Shaker A. Mousa

Omega-3 Fatty Acids EPA and DHA: Health Benefits Throughout Life

Omega-3 [(n-3)] fatty acids have been linked to healthy aging throughout life. Recently, fish-derived omega-3 fatty acids EPA and DHA have been associated with fetal development, cardiovascular function, and Alzheimers disease. However, because our bodies do not efficiently produce some omega-3 fatty acids from marine sources, it is necessary to obtain adequate amounts through fish and fish-oil products. Studies have shown that EPA and DHA are important for proper fetal development, including neuronal, retinal, and immune function. EPA and DHA may affect many aspects of cardiovascular function including inflammation, peripheral artery disease, major coronary events, and anticoagulation. EPA and DHA have been linked to promising results in prevention, weight management, and cognitive function in those with very mild Alzheimers disease.

Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins

An enzymatic synthesis may ultimately offer a more efficient means of producing an important class of anticoagulant drugs. Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.

Metformin and neoplasia: Implications and indications

Metformin has been shown to exert anti-neoplastic and chemopreventive activities in epidemiological and animal studies. This review article discusses the epidemiological studies and examines the possible mechanisms by which metformin exerts its anti-carcinogenic activities in breast, colon, ovarian, lung, and prostate cancers. We performed a systematic review of the clinical studies examining the anti-neoplastic activities of metformin and the potential mechanisms associated with these activities. Several observational and biological studies revealed a significant association between metformin and reduction in cancer incidence. The mechanisms by which metformin exerts these effects are unknown. This action may be mediated through activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) pathway, and inhibition of insulin like growth factors (IGFs), and many others. Further laboratory investigation and large, prospective population clinical trials are required to elucidate metformin anti-neoplastic and chemo-preventive actions.

Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells.

A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10−7 M), T4 significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T4 and T3 to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T4>T3) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T4-induced, but not T3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.

Mechanisms of drug resistance in Mycobacterium tuberculosis and current status of rapid molecular diagnostic testing.

Drug-resistant tuberculosis has become a global problem and a major public health concern. While mechanisms of resistance are fairly well characterized for most agents, particularly the first line agents, our knowledge of drug resistance is by no means exhaustive, and strains continue to emerge that carry novel resistance-related mutations. The purpose of this review is to summarize our current understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis, highlighting emerging areas of research. The development of rapid detection methods has been a major breakthrough in the fight against drug-resistant tuberculosis. Rapid detection methods are available for both rifampin- and isoniazid-resistant tuberculosis, but have yet to be developed for other first line agents. Rapid detection methods will become increasingly important as multi-drug resistant strains of M. tuberculosis become more prevalent, even for detecting tuberculosis that is resistant to second line agents.

Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts.

Thyroid hormone stimulates cell proliferation of several types of cancers and stimulates cancer-relevant angiogenesis. In the present study, we investigated the proliferative effect of thyroid hormone and the anti-proliferative and anti-angiogenic action of its nano-derivative, tetrac-NP, on human non-small cell lung cancer (NSCLC) H1299 cells in vitro and in xenografts. The anti-proliferative activity of unmodified tetrac and tetrac-NP against human H1299 cells was determined in three models: (a) cultured H1299 cells in vitro, (b) tumor cell implants in the fertilized chick chorioallantoic membrane (CAM) system and (c) xenografts in the nude mouse. An integrin αvβ3 antibody inhibited thyroid hormone-induced cell proliferation in vitro, as did unmodified tetrac and tetrac-NP. Pharmacologic inhibition of the mitogen-activated protein kinase pathway also blocked NSCLC cell proliferation in response to thyroid hormone. Tetrac and tetrac-NP arrested tumor growth and tumor-related angiogenesis in H1299 cells grown in the CAM model and both agents prevented chick embryo mortality. Xenografts of H1299 cells were established in nude mice (n=8, treatment and control groups) and when tumor volumes reached 250-300 mm3, tetrac (1 mg/kg) or tetrac-NP (1mg tetrac as the nanoparticle/kg) were administered intraperitoneally every 2 days. Tetrac and tetrac-NP significantly suppressed tumor growth and angiogenesis. Thus, both tetrac and tetrac-NP effectively arrest human NSCLC tumor cell proliferation in vitro and in the CAM assay and in murine xenograft models.

Therapeutics formulated to target cancer stem cells: Is it in our future?

With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs), is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers.

Semisynthesis and pharmacological activities of thyroxine analogs: Development of new angiogenesis modulators

Novel thyroxine analogs with hindered phenol, amino and carboxylic acid groups have been synthesized and the effects of the synthesized compounds on angiogenesis using the chick chorioallantoic membrane and mouse matrigel models have been tested. Pharmacological profiles revealed that thyroxine tolerates numerous modifications on the amino group and remains active. These results provide the rationale for the selection of a novel thyroxine nanoparticle precursor.

Comparative Pharmacodynamic Assessment of the Antiangiogenesis Activity of Heparin and Low-Molecular-Weight Heparin Fractions Structure–Function Relationship

Effects of unfractionated heparin and low-molecular-weight heparins (LMWHs) on human microvascular endothelial cell sprouting (tube formation assay) in vitro were determined. Antiangiogenesis efficacy of commercially available LMWHs tinzaparin and enoxaparin in the chick chorioallantoic membrane (CAM) model of growth factor-induced angiogenesis was compared. The LMWH tinzaparin was fractionated into different molecular weight (MW) pools by size exclusion chromatography; they inhibited CAM angiogenesis depending on their MW distribution, with optimal inhibition at 8 to 12 kDa and no inhibition at <2 kDa. Tinzaparin demonstrated greater antiangiogenesis efficacy than enoxaparin (P < .001); these CAM results correlated with the endothelial tube formation assay results (P < .001, tinzaparin vs enoxaparin). These data point to the variable antiangiogenesis efficacy of different LMWHs as a function of MW and perhaps other structural differences. Our hypothesis confirmed a relationship between lower release of tissue factor pathway inhibitor by lower MW fractions of tinzaparin or enoxaparin leading to reduced antiangiogenesis efficacy.

Fish Oil Metabolites: Translating Promising Findings from Bench to bedside to Reduce Cardiovascular Disease

Cardiovascular disease is an inflammatory process and the leading cause of death in the United States. Novel omega-3 derived potent lipid mediators, termed resolvins and protectins, have been identified as major pathophysiologic players in the resolution phase of the inflammatory response. Potent lipid mediators offer tremendous metabolic and pathophysiologic insights in regard to the risk and treatment of cardiovascular disease. In this review, resolvins and protectins are described and analyzed as accelerators of discovery via their potential role as biomarkers for research and clinical decision making in cardiovascular disease. Specific barriers relating to biomarker validation, laboratory methods, and improvement of risk models are introduced and discussed. Potential therapeutic impacts in cardiovascular disease are also mentioned with special consideration for cost-saving implications with respect to dietary fish oil as an alternative to resolvin and protectin treatment. Given the high tolerability of fish oil supplements and previously described benefits of omega-3 fatty acid intake in cardiovascular disease, we conclude that resolvins and protectins are set to soon take center stage as future biomarkers and well-tolerated therapies for cardiovascular disease.