Nonenzymatic Glycosylafion of Bovine Retinal Microvessel Basement Membranes In Vitro Kinetic Analysis and Inhibition by Aspirin

Incubation of intact bovine retinal microvessels or isolated retinal microvessel basement membranes (RVBM) with radioactive D-glucose or L-glucose, followed by basement membrane collagenous protein purification, resulted in the isolation of nonenzymatically glycosylated RVBM collagens. Type IV collagen was identified in the RVBM by selective salt fractionation, SDS-polyacrylamide gel electrophoresis, amino acid analysis, and immunoprecipitation with specific antibody. Kinetic analysis of the condensation of glucose with RVBM was carried out by labeling retinal microvessel basement membranes with D-[2- C|-glucose. The rate constant for aldimine product formation, k,, was 1.95 ± 0.24 (SD) X 10~4 mM" 1 h~', and the rate constant for the reversed reaction, k_ l9 was 5.9 ± 1.0 X 10~2 h" 1 . Based on a rate constant for the Amadori rearrangement, k 2 , of 8.8 ± 1.0 X 10~3 h" 1 , which was the rate-determining step, the half life of this reaction was 80 ± 9 h. These data may be useful in estimating the glycosylation of retinal microvessel basement membranes in vivo. The nonenzymatic glycosylation of retinal microvessel basement membrane proteins was progressively inhibited by increasing concentrations (0.1 to 2.0 mM) of aspirin. Invest Ophthalmol Vis Sci 25: [884][885][886][887][888][889][890][891] 1 One way hyperglycemia, per se, may play a role in the primary pathology of diabetic retinopathy is by altering the structure and function of retinal microvessel basement membrane proteins through increased nonenzymatic glycosylation. D-glucose, an aldehyde, undergoes a condensation reaction with the amino groups of proteins with the formation of an aldimine or Schiff-base linkage that subsequently may undergo an Amadori rearrangement to form a more stable condensation product. High levels of ambient glucose hav

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Environmental immune disruptors, inflammation and cancer risk

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E₂ , nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://carcin.oxfordjournals.org/. The publisher and the author(s) have made this article open access

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Cancer; an induced disease of twentieth century! Induction of tolerance, increased entropy and ‘Dark Energy’: loss of biorhythms (Anabolism v. Catabolism)

Abstract Maintenance of health involves a synchronized network of catabolic and anabolic signals among organs/tissues/cells that requires differential bioenergetics from mitochondria and glycolysis (biological laws or biorhythms). We defined biological circadian rhythms as Yin (tumoricidal) and Yang (tumorigenic) arms of acute inflammation (effective immunity) involving immune and non-immune systems. Role of pathogens in altering immunity and inducing diseases and cancer has been documented for over a century. However, in 1955s decision makers in cancer/medical establishment allowed public (current baby boomers) to consume million doses of virus-contaminated polio vaccines. The risk of cancer incidence and mortality sharply rose from 5% (rate of hereditary/genetic or innate disease) in 1900s, to its current scary status of 33% or 50% among women and men, respectively. Despite better hygiene, modern detection technologies and discovery of antibiotics, baby boomers and subsequent 2–3 generations are sicker than previous generations at same age. American health status ranks last among other developed nations while America invests highest amount of resources for healthcare. In this perspective we present evidence that cancer is an induced disease of twentieth century, facilitated by a great deception of cancer/medical establishment for huge corporate profits. Unlike popularized opinions that cancer is 100, 200 or 1000 diseases, we demonstrate that cancer is only one disease; the severe disturbances in biorhythms (differential bioenergetics) or loss of balance in Yin and Yang of effective immunity. Cancer projects that are promoted and funded by decision makers are reductionist approaches, wrong and unethical and resulted in loss of millions of precious lives and financial toxicity to society. Public vaccination with pathogen-specific vaccines (e.g., flu, hepatitis, HPV, meningitis, measles) weakens, not promotes, immunity. Results of irresponsible projects on cancer sciences or vaccines are increased population of drug-dependent sick society. Outcome failure rates of claimed ‘targeted’ drugs, ‘precision’ or ‘personalized’ medicine are 90% (± 5) for solid tumors. We demonstrate that aging, frequent exposures to environmental hazards, infections and pathogen-specific vaccines and ingredients are ‘antigen overload’ for immune system, skewing the Yin and Yang response profiles and leading to induction of ‘mild’, ‘moderate’ or ‘severe’ immune disorders. Induction of decoy or pattern recognition receptors (e.g., PRRs), such as IRAK-M or IL-1dRs (‘designer’ molecules) and associated genomic instability and over-expression of growth promoting factors (e.g., pyruvate kinases, mTOR and PI3Ks, histamine, PGE2, VEGF) could lead to immune tolerance, facilitating cancer cells to hijack anabolic machinery of immunity (Yang) for their increased growth requirements. Expression of constituent embryonic factors would negatively regulate differentiation of tumor cells through epithelial–mesenchymal-transition and create “dual negative feedback loop” that influence tissue metabolism under hypoxic conditions. It is further hypothesized that induction of tolerance creates ‘dark energy’ and increased entropy and temperature in cancer microenvironment allowing disorderly cancer proliferation and mitosis along with increased glucose metabolism via Crabtree and Pasteur Effects, under mitophagy and ribophagy, conditions that are toxic to host survival. Effective translational medicine into treatment requires systematic and logical studies of complex interactions of tumor cells with host environment that dictate clinical outcomes. Promoting effective immunity (biological circadian rhythms) are fundamental steps in correcting host differential bioenergetics and controlling cancer growth, preventing or delaying onset of diseases and maintaining public health. The author urges independent professionals and policy makers to take a closer look at cancer dilemma and stop the ‘scientific/medical ponzi schemes’ of a powerful group that control a drug-dependent sick society before all hopes for promoting public health evaporate

INFLAMMATION, CHRONIC DISEASE AND CANCER- CELL AND MOLECULAR BIOLOGY, IMMUNOLOGY AND CLINICAL BASES

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Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs

Abstract For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tremendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment of solid tumors that are bases of drug development. Safety and efficacy of candidate drugs tested in test tubes or experimental tumor models of rats or mice are usually evaluated and approved by FDA. Cost-benefit ratios of such ‘targeted’ therapies are also far from ideal as compared with antibiotics half a century ago. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines (e.g., HPV or flu) targeting young and old populations, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. This article discusses a closer scientific assessment of current cancer therapeutics and vaccines. We also present future logical approaches to cancer research and therapy and vaccines

Evaluation antimicrobial activity of biogenic zinc oxide nanoparticles on two standard gram positive and gram negative strains

Background: Nanoparticles are particles that have at least one dimension between 1 and 100 nanometers. Nanoparticles are a new generation of antimicrobial agents. Nanoparticles with antimicrobial activity, especially as a new class of biomedical materials for use in increasing the level of public health in daily life have emerged.  Zinc oxide nanoparticles have attracted a great attention due to the variety of their applications in medical science. The aim of this study was to evaluate and compare the antimicrobial activity of zinc oxide nanoparticles synthesized by green method. Methods: This experimental study was done in 2017, from March to September in the Bam Research Center of University of Medical Sciences Kerman, Iran. Green synthesis of zinc oxide nanoparticles was investigated using cumin seeds. The physicochemical characteristics of synthesized nanoparticles were studied by UV-visible ultraviolet spectrometer (Analytik Jena AG, Germany), X-ray diffraction and transmission electron microscope (TEM) (Carl Zeiss, Germany). Broth microdilution method was used to investigate the antimicrobial activity of zinc oxide nanoparticles. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of these nanoparticles were determined for Pseudomonas aerogenes and Enterococcus faecalis strains. Results: The UV-visible ultraviolet spectroscopy showed an absorption peak in the range of 370 nm. Transmission electron microscopy shows the synthesis of zinc oxide nanoparticles, mostly spherical, with a size less than 50 nm. Minimum inhibitory concentration of zinc oxide nanoparticles against P. aerogenes and E. faecalis strains was determined at 6.25 and 12.5 μg/ml, respectively. Both bacteria were sensitive to zinc oxide nanoparticles. This sensitivity was higher for gram-negative bacteria. Conclusion: Zinc oxide nanoparticles were produced using Iranian natural resources and our results showed significant antibacterial activity. Nanotechnology creates materials with novel properties every day, and creates new hope for improving environmental pollution. These nanoparticles can be used as a new generation of antimicrobial agents in various medical disciplines. For example, toothpaste containing zinc nanoparticles can be produced and prescribed for patients with immune deficiency to prevent the growth of microbial pathogens in the mouth and its transmission to the patient's body. &nbsp