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Genes & Development Dec 2020Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive... (Review)
Review
Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.
Topics: Aging; Cellular Senescence; Disease Susceptibility; Drug Development; Drug Therapy; Epigenesis, Genetic; Gene Expression Regulation; Humans; Pharmaceutical Preparations; Secretory Pathway; Signal Transduction
PubMed: 33262144
DOI: 10.1101/gad.343129.120 -
Journal of Immunology Research 2019Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.
Topics: Animals; Disease Susceptibility; Environment; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases
PubMed: 31886308
DOI: 10.1155/2019/7247238 -
Experimental Biology and Medicine... Feb 2018Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved... (Review)
Review
Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice, particularly in the fields of chronic disease and nutrition. Clarification of the definitions of different biomarkers and a better understanding of their appropriate application could result in substantial benefits. This review examines biomarker definitions recently established by the U.S. Food and Drug Administration and the National Institutes of Health as part of their joint Biomarkers, EndpointS, and other Tools (BEST) resource. These definitions are placed in context of their respective uses in patient care, clinical research, or therapeutic development. We explore the distinctions between biomarkers and clinical outcome assessments and discuss the specific definitions and applications of diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. We also explore the implications of current biomarker development trends, including complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies. Finally, we discuss the challenges and potential benefits of biomarker-driven predictive toxicology and systems pharmacology, the need to ensure quality and reproducibility of the science underlying biomarker development, and the importance of fostering collaboration across the entire ecosystem of medical product development. Impact statement Biomarkers are critical to the rational development of medical diagnostics and therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice. Clarification of the definitions of different biomarker classes and a better understanding of their appropriate application could yield substantial benefits. Biomarker definitions recently established in a joint FDA-NIH resource place different classes of biomarkers in the context of their respective uses in patient care, clinical research, or therapeutic development. Complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies, together with biomarker-driven predictive toxicology and systems pharmacology, are reshaping development of diagnostic and therapeutic technologies. An approach to biomarker development that prioritizes the quality and reproducibility of the science underlying biomarker development and incorporates collaborative regulatory science involving multiple disciplines will lead to rational, evidence-based biomarker development that keeps pace with scientific and clinical need.
Topics: Biomarkers; Biomarkers, Pharmacological; Disease Susceptibility; Humans; National Institutes of Health (U.S.); Outcome Assessment, Health Care; Patient Care; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 29405771
DOI: 10.1177/1535370217750088 -
Frontiers in Neuroendocrinology Jul 2019Synchronizing circadian (24 h) rhythms in physiology and behavior with the environmental light-dark cycle is critical for maintaining optimal health. Dysregulation of... (Review)
Review
Synchronizing circadian (24 h) rhythms in physiology and behavior with the environmental light-dark cycle is critical for maintaining optimal health. Dysregulation of the circadian system increases susceptibility to numerous pathological conditions including major depressive disorder. Stress is a common etiological factor in the development of depression and the circadian system is highly interconnected to stress-sensitive neurotransmitter systems such as the serotonin (5-hydroxytryptamine, 5-HT) system. Thus, here we propose that stress-induced perturbation of the 5-HT system disrupts circadian processes and increases susceptibility to depression. In this review, we first provide an overview of the basic components of the circadian system. Next, we discuss evidence that circadian dysfunction is associated with changes in mood in humans and rodent models. Finally, we provide evidence that 5-HT is a critical factor linking dysregulation of the circadian system and mood. Determining how these two systems interact may provide novel therapeutic targets for depression.
Topics: Animals; Circadian Rhythm; Depression; Depressive Disorder; Disease Susceptibility; Humans; Serotonin; Stress, Psychological
PubMed: 31002895
DOI: 10.1016/j.yfrne.2019.04.003 -
Immunity Nov 2021Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. This recently implemented definition does not capture... (Review)
Review
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. This recently implemented definition does not capture the heterogeneity or the underlying pathophysiology of the syndrome, which is characterized by concurrent unbalanced hyperinflammation and immune suppression. Here, we review current knowledge of aberrant immune responses during sepsis and recent initiatives to stratify patients with sepsis into subgroups that are more alike from a clinical and/or pathobiological perspective, which could be key for identification of patients who are more likely to benefit from specific immune interventions.
Topics: Disease Susceptibility; Host-Pathogen Interactions; Humans; Immunity; Sepsis
PubMed: 34758337
DOI: 10.1016/j.immuni.2021.10.012 -
Journal of Immunology Research 2019Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically... (Review)
Review
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
Topics: Animals; Autoimmunity; Biomarkers; Combined Modality Therapy; Disease Susceptibility; Hepatitis, Autoimmune; Humans; Risk Factors; Severity of Illness Index; Treatment Outcome
PubMed: 31886312
DOI: 10.1155/2019/9437043 -
Trends in Cancer Jul 2019Cancer immunotherapy aims to arm patients with cancer-fighting immunity. Many new cancer-specific immunotherapeutic drugs have gained approval in the past several years,... (Review)
Review
Cancer immunotherapy aims to arm patients with cancer-fighting immunity. Many new cancer-specific immunotherapeutic drugs have gained approval in the past several years, demonstrating immunotherapy's efficacy and promise as an anticancer modality. Despite these successes, several outstanding questions remain for cancer immunotherapy, including how to make immunotherapy more efficacious in a broader range of cancer types and patients, and how to predict which patients will respond or not respond to therapy. We present a case for integrative systems approaches that will answer these questions. This involves applying mechanistic and statistical modeling, establishing consistent and widely adopted experimental tools to generate systems-level data, and creating sustained mechanisms of support. If implemented, these approaches will lead to major advances in cancer treatment.
Topics: Combined Modality Therapy; Computational Biology; Disease Susceptibility; Humans; Immunotherapy; Immunotherapy, Adoptive; Machine Learning; Models, Theoretical; Neoplasms; Research Design; Treatment Outcome
PubMed: 31311655
DOI: 10.1016/j.trecan.2019.05.010 -
Immunology and Allergy Clinics of North... Feb 2019The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This... (Review)
Review
The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This changing landscape of inflammatory bowel disease reflects the new recognition that the youngest children with inflammatory bowel disease are enriched in cases with underlying primary immunodeficiency and monogenic causes. The management of these cases can be quite different, with specific genetic etiologies supporting unique interventions and some requiring hematopoietic cell transplantation for effective treatment.
Topics: Age of Onset; Autoimmunity; Diagnosis, Differential; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases; Phenotype
PubMed: 30466773
DOI: 10.1016/j.iac.2018.08.008 -
Exercise Immunology Review 2020Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts... (Review)
Review
Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts of short-lasting (i.e. up to 45 minutes) moderate intensity exercise is beneficial for host immune defense, particularly in older adults and people with chronic diseases. In contrast, infection burden is reported to be high among high performance athletes and second only to injury for the number of training days lost during preparation for major sporting events. This has shaped the common view that arduous exercise (i.e. those activities practiced by high performance athletes/ military personnel that greatly exceed recommended physical activity guidelines) can suppress immunity and increase infection risk. However, the idea that exercise per se can suppress immunity and increase infection risk independently of the many other factors (e.g. anxiety, sleep disruption, travel, exposure, nutritional deficits, environmental extremes, etc.) experienced by these populations has recently been challenged. The purpose of this debate article was to solicit opposing arguments centered around this fundamental question in the exercise immunology field: can exercise affect immune function to increase susceptibility to infection. Issues that were contested between the debating groups include: (i) whether or not athletes are more susceptible to infection (mainly of the upper respiratory tract) than the general population; (ii) whether exercise per se is capable of altering immunity to increase infection risk independently of the multiple factors that activate shared immune pathways and are unique to the study populations involved; (iii) the usefulness of certain biomarkers and the interpretation of in vitro and in vivo data to monitor immune health in those who perform arduous exercise; and (iv) the quality of scientific evidence that has been used to substantiate claims for and against the potential negative effects of arduous exercise on immunity and infection risk. A key point of agreement between the groups is that infection susceptibility has a multifactorial underpinning. An issue that remains to be resolved is whether exercise per se is a causative factor of increased infection risk in athletes. This article should provide impetus for more empirical research to unravel the complex questions that surround this contentious issue in the field of exercise immunology.
Topics: Animals; Athletes; Disease Susceptibility; Exercise; Humans; Immune System; Immunity; Infections
PubMed: 32139352
DOI: No ID Found -
Frontiers in Immunology 2019Atherosclerosis is a chronic low-grade inflammatory disease that affects large and medium-sized arteries and is considered to be a major underlying cause of... (Review)
Review
Atherosclerosis is a chronic low-grade inflammatory disease that affects large and medium-sized arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). The high risk of mortality by atherosclerosis has led to the development of new strategies for disease prevention and management, including immunonutrition. Plant-based dietary patterns, functional foods, dietary supplements, and bioactive compounds such as the Mediterranean Diet, berries, polyunsaturated fatty acids, ω-3 and ω-6, vitamins E, A, C, and D, coenzyme Q10, as well as phytochemicals including isoflavones, stilbenes, and sterols have been associated with improvement in atheroma plaque at an inflammatory level. However, many of these correlations have been obtained and in experimental animals' models. On one hand, the present review focuses on the evidence obtained from epidemiological, dietary intervention and supplementation studies in humans supporting the role of immunonutrient supplementation and its effect on anti-inflammatory response in atherosclerotic disease. On the other hand, this review also analyzes the possible molecular mechanisms underlying the protective action of these supplements, which may lead a novel therapeutic approach to prevent or attenuate diet-related disease, such as atherosclerosis.
Topics: Animals; Atherosclerosis; Diet; Dietary Supplements; Disease Susceptibility; Functional Food; Humans; Immunomodulation; Nutrients
PubMed: 31068933
DOI: 10.3389/fimmu.2019.00837