Green tea and Vardenafil: a killer chemotherapy combo
Several recent studies have demonstrated that EGCG, a major constituent of green tea, has anti-cancer properties, but the molecular mechanisms underlying its effects are unknown. In this issue of the Journal of Clinical Investigation, Hirofumi Tachibana and colleagues at Kyushu University in Fukuoka, Japan, demonstrate that EGCG activates the 67-kDa laminin receptor, which elevates intracellular levels of the molecule cGMP to induce cell death. Tachibana and colleagues combined EGCG with vardenafil, a drug used to treat erectile dysfunction, which blocks the activity of PDE5, a protein that degrades cGMP. In a mouse model of multiple myeloma, vardenafil potentiated the effects of EGCG to mediate cancer cell death. Chung Yan and Hong Wang of Rutgers University discuss these findings in a companion commentary.
TITLE: 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
ACCOMPANYING COMMENTARY TITLE: Cancer therapy combination: Green tea and a phosphodiesterase 5 inhibitor?
Researchers explain how coal tar treats eczema
Coal tar soap is one of the oldest remedies for atopic dermatitis (aka eczema), but it is unclear exactly why this treatment is effective. In this issue of the Journal of Clinical Investigation, Ellen van den Bogaard and colleagues at Radboud University in Nijmegen, the Netherlands, identified the aryl hydrocarbon receptor (AHR) as the molecular target of coal tar. Using a skin model of atopic dermatitis, van den Bogaard and colleagues demonstrated that coal tar activates AHR to diminish cell death, expression of inflammatory proteins, and skin cell swelling (spongiosis), and restored barrier proteins that maintain skin integrity. In a companion commentary, Irwin McClean and Alan Irvine of the University of Dundee, detail the history of coal tar as a therapeutic and discuss how these findings could be used to identify new therapies for atopic dermatitis.
TITLE: Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis
ACCOMPANYING COMMENTARY TITLE: Old King Coal – molecular mechanisms underlying an ancient treatment for atopic eczema
iRHOM2: the newest gadget in rheumatoid arthritis
Rheumatoid arthritis (RA) is an inflammatory joint disorder that gradually destroys cartilage, causing loss of joint function and mobility. TNF is a protein that mediates inflammation in RA. TNF is generated when an enzyme known as TACE release TNF from immune cells. Therapeutic targeting of TACE could reduce TNF, but TACE is also important to other physiological processes, making it a poor drug target. In this issue of the Journal of Clinical Investigation, Carl Blobel and colleagues at Weill Cornell University demonstrated that the protein iRHOM2 in immune cells. Blobel and colleagues found that inhibition of iRHOM2 selectively blocked TACE activity in immune cells without disrupting other functions. Additionally, mice lacking iRHOM2 were protected from inflammatory arthritis. In a companion commentary, Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich Germany discusses iRHOM2′s potential as a therapeutic target in RA.
TITLE: iRHOM2 is a critical pathogenic mediator of inflammatory arthritis
ACCOMPANYING COMMENTARY TITLE: iRhom2 takes control of rheumatoid arthritis
Rooting out hormone refractory prostate cancer
Prostate cancer is one of the most common malignancies in men. It is highly treatable in early stages; however, once the cancer becomes metastatic, it cannot be cured. In this issue of the Journal of Clinical Investigation, Fillippo Giancotti and colleagues at Memorial Sloan-Kettering Cancer Center in New York, demonstrate that a significant fraction of advanced, hormone refractory prostate cancers express high levels of the protein β4 integrin. Using a mouse model of prostate cancer, Giancotti and colleagues found that loss of the β4 integrin gene significantly inhibited prostate tumor growth and progression by blocking activation of the oncogenic proteins ErbB2 and c-Met, which are responsible for sustaining prostate cancer stem cells. In a companion commentary Max Wicha of the University of Michigan discusses how targeting of these proteins could be a useful therapeutic strategy for the treatment of advanced prostate cancer.
TITLE: β4 Integrin signaling induces expansion of prostate tumor progenitors
ACCOMPANYING COMMENTARY TITLE: B4 Androgen ablation: Attacking the prostate cancer stem cell
Researchers identify key mediators of sepsis-induced lung injury
Sepsis is an illness in which the body has a severe reaction to a bacterial infection. Bacterial toxins activate the immune system, causing widespread inflammation and increased blood calcium levels, oxidative stress, and inflammatory factors. This increased inflammation and immune activation can cause fatal organ damage, particularly in the lungs. The molecular mechanisms underlying this damage are unknown. In this issue of the Journal of Clinical Investigation, Madesh Muniswamy and colleagues at Temple University identified a signaling pathway that mediates lung injury during sepsis. Using a mouse model of sepsis-induced lung injury, Muniswamy and colleagues demonstrated that the proteins STIM1 and NOX2 drive the body’s response to bacterial toxins, as mice lacking these proteins were not susceptible to lung injury. Additionally, treatment with a calcium channel blocker known as BTP2 halted sepsis-induced lung injury. These findings identify therapeutic targets that could be used to limit sepsis-induced lung injury.
TITLE: Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation
New insight into Liddle syndrome
Liddle syndrome is a form of early onset, severe hypertension that is caused by mutations in the NEDD4 gene. NEDD4 is a ubiquitin ligase, which mediates the destruction of target proteins. Liddle’s syndrome is hypothesized to be caused by the inability of mutant NEDD4 to induce destruction of the kidney sodium channel ENaC, perturbing sodium homeostasis to induce hypertension. In this issue of the Journal of Clinical Investigation, Olivier Staub and colleagues at the University of Lausanne investigated the effects of mutant NEDD4 in the kidney. Staub and colleagues engineered a mouse that only expressed mutant NEDD4 in the renal tubules. Mutant mice exhibited increased ENaC but did not have higher blood sodium levels. These results demonstrate that the current model of Liddle’s syndrome is incorrect. Interestingly, expression of mutant NEDD4 led to an increase in NCC, a sodium/chloride transporter, which could contribute to the elevated sodium and hypertension associated with Liddle’s syndrome. These results indicate that NEDD4 could be a therapeutic target for the treatment of hypertension. In a companion commentary, David Ellison of Oregon Health and Science University discusses how these findings will affect our understanding of hypertension.
TITLE: Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
ACCOMPANYING COMMENTARY TITLE: Ubiquitylation and the pathogenesis of hypertension
Researchers identify ITAM as an important regulator of vascular integrity
Platelets survey blood vessels, searching for blood vessel damage. When damage is detected, the platelets form a clump and release factors that prevent blood loss and promote repair. Atherotrhombosis is the inappropriate clumping of platelets within blood vessels that occludes blood flow and many anti-platelet drugs are under development for the treatment of atherothrombosis. In addition to injury, inflammation caused by infection or stroke can also induce leaky blood vessels. In this issue of the Journal of Clinical Investigation, researchers led by Wolfgang Bergmeier at the University of North Carolina at Chapel Hill identified the protein ITAM as a critical modulator of blood vessel integrity during inflammation. Using a mouse model, Bergmeier and colleagues demonstrated that platelets that lack ITAM could not prevent inflammation-induced hemorrhages. This study highlights potential complications of anti-platelet drugs that target ITAM for the treatment of atherothrombosis.
TITLE: Platelet ITAM signaling is critical for vascular integrity in inflammation