Researchers at the University of California, Davis, have developed a method to prepare chemically well-defined HSA-drug conjugates, such that ligation can occur in vitro or in vivo under physiological condition.

A transgenic zebrafish model enabling controlled pancreatic β-cell ablation to simulate chronic hyperglycemia and study diabetes-related pathology.

Professor Kevin Kou and colleagues from the University of California, Riverside and the City of Hope National Medical Center have developed a chemical synthetic strategy that allows for the efficient generation of a diverse library of oxyberberine derivatives. This technology is advantageous because the family of protoberberine molecules, the best known being berberine, is generally considered non-toxic. As such, protoberberine derivatives are likely to elicit a better safety profile compared to existing AMPK inhibitors that are highly toxic and be developed to treat a range of diseases.  Fig 1: Four of the UCR novel AMPK inhibitors resulting from the UCR synthesis strategy.

Obesity is a complex disorder as illustrated by the heterogenous manifestations as well as serving as a major risk factor for a plethora of related conditions including, but not limited to, hyperglycemia, hypertension, cardiovascular disease, hyperlipidemia, arthritis, gallbladder disease, sleep apnea, chronic back pain, and respiratory dysfunction. There are currently no FDA-approved therapies to address multiple conditions associated with obesity other the long term as well as no approved therapies to address specific manifestations of severe metabolic disease such as metabolic dysfunction-associated fatty liver disease (MAFLD) and steatohepatitis (MASH). Combination therapies utilizing multi- targeting agents with favorable benefit-risk profiles are in need for optimal disease modification. UCB researchers have discovered methods for treating severe metabolic diseases by simultaneously or sequentially administering to an individual an effective amount of a therapeutic compound and at least one metabolism modifier having dual agonism or tri-agonism activity. 

The invention involves compositions and methods that deploy ddhNTPs (deoxy-dihydro-nucleoside triphosphates) as immunomodulatory therapeutics. These tools are designed to modulate P2 receptors, act as nucleotidase inhibitors, and have a wide range of applications including host-acting anti-infectives, oncolytics, anti-aging treatments, tissue regeneration, and green pesticides targeting plant P2K receptors. This invention represents a significant advancement in the field of nucleotide-sensing pathway modulation, offering innovative solutions for both medical and agricultural challenges.

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. 

Brief description not available

Brief description not available

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.

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.

Researchers at UCI have developed a comprehensive platform, Polaris, for personalized diabetes management. By combining standard blood glucose monitoring with activity tracking, Polaris provides users with real-time suggestions that encourage treatment adherence and promote healthy behaviors to better mitigate their symptoms.

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.

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

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.

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.

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.

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).

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.

UCLA researchers in the Departments of Medicine and Cardiology have identified a novel gene and pathway in the regulation of insulin sensitivity and discovered an inhibitor of this gene useful for treating AGPAT5-related diseases.