Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. It can be broadly sub-classified into nonalcoholic fatty liver (NAFL), which is thought to have minimal risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), which is thought to have an increased risk of progression to cirrhosis. The current diagnostic gold standard for differentiating whether a patient with NAFLD has NAFL versus NASH is liver biopsy. However, liver biopsy is an invasive procedure, which is limited by sampling variability, cost, and may be complicated by morbidity and even death, although rare. Accurate, non-invasive, biomarkers for the detection of liver disease and liver disease progression e.g., progression to NASH, are currently also not available.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat is stored in the liver, though not caused by heavy alcohol use. NAFLD is one of the most common causes of liver disease in the United States. NAFLD it typically asymptomatic but when NAFLD advances, it can result in the development of NASH (Nonalcoholic steatohepatitis) where inflammation and fibrosis are widespread in the liver, resulting in nonalcoholic steatohepatitis and liver cirrhosis. Mechanisms of NAFLD progression are poorly understood. Experts estimate that about 20% of people with NAFLD have NASH. Between 30% and 40% of adults in the United States have NAFLD. About 3% to 12% of adults in the United States have NASH. There are no existing FDA‐approved therapies for nonalcoholic fatty liver disease (NAFLD). NAFLD it typically asymptomatic but it can progress to nonalcoholic steatohepatitis and liver cirrhosis. Mechanisms of NAFLD progression are poorly understood. There are many FDA‐approved therapies for type 2 diabetes, including metformin, insulin, sulfonylureas, Glp‐1 receptor agonists, Dpp‐4 inhibitors, and Sglt2 inhibitors. These drugs work through diverse mechanisms such as increasing insulin secretion (sulfonylureas, Glp‐1 receptor agonists, Dpp‐4 inhibitors), direct insulin replacement (insulin), reducing glucose production by the liver (metformin), and stimulating excretion of glucose into urine (Sglt2 inhibitors).

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis with inflammation and liver damage, has become the leading cause of transplant and liver associated death. Moreover, numerous studies suggest that hepatocellular death is the key event triggering progression to fibrosis and cirrhosis for NASH and perhaps other liver diseases.  In normal liver, hepatocyte apoptosis plays a key role in liver homeostasis, maintaining equilibrium between the loss and replacement of hepatocytes. However, pathological conditions such as viral infection, alcoholic or nonalcoholic steatohepatitis and physical injury, lead to extensive hepatocyte apoptosis and liver damage. While inflammation contributes to the pericellular fibrosis at an early stage, sustained liver damage leads to scarring, bridging fibrosis and subsequent development of cirrhosis. Moreover, hepatocellular death is the major contributor to the pathogenesis of cirrhosis and hepatocellular carcinoma. Therefore, understanding the molecular mechanisms by which hepatocellular death is controlled may lead to new treatments for liver diseases.

The global epidemic of type 2 diabetes is increasing at an alarming rate in both Westernized and developing countries. In the United States alone, it is estimated that there are at least 30 million people with this disease. Metabolic syndrome is 2 to 3 times more prevalent than type 2 diabetes and is usually the precursor state for this disease, indicating that this type 2 diabetes epidemic will not abate in the near future. Insulin resistance is a key etiologic feature of the metabolic syndrome and type 2 diabetes, and obesity is far and away the most common cause of insulin resistance in humans. There is a well-known parallel global epidemic of obesity, and the great majority of type 2 diabetic patients are obese. Therefore, it seems logical to conclude that the obesity epidemic is the underlying driver of the type 2 diabetes epidemic. Unfortunately, at the present time there are a limited number of therapeutics available as way of preventing or treating obesity.

A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition. However, we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, aromatic amino acid metabolites, complex polysaccharides, and host sphingolipids and bile acids. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. The synthesis of bile acids takes place in the liver and recent research has shown that bile acids can act as signaling molecules and activate a number of molecules. A primary focus has been on the Farnesoid X receptor (FXR) which plays an important role in bile acid synthesis and in regulation of glucose, lipid and energy metabolism.

Fatty liver disease (or steatohepatis) is often associated with excessive alcohol intake or obesity, but also has other causes such as metabolic deficiencies including insulin resistance and diabetes. The causation of a fatty liver results from triglyceride fat accumulation in vacuoles of the liver cells resulting in decreased liver function, and possibly leading to cirrhosis or hepatic cancer. Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease occurring in the absence of alcohol abuse. There is a clinical need for a simple test to identify individuals with nonalcoholic fatty liver disease (NAFLD) in the population. While circulating lipids have been used for this purpose, the large number of analytes within the human lipidome makes it cumbersome to utilize this approach for high throughput screening.

Diabetes is a major disease affecting all populations and age groups, and society as a whole. All therapies for diabetes are based on achieving close glucose control. Close glucose control achieved by sufficient and timely administration of therapy has been shown to reduce the destructive “long-term complications” of diabetes, such as retinal damage, kidney failure, amputations, and cardiovascular damage, as well as debilitating and life-threatening short-term hypoglycemia. However, attainment of close control requires a means of glucose monitoring and means for correction of glucose imbalances such as administration of insulin, pharmaceuticals, diet adjustment, and exercise, based on the monitored glucose concentration.

Primary liver cancer, with the majority being hepatocellular carcinoma (HCC), is now the second leading cause of cancer mortality and the fifth most common cancer worldwide, claiming approximately 800,000 life every year. HCC is a chemotherapy resistant tumor with limited treatment options including surgical resection, liver transplantation and local ablation at the early stages. Sorafenib, a multi-kinase inhibitor, remains a first-line systemic drug for advanced HCC even with poor outcomes, and similar low therapeutic benefits were reported for regorafenib, lenvatinib, and cabozantinib. Over 100 clinical trials that tested other compounds or approaches have failed to show therapeutic benefit to HCC patients. Immunotherapy by blocking inhibitory pathways in T lymphocytes, such as the PD-L1/PD-1 axis, is being widely tested in various solid tumors. Notably, this emerging therapeutic approach is already in clinical trials for advanced HCC in multi-centers around the globe. Two latest reports on open-label, non-randomized, phase 1/2 trials with pembrolizumab or nivolumab indicated manageable safety in advanced HCC patients with or without prior sorafenib treatment, albeit with very limited therapeutic benefits observed so far. The outcome of immunotherapy for liver cancer can be compounded by the unique immunotolerant microenvironment in the liver. A variety of clinical trials are ongoing to evaluate combination of immune checkpoint inhibitors or with other drugs, without clear justification or support by preclinical data.

The obesity epidemic currently afflicting the US and other developed countries has resulted in a marked increase in the incidence of the metabolic syndrome and its associated pathologies, including nonalcoholic fatty liver disease (NAFLD), estimated to affect 30% of Americans. Although NAFLD is characterized by lipid droplet buildup in hepatocytes, it is not accompanied by liver damage, inflammation, and fibrosis unless combined with other risk factors, such as endoplasmic reticulum (ER) stress or mitochondrial dysfunction. In the context of simple, nonsymptomatic liver steatosis, ER stress or mitochondrial dysfunction trigger nonalcoholic steatohepatits (NASH), a serious disease that can progress to liver cirrhosis, resulting in loss of liver function, and hepatocellular carcinoma (HCC), one of the most deadly cancers. The obesity epidemic currently afflicting the US and other developed countries has resulted in a marked increase in the incidence of the metabolic syndrome and its associated pathologies, including nonalcoholic fatty liver disease (NAFLD), estimated to affect 30% of Americans. Although NAFLD is characterized by lipid droplet buildup in hepatocytes, it is not accompanied by liver damage, inflammation, and fibrosis unless combined with other risk factors, such as endoplasmic reticulum (ER) stress or mitochondrial dysfunction. In the context of simple, nonsymptomatic liver steatosis, ER stress or mitochondrial dysfunction trigger nonalcoholic steatohepatits (NASH), a serious disease that can progress to liver cirrhosis, resulting in loss of liver function, and hepatocellular carcinoma (HCC), one of the most deadly cancers.

The liver is one of the body’s most multifunctional organs, controlling glycolytic and urea metabolism, cholesterol levels, blood detoxification, and the biosynthesis of pivotal hormones and proteins. The most intriguing and amazing character of the liver is its ability to quickly self-regenerate or repair in response to acute liver mass loss or chemical-induced injury. However, the regenerative capacity of the mature hepatocytes is continually and severely compromised during the development of diverse chronic liver diseases, such as non-alcoholic fatty liver disease and chronic viral hepatitis. In this scenario, hepatic progenitor cells (HPCs) become activated and spontaneously copy themselves. Due to the expansion of the hepatocellular carcinoma (HPCs), there is a risk of carcinogenesis and thus raises concerns about the therapeutic use of these cells in the clinic.

Currently, there are no good mouse models to study the development of non-alcoholic steatohepatitis (NASH) and its progression to steatolic hepatocellular carcinoma (HCC) in less than one year. While there are other models of NASH in mice, none of the currently available models closely mimics the human disease and most are models of toxic liver damage associated with weight loss rather than obesity. 

CAP (Cbl associated protein) is an adapter protein that is ubiquitously expressed. CAP acts in concert with Cbl to stimulate glucose uptake in skeletal muscle and adipose tissue as well as to induce the proliferation and migration of macrophages. Whole body CAP gene deletion in mice results in a protection from insulin resistance induced by high fat diet. However, exercise capacity is severely blunted in these mice.

A group of blood biomarkers has been identified for the diagnosis of complications due to cirrhosis. They correlate with the presence or absence of clinically significant increased portal pressure characteristic of chronic liver diseases. The clinically significant level of increased portal pressure is a required threshold for the presence of esophageal varices and their potential for inducing internal bleeding, a major complication in patients with chronic liver diseases.There are approximately 200 million people with Chronic Hepatitis C infection worldwide; 1 million cirrhosis patients admitted to hospitals in Europe and the USA; 4 million with Hepatitis B or C in the USA; 10 million with non-alcoholic steatohepatitis (NASH) related to obesity and Diabetes type 2 in the USA. These chronic liver diseases may develop clinically significant portal hypertension with risk of developing esophageal varices.At present the Standard of Care Guidelines for cirrhosis patients from the American Association for the Study of Liver Diseases recommends Esophagogastroduodenoscopy (‘Upper Endoscopy’) yearly or every other year.The approximate cost of ‘Upper Endoscopy’ is currently $10,000 and the procedure is not without risk to the patient, and has been associated with significant adverse events (respiratory depression; internal bleeding and infections). All of the above patients would benefit from this biomarker screening, as well as any other patient presenting with previously undiagnosed liver symptoms. This biomarker panel would be prescribed for any diagnosed liver patient or any patient presenting with possible liver symptoms to enable clinical decisions to be made for patient care in a medically and financially expeditious manner.

Chromogranin A (CHGA/Chga), a 48-kDa acidic secretory proprotein, gives rise to several peptides of biological importance, which include the dysglycemic hormone pancreastatin, the vasodilator vasostatin, and the antihypertensive peptide catestatin that inhibits catecholamine release. Initially identified as a physiological brake in catecholamine secretion, catestatin has been established as a pleiotropic hormone having effects on promoting angiogenesis and lowering blood pressure.

Hepatic fibroblasts are activated in response to chronic liver injury and are the source of the fibrous scar in liver fibrosis. Fibrosis can be reversible and different cell surface markers are expressed by activated fibroblasts allowing them to be targeted as fibrosis progresses. Mesothelin is a glycosylphosphatidylinositol-linked glycoprotein expressed in hepatic mesothelial cells and malignant mesotheliomas and mediates intracellular adhesion and metastatic spread.

  It has been shown recently that in addition to their classical role in desensitizing G protein coupled receptors (GPCR’s), beta-arrestins can act as signaling molecules  independently and certain ligands (biased ligands)  can selectively activate one pathway but not the other .  Different biological responses have been observed with such beta-arrestin biased agonists, compared with traditional GPCR therapeutics designed to activate G-proteins.  However, the lack of well characterized ligands for the beta-arrestin pathway demonstrates there is a need   for effective screening methods to obtain selective  therapeutics  that could avoid  the side effects of mediating G-protein signaling.

Brief description not available

Brief description not available

The number one cause of death due to fires is smoke inhalation. An estimated 60-80% of fire deaths are the result of smoke inhalation injuries rather than burns. Cyanide, as one of the major toxic chemicals generated in household fires, contributes to these smoke inhalation-related deaths. Cyanide may also cause toxicity through ingestion or dermal absorption.

MitoNEET is an outer mitochondrial membrane protein that binds pioglitzaone (ActosTM), an insulin-sensitizing drug of the thiazolidinedione class used in the treatment of Type II diabetes. This protein has a unique dimeric structure where the two components interact to form a new fold not previously seen in any Fe-S protein structures or in any know protein. This new fold forms a binding domain between two acid labile 2Fe-2S clusters. Defects in the ability of the mitoNEET protein to control assembly and transfer of Fe-S clusters typically result in mitochondrial dysfunction such as that found in Type II diabetes.