Khiem Tran

Reactive oxygen species in inflammation and tissue injury.

Abstract Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood–Brain Barrier Integrity and Central Nervous System Homeostasis

Background— The blood–brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results— Using a mouse model with tamoxifen-inducible endothelial cell–restricted disruption of ctnnb1 (iCKO), we show here that endothelial &bgr;-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial &bgr;-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear &bgr;-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. Conclusions— These results demonstrate the prerequisite role of endothelial &bgr;-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective &bgr;-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation.

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and CNS Homeostasis

Background— The blood–brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results— Using a mouse model with tamoxifen-inducible endothelial cell–restricted disruption of ctnnb1 (iCKO), we show here that endothelial &bgr;-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial &bgr;-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear &bgr;-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. Conclusions— These results demonstrate the prerequisite role of endothelial &bgr;-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective &bgr;-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation.

MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy.

The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy.

Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury.

Adult stem cell treatment is a potential novel therapeutic approach for acute respiratory distress syndrome. Given the extremely low rate of cell engraftment, it is believed that these cells exert their beneficial effects via paracrine mechanisms. However, the endogenous mediator(s) in the pulmonary vasculature remains unclear. Using the mouse model with endothelial cell (EC)‐restricted disruption of FoxM1 (FoxM1 CKO), here we show that endothelial expression of the reparative transcriptional factor FoxM1 is required for the protective effects of bone marrow progenitor cells (BMPC) against LPS‐induced inflammatory lung injury and mortality. BMPC treatment resulted in rapid induction of FoxM1 expression in wild type (WT) but not FoxM1 CKO lungs. BMPC‐induced inhibition of lung vascular injury, resolution of lung inflammation, and survival, as seen in WT mice, were abrogated in FoxM1 CKO mice following LPS challenge. Mechanistically, BMPC treatment failed to induce lung EC proliferation in FoxM1 CKO mice, which was associated with impaired expression of FoxM1 target genes essential for cell cycle progression. We also observed that BMPC treatment enhanced endothelial barrier function in WT but not in FoxM1‐deficient EC monolayers. Restoration of β‐catenin expression in FoxM1‐deficient ECs normalized endothelial barrier enhancement in response to BMPC treatment. These data demonstrate the requisite role of endothelial FoxM1 in the mechanism of BMPC‐induced vascular repair to restore vascular integrity and accelerate resolution of inflammation, thereby promoting survival following inflammatory lung injury. Stem Cells 2014;32:1855–1864

Oncolytic reactivation of KSHV as a therapeutic approach for primary effusion lymphoma

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposis sarcoma-associated herpesvirus (KSHV) infection. Currently, treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anticancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-κB pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. Mol Cancer Ther; 16(11); 2627–38. ©2017 AACR.

Multi-Center Randomized Clinical Study of The Effects of Natural Oils on Xerosis and Skin Barrier Properties

Objective : To compare the effect of natural oils and white petrolatum on skin barrier function in patients with xerosis. Design, Setting, and Participants : Randomized, open label, comparison pilot study (NCT03093597). Interventions : Participants were randomized to apply 1 of 4 moisturizers to assigned treatment areas twice daily for 2 weeks. Clinical dry skin score, stratum corneum hydration, and transepidermal water loss (TEWL) were assessed at baseline, 1 week, and 2 weeks. Results : Thirty-two participants completed the study. Neither TEWL nor hydration were statistically different among the moisturizers at each visit. All four moisturizers led to significant initial increase in TEWL at week 1 (p < 0.05) with an associated increase in hydration for coconut oil, jojoba oil, and white petrolatum. All four moisturizers led to significant increase in hydration by week 2 (p < 0.01). The preferred moisturizers were almond oil and coconut oil, which were most “liked” by 38% and 31% of the participants, respectively. The least preferred moisturizer was white petrolatum. Conclusions : Almond oil, jojoba oil, and coconut oil significantly increased hydration after 2 weeks, and are as effective as white petrolatum as daily moisturizers for xerosis. The participants preferred natural oils to white petrolatum, implying that these moisturizer options may improve patient compliance.