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Lead poisoning is an epidemic that can affect anyone. Lead toxicity most commonly affects children and causes neurodevelopmental problems chronically. Lead is a heavy metal that alters calcium metabolism and deactivates enzymes essential in activating heme in the blood. Heme is an integral part of homeostasis and body defense in the shuttling of oxygen throughout the tissues, most notably the brain metabolism. The lack of oxygen throughout the brain slows down brain development (e.g., Neuronal cell migration, polarization, neuronal cell differentiation) and leads to lower IQs, learning disabilities, and lifelong ailments. The most common form of lead exposure comes from lead-based paint, toys, cosmetic materials, other household materials, various environments, and occupational pollutants. The current biomarkers used for lead toxicity successfully detect current lead levels in the blood but are not excellent at determining duration. Bone-Pb allows for the detection of lead toxicity duration, but it is not widely accepted throughout the United States. Significant limitations exist because all biomarkers test for lead poisoning after it has already happened which makes it challenging to prevent lead exposure in a clinical setting. Prevention needs to happen at the governmental and, more importantly at the individual levels. The focus of this study is on lead toxicity and prevention followed by reducing risk and improvement of detection utilized tools-driven molecular-based assessment along with visual imaging technique. It examines how lead finds its way into the human body for storage or metabolomic by-products. Identifying the risks of exposure would inform the mechanisms that can be employed to prevent further exposure and toxicity in other organs or intervene with metabolism or biotransformation. It predicts the potential counteract mechanisms through which lead affects the health of pregnant mothers, or interaction between prenatal,orthe unborn, and post-natal status, different stages of developmental, and post-menopausal women. The study outlines the various ways of detecting the presence of low levels of lead in the blood and bones using non-invasive fluorescence combined with multidimensional omics such as metabolomic and proteomic by which early detection of organ dysfunction can be used to monitor Ca2+ metabolism in the cell or tissue/organ level before the onset of disease

Autism spectrum disorder (ASD) is characterized by qualitative impairments in social interaction, communication, and stereotyped behavior patterns. The cost burden for health coverage for ASD is focused on educational applied behavioral analysis and psychotropic drugs to decrease maladaptive behaviors and support learning and development. Determinants of either risk factors or prevention related to ASD covering environmental, social-behavioral, and genetic are still unknown. This review focuses on the multifold risks of Autistic disorder (ASD), including environmental, genetic, and food supplemental concerns and health policies and regulations.

Autism Spectrum Disorder (ASD) is characterized by complicated phenotypic symptoms, including intervention with social activity, communication, and unusually behavioral abnormality. ASD is a lifelong developmental condition affecting one in 88 children and is considered one of today's most urgent public health challenges. Individuals with ASD tend to respond inappropriately in conversation and may struggle to build relationships. Currently, the prime cause of ASD remains unclear, even though emerging findings emphasize the role of genetic and environmental factors in the development of autistic behavior could be examined. At present, risks such as exposure to unknown chemicals as an environmental factor in ASD are less appreciated. This review will discuss potential risks include air pollution and particle matters in alignment with detection strategies, like multidimensional Omics and the transcriptomic approach, which may empower the capability of predicting potential risk from gene expression to phenotype level as a hallmark of transformation outcome. In addition, this genomic-driven validation process saves time and quality of accuracy in the process of finding molecular determinants in the early stage of disease onset. Currently, the genomics era brings prediction models with various algorithms, and its intervention alternatives speed up to analyze the environmental risk of chemical stressors, such as hazardous chemicals, air pollutants, and/or nanoparticles, in compliance with regulatory measures of exploring molecular determinants associated with chronic disease and metabolic disorders. The value chain of disease prevention along with surveillance platform closely interacts with the prediction of risk assessment using a molecular-based platform. Efficacy of a sequential workout, including exploring, monitoring, and the translational application process in cellular or in vitro systems, could crosstalk with a transgenic animal model. Targeting molecule implication, such as gain- or loss-of-functional reverse genetic technology to verify its functional analysis, multi-dimensional omics could be beneficial in the field of environmental risk assessment, including safety evaluation: food and drug screening in ASD combined with imaging technology.

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide responsible for over 1.5 million deaths annually. It is caused by hazardous biological pathogen (i.e.,Mycobacterium tuberculosis(MTB)) with single infectious agent, surpassing even HIV/AIDS. Roughly one-quarter of the world's population has latent TB, meaning that people have been infected by tuberculosis bacteria but have not yet developed the disease. Patients with active tuberculosis on average infect five to fifteen other people via airborne droplets. Once infected, people with HIV are 19 times more likely to develop active tuberculosis which has almost 100% mortality for this group, if not treated properly. Comparatively, 45% of HIV negative people will die if they develop active tuberculosis and are not adequately medicated. This is concerning since 95% of cases and deaths are in developing countries, where treatments and diagnosis may not be timely. Additionally, current detection methods do not distinguish active tuberculosis from a cleared or latent infection while microbiological culture of mycobacteria is slow. However, medical discoveries and newly developed technologies allowed for unification of disciplines incorporating omics into everyday biological research. The goal of this short review is to demonstrate ways in which field of multidimensional Omics could contributed to the advanced detection of infectious disease by improving accuracy and quality of patient care by implementing molecular based detection of pathogen (i.e., antigenicity and metabolomics tools) as well as personal care with follow-up monitoring care (i.e., immunogenicity and vaccinomics tools) in the diagnosis, treatment, and prevention of tuberculosis.&nbsp

A characteristic of cytochrome P450 (CYP) enzymes is their ability to generate H

Food addiction is widely debated to resolve various disease connectivity in the scientific community. There are significant similarities between food addiction and other addictive disorders including decreased sensitivity of the dopamine-reward system, genetic polymorphisms (DRD2 and OPRM1), and behavioral indicators of addiction. An individual’s response to environmental factors can play a role in their vulnerability to food addiction. The social environment and gene-environment interactions are important considerations as to why certain individuals are more susceptible to food addiction. These interactions along with biomarkers can provide a clear picture of why a person may fall prey to addiction. Several biomarkers have been associated with food addiction. These biomarkers include bacterial genera (Bacteroides, Megamonas, Eubacterium, and Akkermansia), fumarate hydratase (FH), ATP synthase subunit alpha (ATP5a1), and transketolase (TKT) in the nucleus accumbens, and striatal D2 receptor availability. Omics technologies have been beneficial in identifying many of these biomarkers and will be necessary for future findings related to food addiction. This review discusses common environmental factors and biomarkers impacting food addiction with an emphasis on the importance of omics technologies in this field.

A sensitive fluorescence assay based on Amplex Red (AR) oxidation by horseradish peroxidase (AR/HRP) is described which continuously monitor rates of H(2)O(2) production by microsomal enzymes in the presence of relatively high concentrations of NADPH. NADPH and NADH are known to interact with HRP and generate significant quantities of superoxide anion, a radical that spontaneously dismutates to form H(2)O(2) which interferes with the AR/HRP assay. Microsomal enzymes generate H(2)O(2) as a consequence of electron transfer from NADPH to cytochrome P450 hemoproteins with subsequent oxygen activation. We found that superoxide anion formation via the interaction of NADPH with HRP was inhibited by superoxide dismutase (SOD) without affecting H(2)O(2) generation by microsomal enzymes. Using SOD in enzyme assays, we consistently detected rates of H(2)O(2) production using microgram quantities of microsomal proteins (2.62 ± 0.20 picomol/min/μg protein for liver microsomes from naïve female rats, 12.27 ± 1.29 for liver microsomes from dexamethasone induced male rats, and 2.17 ± 0.25 picomol/min/μg protein for human liver microsomes). This method can also be applied to quantify rates of H(2)O(2) production by oxidases where superoxide anion generation by NADH or NADPH and HRP can interfere with enzyme assays.

Due to the ever-increasing prevalence of Food Allergy (FA) in the United States, many studies have been conducted to better understand mechanisms of Food Allergy, diagnosis, and treatment. Traditional diagnosis of FA can be time-consuming, less dependable, and can lead to severe allergic reaction in some patients. In this review, the latest evidence on testing, appropriate biomarkers for diagnosis, and treatment options are presented. The benefits of trained immunity (TRIM), oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and Epicutaneous immunotherapy (EPIT) are discussed in this review as well. Common biomarkers of food allergies are discussed, including 2S albumins, T-cells, and basophil activation markers. The benefits of a multi-omics approach are highlighted by the complex nature of food allergies and the relationship between genes, proteins, metabolites, and the microbiome in response to allergens. Future possibilities of omics studies pertaining to food allergies are also presented to guide future research.

Environmental threats to mental equity have recently gained much attention in the sphere of public and curative health due to their toll on the individual, families, the public, and their economic sphere. Mental health or soundness of mindis important at every stage of life from childhood and adolescence through adulthood to protect the brain from environmental stress. What makes mental health unlike genetic rare disorders is that there is no known single cause for this rising public health issue because it arises from multiple factors. These factors includeearly adverse life experiences, such as trauma or a history of abuse either because of child abuse, sexual assault or seeing any form of violence,experiences related to other ongoing (chronic) medical conditions, such as cancer or diabetes,biological factors or chemical exposure resulting in hormonal imbalances in the brain,and to a large extenthaving feelings of loneliness or isolation leading to suicidal action.Furthermore, the increase in mental health and its accompanying conditions depend on environmental with or without behavioral changes due to genetic stability may be associated with drug, alcohol, or substance abuse which is associated with the brain reward circuit which may need to compromise the neural circuit over a wide range of stressors on the human body interacting with the sequential neuronal cell cascade. Although humoral networking is associated with socio-behavioral change, work through family, religious, organizational engagement, and community support play major roles in its solution and management, it is consensually accepted that defining key determinants underlying molecular network altering by epigenetic and genetic factors have promise in empowering future systematic health and personal care including surveillance, prevention, treatment, and monitoring process. In the modern global and urbanization era, emerging new biomedical technological advances such as epigenetic tools, genomics editing, human genomics study utilizing sequencing technology, and reverse genetic resources from worm to animal models have enabled us to take a closer look at mechanisms that could be involved in mental illness and drug abuse or addiction using a pattern of metabolomics and its connectivity reflecting the interplay between mental illness and drug abuse and/or addiction. This paper describes a molecular-driven surveillance platform as a part of the power of prevention to care of populational health which could be beneficial by predicting risk and unfolding the impact of daily lifestyle on human behavior such as food intake, alcohol intoxication, and its outcome likely the effect of metabolism on mental illness and drug abuse. Interaction between environmental cues to neural circuits which may interplay with metabolic networks as well as potential risk resulting in various forms of phenotypic complications and behavioral alteration might be detectable using multi-omics platforms.

Cytotoxic blistering agents such as sulfur mustard and nitrogen mustard (HN2) were synthesized for chemical warfare. Toxicity is due to reactive chloroethyl side chains that modify and damage cellular macromolecules including DNA and proteins. In response to DNA damage, cells initiate a DNA damage response directed at the recruitment and activation of repair-related proteins. A central mediator of the DNA damage response is p53, a key protein that plays a critical role in regulating DNA repair. We found that HN2 causes cytosolic and nuclear accumulation of p53 in HaCaT keratinocytes; HN2 also induced post-translational modifications on p53 including S15 phosphorylation and K382 acetylation, which enhance p53 stability, promote DNA repair, and mediate cellular metabolic responses to stress. HN2 also cross-linked p53, forming dimers and high-molecular-weight protein complexes in the cells. Cross-linked multimers were also modified by K48-linked ubiquitination indicating that they are targets for proteasome degradation. HN2-induced modifications transiently suppressed the transcriptional activity of p53. Using recombinant human p53, HN2 alkylation was found to be concentration- and redox status-dependent. Dithiothreitol-reduced protein was more efficiently cross-linked indicating that p53 cysteine residues play a key role in protein modification. LC-MS/MS analysis revealed that HN2 directly modified p53 at C124, C135, C141, C176, C182, C275, C277, H115, H178, K132, and K139, forming both monoadducts and cross-links. The formation of intermolecular complexes was a consequence of HN2 cross-linked cysteine residues between two molecules of p53. Together, these data demonstrate that p53 is a molecular target for mustard vesicants. Modification of p53 likely mediates cellular responses to HN2 including DNA repair and cell survival contributing to vesicant-induced cytotoxicity.

Cardiovascular Disease (CVD) is characterized by multidimensional risks including drug, diet, lifestyle, stress, and metabolomics diseases which cause mortality and morbidity depending on age and status of chronic diseases. However, emerging evidence indicated it is preventable health complications that depend on risk management along with lifestyle change, and personalized medication that include alternative measures like Diet use following molecular diagnostic and imaging analysis. CVD is mainly attributed to the narrowing of blood vessels through atherosclerotic lesions and/or thrombosis. Hypertension, obesity, and hyperlipidemia are major risk factors for the development of CVD and treating these diseases is essential in slowing down progression of CVD. Inflammation appears to play a pivotal role in CVD and can be measured through a simple blood assay (CRP). Multi-omics approaches have been essential in the development of treatments for CVD, in the prevention of CVD, and in the diagnosis of CVD. There are many outcomes available to help with diagnosing CVD and omics platforms have helped scientists and clinician develop these diagnostic tools. Radiomics has played a key part in the diagnosis of CVD as being able to view the diseased heart is essential in determining CVD progression and the treatment options suitable for that secondary disease related. Nutrigenomics is emerging as the future of medicine such as utilizing treatment strategy innovation instead of medications, but it is still in its infancy. Nutrigenomics will open the doors to different therapeutic drug targets and allow us the ability to be more specific in our treatment options. There are only a few gene-diet interactions documented that increase a person’s chances of developing CVD. Curating an individual diet and treatment plan based on somebody’s genetic disposition or skewed immune responses following personalized diagnosis will be essential in the survival of these severe CVD patients. Key issues referring to risk surveillance and prevention is a distant approach which reflects several factors: for example, what type of tools can be used to conduct diagnosis, molecular diagnostic tools detect what type of biomarkers are present prior to prescribing the personalized diet and to ensure diagnostic accuracy. Recently, increasing findings emphasize dual aspects of diet such as immune enhancers and modulators in which gut microbiota has been proven to play a major factor in development of CVD. The future direction of omics studies will foster the ability to test the impact of gut microbiome of a patient with CVD following diet driven organ protection as well as prescribe essential components of the diet that can be adjusted with proper probiotic medication. Proper diet adjustments can correct the organ dysfunction that occurred due to interaction between molecular mismatch and cellular damage following stress-mediated damage or chronic disease. Further micro-scale assays and molecular diagnostic techniques following nutrigenomics application to the patient could be beneficial to allow patient’ care shift from physician driven and clinic based to self-management with knowledge based at home treatment programs that work by envisioning molecular reprogramming and rejuvenation of damaged organ. These at home treatments can be utilized with development of radiological data with innovation of software. The aim of the short review is to visualize the current role of nutrigenomics and diet formulation for integrative care (e.g., diagnosis, prevention, and treatment of CVD) which would take advantage of earlier prevention synchronized with current medical tests, imaging techniques. Health economy like management can reduce medical cost with disease prevention disease and could modulate the following: enhance knowledge-based interaction between body and diet, discuss cognitive enhancement how sensing with molecular behavior under image-management platform, monitor drug surveillance of current treatment options in CVD and the pitfalls of current omics application and data transformation needs for patient care in the future.

Chronic obstructive pulmonary disease (COPD) represented as inflammatory complication of chronic bronchitis which is characterized by oxidative stress driven phenotypic changes likely enlarged alveoli and increased mucus along with tightened smooth muscle which exaggerate pathological consequences such as breathing problems. The association between COPD and obesity as a metabolic disorder following a variety of environmental stressors include lifestyle change (e.g., diet and e-smoking or marijuana) and air pollution are less likely to be evaluated. People who are suffering with COPD developed extensive suffocation and difficulty breathing, which ultimately leads to fatal conditions in severe cases, for example lung cancer, heart attack, and stroke. Previous studies showed metabolic disorder like obesity appeared as a risk determinant to COPD like breathing problem or deep vein thrombosis and its genetic modification resulted from abnormality of molecular dynamics turned out key trigger in case of immune alteration and inflammation following exposure of several environmental factors which could be linked with comorbidity in secondary chronic diseases pairing with other metabolic disorders (e.g., diabetes, heart disease, cancer or fatty liver disease). Lifestyle changes along with physical activities and management of the diet is worth to reduce COPD symptomatic firing. However, environmental factors like air pollution or particle matter owing to industrialization and urbanization include a variety of dust within indoor life, certain type of e-smoke also triggers the establishment of emphysema and enhances the progression of COPD aligned with molecular alteration in the lung tissue or interaction between different organs. Prediction and prevention skills as key tools of health management and evaluation in case of COPD remains unclear. Integrative care includes clinic assessment (e.g., the body mass index, diets, and metabolic profile using survey following physician guidance) could be coupled cellular and topological interaction between obesity and COPD supplemented with advanced functional and genetic variation utilize human genomics study like single nucleotide polymorphism (SNP). To understand the impact of environmental risk better (e.g., air pollution or particle matter) on pathogenesis of disease or onset of the disease underlying the pulmonary system stratified lifestyle, age, metabolic disorders, diets, and medications, we envision exploring risks such as disease barrier and social determinants along with detection tools which may assess molecular dynamics and their alteration following stress might be associated with COPD in the pathogenesis. Environmental stressors (e.g., air pollution, particle matter, food addictive chemicals, and stress) as epigenetic modifiers could attribute to early phase of COPD onset and pathogenesis which reflect the molecular dynamics and redirection of networking pathways depending on gut immunity. Profiling of secondary metabolites is worth to explicate intervention of metabolism cascade owing to alter molecular sensitivity and connectivity. Utilized multi-dimensional omics such as metabolomics, genomics with exome sequencing, and epigenomics, prevention and prediction skills could visualize a new angle of disease diagnostic under the platform of integrative health care and surveillance supporting to patient’s quality of life.

Metabolic disorders are known as one of the largest obesity epidemics and associated with health-related problems such as cardiovascular disease, diabetes, hypertension and hyperlipidemias in the US. Obesity related to an imbalance of metabolism from environmental stressors impacting metabolic rate, reflects the multi-dimensional molecular network. Obesity is also associated with the genetic predisposition of a build-up of adipose tissue dynamics, which is unable to properly undergo lipolysis and breakdown at the tissue level, or it can be a hormonal issue, where the patient is producing too much ghrelin or diminishing supply of leptin. Omics, a detection platform for macromolecules (i.e., DNA, RNA, and protein level), can be developed for use in many different types of illnesses based on the pathophysiology behind the ailment or disease, including obesity. Personalized care focused on molecule assessment can help decrease the need for synthetic insulin, increase the body’s own ability to use it’s already producing pancreatic beta cells of insulin, and decrease the likelihood of other comorbidities from progressing by adapting part of Omics metabolomics. Metabolomics is more advantageous than determining the pathologic structure of molecular behavior in ghrelin and leptin. In the future, metabolomics has strong potential to be considered as an alternative preventive tool to fight against obesity, hyperlipidemia, or secondary health complications, including cardiovascular and cancer mortality.

Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2), and sulfur mustard are potent vesicants that modify and disrupt cellular macromolecules, including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia mutated- and Rad3-related (ATR), as well as DNA-dependent protein kinase catalytic subunit (DNA-PKcs). In the present studies, we investigated crosstalk between HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1–20 µM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2’-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (Ser1981), Chk2 (Thr68), H2AX (Ser139), and p53 (Ser15). Activation of DNA damage signaling was most pronounced in S phase cells followed by G2/M phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PKcs inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PKcs signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.

Sulfur mustard (SM; bis(2-chloroethyl) sulfide) is a highly reactive bifunctional alkylating agent synthesized for chemical warfare. The eyes are particularly sensitive to SM where it causes irritation, pain, photophobia, and blepharitis, depending on the dose and duration of exposure. In these studies, we examined the effects of SM vapor on the corneas of New Zealand white male rabbits. Edema and hazing of the cornea, signs of acute injury, were observed within one day of exposure to SM, followed by neovascularization, a sign of chronic or late phase pathology, which persisted for at least 28 days. Significant epithelial-stromal separation ranging from ~8-17% of the epithelial surface was observed. In the stroma, there was a marked increase in CD45

Emerging evidence indicate various environmental factors include stressors cause mental illness. Currently, unmet medical outcomes and surveillance platform demand in the field of mental disorders to implement of sensitivity associated along with key biomarker in the process of detection, evaluation and validation. The use of omics, based on macromolecule dependent data analysis such as bioinformatics in mental disorders and in a health care assessment platform, has the potential to increase identification of risk genes and treatment option by validate functional efficacy of drug or recovery status of brain function utilize behavioral assessment and metabolomics include neuro-pharmacogenomics study. This concept sounds futuristic but ideal. If the multiple data bases around the world continue to grow, making identification of a strand more likely, then health professional include clinicians and lab scientists could predict the likelihood of a disease outbreak, drug addiction, and the probability of synaptic malfunction that a treatment will work. Being able to stratification of risk gene profile and biomarker monitoring prior to disease dissemination has the potential to greatly diminish the current health care economic burden. However, the implementation in the clinical setting may take time; the therapeutic alternative includes biological and synthetic product will be worth the wait. Herein, to visualize impact of molecular connectivity and dynamics on functional imbalance resulted in phenotypic changes which reflect gene alterations such as single nucleotide polymorphism in several mental disorders, we conducted short review of mental illness which predominantly occurred and unknown causes by visualize identifying risk genes and functional susceptibility in the molecular diagnostic advances using Omics platform. In the future, it is likely that a majority of our treatment and care for patients or personal medicine/population medicine will be based on an omics strategy, molecular based risk assessment tools, as a safe and empower sensitivity to validate potential risk gene or therapeutic gene by adopting early detection risk management such as Integrated Omics.

The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320–400 nm), also referred to as PUVA therapy, is used for the treatment of cutaneous proliferative disorders including psoriasis, vitiligo and mycosis fungoides. The use of 8-MOP (3) is limited by its poor water solubility and there remains a need to develop more water-soluble psoralens to enhance bioavailability following oral administration of the drug. In the present studies a water-soluble dimethylaminoethyl ether analog of 8-MOP was synthesized and analyzed for biological activity. This analog, (8-[2-(N,N-dimethylamino)ethoxy]-psoralen hydrochloride (1) [or CAS name: 9-[2-(dimethylamino)ethoxy]-7H-furo[3,2-g][1]benzopyran-7-one, hydrochloride], was found to be significantly more active than 3 in keratinocyte growth inhibition assays (IC(50) = 12 nM and 130 nM for 1 and 3, respectively). The partially reduced dihydro derivative of 1, 8-[2-(N,N-dimethylamino)ethoxy]-4’,5’-dihydropsoralen hydrochloride (2) [or CAS name: 9-[2-(dimethylamino)ethoxy]-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one, hydrochloride] and the partially reduced 4’,5’-dihydro-8-methoxypsoralen (4) lacking the water-solubilizing side-chain were significantly less active. As inhibitors of keratinocyte growth they ranked as IC(50) = 13,000 nM and 70,000 nM for 2 and 4, respectively, indicating that an unsaturated furan ring in the psoralen was required for maximal activity. Compound (1) was found to readily intercalate and damage DNA following UVA light treatment as determined by plasmid DNA nicking and unwinding experiments in neutral and alkaline agarose gels. Taken together, these data demonstrate that a water-soluble dimethylaminoethyl ether psoralen targets DNA, is highly active as a photosensitizer, and may be useful in the treatment of skin diseases involving abnormal keratinocyte proliferation.

Pulmonary arterial hypertension (PAH) is a debilitating lung condition for which there has been no cure that leads to complications on the right side of the heart. This disorder is currently distinguished from other conditions of the right ventricle by a DNA biorepository, invasive hemodynamics, echocardiography, genotype-tissue expression, imaging, and other diagnostic tools. Present treatment strategies include mainly medications and oxygen therapy choices. Advanced omics developments, including next generational genetic analysis, massively parallel gene-editing, metabolomics, and pharmacogenomics have significantly improved the volume of information that can be analyzed effectively in individuals with pulmonary arterial high blood pressure among other chronic illnesses. Emerging molecular-driven and gene targeting-driven evidence shed light on a new era of innovation as advanced clinical technology for providing patients quality of care in case of systemic arterial morbidity recognition, early diagnosis, therapeutic validation, and safety, including precision treatments based on patients’ genomic data pool obtained through genetic imprinting or genetic mapping.

Neurodegenerative diseases (ND) affect a large portion of our elder population with cognitive impairment, impaired movement due to loss of balance or muscle weakness in motor neuron. Due to their irreversible nature they present a significant public health burden through the demand on our health care system as well as by unmet therapeutic measures that influence socioeconomic decision processes, while our current population is transitioned to an aged community. Here we introduce top 3 of the most prevalent NDs and examine preventive alternatives along with the available research on both genetic and environmental risk factors. While many questions remain, genetic predisposition combined with environmental exposures may be to blame for a large number of these cases. Utilizing emerging multi-fold omics technologies, early prevention aided by development of biomarker can help to identify risk factors and to envision new avenue in new treatments option in the future.

Mustard vesicants, including sulfur mustard (2,2′-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents synthesized for chemical warfare. Because they contain highly reactive electrophilic chloroethyl side chains, they readily react with cellular macromolecules like DNA forming monofunctional and bifunctional adducts. By targeting DNA, mustards can compromise genomic integrity, disrupt the cell cycle, and cause mutations and cytotoxicity. To protect against genotoxicity following exposure to mustards, cells initiate a DNA damage response (DDR). This involves activation of signaling cascades including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Signaling induced by the DDR leads to the recruitment and activation of repair related proteins such as phospho H2AX and phospho p53 to sites of DNA lesions. Excessive DNA modifications by mustards can overwhelm DNA repair leading to single and double strand DNA breaks, cytotoxicity and tissue damage, sometimes leading to cancer. Herein we summarize DDR signaling pathways induced by SM, HN2 and the half mustard, 2-chloroethyl ethyl sulfide (CEES). At the present time, little is known about how mustard-induced DNA damage leads to the activation of DDR signaling. A better understanding of mechanisms by which mustard vesicants induce the DDR may lead to the development of countermeasures effective in mitigating tissue injury.

NADH cytochrome b(5) reductase mediates electron transfer from NADH to cytochrome b(5) utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b(5) is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity was oxygen-dependent and preferentially utilized NADH as a co-substrate; NADH was 5–10 times more active than NADPH in supporting redox cycling. Redox cycling activity was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione), nitrofurantoin and 2-hydroxyestradiol. Using menadione as the substrate, quinone redox cycling was found to inhibit reduction of cytochrome b(5) by cytochrome b(5) reductase, as measured by heme spectral changes in cytochrome b(5). Under anaerobic conditions where redox cycling is inhibited, menadione had no effect on the reduction of cytochrome b(5). Chemical redox cycling by cytochrome b(5) reductase may be important in generating cytotoxic reactive oxygen species in target tissues. This activity, together with the inhibition of cytochrome b(5) reduction by redox-active chemicals and consequent deficiencies in available cellular cytochrome b(5), are likely to contribute to tissue injury following exposure to quinones and related redox active chemicals.

Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal appendages and at the dermal/epidermal junction. In control mice, 48–61% of mast cells were degranulated. SM exposure (1.4 g/m(3) in air for 6 min) resulted in increased numbers of degranulated mast cells 1–14 days post-exposure. Treatment of mice topically with an indomethacin choline bioisostere containing prodrug linked by an aromatic ester-carbonate that targets cyclooxygenases (COX) enzymes and acetylcholinesterase (1% in an ointment) 1–14 days after SM reduced skin inflammation and injury and enhanced tissue repair. This was associated with a decrease in mast cell degranulation from 90% to 49% 1–3 days post SM, and from 84% to 44% 7–14 days post SM. These data suggest that reduced inflammation and injury in response to the bifunctional indomethacin prodrug may be due, at least in part, to abrogating mast cell degranulation. The use of inhibitors of mast cell degranulation may be an effective strategy for mitigating skin injury induced by SM.

Photosensitizers are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. In these studies, a ring-expanded carbon homolog of the linear psoralen (furo[3,2-g]benzopyran-7-one) class of photosensitizers, 4,10-dimethyl-2H,8H-benzo[1,2-b:5,4-b']dipyran-2-one (NDH2476), was synthesized and analyzed for biological activity. Following activation by ultraviolet light (UVA, 320-400 nm), NDH2476 was found to be a potent inhibitor of keratinocyte growth (IC50 = 9 nm). Similar derivatives methylated in the pyran ring, or containing a saturated pyran ring structure, were markedly less active or inactive as photosensitizers. NDH2476 was found to intercalate and damage DNA following UVA light treatment as determined by plasmid DNA unwinding and nicking experiments. Taken together, these data demonstrate that an intact furan ring in psoralen photosensitizers is not required for keratinocyte growth inhibition or DNA damage. Our findings that low nanomolar concentrations of a benzopyranone derivative were active as a photosensitizer indicates that this or a structurally related compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation.

Both inorganic mercury and organic mercury compounds, including methyl mercury and ethyl mercury, are noxious pollutants known to cause deleterious neurological and cardiovascular effects in humans and profoundly affect the brains and development of infants and children (for review see Bernhoft RA. J Environ Public Health, 2012; Jung-Duck Park, Wei Zheng. J Prev Med Public Health. 45(6):344–352, 2012; Charles TD, Robert PM, Hing MC, Daniel JJ, Nicola P. J Prev Med Public Health 45(6):344–352, 2012; Bjorklund G, Dadar M, Mutter J, Aaseth J. Environ Res. 159:545–554: 2017; Counter SA, Buchanan LH, Toxicol Appl Pharmacol, 198(2):209–30, 2004). Mercury vapor released into the air from fossil fuel–generating plants and industrial processes can remain aloft for hours to days and be transported thousands of miles until it contaminates aquatic ecosystems and, ultimately, the world’s oceans. In contaminated aquatic environments, microbes convert inorganic mercury to organic mercury and the resultant compounds bioaccumulate in the aquatic food chain (Bernhoft RA. J Environ Public Health, 2012; Jung-Duck Park, Wei Zheng. J Prev Med Public Health. 45(6):344–352, 2012; Charles TD, Robert PM, Hing MC, Daniel JJ, Nicola P. J Prev Med Public Health 45(6):344–352, 2012; Bjorklund G, Dadar M, Mutter J, Aaseth J. Environ Res. 159:545–554: 2017; Counter SA, Buchanan LH, Toxicol Appl Pharmacol, 198(2):209–30, 2004). This presents a serious risk worldwide as human fish consumption supports nutrition around the globe. Human exposure to inorganic mercury is generally through inhalation, whereas exposure to organic mercury is largely due to its consumption of organomercury-containing foodstuffs (Chang LW. J Toxicol Sci, 15(Suppl 4):125–51, 1990; Sunderland EM, Krabbenhoft DP, Moreau JW, Strode SA, Landing WM. Glob Biogeochem Cycles, 23(2):GB2010, 2009).Recently, U.S. federal regulatory requirements have spurred the development of technologies and changes in industrial practices in the U.S. and industrialized nations that have significantly reduced mercury levels in the air and organic mercury levels in fish (Griggs MB. Pop Sci, 2015; Lafontaine S, Schrlau J, Butler J, Jia Y, Harper B, Harris S, Bramer LM, Waters KM, Harding A. Environ Sci Technol, 2015; Cheng-Shiuan L, Molly EL, Emily C, Daniel JM, Robert MC, Nicholas SF. Environ Sci Technol, 2016). However, current rollbacks of regulations in industrialized nations and unregulated emissions from developing nations are once again increasing levels of airborne inorganic and waterborne organic mercury. It is critical for future generations to foster the development of better, cheaper, and more efficient technologies to limit mercury pollution and protect aquatic components of the world’s food supply.

Sulfur mustard (SM; bis (2-chloroethyl) sulfide) is a potent vesicant which causes irritation of the conjunctiva and damage to the cornea. In the present studies, we characterized the ocular effects of SM in New Zealand white rabbits. Within one day of exposure to SM, edema and hazing of the cornea were observed, followed by neovascularization which persisted for at least 28 days. This was associated with upper and lower eyelid edema and conjunctival inflammation. The conjunctiva is composed of a proliferating epithelium largely consisting of stratified columnar epithelial cells overlying a well-defined dermis. Superficial layers of the conjunctival epithelium were found to express keratin 1, a marker of differentiating squamous epithelium, while in cells overlying the basement membrane expressed keratin 17, a marker of stratified squamous epithelium. SM exposure upregulated keratin 17 expression. Mucin 5 ac producing goblet cells were interspersed within the conjunctiva. These cells generated both acidic and neutral mucins. Increased numbers of goblet cells producing neutral mucins were evident after SM exposure; upregulation of expression of membrane-associated mucin 1 and mucin 4 in the superficial layers of the conjunctival epithelium were also noted. These data demonstrate that ocular exposure of rabbits to SM causes significant damage not only to the cornea, but to the eyelid and conjunctiva, suggesting multiple targets within the eye that should be assessed when evaluating the efficacy of potential countermeasures.

The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.

Incidences of pesticide poisonings are a significant cause of morbidity and mortality worldwide. The seizure-inducing rodenticide tetramethylenedisulfotetramine is one of the most toxic of these agents. Although banned, it has been responsible for thousands of accidental, intentional, and mass poisonings in mainland China and elsewhere. An optimal regimen for treatment of poisoning has not been established. Its facile synthesis from easily obtained starting materials, extreme potency, and lack of odor, color, or taste make it a potential chemical threat agent. This review describes the toxicologic properties of this agent, more recent advances in our understanding of its properties, and recommendations for future research.

In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the duration of exposure. Initial responses include erythema, pruritus, edema, and xerosis; this is followed by an accumulation of inflammatory leukocytes in the tissue, activation of mast cells, and the release of mediators, including proinflammatory cytokines and bioactive lipids. These proinflammatory mediators contribute to damaging the epidermis, hair follicles, and sebaceous glands and to disruption of the epidermal basement membrane. This can lead to separation of the epidermis from the dermis, resulting in a blister, which ruptures, leading to the formation of an eschar. The eschar stimulates the formation of a neoepidermis and wound repair and may result in persistent epidermal hyperplasia. Epidermal damage and repair is associated with upregulation of enzymes generating proinflammatory and pro-growth/pro-wound healing mediators, including cyclooxygenase-2, which generates prostanoids, inducible nitric oxide synthase, which generates nitric oxide, fibroblast growth factor receptor 2, and galectin-3. Characterization of the mediators regulating structural changes in the skin during SM-induced tissue damage and wound healing will aid in the development of therapeutic modalities to mitigate toxicity and stimulate tissue repair processes.

Nitrogen mustard (NM) is a bifunctional alkylating agent that is highly reactive in the skin causing extensive tissue damage and blistering. In the present studies, a modified cutaneous murine patch model was developed to characterize NM-induced injury and to evaluate the efficacy of an indomethacin pro-drug in mitigating toxicity. NM (20 µmol) or vehicle control was applied onto 6 mm glass microfiber filters affixed to the shaved dorsal skin of CD-1 mice for 6 min. This resulted in absorption of approximately 4 µmol of NM. NM caused localized skin damage within 1 d, progressing to an eschar within 2–3 d, followed by wound healing after 4–5 d. NM-induced injury was associated with increases in skin thickness, inflammatory cell infiltration, reduced numbers of sebocytes, basal keratinocyte double stranded DNA breaks, as measured by phospho-histone 2A.X expression, mast cell degranulation and increases in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Wound healing was characterized by epidermal hyperplasia and marked increases in basal cells expressing proliferating cell nuclear antigen. A novel indomethacin-anticholinergic prodrug (4338) designed to target cyclooxygenases and acetylcholinesterase (AChE), was found to markedly suppress NM toxicity, decreasing wound thickness and eschar formation. The prodrug also inhibited mast cell degranulation, suppressed keratinocyte expression of iNOS and COX-2, as well as markers of epidermal proliferation. These findings indicate that a novel bifunctional pro-drug is effective in limiting NM mediated dermal injury. Moreover, our newly developed cutaneous patch model is a sensitive and reproducible method to assess the mechanism of action of countermeasures.

Sulfur mustard (SM) and nitrogen mustard (NM) are cytotoxic alkylating agents that cause severe and progressive injury to the respiratory tract, resulting in significant morbidity and mortality. Evidence suggests that macrophages and the inflammatory mediators they release play roles in both acute and long-term pulmonary injuries caused by mustards. In this article, we review the pathogenic effects of SM and NM on the respiratory tract and potential inflammatory mechanisms contributing to this activity.

A set of 4-(R(2)-imino)-3-mercapto-5-(R(1))-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and growth inhibition cytotoxicity. Noticeably, the compounds designed to be nitrofurantoin mimics were the most potent anti-neoplastic agents.

Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soaks. Animals were then euthanized, and full thickness skin biopsies prepared for histology and immunohistochemistry. Control skin contained a well differentiated epidermis with a prominent stratum corneum. A well-developed eschar covered the skin of SM treated animals, however, the epidermis beneath the eschar displayed significant wound healing with a hyperplastic epidermis. Stratum corneum shedding and a multilayered basal epithelium consisting of cuboidal and columnar cells were also evident in the neoepidermis. Nuclear expression of proliferating cell nuclear antigen (PCNA) was contiguous in cells along the basal epidermal layer of control and SM exposed skin; SM caused a significant increase in PCNA expression in basal and suprabasal cells. SM exposure was also associated with marked changes in expression of markers of wound healing including increases in keratin 10, keratin 17 and loricrin and decreases in E-cadherin. Trichrome staining of control skin showed a well-developed collagen network with no delineation between the papillary and reticular dermis. Conversely, a major delineation was observed in SM-exposed skin including a web-like papillary dermis composed of filamentous extracellular matrix, and compact collagen fibrils in the lower reticular dermis. Although the dermis below the wound site was disrupted, there was substantive epidermal regeneration following SM-induced injury. Further studies analyzing the wound healing process in minipig skin will be important to provide a model to evaluate potential vesicant countermeasures.

Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mice. NM caused structural damage to the stratum corneum as reflected by increases in transepidermal water loss and skin hydration. This was coordinate with edema, mast cell degranulation and epidermal hyperplasia. Within 3 h of NM exposure, a 4-fold increase in phosphorylated histone H2AX, a marker of DNA double-stranded breaks, and a 25-fold increase in phosphorylated p53, a DNA damage marker, were observed in the epidermis. This was associated with a 40% increase in 8-oxo-2'-deoxyguanosine modified DNA in the epidermis and a 4-fold increase in 4-hydroxynonenal modified epidermal proteins. At 12 h post NM, there was a 3-75 fold increase in epidermal expression of antioxidant/stress proteins including heme oxygenase-1, thioredoxin reductase, superoxide dismutase, glutathione reductase, heat shock protein 27 and cyclooxygenase 2. These data indicate that NM induces early oxidative epidermal injury in mouse skin leading to an antioxidant/stress response. Agents that enhance this response may be useful in mitigating mustard-induced skin injury.

Seventy-one 7-oxycoumarins, 66 synthesized and 5 commercially sourced, were tested for their ability to inhibit growth in murine PAM212 keratinocytes. Forty-nine compounds from the library demonstrated light-induced lethality. None was toxic in the absence of UVA light. Structure-activity correlations indicate that the ability of the compounds to inhibit cell growth was dependent not only on their physiochemical characteristics, but also on their ability to absorb UVA light. Relative lipophilicity was an important factor as was electron density in the pyrone ring. Coumarins with electron withdrawing moieties – cyano and fluoro at C3 – were considerably less active while those with bromines or iodine at that location displayed enhanced activity. Coumarins that were found to inhibit keratinocyte growth were also tested for photo-induced DNA plasmid nicking. A concentration-dependent alteration in migration on neutral gels caused by nicking was observed., SCOPUS: ar.j, info:eu-repo/semantics/published

Linear furocoumarins, also known as psoralens, are clinically useful photo-activated pharmaceuticals employed to address hyperproliferative skin diseases. Seven diverse cytotoxic pharmacophores have been synthetically attached to 8-methoxypsoralen via a 5-amino functionality. The resulting unique set of compounds was evaluated for dark and light toxicity against PAM212 keratinocytes in culture.

Cytochrome P450 (CYP) enzymes mediate mixed-function oxidation reactions important in drug metabolism. The aromatic heterocyclic cation, diphenyleneiodonium (DPI), binds flavin in cytochrome P450 reductase and inhibits CYP-mediated activity. DPI also inhibits CYP by directly interacting with heme. Herein, we report that DPI effectively inhibits a number of CYP-related monooxygenase reactions including NADPH oxidase, a microsomal enzyme activity that generates hydrogen peroxide in the absence of metabolizing substrates. Inhibition of monooxygenase by DPI was time and concentration dependent with IC50's ranging from 0.06 to 1.9 μM. Higher (4.6-23.9 μM), but not lower (0.06-1.9 μM), concentrations of DPI inhibited electron flow via cytochrome P450 reductase, as measured by its ability to reduce cytochrome c and mediate quinone redox cycling. Similar results were observed with inducible nitric oxide synthase (iNOS), an enzyme containing a C-terminal reductase domain homologous to cytochrome P450 reductase that mediates reduction of cytochrome c, and an N-terminal heme-thiolate oxygenase domain mediating nitric oxide production. Significantly greater concentrations of DPI were required to inhibit cytochrome c reduction by iNOS (IC50 = 3.5 µM) than nitric oxide production (IC50 = 0.16 µM). Difference spectra of liver microsomes, recombinant CYPs, and iNOS demonstrated that DPI altered heme-carbon monoxide interactions. In the presence of NADPH, DPI treatment of microsomes and iNOS yielded a type II spectral shift. These data indicate that DPI interacts with both flavin and heme in CYPs and iNOS. Increased sensitivity for inhibition of CYP-mediated metabolism and nitric oxide production by iNOS indicates that DPI targets heme moieties within the enzymes.

Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and the inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity.

Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28–86 μM; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O tetradecanoylphorbol-13-acetate (TPA)-induced inflammation by 40 %. Furthermore, these molecules have physicochemical properties in the range of other CNS drugs. These molecules have the potential to treat inflammation; they could also dually target Alzheimer’s disease through restoration of cholinergic balance and inflammation suppression.

Sulfur mustard and nitrogen mustard (mechlorethamine, HN2) are potent vesicants developed as chemical warfare agents. These electrophilic, bifunctional alkylating agents cause skin injury, including inflammation, edema, and blistering. HN2 covalently modifies macromolecules such as DNA, RNA, and proteins or is scavenged by glutathione, forming adducts that can contribute to toxicity. Multidrug resistance-associated protein 1 (Mrp1/MRP1) is a transmembrane ATPase known to efflux glutathione-conjugated electrophiles. In the present studies, we examined the effects of modulating Mrp1-mediated transport activity on the sensitivity of primary and PAM212 mouse keratinocytes to HN2. Primary keratinocytes, and to a lesser extent, PAM212 cells, express Mrp1 mRNA and protein and possess Mrp1 functional activity, as measured by calcein efflux. Sulforaphane, an activator of Nrf2, increased Mrp1 mRNA, protein, and functional activity in primary keratinocytes and PAM212 cells and decreased their sensitivity to HN2-induced growth inhibition (IC(50) = 1.4 and 4.8 µM in primary keratinocytes and 1 and 13 µM in PAM212 cells, in the absence and presence of sulforaphane, respectively). The Mrp1 inhibitor, MK-571, reversed the effects of sulforaphane on HN2-induced growth inhibition in both primary keratinocytes and PAM212 cells. In primary keratinocytes from Nrf2(-/-) mice, sulforaphane had no impact on Mrp1 expression or activity, or on sensitivity to HN2, demonstrating that its effects depend on Nrf2. These data suggest that Mrp1-mediated efflux is important in regulating HN2-induced keratinocyte growth inhibition. Enhancing HN2 efflux from keratinocytes may represent a novel strategy for mitigating vesicant-induced cytotoxicity.

The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or simultaneous administration of, these two agents in treating TMDT poisoning.