The invention is a recombinant form of an endogenous protein that can be used to increase fat absorption and modulate gastric motility. (more...)

Breast cancer is the most common type of cancer that occurs in women in the US and ranks as the second leading cause of cancer death after lung cancer. Of the 230,480 invasive breast cancer cases diagnosed in the US in 2011, approximately 15-20% were "triple negative breast cancer" (TNBC), a subtype of breast cancer that lacks clinical expression of estrogen receptor-alpha (ERα), progesterone receptor, and HER-2 receptors. TNBC tends to occur often in younger and African American women, and it is associated with high proliferative rates, and poor survival. Despite initial responsiveness to some types of chemotherapy, TNBC often recurs early with distant metastases. Treatment of TNBC has also been hindered by its insensitivity to widely-used targeted therapies including trastuzumab, lapatinib, tamoxifen, and aromatase inhibitors. Due to the aggressive nature of TNBC, it accounts for nearly half of all breast cancer deaths. Therefore, there is an urgent need to develop new and more effective therapies for this deadly subtype of breast cancer. The use of novel metformin analogues detailed below may present a promising new treatment for TNBC. (more...)

Researchers at the University of California, Irvine have developed a nanofluidic device that may be used to trap and analyze single mitochondria. (more...)

A number of diabetogenic stimuli interact to influence insulin promoter activity. High-Throughput Screening (HTS) for insulin promoter modulators has the potential to reveal novel inputs into the control of that central element of the pancreatic β-cell. HTS for insulin promoter modulators can both serve to identify compounds that can serve as a treatment to diabetes as well as identify unintended side effects of insulin promotion in other drug candidates. (more...)

Certain diseases of metabolism may be the result of a decrease or blockage of one more autophagic pathways (pexophagy, mitophagy,or ribophagy).An example, such as SSADH (succinate semialdehyde dehydrogenase deficiency) which causes developmental delay, hypotonia and mental retardation.Patients exhibit increasedlevels of GABA and GABA metabolites, and UCSD researchers have found that this is indicative of blockagesin autophagy-related pathways, which may account for the symptoms of the disease(s).Autophagy inducing drugs, such as rapamycin, may affect a decrease in the associated symptoms. (more...)

Oleylethanolamide (OEA) is a natural lipid of previously unknown biological function. Circulating levels of OEA rise dramatically during starvation with the onset of fat metabolism. This surge is caused by an increase in OEA formation, which is restricted to adipose tissue. Our results indicate that OEA is an adipose-derived hormone-like molecule involved in energy homeostasis. (more...)

Researchers at the University of California, Irvine have found a new use for a known compound for treatment of fatty liver disease which has been shown to be effective in animal studies. (more...)

Researchers at the University of California, Davis have discovered that pharmaceutical targeting of galentin-12 may prove beneficial by both reducing adiposity and improviing insulin sensitivity. (more...)

Hepatic fibroblasts are activated in response to chronic liver injury and are the source of the fibrous scar in liver fibrosis. Liver fibrosis is known to be reversible. It is thought that reversal of fibrosis is accompanied by senescence and/or apoptosis of the myofibroblasts, which are responsible for the fibrosis. However, it was unknown if myofibroblasts can escape cell death and revert to an inactive phenotype during regression of fibrosis. (more...)

Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in triglyceride synthesis.  Inhibitors of DGAT-1 are currently in clinical trials as treatments for diabetes and obesity. (more...)

Much evidence has been presented that implicates the abnormalities in particular genes with the development of hypertension (high blood pressure) and other components of the metabolic syndrome, such as insulin resistance and vascular inflammation. Plasma levels of particular gene products are elevated in human essential hypertension. Polymorphisms in these genes are associated with hypertensive renal disease. (more...)

Scripps Institution of Oceanography (SIO) at UC San Diego is one of the oldest, largest, and most important centers for global science research and education in the world. With the oceans covering 70 percent of the earth's surface, it is no surprise that approximately two-thirds of the world's animal phyla are found in marine environments and many are exclusively marine. SIO scientists were among the first to explore the natural product chemistry of marine organisms and this research helped to develop the field of marine natural products chemistry and the realization that the oceans harbor myriad new organic molecules with utility for the development of pharmaceuticals and other products. This research led to the discovery of hundreds of new compositions of matter for new products—some of which are already well progressed into commercial development. Two compounds are now entering phase II clinical trials. One of these, Salinosporamide A, is a potent proteasome inhibitor. The second compound, which is derived from the fungal metabolite halimide, acts as a vascular disrupting agent. (more...)

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 themselves. Thus, it is now widely held that GPCR’s are able to signal through parallel G-Protein and beta-arrestin pathways. Next generation GPCR therapeutics will be advanced by fine-tuning the actions along these pathways. GPCR ligands that preferentially activate the latter pathway are called beta-arrestin “biased” agonists. Different biological responses have been observed with such beta-arrestin biased agonists, compared with traditional GPCR therapeutics designed to activate G-proteins. (more...)

Scientists at UC San Diego have discovered that the combination of trehalose and dimethyl sulfoxide (DMSO) is an unusually effective cryoprotectant for islets and islet-like cell clusters (ICC), as well as platelets. When islets and ICCs are cooled through the thermotropic phase transition in the presence of the treatment agents and then returned to physiologic temperature, they retain their functionality. The success of the cryoprotectant combination is evident by observation of the low rate of DNA synthesis and the higher rate of insulin concentration in the cells after freezing and thawing. The use of the trehalose-DMSO combination in a cryopreservation protocol thus leads to previously unobtainable survival rates of functional human endocrine tissue. It has further been discovered that the trehalose-DMSO combination is useful in the cryopreservation of platelets, enabling them to be frozen and thawed while retaining their ability to be activated with the appropriate stimuli. Platelets can thus be stored for extended periods of time at temperatures sufficiently low to control bacterial infection and platelet storage lesion without the risk of premature activation. These discoveries have led to a further discovery, that trehalose can be incorporated into the interiors of eukaryotic cells when the cell walls contain a lipid bilayer. This is done by suspending the cells in a liquid solution of trehalose and cooling or warming the suspension through the thermotropic lipid phase transition of the cells. This occurs independently of the presence or absence of DMSO. (more...)

Determining oxygen levels in tumors is critical for advancing cancer diagnosis and therapy. A detailed knowledge of real-time changes in oxygen gradients within a tumor can assist in the profiling of tumor growth and improve the effectiveness of current treatment strategies, which function optimally at different oxygen concentrations. Small molecule luminescence has been suggested as a low cost, non-invasive alternative to traditional methods for sensing oxygen levels that are invasive, expensive, and/or lack sufficient spatio-temporal resolution to monitor real-time changes. In addition to sensing oxygen in tumors, luminescent small molecules, such as porphyrins, have been used for photodynamic therapy (PDT) to treat certain cancers by sensitizing oxygen for the production of cytotoxic reactive oxygen species (ROS). However, the utility of porphyrins has been hampered by low biocompatibility, lack of targetable delivery, and limited photophysical properties. The current invention describes a method for incorporating emissive porphyrins into proteins that offers a novel platform to enhance both oxygen sensing capabilities and targeted delivery to tumors. The bioluminescent proteins described not only have promising photophysical properties for biological use, but also are readily modifiable, biocompatible, and biostable. (more...)

Sleep disorders affect over 40 million Americans each year, many which are undiagnosed and never treated. One such sleep disorder is narcolepsy, which affects about 1 in 2,000 people. Patients experience cataplexy (sudden loss of muscle tone), excessive and uncontrollable daytime sleepiness, and fragmented sleep throughout the night. Evidence also shows that people who suffer from sleep disorders are at a higher risk of obesity than compared to the general population. Research on humans suggests that narcolepsy results from reduced levels of Hypocretin-1 (Hcrt-1), other known as orexin-A, in cerebrospinal fluids. In narcoleptic animals such as dogs and mice, there is a mutation in the gene responsible for the Hcrt receptor or peptides respectively. Due to the serious emotional and social repercussions of this disorder, there is a need for an effective treatment to help those who suffer from sleep disorders, such as narcolepsy. (more...)

Energy intake, expenditure and storage in humans and other organisms are highly regulated and disturbances lead to severe problems such as obesity and diabetes. Glucose is a major unit of currency in energy metabolism and the body goes to great lengths to regulate the level of glucose in the blood to ensure adequate delivery to the brain, muscle and other cells and tissues of the body. The cells of the pancreas can directly sense variations in the blood glucose concentrations, but glucose sensors are distributed throughout the body to modulate pancreatic and other responses. Until now, the molecular identity of these glucosensors has largely been unknown. (more...)

It has been demonstrated that pancreastatin can inhibit glucose-induced insulin secretion from pancreas, insulin signaling in adipocytes and hepatic cells via activation of conventional PKC, and leptin and adiponectin production from adipose tissue, but stimulate nitric oxide production. It has been shown also that circulating pancreastatin levels in diabetic patients are higher than healthy subjects. However, it has not been shown whether pancreastatin regulates expression of genes responsible for glucose production and lipid metabolism and whether the effects on those gene expressions are PKC and nitric-oxide dependent or not. (more...)

Insulin regulates glucose uptake into fat and muscle cells through glucose transporters (GLUT4) that are translocated from an intracellular membrane storage pool to the plasma membrane. A Type II diabetic either does not produce enough insulin or is resistant to insulin produced by the pancreas. Improperly metabolized glucose and increased serum glucose levels can trigger heart disease, kidney disease, blindness, and limb amputations. Several oral medications can be prescribed to those who have been diagnosed with Type II diabetes and to those who are otherwise insulin resistant. Currently, there are two classes of oral anti-diabetic insulin sensitizers that can be used to treat Type II disease: biguanides (metformin or Glucophage ®) and thiazolidinediones (rosiglitazone or Avandia ®, and pioglitazone or Actos ®). However, there are side effects from these drugs that are especially acute in those whose kidneys or liver are not functioning normally. Also, although Type II diabetics can take oral drugs currently offered, over time, most will need insulin injections to control their disease. (more...)

Heart disease is the lead cause of mortality among diabetic patients in the U.S. UC San Diego researchers have developed a method to treat diabetic cardiomyopathy by gene therapy using an enzyme specific for the removal of a single sugar molecule from proteins such as transcription factors. The researchers demonstrated that elevated extra-cellular glucose levels result in impaired calcium cycling in myocytes, leading to impaired cardiac contractility and poor myocardial performance, by a mechanism involving O-linked glycosylation of nuclear proteins. They found that these effects can be reversed by gene therapy with an enzyme, O-GlcNAcase, which can remove specific O-linked hexosamines from proteins. Delivery of viral vectors encoding O-GlcNAcase to myocytes from diabetic rats markedly improved calcium flux and contractile function. (more...)

Cell surface proteins have been identified on insulin-producing islet beta cells by UC San Diego inventors. These molecules include a family of protein molecules that had never previously been associated with beta cells. In fact, until now, there have been no known targets expressed on the surface of islet beta cells. This technology is a method to target specific antibodies or other molecules to islet beta cells or beta cell tumors. Because these proteins are found only on islet beta cells and in some CNS cells protected by the blood-brain barrier, this technology offers a highly specific method for targeting islet beta cells. Specifically, this technology provides a means to image the islet cell mass or further quantify the islet cells. Antibodies or other proteins that bind to these surface markers may be tagged with radiolabels or other tracer molecules to permit visualization by various medical imaging techniques (e.g. PET, MRI, CT, etc.). For treatment of tumor cells, antibodies specific to these cell-surface markers may be conjugated to a toxin or other therapeutic agent. This technology also offers an effective means to isolate and quantify islet cell mass in patients. By immobilizing islet beta protein-specific antibodies to a plate or column, one can readily separate islet cells from non-islet cells. The inventors, Steven Chessler and Arthur Suckow, have verified the expression of these cell surface markers by polymerase chain reaction, Western blotting, and Immunostaining. (more...)

Although algorithms and chemistries for developing new therapeutic entities are constantly evolving, none can replicate the path and novelty of natural selection over eons of time. Inventors at the Scripps Institution of Oceanography have engaged their fleet of research ships to cull the oceans for marine organisms from which new compositions are isolated.  Using a variety of culture systems, selective fractionation and bioassays, two, distinct classes of compounds, isolated from actinomycetes, have demonstrated potent anti-tumor activity and considerable selectivity toward some cancers. One class of compounds, the ammosamides, are unique molecules that target a previously untargeted intracellular pathway. It is anticipated that proprietary methods and naturally evolved compositions may yield therapeutics that are significantly differentiated from those developed by limited iteration of pre-defined platforms. (more...)

To meet the constant energy requirement in the face of highly variable food supply, mammals employ intricate and precise mechanisms for energy storage. When total energy intake is in excess of energy expenditure such as after a meal, excess carbohydrates are converted to fatty acids (de novo lipogenesis). Excess fatty acids are then converted to triacylglycerol to be stored in adipose tissue and released as oxidative fuels for other tissues during times of energy need such as fasting and exercise. The present invention describes for the first time that DNA-dependent protein kinase, DNA-PK, is connected to the signaling pathway involved in the formation of fat from carbohydrate in the liver. The enzymes that are involved in fatty acid and fat synthesis are tightly regulated during fasting/feeding. In the fed condition, especially after a high carbohydrate meal, activities of these enzymes drastically increase as blood glucose and insulin levels rise. The present invention demonstrates that DNA-PK regulates the transcription of fatty acid synthase (FAS), a central lipogenic enzyme that plays a crucial role in de novo lipogenesis by catalyzing all of the seven reactions involved in fatty acid synthesis. Therefore, DNA-PK is a pharmacological target for regulation of obesity and diabetes due to a diet high in carbohydrates. (more...)

The compound prosaposin and its methods of use, already tested successfully in Phase I clinical trials, is available for licensing. Prosaposin is the precursor of the saposins and has both neurotrophic and myelinotrophic activity in vitro and in vivo. It is an injury-repair protein that acts on both neurons and glia.Prosaposin also has myotrophic properties and can attenuate loss of muscle mass after nerve injury. Prosaposin and peptide derivatives of it will promote neurite outgrowth in vitro. A peptide consensus sequence was determined by comparing the active neurite outgrowth-inducing saposin C peptide sequence with that of various hematopoietic and neuropoietic cytokines. These cytokine-derived peptides will promote the same processes as their corresponding cytokines. In addition, prosaposin and saposin C promote increased nerve cell myelination ex vivo. Demyelination is a defect common to a number of central nervous system disorders, the most common being multiple sclerosis. (more...)

Actinomycetes are well known soil bacteria that were once believed to occur in the ocean only when washed in from land. Today, it is clear that unique populations of marine actinomycetes reside in ocean sediments and that these bacteria are fundamentally different from those on land. Although terrestrial actinomycetes have been the source of many of today's more than 120 drugs, marine actinomycetes have only recently been incorporated into the discovery process. These bacteria are now proving to be a particularly rich source of unique natural products, many of which display potent biological activities. (more...)

BACKGROUND: In recent years, there has been a dramatic increase in the incidence of diabetes worldwide. According to the International Diabetes Foundation, about 246 million people worldwide have diabetes and this number is expected to increase to 380 million by 2025. Type 2 diabetes accounts for about 90% of all cases. The current gold standard for diagnosing diabetes is a test for elevated blood sugar level following an overnight fast. Another test frequently used is the oral glucose tolerance test. However, these tests based on blood glucose can overlook approximately 25% of people who will develop type 2 diabetes, yet have normal blood glucose levels several years before diagnosis. Just in the US alone, 57 million people have pre-diabetes with blood glucose levels that are higher than normal but not high enough to be classified as diabetes. Recent research has shown that some long-term damage to the body, especially the heart and circulatory system, may already be occurring during pre-diabetes. Therefore, there is a need for assays to detect risk for type 2 diabetes a) prior to the onset of pre-diabetes as well as b) in individuals who have normal blood glucose levels. DESCRIPTION: Researchers at UCSF in collaboration with researchers at the University of Catanzaro have discovered mutations in a nuclear regulatory gene that are predictive of type 2 diabetes. The gene encodes a transcription factor necessary for cells to make insulin receptor, and low levels of insulin receptor lead to insulin resistance and type 2 diabetes. Researchers sequenced genomic samples from 3000 type 2 diabetes patients and 2000 sex and age matched non-diabetic controls. These mutations were observed in 10% of type 2 diabetes patients, while mutations were observed in less than half a percent of control patients. Since these mutations were 20-fold lower in controls, a robust diagnostic with high positive predictive value can be developed. Such a gene-based approach to assessing susceptibility to type 2 diabetes provides a more definitive diagnosis than todays diagnostics, allowing physicians to change patient care. Furthermore, genetic tests are accurate as early as infancy, when diet and exercise habits are being formed. (more...)

In mammals, Melanin Concentrating Hormone (MCH), a GPCR, has been shown to regulate food consumption and energy metabolism. Central administration of MCH has been shown to promote feeding while mRNA levels of the MCH Receptor 1 (MCHR1) rise as a result of starvation and leptin deficiency. MCH also stimulates insulin and leptin relase in insulinoma cell lines and adipose cells respectively and regulates pituitary hormones. Mice devoid of MCH are lean and hypophagic, while mice over-expressing MCH are obese and hyperphagic. Genetic disruption of MCHR1 on the other hand results in mice that are hyperphagic, but also hypermetabolic and obesity-resistant. (more...)

A wide number of pathological conditions are characterized by over-secretion of gastric acid, such as Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), peptic ulcer disease, duodenalulcers, atrophic gastritis, esophagitis, and the like. Conditions such as ZES and peptic ulcers, in particular, can have serious complications and represent some of the most prevalent diseases in industrialized nations. Current therapies require high and repeated doses of acid output (AO) inhibiting agents, such as histamine H2-antagonists, to reduce intragastric acidity. However, the inconsistent and diminishing effect of the antagonist, as well as the adverse side effects associated with the use of larger doses has lead to the use of proton pump inhibitors (PPI).  PPIs reduce potent gastric acid secretion by inhibiting H+/K+ -ATPase, an enzyme that plays a crucial role in preventing the aggravation of peptic ulcers by reducing pH levels in the stomach. However, the use of PPIs has been hindered due to the large dose requirements. Therefore, there is an emerging need to develop a method for the treatment of GI inflammatory diseases that require lower dosages of PPIs. (more...)