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Hindsight

  • 32 Articles
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Blood endothelial cells: utility from ambiguity
Robert P. Hebbel
Robert P. Hebbel
Published May 1, 2017
Citation Information: J Clin Invest. 2017;127(5):1613-1615. https://doi.org/10.1172/JCI93649.
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Blood endothelial cells: utility from ambiguity

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Abstract

In the mid-1990s, my research group began to devise a method to establish endothelial cell cultures from human peripheral blood, with an ultimate goal of examining interindividual heterogeneity of endothelial biology. The initial work, published in the JCI in 2000, described the method enabling successful attainment of blood outgrowth endothelial cells (BOEC). Truly endothelial, BOEC are progeny of a transplantable cell that originates in bone marrow, a putative endothelial progenitor. Our subsequent experimental work focused upon practical applications of BOEC: their use for gene therapy, tissue engineering, assessment of mutant gene effect, and discovery of heterogeneity in endothelial biology.

Authors

Robert P. Hebbel

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Abdominal obesity: a marker of ectopic fat accumulation
Ulf Smith
Ulf Smith
Published May 1, 2015
Citation Information: J Clin Invest. 2015;125(5):1790-1792. https://doi.org/10.1172/JCI81507.
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Abdominal obesity: a marker of ectopic fat accumulation

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Abstract

In the early 1980s, we analyzed the metabolic profile of 930 men and women and concluded that an abdominal distribution of fat for a given BMI is associated with increased insulin resistance and risk of developing type 2 diabetes and cardiovascular disease. The correlation between abdominal fat and metabolic dysfunction has since been validated in many studies, and waist circumference is now a criterion for the diagnosis of metabolic syndrome. Several mechanisms for this relationship have been postulated; however, we now know that visceral fat is only one of many ectopic fat depots used when the subcutaneous adipose tissue cannot accommodate excess fat because of its limited expandability.

Authors

Ulf Smith

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Nuclear receptor PXR: discovery of a pharmaceutical anti-target
Steven A. Kliewer
Steven A. Kliewer
Published April 1, 2015
Citation Information: J Clin Invest. 2015;125(4):1388-1389. https://doi.org/10.1172/JCI81244.
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Nuclear receptor PXR: discovery of a pharmaceutical anti-target

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Abstract

Transcriptional induction of the gene encoding cytochrome P450 3A oxygenase (CYP3A) causes a prominent class of dangerous drug-drug interactions wherein one drug accelerates the metabolism of another. In our 1998 JCI paper, we reported the cloning of the human nuclear receptor PXR and demonstrated that it mediates CYP3A induction. We determined that PXR is expressed in liver, acts through a DNA response element located in the CYP3A promoter, and is activated by a structurally diverse collection of drugs that induce CYP3A. Our findings revealed the molecular basis for the CYP3A induction class of drug-drug interactions and provided a high-throughput means for screening out drug candidates with this activity.

Authors

Steven A. Kliewer

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Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions
Avi Ashkenazi
Avi Ashkenazi
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(2):487-489. https://doi.org/10.1172/JCI80420.
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Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions

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Abstract

Apoptosis is a metazoan process of controlled cell elimination that plays critical roles in embryonic development and adult tissue homeostasis. Apoptosis dysregulation contributes to several important diseases, including cancer. Two distinct yet interconnected signaling pathways control apoptosis by activating a core intracellular machinery of death proteases called caspases. The intrinsic apoptotic pathway engages caspases via members of the BCL-2 protein family and the mitochondria in reaction to severe cellular damage or stress. The extrinsic pathway activates caspases via cell-surface death receptors, which respond to cognate death ligands expressed on immune-effector cells. Tumor cells can acquire various apoptosis-evasion mechanisms; nevertheless, the transformed state of these cells makes them uniquely susceptible to apoptosis reactivation if resistance is circumvented. Molecular approaches to reengage the apoptotic pathways in cancer have been underway for over two decades. Gratifyingly, BCL-2 antagonists — which drive the intrinsic pathway — are beginning to bear clinical fruit. In contrast, clinical attempts to stimulate the extrinsic pathway with proapoptotic receptor agonists (PARAs) have been disappointing, despite compelling preclinical efficacy with this class of agents. Here, I discuss some of the possible reasons for this translational discrepancy and suggest strategies to overcome it with the next generation of PARAs.

Authors

Avi Ashkenazi

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Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs
Cezmi A. Akdis, Mübeccel Akdis
Cezmi A. Akdis, Mübeccel Akdis
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(11):4678-4680. https://doi.org/10.1172/JCI78891.
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Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs

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Abstract

During the past 20 years, major advances have been made in understanding the molecular and cellular mechanisms of allergen tolerance in humans. The demonstration of T cell tolerance, particularly that mediated by the immune-suppressive functions of IL-10, led to a major conceptual change in this area. Currently, the known essential components of allergen tolerance include the induction of allergen-specific regulatory subsets of T and B cells, the immune-suppressive function of secreted factors, such as IL-10 and TGF-β, the production of IgG4 isotype allergen–specific blocking antibodies, and decreased allergic inflammatory responses by mast cells, basophils, and eosinophils in inflamed tissues.

Authors

Cezmi A. Akdis, Mübeccel Akdis

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CXCR3+CCR5+ T cells and autoimmune diseases: guilty as charged?
Charles R. Mackay
Charles R. Mackay
Published September 2, 2014
Citation Information: J Clin Invest. 2014;124(9):3682-3684. https://doi.org/10.1172/JCI77837.
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CXCR3+CCR5+ T cells and autoimmune diseases: guilty as charged?

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Abstract

Prior to the 1990s, genetic analyses indicated that many autoimmune diseases are driven by T cell responses; however, the identity of the pathogenic T cell populations responsible for dysfunctional autoimmune responses remained unclear. Some 20 years ago, the discovery of numerous chemokines and their receptors along with the development of specific mAbs to these provided a distinct advance. These new tools revealed a remarkable dichotomy and disclosed that some chemokine receptors guided the constitutive migration of T cells through lymphoid tissues, whereas others, such as CCR5 and CXCR3, guided effector and memory T cell migration to inflammatory lesions. These T cell markers enabled a new understanding of immune responses and the types of T cells involved in different inflammatory reactions.

Authors

Charles R. Mackay

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The intestinal epithelium is an integral component of a communications network
Martin F. Kagnoff
Martin F. Kagnoff
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(7):2841-2843. https://doi.org/10.1172/JCI75225.
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The intestinal epithelium is an integral component of a communications network

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Abstract

The epithelial lining of the intestine forms a barrier that separates the intestinal lumen from the host’s internal milieu and is critical for fluid and electrolyte secretion and nutrient absorption. In the early 1990s, my laboratory discovered that intestinal epithelial cells could alter their phenotype and produce proinflammatory chemokines and cytokines when stimulated by pathogenic enteric luminal microbes or proinflammatory agonists produced by cells in the underlying mucosa. It is now well accepted that intestinal epithelial cells can be induced to express and secrete specific arrays of cytokines, chemokines, and antimicrobial defense molecules. The coordinated release of molecules by intestinal epithelial cells is crucial for activating intestinal mucosal inflammatory responses as well as mucosal innate and adaptive immune responses. More recent studies have focused on the intestinal epithelial signaling pathways that culminate in immune activation as well as the role of these pathways in host defense, mucosal injury, mucosal wound healing, and tumorigenesis. The emerging picture indicates that intestinal epithelial cells represent an integral component of a highly regulated communications network that can transmit essential signals to cells in the underlying intestinal mucosa, and that intestinal epithelial cells, in turn, serve as targets of mucosal mediators. These signals are essential for maintaining intestinal mucosal defense and homeostasis.

Authors

Martin F. Kagnoff

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Diabetes, aging, and their tissue complications
Rick Bucala
Rick Bucala
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(5):1887-1888. https://doi.org/10.1172/JCI75224.
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Diabetes, aging, and their tissue complications

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Abstract

The inactivation of NO by advanced glycation endproducts (AGEs), which accumulate on tissue proteins as a function of age and hyperglycemia, focused attention on the role of these ubiquitous posttranslational modifications in acquired impairments of vascular reactivity and other signaling processes. This observation occurred during a watershed period of basic and translational research in glycation that encompassed new pathologic phenomena and novel intervention strategies. How has the AGE paradigm for the tissue complications of aging and diabetes fared since the identification of the link between these glycation products and NO inactivation, and what lessons may be offered for future investigations?

Authors

Rick Bucala

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Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity
François Abboud, Ravinder Kumar
François Abboud, Ravinder Kumar
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(4):1454-1457. https://doi.org/10.1172/JCI70420.
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Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity

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Abstract

Nearly two decades ago, we evaluated ten patients with obstructive sleep apnea (OSA). We determined that alarming nocturnal oscillations in arterial pressure and sympathetic nerve activity (SNA) were caused by regulatory coupling and neural interactions among SNA, apnea, and ventilation. Patients with OSA exhibited high levels of SNA when awake, during normal ventilation, and during normoxia, which contributed to hypertension and organ damage. Additionally, we achieved a beneficial and potentially lifesaving reduction in SNA through the application of continuous positive airway pressure (CPAP), which remains a primary therapeutic approach for patients with OSA. With these results in hindsight, we herein discuss three concepts with functional and therapeutic relevance to the integrative neurobiology of autonomic cardiovascular control and to the mechanisms involved in excessive sympathoexcitation in OSA.

Authors

François Abboud, Ravinder Kumar

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From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production
David G. Harrison
David G. Harrison
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(2):473-475. https://doi.org/10.1172/JCI70336.
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From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production

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Abstract

As a young medical resident, I encountered a patient suffering from spontaneous coronary vasospasm and was puzzled by these dramatic alterations in vasomotion. This encounter piqued my interest in understanding the drivers of vascular reactivity. In a paper published in the JCI, my colleagues and I revealed a role for superoxide production in the vascular dysfunction associated with hypercholesterolemia. Subsequent work by our group and others has unveiled complex associations between ROS generation and vascular disease.

Authors

David G. Harrison

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