Develop natural compound emodin as a novel therapy for calcific aortic valve disease (R41HL172481)
Calcific aortic valve disease (CAVD) is a common progressive heart disease. It ranges from aortic valve sclerosis to aortic valve stenosis, characterized by aortic valve calcification with impaired leaflet function. CAVD affects 25% of the population over 65 years of age and about 50% of those over 85 years old. Currently, the standard-of-care treatment of CAVD is surgical valve replacement. There are no drugs approved by the FDA for CAVD treatment.
Aberrant transforming growth factor β (TGFβ) signaling plays a key role in the pathogenesis of CAVD. We developed in vitro cell culture and in vivo mouse models that display aberrant TGFβ signaling and can be used for the development of drugs for CAVD prevention and treatment. Using these models, we found that natural compound emodin could block the progression of valve interstitial cells calcification in vitro and attenuate aortic valve calcification in mice. In this STTR Phase 1 project, we will test a hypothesis that emodin may block the development and progression of CAVD and even lead to a reversal of CAVD by tempering the aberrant TGFβ signaling. These studies will enable us to collect data towards filing an investigational new drug (IND) application to FDA.
Develop a novel strategy to deliver N-acetylcysteine for AD treatment (NIH R41AG087769)
After decades of intensive research and drug development efforts, there are still no cures or substantially effective treatments for Alzheimer’s disease (AD). Studies of AD have been mainly focused on Aβ plaques and tau protein-formed neurofibrillary tangles in the brain. However, in recent years, it is increasingly clear that the development of AD is the collective consequence of the toxicities induced by Aβ plaques, tau protein-formed neurofibrillary tangles, and malfunctions of microglia.
Nacetylcysteine (NAC) is a derivative of amino acid cysteine; it has been studied for its potential effects on AD, largely due to its antioxidant and anti-inflammatory activities, particularly its beneficial effects on microglia. However, NAC cannot penetrate the BBB and reach the brain sufficiently. To realize NAC’s potential as an AD treatment, we developed a brain targeted NAC delivery system (TN-NAC). Our preliminary data demonstrate that TN-NAC can effectively cross the BBB, quench the elevated ROS, attenuate the activation of microglia, reduce Aβ burden, and eliminate senescent cells in the brain in an AD mouse model, and improve the performance of the animals in behavior tests. Based on these exciting data, in this Phase I STTR study, we will test the feasibility to develop TN-NAC as a therapy for AD.
Targeting macrophage maladaptation for bacterial sepsis treatment (NIH R41AI174362)
Bacterial sepsis is a severe and potentially life-threatening condition that occurs when the body's response to bacteria damages its own tissues and organs. It can lead to shock, multiple organ failure, and death. It is increasingly clear that sepsis is a bi-phasic process comprised of 1) an early high-energy demanding hyperinflammation state that can cause inflammatory shock and 2) a low-energy supply immunosuppression state that promotes immunometabolic paralysis while countering oxidative damage. These two phases are seamlessly connected or even concurrent. This makes sepsis treatment extremely difficult, and many therapies, such as anti-inflammatory corticosteroids, often worsen the outcome.
We are developing a promising new treatment for bacterial sepsis; it is a small-molecule synthetic compound called JX06. JX06 works by blocking a protein called pyruvate dehydrogenase kinase 1 (PDHK1). PDHK1 is involved in macrophage glucose metabolism and inflammation; blocking it can help to reduce inflammation and prevent cell death. In this STTR project funded by the National Institute of Allergy and Infectious Diseases (NIAID), we propose 1) to determine the toxicity of JX06 in cultured primary mouse and human cells in vitro and mice in vivo, and to study its pharmacokinetics in mice; and 2) to establish the effectiveness of JX06 in various mouse strains using the mouse cecal ligation and puncture (CLP) sepsis model.
Developing natural compound emodin as a therapy for alcoholic cardiomyopathy (NIH UT1AA030690)
Alcohol abuse is a widespread problem that harms many organs in the body, including the heart. A condition called alcoholic cardiomyopathy (ACM) can develop following long-time alcohol use, leading to heart failure. ACM is characterized by the weakening of the heart muscle and the enlargement of the heart chambers. Currently, there are no approved treatments for ACM.
Scientists at AcePre are developing the natural compound emodin as a potential preventive and therapeutic agent for ACM. Emodin has various beneficial effects, including reducing inflammation and preventing fibrosis (excessive tissue scarring). We have found that emodin can inhibit the transforming growth factor beta (TGFβ) signaling pathway, which is involved in the development of cardiac fibrosis. We have also observed that emodin protects heart cells from alcohol-induced damage and reduces fibrosis in mouse models. With the support of a STTR grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), we are performing further studies to investigate the safety and effectiveness of emodin in mouse, rat and pig models of ACM.
The development of a multifunctional nanoenzyme for AD treatment (NIH R41AG081124)
Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia, which is a general term for memory loss and cognitive decline. It is named after Dr. Alois Alzheimer, who first described the disease in 1906. The disease is characterized by the formation of amyloid plaques (abnormal clumps of a protein called β-amyloid) and neurofibrillary tangles (aggregates of the tau protein) in the brain, along with a loss of connections between neurons. The cause of AD is largely unknown, and inflammation and oxidative stress in the brain are believed to contribute to the pathogenesis. Currently there is no cure for this disease. Existing medicines including the most used drug Aricept and the recently approved drug Leqembi can only slightly slow down the progression of the disease. More effective drugs are urgently needed.
Our scientists at AcePre are developing a new AD treatment. We propose to deliver an anti-inflammatory and antioxidative agent cerium oxide using a novel type of nanoparticles with brain targeting property, called T-CeNP. We expect that T-CeNP can effectively get into the brain and exert its strong anti-inflammatory and antioxidative activities in the brain, thereby reducing β-amyloid deposition and tau protein aggregation. In this small business grant funded by the National Institute of Aging (NIA), we will test the safety and efficacy of T-CeNP using mouse models of AD.
Using Novel Natural Compound Sparstolonin B to Treat Bacterial Sepsis (NIH R41AI157378)
Sepsis results from an infection of microorganisms, with bacteria being the most common culprit. Pathogen-associated molecular patterns (PAMPs) such as lipopolysacchardies (LPS) activate innate immune cells and tissue resident cells. Some of these activated immune cells, such as macrophages, engulf and kill the invading microbes. While these activated macrophages can do good things such as kill microbes and limit infection, they can also cause a very strong inflammatory response by secreting excessive amounts of cytokines and oxidative molecules, which can lead to tissue damage.
These damaged tissues release endogenous damage-associated molecular patterns (DAMPs), which act on toll-like receptors (TLRs) to further escalate the inflammatory cascade on immune cells and tissue resident cells. This leads to multi-organ injury and eventually death. The quick evolution and complexity of the pathology of bacteria sepsis makes it extremely difficult to treat. We have isolated a new compound named Sparstolonin B (SsnB) and characterized it as a TLR2/4 antagonist, effectively inhibiting inflammatory responses. On the basis of these achievements, our long-term goal is to develop SsnB as a novel therapy for bacterial sepsis.
A Novel Polymer-metal Nanocomplex for Ovarian Cancer Treatment (R41CA254500)
Ovarian cancer is the leading cause of death from gynecologic malignancy. Most women are diagnosed with metastatic ovarian cancer, and the 5-year survival rate for this late stage disease is less than 28%. The mainstay of treatment for ovarian cancer entails debulking cytoreductive surgery in combination with adjuvant chemotherapies. Unfortunately, severe side effects of these chemotherapies compromise the quality of life and result in poor patient compliance, and the relapse rate is high due to intrinsic and acquired therapy resistance. Therefore, there is a pressing need for the development of new safe and effective treatment strategies.
Our group has developed a novel pH and redox potential dual responsive polymer, poly[(2-(pyridin- 2-yldisulfanyl)-co-[poly(ethylene glycol)]] (PDA-PEG), which can be degraded intracellularly. If used as a drug carrier, this polymer system significantly improves the cancer cell killing effect and potentially reduces the off-target toxicity of the carried chemotherapeutic drugs. More excitingly, follow-up studies revealed that the combination of PDA-PEG and copper ions, termed polymer-metal nanocomplex (PMC), without being loaded with any chemotherapeutic drugs, could effectively kill a large variety of cancer cells, including drug-resistant ovarian cancer cells. Importantly, the PMC showed excellent cancer cell-selective killing. Based on these technology advancements and exciting in vitro and in vivo results, our goal is to eventually develop the PDA-PEG/Cu PMC into a novel safe and effective therapy for ovarian cancer and possible other malignant tumors.
Development of Dietary Quercetin to Treat Muscle Wasting Disorders (NIH R43AT011171)
Cachexia is the unintentional loss of body weight resulting in reduced physical function, a decreased tolerance for treatment, and increased mortality rates. It is commonly seen in chronic diseases and associated treatments. Cachexia has been reported following chemotherapy treatment. Furthermore, the loss of lean muscle mass associated with cachexia impairs chemotherapy treatment tolerance. Currently, there are no approved therapies for cachexia.
Quercetin, a natural polyphenol that is found in various fruits and vegetables, has been recognized for its anti-inflammatory properties and its ability to increase mitochondrial biogenesis. We have reported that quercetin can reduce cancer-induced cachexia, reduce the physical fatigue associated with chemotherapy, increase physical performance by increasing mitochondrial biogenesis, and reduce inflammation in a number of disease models. Our long-term goal is to have quercetin established alongside chemotherapy regimes in order to reduce the side effects of chemotherapy, thereby improving the efficacy of the treatment and patients’ quality of life.
Emodin as a Complementary Dietary Therapy to Reduce Toxicity of 5 Fluorouracil (NIH R41AT009964)
5 fluorouracil (5FU) has been the first-choice chemotherapy drug for colorectal cancer (CRC) for many years. However, its clinical utility remains hindered by hematopoietic and gastrointestinal toxicities resulting from its non-selectivity, resulting in side effects such as fatigue, loss of appetite, and diarrhea. Given that inflammation has been linked to 5FU-associated toxicities, targeting inflammation may minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. Therefore, identifying strategies to reduce the toxicity of 5FU is critical to prevent discontinued or deescalated treatment.
Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been recognized for its ability to target NF-κB and subsequently reduce inflammation. We have found that emodin is an effective anti-inflammatory agent that acts directly on NF-κB, is effective at reducing tumorigenesis, can abolish 5FU chemotherapy-induced intestinal inflammation and mucositis, and is indicated to be able to offset other side effects associated with 5FU chemotherapy. We have also shown that the dose of emodin that promotes these benefits does not exhibit side effects. The long-term goal for this project is to have this complementary dietary compound utilized as an innovative agent with chemotherapy.