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Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases

eScholarship@UMMS - Wed, 01/11/2017 - 10:15am

Mitogen-activated kinase kinase kinase kinase 4 (Map4k4), originally identified in small interfering (si)RNA screens and characterized by tissue-specific gene deletions, is emerging as a regulator of glucose homeostasis and cardiovascular health. Recent studies have shown that Map4k4 gene ablation or inhibition of its kinase activity attenuates hyperglycemia and plaque formation in mouse models of insulin resistance and atherosclerosis, and suggest roles for Map4k4 in multiple signaling systems, including NFkappaB activation, small GTPase regulation, the Hippo cascade, and regulation of cell dynamics by FERM domain proteins. This new and promising area of inquiry raises key questions that need to be addressed, such as defining which of the above or other effectors mediate Map4k4 control of metabolic and vascular functions, and identifying upstream activators of Map4k4.

Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice

eScholarship@UMMS - Wed, 01/11/2017 - 10:15am

BACKGROUND: Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis, and inflammation. In this article, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology.

METHODS: A 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis.

RESULTS: We found that binge drinking induced significant SYK activation (SYK(Y525/526) ) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-nuclear factor kappa beta (NF-kappaB) p65, NF-kappaB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis.

CONCLUSIONS: Our novel observations demonstrate the role of SYK, activation in the pathomechanism of binge drinking-induced liver disease highlighting SYK a potential multifaceted therapeutic target.

Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

eScholarship@UMMS - Wed, 01/11/2017 - 10:15am

Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll-like receptors, e.g., Toll-like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL-1 by IL-1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL-1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL-1 pathway might be an attractive treatment strategy in the future. An important role for IL-1-type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL-1-type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation.

CONCLUSION: IL-1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease.

How Much Are Docs Responsible for Patients' Opioid Abuse?

Headlines from MedPage Today® - Wed, 01/11/2017 - 10:00am
(MedPage Today) -- F. Perry Wilson, MD, looks at the data on how patients get hooked

What’s killing the world’s shorebirds?

news@nature - Wed, 01/11/2017 - 9:21am

Researchers brave polar bears, mosquitoes and gull attacks in the Canadian Arctic to investigate an alarming die off

Nature 541 16 doi: 10.1038/541016a

Morning Break: Fast Access for Cancer Drugs; More Outpatient Surgery; Nutella Woes

Headlines from MedPage Today® - Wed, 01/11/2017 - 8:15am
(MedPage Today) -- Health news and commentary from around the Web, gathered by the MedPage Today staff

Treating Diabetes: Where Are We Now?

Headlines from MedPage Today® - Wed, 01/11/2017 - 8:00am
(MedPage Today) -- Incremental progress or real advances?

NASA sets sights on asteroid exploration

news@nature - Wed, 01/11/2017 - 7:21am

Agency plans to launch a mission to visit the Trojan asteroids in 2021, and one to the metallic asteroid Psyche in 2023.

Nature News doi: 10.1038/nature.2016.21234

Mysterious cosmic radio blasts traced to surprising source

news@nature - Wed, 01/11/2017 - 6:21am

Repeating bursts come from a faint, distant dwarf galaxy.

Nature News doi: 10.1038/nature.2016.21235

Google reveals secret test of AI bot to beat top Go players

news@nature - Wed, 01/11/2017 - 3:21am

Updated version of DeepMind's AlphaGo program behind mystery online competitor.

Nature 541 142 doi: 10.1038/nature.2017.21253

Cancer Centers Back HPV Vaccine

Headlines from MedPage Today® - Tue, 01/10/2017 - 11:01pm
(MedPage Today) -- Underused vax is 'rare opportunity' to prevent associated cancers

CDC: U.S. 40% of the Way Toward Healthy People 2020 Goals

Headlines from MedPage Today® - Tue, 01/10/2017 - 11:01pm
(MedPage Today) -- Health disparities, inequities may influence results

U.S. Restaurant Menus for Kids Still Short on Nutrition (CME/CE)

Headlines from MedPage Today® - Tue, 01/10/2017 - 11:01pm
(MedPage Today) -- Voluntary program to boost food quality barely followed

Healthcare a Repeated Presence in Obama's Farewell Address

Headlines from MedPage Today® - Tue, 01/10/2017 - 9:56pm
(MedPage Today) -- Affordable Care Act goes unmentioned by name

Trump Denies Naming Vax Skeptic to Safety Panel

Headlines from MedPage Today® - Tue, 01/10/2017 - 7:28pm
(MedPage Today) -- Docs outraged, Trump says no decision yet

Integrative Psychiatry May Help Kids: Psychiatric Times & Neurology Times

Headlines from MedPage Today® - Tue, 01/10/2017 - 7:00pm
(MedPage Today) -- Also, the role of zinc and magnesium in depression

By the Numbers: ACA Enrollment Up Again

Headlines from MedPage Today® - Tue, 01/10/2017 - 6:30pm
(MedPage Today) -- Defying predictions of 'death spiral' from rising premiums

Want to Stop Kids From Whining? Take a Note from Casinos

Headlines from MedPage Today® - Tue, 01/10/2017 - 6:00pm
(MedPage Today) -- They can teach us a lot about rewards

Migraine Tied to Perioperative Stroke Risk (CME/CE)

Headlines from MedPage Today® - Tue, 01/10/2017 - 5:30pm
(MedPage Today) -- 30-day ischemic stroke risk higher for those with migraine with aura

Schaffner Dismayed by Kennedy's Reported Appointment to Vaccine Panel

Headlines from MedPage Today® - Tue, 01/10/2017 - 5:04pm
(MedPage Today) -- Fears commission could 'turn back clock' on vaccine advances
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