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Methods of Treating the Metabolic Syndrome, NAFLD/NASH and Type 2 Diabetes

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major source of liver disease globally. Clinically, NAFLD describes a spectrum of hepatic events ranging from moderate lipid accumulation to more aggressive steatosis with associated inflammation, ballooning hepatocytes, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma (HCC). The excessive accumulation of lipids is a major risk factor for disease progression from the clinically silent NAFLD to the inflammatory, fibrotic, and cirrhotic nonalcoholic steatohepatitis (NASH) stage. Thus, there is a need for methods of treating metabolic disorders.   UC Berkeley researchers have discovered compounds that can be used to treat people with metabolic diseases.  

Screening method for identifying compounds that treat disorders in circadian rhythms

The CRY1:CLOCK:BMAL1 sits at the core of the integrated transcription-translation feedback loop that regulates the expression of proteins that are dependent upon circadian rhythms. Disruption of circadian rhythms has been linked to altered cell homeostasis and diseases. 

Conjugates That Combine HDAC Inhibitors and Retinoids into Disease Preventatives/Treatments

Researchers at the University of California, Davis have developed methods for creating compositions with the potential to prevent or treat cancer or metabolic diseases. These compositions combine conjugates with covalently linked HDAC inhibitors and retinoids.

Mitochondrial Transplantation to alter energy metabolism

Mitochondrial cardiomyopathy occurs when cardiomyocytes possess defective mitochondrial DNA. There is no cure and current treatment involves providing patients various dietary supplements. A novel biotherapy in which healthy mitochondria are transplanted directly into cells can help pave the way for treating mitochondrial-related diseases.

Development of Methods and Assay for Measurement of Total Oxidized Phospholipid (OxPL)

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.

Drug Repurposing for Treatment of Fatty Liver Disease and Diabetes

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).

Methods of Inhibiting Caspase-6 for the Treatment Of Nash

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.

Brown Adipose Tissue Myosin II Activators for Metabolic Therapy

The inventors have uncovered a novel brown adipose tissue (BAT) activation pathway based on cellular tension generated by actomyosin. Initial tests of predicted myosin II activators show the ability to increase the expression of uncoupling protein 1 (UCP1), a pivotal determinant of uncoupled respiration, in murine and human brown and beige cells. This strategy could be the foundation for a novel strategy to treat obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease.

Anti-Obesity Target

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.

Mitochondrial Transplantation for Treating Mitochondrial Cardiomyopathy

Mitochondrial cardiomyopathy occurs when cardiomyocytes possess defective mitochondrial DNA. There is no cure and current treatment involves providing patients various dietary supplements. A novel biotherapy in which healthy mitochondria are transplanted directly into cells can help pave the way for treating mitochondrial-related diseases.Mitochondrial cardiomyopathy occurs when cardiomyocytes possess defective mitochondrial DNA. There is no cure and current treatment involves providing patients various dietary supplements. A novel biotherapy in which healthy mitochondria are transplanted directly into cells can help pave the way for treating mitochondrial-related diseases.

A Method to Prevent the Myelin Abnormalities Associated with Arginase Deficiency

UCLA researchers in the Department of Surgery have developed a gene therapy to prevent dysmyelination (and other CNS abnormalities) as a result of arginase deficiency.

Treatment for Restoring Ureagenesis in Carbamoyl Phosphate Synthetase 1 Deficiency

UCLA researchers in the Department of Surgery have developed a gene therapy to treat carbamoyl phosphate synthetase 1 deficiency.

Drug Repurposing To Explore Novel Treatment For Cushing Disease

UCLA researchers in the Department of Medicine and the Department of Molecular and Medicinal Pharmacology have identified several small molecule reagents to treat Cushing disease.

Prevention Of The Late Complications Of Acute Pancreatitis

UCLA researchers in the Department of Medicine and Surgery have developed a novel therapeutic for the prevention of late inflammatory complications in severe acute pancreatitis patients.

Targeting Sterol Transporters In Metabolic Disease

UCLA researchers in the Department of Pathology have characterized a novel mechanism of cholesterol transport in mammalian cells between plasma membrane the ER.  It is nonvesicular, lysosome independent and critical for lipid homeostasis.

Methods of Discovering New Bile Acids and Use in Treating Inflammatory Diseases

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.

Circulating Lipidomic Signature To Identify Nonalcoholic Fatty Liver Disease

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.

A Method and Device for the Estimation of Blood Glucose Concentration from Signals of Sensors Implanted in Tissues

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.

Combination Immunotherapies for Treatment of Liver Cancer

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.

MiR-22 as a Potential Treatment Target for Steatohepatitis and Type 2 Diabetes Mellitus

Researchers at the University of California, Davis have developed miR-22 inhibitors as a potential treatment for metabolic syndrome.

Three-Step Method For Universal Enrichment, Expansion, And Maturation Of Skeletal Muscle Cells Derived From Human Pluripotent Stem Cells

UCLA researchers have developed a novel method for enriching, expanding, and maturing populations of skeletal muscle progenitor cells (SMPCs) from human pluripotent stem cells (hPSCs).

Diagnostic for Precursor Lesions of Pancreatic Cancer

These highly specific biomarkers distinguish potentially malignant mucinous cysts from benign nonmucinous cysts in the pancreas to help diagnose precursor lesions of pancreatic ductal adenocarcinoma. The biomarkers can be detected through enzymatic assays with exceptional accuracy and sensitivity.

Identification Of OLMAINC as a Biomarker for NAFLD, NASH, Metabolic Syndrome, Hepatic Fibrosis

UCLA researchers in the Departments of Medicine and Human Genetics have identified a sequence of long, non-coding RNA that plays a role in the regulation of intracellular lipogenesis and holds potential for diagnosing and treating metabolic diseases, including NAFLD and NASH.

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