scholarly journals Molecular Mechanisms and Treatment of Sarcopenia in Liver Disease: A Review of Current Knowledge

2021 ◽  
Vol 22 (3) ◽  
pp. 1425
Author(s):  
Hiroteru Kamimura ◽  
Takeki Sato ◽  
Kazuki Natsui ◽  
Takamasa Kobayashi ◽  
Tomoaki Yoshida ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Molecular Mechanisms ◽  
Hospital Admissions ◽  
Current Knowledge ◽  
Therapeutic Approaches ◽  
Negative Prognostic Factor ◽  
Increased Risk ◽  
Catabolic State ◽  
Relationship Of

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength that occurs with aging or in association with various diseases. The condition is prevalent worldwide and occurs more frequently in patients with chronic diseases owing to the intrinsic relationship of muscles with glucose, lipid, and protein metabolism. Liver cirrhosis is characterized by the progression of necro-inflammatory liver diseases, which leads to fibrosis, portal hypertension, and a catabolic state, which causes loss of muscle tissue. Sarcopenia is of significant concern in the state of liver cirrhosis because sarcopenia has been associated with higher mortality, increased hospital admissions, worse post-liver transplant outcomes, decreased quality of life, and increased risk for other complications associated with cirrhosis. Therefore, sarcopenia is also an important feature of liver cirrhosis, representing a negative prognostic factor and influencing mortality. An increased understanding of sarcopenia could lead to the development of novel therapeutic approaches that could help improve the cognitive impairment of cirrhotic patients; therefore, we present a review of the mechanisms and diagnosis of sarcopenia in liver disease and existing therapeutic approaches.

scholarly journals Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qingfei Chu ◽  
Xinyu Gu ◽  
Qiuxian Zheng ◽  
Jing Wang ◽  
Haihong Zhu
Keyword(s):  
Cell Death ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Cellular Energetics ◽  
Liver Cell Death

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

Epigenetics

2019 ◽  
pp. 56-70
Author(s):  
Edward Hookway ◽  
Nicholas Athanasou ◽  
Udo Oppermann
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tumour Suppressor Genes ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

scholarly journals A case of pneumonia and sepsis in cirrhosis as paradigm of the problems in the management of bacterial infections in cirrhosis and of the limitations of current knowledge

2013 ◽  
pp. 209-214
Author(s):  
Manuel Tufoni ◽  
Alessandra Tovoli ◽  
Caterina Maggioli ◽  
Lucia Napoli ◽  
Carmen Serena Ricci ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Hepatic Encephalopathy ◽  
Hepatitis C ◽  
Antibiotic Therapy ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Clinical Presentation ◽  
Current Knowledge ◽  
Empirical Antibiotic Therapy ◽  
Increased Risk

Bacterial infections are a major problem in the management of liver cirrhosis. They represent the first precipitating cause of death since patients with cirrhosis carry an increased risk of sepsis, sepsis-induced organ failure and death. Although the clinical presentation is often misleading, the presence of bacterial infection should always be actively searched and ruled out with certainty whenever a cirrhotic patient is admitted to the hospital with an acute clinical deterioration. Major changes in the epidemiology of bacterial infections have also occurred in the last decade making the choice of empirical antibiotic therapy a challenge. We report a paradigmatic case of a 54-year old man with hepatitis C-related cirrhosis admitted to the hospital for worsening of his ascites and onset of hepatic encephalopathy, an excellent example for the difficulties of management of sepsis in cirrhosis and the limits of current knowledge.

scholarly journals Burden of Liver Cirrhosis in Portugal between 2010 and 2017

2020 ◽  
pp. 1-9
Author(s):  
João Manuel Silva ◽  
Mário Jorge Silva ◽  
Filipe Calinas ◽  
Paulo Jorge Nogueira
Keyword(s):  
Liver Cirrhosis ◽  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Virus Infection ◽  
Chronic Liver Disease ◽  
Hospital Admissions ◽  
Chronic Liver ◽  
Years Of Life Lost ◽  
Hepatitis C Virus Infection

<b><i>Introduction:</i></b> Liver cirrhosis is a prevalent disease in Portugal. Recent changes in alcohol consumption, as well as the wide use of direct-acting antivirals for hepatitis C since 2015, may be contributing to changes in the national burden of liver cirrhosis in the last few years. <b><i>Objectives:</i></b> We aim to characterize the burden of cirrhosis in Portugal between 2010 and 2017. <b><i>Patients and Methods:</i></b> We analyzed all hospital admission episodes due to cirrhosis in Portugal Mainland between 2010 and 2017, registered in the national Diagnosis-Related Group database, according to etiology of cirrhosis. We also analyzed data on mortality and potential years of life lost from liver cirrhosis and chronic liver disease, retrieved from Statistics Portugal (National Institute for Statistics). <b><i>Results:</i></b> Between 2010 and 2017, a total of 51,438 admissions for liver cirrhosis occurred in Portugal. The annual number of admissions decreased (<i>p</i> = 0.044) during the analyzed period. The most frequent cause of cirrhosis was alcoholic liver disease, present in 78.9% of all admissions (<i>n</i> = 40,595), followed by chronic hepatitis C virus infection, present in 11.3% (<i>n</i> = 5,823). A male predominance was identified in the admissions for every analyzed cause of cirrhosis. Annual admissions for alcoholic cirrhosis remained stable (<i>p</i> = 0.075) during the 8-year period. The same stable tendency was observed in the number of admissions for cirrhosis caused by hepatitis C virus (<i>p</i> = 0.861) and alcohol plus hepatitis C virus infection (<i>p</i> = 0.082), although these admissions for hepatitis C-related cirrhosis increased until 2014–2015 and steadily decreased thereafter. Annual deaths due to liver cirrhosis and chronic liver disease decreased from 1,357 in 2010 to 1,038 in 2017 (<i>p</i> = 0.002). The number of potential years of life lost decreased as well in the period (<i>p</i> = 0.001). <b><i>Conclusion:</i></b> The burden of cirrhosis, evaluated by hospital admissions, mortality, and potential years of life lost, decreased in Portugal between 2010 and 2017.

scholarly journals The Association of Vitamin D with Brain Cognitive Functions: A Literature Review

2020 ◽  
pp. 97-113
Author(s):  
Yahya A. Alzahrani ◽  
Mohammed A. Alomary ◽  
Abdulmajeed A. Alzahrani ◽  
Mawaddah M. Eskandarani ◽  
Iman S. Aljabry ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Current Knowledge ◽  
Neuroprotective Effect ◽  
Cochrane Library ◽  
Calcium Balance ◽  
Increased Risk

Vitamin D is a well-known steroid hormone that plays an important role in controlling bone levels of calcium, phosphorus, and overall mineralization. Several animal and human studies indicate that vitamin D hypovitaminosis may be linked to an increased risk of developing Alzheimer's disease and dementia. The objective of the present review is to summarize current knowledge of the effects of vitamin D deficiency and vitamin D intake on cognitive function. The possible underline mechanisms of these effects were also discussed. We reviewed the literature starting from 1986 to 2019 by searching PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases for all observational studies, randomized clinical trials, meta-analyses, and systematic reviews using the keywords  “vitamin D and Alzheimer disease”, “neuroprotective effect of vitamin D”, “vitamin D deficiency and Alzheimer ”, “role of vitamin D in neurodegenerative diseases ”, ” vitamin D and amyloidogenesis”, “acetylcholine and vitamin D”, and “memory and vitamin D ”.We also referred to animal and in vitro studies that dealt with the possible mechanisms of actions of the neuroprotective effect of vitamin D. Our findings showed that Vitamin D supplementation improves cognitive performance via reducing amyloidogenesis, restoration of neurotransmission, maintaining calcium balance, regulating neurotrophic factors, anti-inflammatory action, apoptosis regulation, antioxidant, and vascular processes. This review might be open new horizons in the understanding of the molecular mechanisms of the disease and neurodegeneration and enable the development of new approaches in treatment and prevention of the disease.

scholarly journals An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

2021 ◽  
Vol 8 ◽  
Author(s):  
Marcella Massimini ◽  
Mariarita Romanucci ◽  
Raffaella De Maria ◽  
Leonardo Della Salda
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Human Cancer ◽  
Vasculogenic Mimicry ◽  
Human Osteosarcoma ◽  
Increased Risk ◽  
Veterinary Pathology ◽  
Canine Tumors ◽  
Novel Biomarkers ◽  
Cancer Types

Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.

scholarly journals Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts

2021 ◽  
Vol 22 (16) ◽  
pp. 8798
Author(s):  
Xiaoqiang Wang ◽  
Desiree Ha ◽  
Ryohei Yoshitake ◽  
Yin S. Chan ◽  
David Sadava ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Extensive Literature ◽  
Industrial Chemicals ◽  
Therapeutic Approaches ◽  
Human Cancers ◽  
Systemic Level ◽  
Critical Timing ◽  
New Applications ◽  
Female Lifespan

Xenoestrogens and phytoestrogens are referred to as “foreign estrogens” that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers.

scholarly journals Germline Structural Variations in Cancer Predisposition Genes

2021 ◽  
Vol 12 ◽  
Author(s):  
Tímea Pócza ◽  
Vince Kornél Grolmusz ◽  
János Papp ◽  
Henriett Butz ◽  
Attila Patócs ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cancer Predisposition ◽  
Detection Methods ◽  
Small Scale ◽  
Structural Variations ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Cancer Syndromes ◽  
Risk Of Cancer

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

scholarly journals Phagocytosis, Degranulation and Extracellular Traps Release by Neutrophils—The Current Knowledge, Pharmacological Modulation and Future Prospects

2021 ◽  
Vol 12 ◽  
Author(s):  
Barbara Gierlikowska ◽  
Albert Stachura ◽  
Wojciech Gierlikowski ◽  
Urszula Demkow
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Innate Immune ◽  
Therapeutic Approaches ◽  
Effector Functions ◽  
Pharmacological Modulation ◽  
Synthetic Drugs ◽  
Extracellular Traps

Neutrophils are crucial elements of innate immune system, which assure host defense via a range of effector functions, such as phagocytosis, degranulation, and NET formation. The latest literature clearly indicates that modulation of effector functions of neutrophils may affect the treatment efficacy. Pharmacological modulation may affect molecular mechanisms activating or suppressing phagocytosis, degranulation or NET formation. In this review, we describe the role of neutrophils in physiology and in the course of bacterial and viral infections, illustrating the versatility and plasticity of those cells. This review also focus on the action of plant extracts, plant-derived compounds and synthetic drugs on effector functions of neutrophils. These recent advances in the knowledge can help to devise novel therapeutic approaches via pharmacological modulation of the described processes.

Investigating the Biological and Molecular Mechanisms Underpinning the Engraftment/Selection Advantage Conferred to Hematopoietic Stem Cells by HOXB4.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2101-2101
Author(s):  
Michael D. Milsom ◽  
Laura Hollins ◽  
Dorothy Gagen ◽  
Lorna B. Woolford ◽  
Leslie J. Fairbairn
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Vitro Analysis

Abstract We have recently demonstrated that co-expression of HOXB4 enables the enhanced delivery of HSC harbouring a second therapeutic trans-gene. Nonetheless, it is of great importance to elaborate the current knowledge about the mechanism of HOXB4 action in order to both evaluate the safety implications of its use in a clinical strategy, and to gain greater insight into the regulation of HSC self-renewal/expansion. To these ends we have performed an extensive in vitro analysis of the consequences of HOXB4 overexpression in primary murine BMC and in a murine multipotent myeloid progenitor cell line (FDCP-mix). We demonstrate for the first time in murine cells, that ectopic HOXB4 reduces the responsiveness of murine hematopoietic cells to differentiation stimuli. Furthermore, by performing a detailed investigation into the kinetics of FDCP-mix differentiation, we reveal that HOXB4 overexpression results in a specific differentiation delay as opposed to an outright block. We propose that an analogous delay is in operation in repopulating cells in order that the shift to increased assymetrical self-renewal, a requirement for stem cell expansion, is achieved. Notwithstanding this, it is clear that any perturbation in differentiation constitutes an increased risk of cellular transformation if this technology were transferred to a clinical setting. In order to further define the repercussions of ectopic HOXB4 delivery, we have developed a retroviral vector which encodes an activatable version of HOXB4. We have shown that this vector is able to mediate an in vitro differentiation delay in primary murine BMC and FDCP-mix as well as enable enhanced engraftment of BMC in vivo, both dependent upon the addition of the estrogen analogue; tamoxifen. Using this system, we are currently examining the effect of ectopic HOXB4 on the transcriptome of FDCP-mix cells, in addition to performing an in depth study into the biological mechanisms affected by HOXB4 overexpression in BMC in vivo. We envisage that these model systems will be particularly amenable to the manipulation required for target gene identification/validation.

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