Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention.
Elena Goleva, Evgeny Berdyshev, Donald Y.M. Leung
Environmental exposures interplay with human host factors to promote the development and progression of allergic diseases. The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Research shows an association between the rise of allergic diseases and increasingly modern Westernized lifestyles, which are characterized by increased urbanization, time spent indoors, and antibiotic usage. These environmental changes result in increased exposure to air and traffic pollution, fungi, infectious agents, tobacco smoke, and other early-life and lifelong risk factors for the development and exacerbation of asthma and allergic diseases. It is increasingly recognized that the timing, load, and route of allergen exposure affect allergic disease phenotypes and development. Still, our ability to prevent allergic diseases is hindered by gaps in understanding of the underlying mechanisms and interaction of environmental, viral, and allergen exposures with immune pathways that impact disease development. This Review highlights epidemiologic and mechanistic evidence linking environmental exposures to the development and exacerbation of allergic airway responses.
Liza Bronner Murrison, Eric B. Brandt, Jocelyn Biagini Myers, Gurjit K. Khurana Hershey
The Hedgehog pathway is critical for the development of diverse organs. Misactivation of the Hedgehog pathway can cause developmental abnormalities and cancers, including medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States. Here, we review how basic, translational, and clinical studies of the Hedgehog pathway have helped reveal how cells communicate, how intercellular communication controls development, how signaling goes awry to cause cancer, and how to use targeted molecular agents to treat both inherited and sporadic cancers.
David R. Raleigh, Jeremy F. Reiter
The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.
Jane E. Churpek, Emery H. Bresnick
The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the “PTEN-opathies.” Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.
Lamis Yehia, Joanne Ngeow, Charis Eng
The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
John C. Chappell, Laura Beth Payne, W. Kimryn Rathmell
Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis — conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for “resolution therapeutics” in vascular patients.
Michael S. Conte, Tejal A. Desai, Bian Wu, Melinda Schaller, Evan Werlin
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic in obese children and adults, and the onset might have fetal origins. A growing body of evidence supports the role of developmental programming, whereby the maternal environment affects fetal and infant development, altering the risk profile for disease later in life. Human and nonhuman primate studies of maternal obesity demonstrate that risk factors for pediatric obesity and NAFLD begin in utero. The pathologic mechanisms for NAFLD are multifactorial but have centered on altered mitochondrial function/dysfunction that might precede insulin resistance. Compared with the adult liver, the fetal liver has fewer mitochondria, low activity of the fatty acid metabolic enzyme carnitine palmitoyl-CoA transferase-1, and little or no gluconeogenesis. Exposure to excess maternal fuels during fetal life uniquely alters hepatic fatty acid oxidation, tricarboxylic acid cycle activity, de novo lipogenesis, and mitochondrial health. These events promote increased oxidative stress and excess triglyceride storage, and, together with altered immune function and epigenetic changes, they prime the fetal liver for NAFLD and might drive the risk for nonalcoholic steatohepatitis in the next generation.
Peter R. Baker II, Jacob E. Friedman
Mammalian cells use a complex network of redox-dependent processes necessary to maintain cellular integrity during oxidative metabolism, as well as to protect against and/or adapt to stress. The disruption of these redox-dependent processes, including those in the mitochondria, creates a cellular environment permissive for progression to a malignant phenotype and the development of resistance to commonly used anticancer agents. An extension of this paradigm is that when these mitochondrial functions are altered by the events leading to transformation and ensuing downstream metabolic processes, they can be used as molecular biomarkers or targets in the development of new therapeutic interventions to selectively kill and/or sensitize cancer versus normal cells. In this Review we propose that mitochondrial oxidative metabolism is altered in tumor cells, and the central theme of this dysregulation is electron transport chain activity, folate metabolism, NADH/NADPH metabolism, thiol-mediated detoxification pathways, and redox-active metal ion metabolism. It is proposed that specific subgroups of human malignancies display distinct mitochondrial transformative and/or tumor signatures that may benefit from agents that target these pathways.
Yueming Zhu, Angela Elizabeth Dean, Nobuo Horikoshi, Collin Heer, Douglas R. Spitz, David Gius
Diabetes profoundly alters fuel metabolism; both insulin deficiency and insulin resistance are characterized by inefficient mitochondrial coupling and excessive production of reactive oxygen species (ROS) despite their association with normal to high oxygen consumption. Altered mitochondrial function in diabetes can be traced to insulin’s pivotal role in maintaining mitochondrial proteome abundance and quality by enhancing mitochondrial biogenesis and preventing proteome damage and degradation, respectively. Although insulin enhances gene transcription, it also induces decreases in amino acids. Thus, if amino acid depletion is not corrected, increased transcription will not result in enhanced translation of transcripts to proteins. Mitochondrial biology varies among tissues, and although most studies in humans are performed in skeletal muscle, abnormalities have been reported in multiple organs in preclinical models of diabetes. Nutrient excess, especially fat excess, alters mitochondrial physiology by driving excess ROS emission that impairs insulin action. Excessive ROS irreversibly damages DNA and proteome with adverse effects on cellular functions. In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with enhancement of insulin action. This Review discusses the association between both insulin-deficient and insulin-resistant diabetes and alterations in mitochondrial proteome homeostasis and function that adversely affect cellular functions, likely contributing to many diabetic complications.
Gregory N. Ruegsegger, Ana L. Creo, Tiffany M. Cortes, Surendra Dasari, K. Sreekumaran Nair
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