Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. In the United States, NAFLD and its subtype, nonalcoholic steatohepatitis, affect 30% ...and 5% of the population, respectively. Considering the ongoing obesity epidemic beginning in childhood, the rise in diabetes, and other factors, the prevalence of NAFLD along with the proportion of those with advanced liver disease is projected to continue to increase. This will have an important impact on public health reflected in health care costs, including impact on the need for liver transplantation, for which nonalcoholic steatohepatitis is already close to becoming the most common indication. NAFLD patients with evidence of nonalcoholic steatohepatitis and advanced fibrosis are at markedly increased risk of adverse outcomes, including overall mortality, and liver-specific morbidity and mortality, respectively. Identification of this cohort of NAFLD patients is paramount, given the associated poorer outcomes, in order to target resources to those who need it most. Various noninvasive tools have been developed in this regard. This review provides an update on the epidemiology, clinical and prognostic features, and diagnostic approach to patients with NAFLD.
In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate ...balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
3.
ROS signalling in the biology of cancer Moloney, Jennifer N.; Cotter, Thomas G.
Seminars in cell & developmental biology,
August 2018, 2018-08-00, 20180801, Letnik:
80
Journal Article
Recenzirano
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•Different types of tumour cells produce elevated levels of reactive oxygen species (ROS) compared to their normal counterparts.•Mitochondria and NADPH oxidases (NOX) are two major ...contributors of endogenous ROS in tumour cells.•The antioxidant capacity of tumour cells strives to scavenge excessive ROS while maintain pro-tumourigenic signalling and resistance to apoptosis.•Increased ROS levels can also activate anti-tumourigenic signalling resulting in oxidative stress induced-cancer cell death.•Specific modifications of ROS generation and antioxidant defences are identified as targets in cancer therapy.
Increased reactive oxygen species (ROS) production has been detected in various cancers and has been shown to have several roles, for example, they can activate pro-tumourigenic signalling, enhance cell survival and proliferation, and drive DNA damage and genetic instability. Counterintuitively ROS can also promote anti-tumourigenic signalling, initiating oxidative stress-induced tumour cell death. Tumour cells express elevated levels of antioxidant proteins to detoxify elevated ROS levels, establish a redox balance, while maintaining pro-tumourigenic signalling and resistance to apoptosis. Tumour cells have an altered redox balance to that of their normal counterparts and this identifies ROS manipulation as a potential target for cancer therapies. This review discusses the generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer. It also provides an insight into how pro- and anti-tumourigenic ROS signalling pathways could be manipulated in the treatment of cancer.
Reactive oxygen species (ROS) have been long regarded as by‐products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have ...detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox‐regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox‐signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox‐sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox‐modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology.
The recognition of ROS as mediators of cellular communications has led to their re‐classification as signalling molecules. Identification of redox‐sensitive kinases such as Src has prompted the emergence of a role for redox regulation of kinases. This review assesses the evidence for kinase regulation by direct oxidation, and proposes future directions for this crucial aspect of redox biology.
Currently, nonalcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation (LT), behind alcohol‐related liver disease. After transplant, both recurrent and de novo ...nonalcoholic fatty liver disease are common; however, recurrence rates of NASH and advanced fibrosis are low. Identification of high‐risk groups and optimizing treatment of metabolic comorbidities both before and after LT is paramount to maintaining a healthy allograft, especially with the additional consequences of longterm immunosuppression. In addition, NASH LT recipients are at an increased risk of cardiovascular events and malignancy, and their condition warrants a tailored approach to management. The optimal approach to NASH LT recipients including metabolic comorbidities management, tailored immunosuppression, the role of bariatric surgery, and nutritional and pharmacotherapy of NASH are discussed in this review. Overall, aggressive management of metabolic syndrome after LT via medical and surgical modalities and a minimalist approach to immunosuppression is advised.
Reactive oxygen species (ROS) were seen as destructive molecules, but recently, they have been shown also to act as second messengers in varying intracellular signaling pathways. This review ...concentrates on hydrogen peroxide (H2O2), as it is a more stable ROS, and delineates its role as a survival molecule. In the first part, the production of H2O2 through the NADPH oxidase (Nox) family is investigated. Through careful examination of Nox proteins and their regulation, it is determined how they respond to stress and how this can be prosurvival rather than prodeath. The pathways on which H2O2 acts to enable its prosurvival function are then examined in greater detail. The main survival pathways are kinase driven, and oxidation of cysteines in the active sites of various phosphatases can thus regulate those survival pathways. Regulation of transcription factors such as p53, NF-kappaB, and AP-1 also are reviewed. Finally, prodeath proteins such as caspases could be directly inhibited through their cysteine residues. A better understanding of the prosurvival role of H2O2 in cells, from the why and how it is generated to the various molecules it can affect, will allow more precise targeting of therapeutics to this pathway.
Hepatitis B virus reactivation (HBVr) can occur in patients treated with immunosuppressive medications. Risk stratification for HBVr based on hepatitis B virus (HBV) serology and viral load is an ...important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use. Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies. Tumor necrosis factor (TNF)-α inhibitors have been widely used for patients with inflammatory bowel disease, psoriasis, and rheumatic diseases. Further, the clinical benefits of interleukin (IL)-12/23, IL-17, or Janus kinases inhibitors have been demonstrated in these patients. It is well known that TNF-α inhibitor use can lead to HBVr, however, the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood. In this review, we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics, and immunological mechanisms of these medications causing HBVr.
Direct‐acting antiviral (DAA) therapy has altered the frequency and outcome of liver transplantation (LT) for hepatitis C virus (HCV). The high efficacy and tolerability of DAA therapy has also ...created a rationale for utilizing HCV‐viremic (HCV‐RNA–positive) donors, including into HCV‐negative recipients. We examined trends in frequency of organ utilization and graft survival in recipients of HCV‐viremic donors (HCV‐RNA positive as measured by nucleic acid testing NAT). Data were collected from the Scientific Registry of Transplant Recipients (SRTR) on adult patients who underwent a primary, single‐organ, deceased donor LT from January 1, 2008 to January 31, 2018. Outcomes of HCV‐negative transplant recipients (R–) who received an allograft from donors who were HCV‐RNA positive (DNAT+) were compared to outcomes for R– patients who received organs from donors who were HCV‐RNA negative (DNAT–). There were 11,270 DNAT–/R–; 4,748 DNAT–/R+; 87 DNAT+/R–; and 753 DNAT+/R+ patients, with 2‐year graft survival similar across all groups: DNAT–/R– 88%; DNAT–/R+ 88%; DNAT+/R– 86%; and DNAT+/R+ 90%. Additionally, there were 2,635 LTs using HCV antibody‐positive donors (DAb+): 2,378 DAb+/R+ and 257 DAb+/R–. The annual number of DAb+/R– transplants increased from seven in 2008 to 107 in 2017. In the post‐DAA era, graft survival improved for all recipients, with 3‐year survival of DAb+/R– patients and DAb+/R+ patients increasing to 88% from 79% and to 85% from 78%, respectively. Conclusion: The post‐DAA era has seen increased utilization of HCV‐viremic donor livers, including HCV‐viremic livers into HCV‐negative recipients. Early graft outcomes are similar to those of HCV‐negative recipients. These results support utilization of HCV‐viremic organs in selected recipients both with and without HCV infection.
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