RSS 1.0Faculty, Student Works School of Dentistry
Browse by
Recent Submissions
-
Metformin and other metabolic inhibitors attenuate neuropathic pain and tumor growth in mice with paraneoplastic syndrome and CIPNChemotherapy-induced peripheral neuropathy (CIPN) and paraneoplastic neurological syndrome are two conditions that can cause significant pain and discomfort in cancer patients. CIPN is a common side effect of certain chemotherapeutics and can result in numbness, tingling, and pain. Paraneoplastic neurological syndrome, on the other hand, is a rare disorder that occurs when cancer-fighting antibodies attack parts of the nervous system. Both neuropathies can persist which can adversely affect the quality of life and the rehabilitation of cancer patients. Unfortunately, therapies that can alleviate tumor or chemotherapy-induced neuropathic pain that do not interfere with tumor growth do not currently exist. The main goal of this study was to identify a therapeutic strategy that can achieve both anti-tumor and analgesic effects. The chemotherapeutic, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons which lead to bortezomib-induce neuropathic pain. Aerobic glycolysis is also a hallmark of cancer cells, suggesting a common metabolic vulnerability. Paraneoplastic neuropathies are commonly associated with lung cancers. Hence, we used Lewis Lung Carcinoma cells (LLC1) to develop a mouse model of paraneoplastic neuropathy. We hypothesized that blocking metabolic pathways could alleviate CIPN and paraneoplastic neuropathic pain without compromising on tumor control. To test our hypothesis, we demonstrated that mice implanted with LLC1 developed significant allodynia. Treatment with bortezomib attenuated tumor growth but exacerbated the neuropathic pain. However, co-treatment with metformin, which blocks bortezomib- induced aerobic glycolysis in sensory neurons and prevents CIPN, attenuated both tumor growth and neuropathic pain. Similarly, inhibition of lactate dehydrogenase and pyruvate dehydrogenase kinase with oxamate and dichloroacetate respectively, also reduced tumor growth and pain. These results suggest that targeting metabolic pathways is a promising strategy to improve oncologic outcomes and alleviate neuropathic pain in cancer patients.
-
Long-Term Post-COVID-19 Associated Oral Inflammatory SequelaeThe oral cavity remains an underappreciated site for SARS-CoV-2 infection despite the myriad oral conditions observed in COVID-19 patients. Recently, replicating SARS-CoV-2 was found inside salivary epithelial cells resulting in inflammation and atrophy of salivary glands. Saliva possesses healing properties crucial for maintaining the health of the oral mucosa. Specifically, salivary antimicrobial peptides, most notable, histatin-5 exclusively produced in salivary glands, plays a vital role in innate immunity against colonizing microbial species. The demonstration of SARS-CoV-2 destruction of gland tissue where histatin-5 is produced strongly indicate that histatin-5 production is compromised due to COVID-19. Here we present a case of a patient presenting with the patient and matched healthy subject for histatin-5 and key cytokines. Findings demonstrated significantly reduced histatin-5 levels in patient’s saliva and activation of the Th17 inflammatory pathway. As histatin-5 exhibits potent activity against the opportunistic oral pathogen Candida albicans, we evaluated saliva potency against C. albicans ex vivo. Compared to control, patient saliva exhibited significantly reduced anti-candidal efficacy. Although speculative, based on history and salivary analysis we hypothesize that salivary histatin-5 production may be compromised due to SARS-CoV-2 mediated salivary gland destruction. With the current lack of emphasis on implications of COVID-19 on oral health, this report may provide lacking mechanistic insights that may lead to reassessment of risks for oral opportunistic infections and mucosal inflammatory processes in acutely-ill and recovered COVID-19 patients.
