Therapeutic Approaches to Alter Mineral Formation and Growth in Vascular Calcification

Cardiovascular diseases represent the global leading cause of morbidity and mortality. Cardiovascular calcification is the most significant predictor of cardiovascular events, but no therapeutic options exist to prevent or treat mineral formation in the vasculature. The presence of bone-like mineral increases cardiac work required to move blood through systemic circulation and can lead to mechanical stress in atherosclerotic plaques, promoting plaque rupture events that cause heart attacks. Clinical trials correlated bisphosphonates (BiPs), common anti-osteoporosis pharmaceuticals, with contradicting cardiovascular outcomes. Here, we demonstrated the importance of treatment timing in BiP-induced mineral disruption or promotion. We showed that BiPs can alter morphological features of calcifications within the atherosclerotic plaque of hyperlipidemic mice, which may affect plaque rupture risk. Osteogenic differentiation of resident vascular smooth muscle cells (VSMCs) and release of calcifying extracellular vesicles (EVs) mediate cardiovascular calcification, which imitates bone mineralization by osteoblasts. Formation of calcifying EVs by VSMCs requires caveolin-1 (CAV1), a scaffolding membrane protein. Targeting cellular mechanisms that involve CAV1 may represent ideal strategies to develop therapeutics for cardiovascular calcification. We studied the effect of inhibiting several upstream and downstream molecules that are involved in CAV1 activation and trafficking. Interestingly, we showed that altering CAV1 trafficking does not negatively impact physiological mineralization of osteoblasts. We concluded that despite shared mineralization characteristics, the mechanism(s) of bone and vascular calcification is/are distinct. Furthermore, we demonstrated that epidermal growth factor receptor (EGFR) inhibition prevents vascular calcification by mitigating the biogenesis of calcifying EVs. We showed that EGFR inhibition reduces the release of pro-calcific CAV1-positive EVs and prevents calcification in osteogenic VSMC cultures and in chronic kidney disease mice fed a high-phosphate diet. EGFR inhibitors are clinically approved and widely used in cancer therapies and may represent an appropriate strategy to treat vascular calcification

FAIR and bias-free network modules for mechanism-based disease redefinitions

Even though chronic diseases are the cause of 60% of all deaths around the world, the underlying causes for most of them are not fully understood. Hence, diseases are defined based on organs and symptoms, and therapies largely focus on mitigating symptoms rather than cure. This is also reflected in the most commonly used disease classifications. The complex nature of diseases, however, can be better defined in terms of networks of molecular interactions. This research applies the approaches of network medicine – a field that uses network science for identifying and treating diseases – to multiple diseases with highly unmet medical need such as stroke and hypertension. The results show the success of this approach to analyse complex disease networks and predict drug targets for different conditions, which are validated through preclinical experiments and are currently in human clinical trials

Modulators of Oxidative Stress

The book starts with the editors’ preface summarizing the contributions of each of the following thirteen articles dealing with chemical and pharmacological aspects of the molecular modulators of the oxidative stress in regard to various therapeutic approaches in cardiovascular and neurodegenerative diseases, cancer, and diabetes. The seven articles present data from original research studies enlightening the roles and mechanisms of action of small molecular weight compounds (natural and synthetic; ascorbic acid/vitamin C, deferoxamine, N-acetylcysteine, MitoVitE, α-tocopherol, trolox, and ezetimibe) or proteins (SIRT3) in modulation of oxidative stress. In the six review papers, the authors present and discuss the possible therapeutic potential of novel approaches and compounds that are promising and deserve further investigation, in modulation of oxidative stress

ID3, Estrogenic Chemicals, and the Pathogenesis of Tumor-Like Proliferative Vascular Lesions

Tumor-like proliferative vascular lesions manifest in several diseases such as peripheral arterial disease (PAD) and atherosclerosis (AS) after arterial injury. The cause of the vascular cell dysfunction in PAD patients is not known. Our recent novel discovery shows that inhibitor of differentiation 3 (ID3) is highly expressed in intimal lesions of clinical vascular disease samples. The central hypothesis of our study is: estrogenic chemical induced dysregulation of ID3 target genes is involved in the development of vascular disease. NHANES data analysis demonstrated higher geometric levels of all 6 PCB congeners in both PAD diagnosed participants and participants at risk of AS when compared to the rest of the population. Adjusted models showed association between higher exposure of PCBs, phthalates, BPA, and increased risk of PAD. Furthermore PCB153 was shown to have the highest geometric mean amongst all PCB congeners in both participants diagnosed with PAD and at risk of AS. Gene expression of ID3 & ID3 candidate targets in blood & tissue studies identified ID3 & ID3 candidate target genes as a driver of vascular disease. Overlapping ID3 & ID3 candidate target genes included: ABCB6, ACP1, BYSL, CAD, CDH15, DCBLD2, DHRS3, DNMT1, ID3, MCM4, and NDUFA7. The ID3 target genes involved in the: focal adhesion pathway were ACTN1, COL1A2, COL3A1, COL6A1, CTNNB1, IBSP, ID3, ITGA8, and MYL2; ECM-receptor interaction were COL1A2, COL3A1, COL6A1, IBSP, ID3, and ITGA8; oxidative phosphorylation pathway ATP5D, ATP5H, ATP6V0B, ATP6V0D1, ATP6V1B2, COX5A, COX7C, COX8A, CYC1, ID3, NDUFA1, NDUFA7, NDUFS4, NDUFV1, NDUFV2; and cell cycle pathway ANAPC10, ATM, CDKN2B, E2F5, MCM3, and MCM4. In summary our results showed an association between exposure to PCBs, phthalates, BPA, and increased risk of PAD and AS, and possible molecular mechanisms of interaction of ID3 target genes and estrogenic chemicals involved in PAD and AS

Oxidative Stress in Diabetic Retinopathy

The combination of an increasing prevalence of diabetes and the aging of populations enables the appearance of a greater number of associated complications such as diabetic retinopathy. Diabetic retinopathy is the leading cause of preventable vision loss in working-age adults. The objective of this Special Issue is to highlight the existing evidence regarding the relationship between oxidative stress and low-grade chronic inflammation induced by hyperglycemia with the development and progression of diabetic retinopathy, with an emphasis on the importance of early diagnosis and the use of antioxidant and anti-inflammatory approaches to prevent or delay the harmful effects of diabetes on retinal tissue

Orchestration of the neural stem cell fate by NRF2 and TAZ

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 11-10-2019Neurogenesis is a multiple step process that must be tightly regulated or otherwise results in pathological events. Therefore, a deep characterization of the molecular mechanisms that control the biology of neural stem/progenitor cells (NSPCs) will provide a better understanding of the role of neurogenic niches and new therapeutic strategies for neurodegenerative diseases and brain tumours. In this thesis we have analyzed the regulation of NSCs fate by the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is considered a master regulator of cellular homeostasis, and the Transcriptional co-activator with PDZ-binding motif (TAZ), a major effector of the Hippo pathway. NRF2 controls the expression of a wide battery of cytoprotective genes that have a tremendous impact on physiological responses such as inflammation, senescence or metabolism. However, its relevance in neurogenesis is just starting to be unveiled. On the other hand, TAZ is a major effector of the Hippo pathway, which plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. However, the implication of TAZ in neurogenesis has not been analyzed. In this study, we have identified NRF2 as a regulator of hippocampal NSCs self-renewal and differentiation. We show that genetic manipulation of NRF2 results in the modulation of NSPCs differentiation and proliferation capacity. To assess the functional relevance of NRF2 in neurogenesis under pathological conditions, we analyzed the impact of NRF2 deficiency in neurogenesis of the subgranular zone (SGZ) of the hippocampus in a mouse model of Alzheimer´s Disease (AD). We found that NRF2 deficiency results in an accelerated loss of NSCs, loss of synaptic plasticity measured as long term potentiation (LTP) and impaired the execution of cognitive tasks. At the molecular level, we have identified NRF2 enhancer sequences, termed Antioxidant Response Elements (AREs), in the promoter region of the TAZ coding gene. Consequently, we show that genetic and pharmacological manipulation of NRF2 results in the modulation of TAZ gene expression in NSPCs. These findings open a new window to understand the molecular mechanisms underlying NRF2 function in stemness. We have also established a novel role of TAZ as repressor of neuronal differentiation, based on the transcriptional repression of SOX2 and the basic helix-loop-helix (bHLH) factors ASCL1, NEUROG2 and NEUROD1. Data mining of The Cancer Genome Atlas showed a negative correlation between TAZ and the expression of these proneurogenic factors in lower grade gliomas and glioblastomas. We found that TAZ favours glioblastoma CSCs tumorigenic capacity and that genetic modulation of TAZ in these cells inversely correlated with proneurogenic genes expression. Due to the relevance of these proneurogenic factors in the ablation of glioblastoma cancer stem cells (CSCs), this novel TAZ/proneurogenic factors axis may have important implications in the development of this type of brain tumours. The characterization of molecular mechanism governing NSPCs fate provides new insights to harness these cells for brain repair. Overall, this thesis describes a novel role of NRF2 and TAZ in the control of neural stem cell fate, suggesting a new strategy to combat brain pathology

2016 Touro College & University System Faculty Publications

This is the 2016 edition of the Faculty Publications Book of the Touro College & University System. It includes all eligible 2016 publication citations of faculty within the Touro College & University System, including New York Medical College (NYMC). It was produced as a joint effort of the Touro College Libraries and the Health Sciences Library at NYMC.https://touroscholar.touro.edu/facpubs/1000/thumbnail.jp

The Future of Medicine: Frontiers in Integrative Health and Medicine

Contemporary healthcare trends indicate that many chronic and communicable diseases are related to lifestyle, stress, personal choices and systemic factors. In response to the shortfalls of modern medicine regarding the prevention of these diseases and the promotion of whole-person health, providers and consumers worldwide are exploring integrative, natural and complementary approaches to prevention, treatment and health promotion. These trends harbor the future of medicine. The issues of clinician burnout, high rates of adverse effects, high cost, and lack of rigorous methods to promote individual and collective immunity are addressed by leading physicians and scientists from around the world. The original research and reviews in this volume investigate efficacy, molecular mechanisms and hypotheses that suggest that traditional systems of medicine and health, e.g., Ayurveda, yoga, traditional Chinese medicine, and mind–body–lifestyle medicine, may offer preventive and cost-effective solutions to contemporary health care challenges. Integrating innovative health approaches with conventional medicine offers a whole system of medicine that encompasses the individual, family, community and environment—from single person to planetary health