Sulforaphane Potentiates RNA Damage Induced by Different Xenobiotics

Background: The isothiocyanate sulforaphane (SFN) possesses interesting anticancer activities. However, recent studies reported that SFN promotes the formation of reactive oxygen species (ROS) as well as DNA breakage. Methodology/Principal Findings: We investigated whether SFN is able to damage RNA, whose loss of integrity was demonstrated in different chronic diseases. Considering the ability of SFN to protect from genotoxicity, we also examined whether SFN is able to protect from RNA damage induced by different chemicals (doxorubicin, spermine, S-nitroso-Nacetylpenicillamine, H2O2). We observed that SFN was devoid of either RNA damaging and RNA protective activity in human leukemic cells. It was able to potentiate the RNA damage by doxorubicin and spermine. In the first case, the effect was attributable to its ability of modulating the bioreductive activation of doxorubicin. For spermine, the effects were mainly due to its modulation of ROS levels produced by spermine metabolism. As to the cytotoxic relevance of the RNA damage, we found that the treatment of cells with a mixture of spermine or doxorubicin plus SFN increased their proapoptotic potential. Thus it is conceivable that the presence of RNA damage might concur to the overall toxic response induced by a chemical agent in targeted cells. Conclusions/Significance: Since RNA is emerging as a potential target for anticancer drugs, its ability to enhance spermineand doxorubicin-induced RNA damage and cytotoxicity could represent an additional mechanism for the potentiatin

Lung Function and Risk of Type 2 Diabetes and Fatal and Nonfatal Major Coronary Heart Disease Events: Possible Associations With Inflammation

OBJECTIVE - We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations. RESEARCH DESIGN AND METHODS - A prospective study of 4,434 men aged 40-59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years. RESULTS - There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEY1) but not FEV1-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07-2.56) and 1.74 (1.16-2.61) for FVC and FEV1, respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00-2.21) and 1.81 (1.19-2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6; the inverse associations with type 2 diabetes for FVC and FEV1 were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively). CONCLUSIONS - Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation

Risk of venous thromboembolism after total hip and knee replacement in older adults with comorbidity and co-occurring comorbidities in the Nationwide Inpatient Sample (2003-2006)

<p>Abstract</p> <p>Background</p> <p>Venous thromboembolism is a common, fatal, and costly injury which complicates major surgery in older adults. The American College of Chest Physicians recommends high potency prophylaxis regimens for individuals undergoing total hip or knee replacement (THR or TKR), but surgeons are reluctant to prescribe them due to fear of excess bleeding. Identifying a high risk cohort such as older adults with comorbidities and co-occurring comorbidities who might benefit most from high potency prophylaxis would improve how we currently perform preoperative assessment.</p> <p>Methods</p> <p>Using the Nationwide Inpatient Sample, we identified older adults who underwent THR or TKR in the U.S. between 2003 and 2006. Our outcome was VTE, including any pulmonary embolus or deep venous thrombosis. We performed multivariate logistic regression analyses to assess the effects of comorbidities on VTE occurrence. Comorbidities under consideration included coronary artery disease, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), diabetes, and cerebrovascular disease. We also examined the impact of co-occurring comorbidities on VTE rates.</p> <p>Results</p> <p>CHF increased odds of VTE in both the THR cohort (OR = 3.08 95% CI 2.05-4.65) and TKR cohort (OR = 2.47 95% CI 1.95-3.14). COPD led to a 50% increase in odds in the TKR cohort (OR = 1.49 95% CI 1.31-1.70). The data did not support synergistic effect of co-occurring comorbidities with respect to VTE occurrence.</p> <p>Conclusions</p> <p>Older adults with CHF undergoing THR or TKR and with COPD undergoing TKR are at increased risk of VTE. If confirmed in other datasets, these older adults may benefit from higher potency prophylaxis.</p

Mitochondrial Pathway Mediates the Antileukemic Effects of Hemidesmus Indicus, a Promising Botanical Drug

Although cancers are characterized by the deregulation of multiple signalling pathways, most current anticancer therapies involve the modulation of a single target. Because of the enormous biological diversity of cancer, strategic combination of agents targeted against the most critical of those alterations is needed. Due to their complex nature, plant products interact with numerous targets and influence several biochemical and molecular cascades. The interest in further development of botanical drugs has been increasing steadily and the FDA recently approved the first new botanical prescription drug. The present study is designed to explore the potential antileukemic properties of Hemidesmus indicus with a view to contributing to further development of botanical drugs. Hemidesmus was submitted to an extensive in vitro preclinical evaluation.A variety of cellular assays and flow cytometry, as well as a phytochemical screening, were performed on different leukemic cell lines. We have demonstrated that Hemidesmus modulated many components of intracellular signaling pathways involved in cell viability and proliferation and altered the protein expression, eventually leading to tumor cell death, mediated by a loss of mitochondrial transmembrane potential and increased Bax/Bcl-2 ratio. ADP, adenine nucleotide translocator and mitochondrial permeability transition pore inhibitors did not reverse Hemidesmus-induced mitochondrial depolarization. Hemidesmus induced a significant [Ca(2+)](i) raise through the mobilization of intracellular Ca(2+) stores. Moreover, Hemidesmus significantly enhanced the antitumor activity of three commonly used chemotherapeutic drugs (methotrexate, 6-thioguanine, cytarabine). A clinically relevant observation is that its cytotoxic activity was also recorded in primary cells from acute myeloid leukemic patients.These results indicate the molecular basis of the antileukemic effects of Hemidesmus and identify the mitochondrial pathways and [Ca(2+)](i) as crucial actors in its anticancer activity. On these bases, we conclude that Hemidesmus can represent a valuable tool in the anticancer pharmacology, and should be considered for further investigations

Examining the Interactome of Huperzine A by Magnetic Biopanning

Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Frequency of left ventricular hypertrophy in non-valvular atrial fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p &lt;0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p &lt;0.0001), age (OR 1.03 per year, p &lt;0.001), hypertension (OR 2.30, p &lt;0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention

FTIR studies of the similarities between pathology induced protein aggregation in vivo and chemically induced protein aggregation ex vivo

© 2016 Elsevier B.V.Fourier transform infrared (FTIR) spectroscopy has been well documented to discriminate between protein secondary structures, at the micron scale. This capability has enabled in situ localization of ß-sheet aggregate accumulation within the central nervous system during pathological protein misfolding associated with Prion disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, Alzheimer's' Disease, and Parkinson's Disease. In addition to the above diseases, similar spectral alterations occurring over the range ~1625-1630cm-1 have been reported in other biological systems, including inclusion body formation within bacteria and during the formation of high molecular weight protein aggregates via protein oxidation and denaturation. Thus, the characteristic spectral alterations to the amide-I band observed during protein misfolding in neurological disorders are likely not specific to these diseases, but rather, reflect an aggregated protein end point, which can result from a range of biochemical events. For example, a common pathogenic component of many neurological conditions is oxidative stress, protein oxidation and altered ion homeostasis, which have the potential to denature proteins and promote the formation of high molecular weight aggregates.Oxidative stress is a generic feature of neurodegenerative diseases and also occurs during neurodegenerative conditions, such as stroke, multiple sclerosis, epilepsy and cerebral malaria. These neuropathological disorders do not have an established protein misfolding pathology, in contrast to Prion disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, Alzheimer's' Disease, which do have an established protein misfolding pathology. Interestingly, recent studies using FTIR have confirmed the presence of protein aggregates within the central nervous system during stroke, cerebral malaria, epilepsy, multiple sclerosis. Such reports suggest FTIR spectroscopy may be a highly valuable research tool to study protein aggregation as a marker of oxidative stress and neurodegeneration in many diseases, not just those with a characteristic pathology for protein misfolding. This manuscript extends the recent literature and reports further characterization of the alterations to the amide I band that result from ubiquitous . ex vivo protein aggregation in cerebral tissue. The new data presented highlights that the spectroscopic alterations to the amide I band often reported for amyloid-ß plaques in Alzheimer's disease, are spectroscopically very similar to spectroscopic alterations observed during ischemia induced neurodegeneration (stroke) and . ex vivo induced protein aggregation. As such, this study further validates FTIR as a useful platform to study protein aggregation in neurological disorders, including those not characterized by protein misfolding pathology