

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