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Proceedings of the National Academy of... Oct 2014Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly... (Randomized Controlled Trial)
Randomized Controlled Trial
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.
Topics: Adolescent; Adult; Child Development Disorders, Pervasive; Humans; Isothiocyanates; Male; Placebos; Social Behavior; Sulfoxides; Treatment Outcome; Young Adult
PubMed: 25313065
DOI: 10.1073/pnas.1416940111 -
Ugeskrift For Laeger Mar 2022Isocyanates are often found in workplaces in e.g., glue, paint, plastics and foam products. Asthma caused by isocyanates is one of the most common forms of occupational... (Review)
Review
Isocyanates are often found in workplaces in e.g., glue, paint, plastics and foam products. Asthma caused by isocyanates is one of the most common forms of occupational asthma, though it is difficult to diagnose, as described in this review. It is not possible to demonstrate sensitisation with available allergy tests. A certain diagnosis can only be made with the help of specific bronchial provocation, which is performed at three centres in Denmark. A correct diagnosis is important, as it helps provide optimal treatment as well as alerting the employer, that improvements are needed at the workplace.
Topics: Asthma, Occupational; Humans; Isocyanates; Occupational Diseases; Workplace
PubMed: 35319454
DOI: No ID Found -
International Journal of Molecular... Nov 2022Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for about 90% of cases. Sorafenib, lenvatinib, and the combination of... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for about 90% of cases. Sorafenib, lenvatinib, and the combination of atezolizumab and bevacizumab are considered first-line treatments for advanced HCC. However, clinical application of these drugs has also caused some adverse reactions such as hypertension, elevated aspartate aminotransferases, and proteinuria. At present, natural products and their derivatives have drawn more and more attention due to less side effects as cancer treatments. Isothiocyanates (ITCs) are one type of hydrolysis products from glucosinolates (GLSs), secondary plant metabolites found exclusively in cruciferous vegetables. Accumulating evidence from encouraging in vitro and in vivo animal models has demonstrated that ITCs have multiple biological activities, especially their potentially health-promoting activities (antibacterial, antioxidant, and anticarcinogenic effects). In this review, we aim to comprehensively summarize the chemopreventive, anticancer, and chemosensitizative effects of ITCs on HCC, and explain the underlying molecular mechanisms.
Topics: Animals; Anticarcinogenic Agents; Carcinoma, Hepatocellular; Liver Neoplasms; Isothiocyanates
PubMed: 36430307
DOI: 10.3390/ijms232213834 -
Molecules (Basel, Switzerland) Oct 2023Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a... (Review)
Review
Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a neuroprotective and anticancer agent. This review aims to critically evaluate the current evidence supporting the neuroprotective and anticancer effects of SFN and the potential mechanisms through which it exerts these effects. SFN has been shown to exert neuroprotective effects through the activation of the Nrf2 pathway, the modulation of neuroinflammation, and epigenetic mechanisms. In cancer treatment, SFN has demonstrated the ability to selectively induce cell death in cancer cells, inhibit histone deacetylase, and sensitize cancer cells to chemotherapy. SFN has also shown chemoprotective properties through inhibiting phase I metabolizing enzymes, modulating phase II xenobiotic-metabolizing enzymes, and targeting cancer stem cells. In addition to its potential as a therapeutic agent for neurological disorders and cancer treatment, SFN has shown promise as a potential treatment for cerebral ischemic injury and intracranial hemorrhage. Finally, the ongoing and completed clinical trials on SFN suggest potential therapeutic benefits, but more research is needed to establish its effectiveness. Overall, SFN holds significant promise as a natural compound with diverse therapeutic applications.
Topics: Neuroprotection; Isothiocyanates; Sulfoxides; Histone Deacetylases
PubMed: 37836745
DOI: 10.3390/molecules28196902 -
PloS One 2022Isocyanate chemicals known to cause adverse health effects when inhaled are essential to making important products and are used in multiple industries. Glutathione...
Isocyanate chemicals known to cause adverse health effects when inhaled are essential to making important products and are used in multiple industries. Glutathione (GSH), a major antioxidant of the lower airways with a well described role in xenobiotic metabolism, is a primary reaction target for di-isocyantes. However, GSHs reactivity with poly-isocyanates which have largely replaced diisocyanates (particularly aliphatic) in most end-user settings remains uncertain. We hypothesized aliphatic polyisocyanates would readily react with glutathione under physiologic conditions and the products could be identified using liquid chromatography (LC) coupled-mass spectrometry (MS) and tandem MS/MS. The data identified (tris)GSH-isocyanate adducts as the major reaction product of GSH with the most commonly used contemporary polymeric (tri-isocyanate) formulations of hexamethylene diisocyanate (HDI), the isocyanurate and biuret, as [M+H]+ ions of 1426.53 and 1400.55 m/z respectively in reverse phase LC-MS using electrospray in positive ion mode. The uretdione form of HDI, a stabilized dimer, formed two reaction products with GSH, a tris(GSH)-isocyanate reaction product recognized as a 1258.44 m/z [M+H]+ ion, and a bis(GSH)-isocyanate product identified as a 951.36 m/z [M+H]+ ion. Predicted structures for the newly described GSH-polyisocyanate reaction products, modeled based on collision induced dissociation (CID) fragmentation patterns in tandem MS/MS, support S-linkage of the GSH to N = C = O groups. In summary, industrially-used aliphatic polyisocyanates readily react with GSH to form primarily S-linked tris(GSH)-conjugates, a process that may play an important role in response to respiratory tract exposure.
Topics: Chromatography, Liquid; Glutathione; Ions; Isocyanates; Polyurethanes; Tandem Mass Spectrometry
PubMed: 35839242
DOI: 10.1371/journal.pone.0271471 -
Molecules (Basel, Switzerland) Sep 2022In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic... (Review)
Review
In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic species involved are isocyanate cation and acylium cation, respectively, and both have a common C=O structure, which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However, aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion. Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame the superelectrophilic character.
Topics: Acids; Acylation; Ammonium Compounds; Carbamates; Carboxylic Acids; Cations; Isocyanates; Lewis Bases; Molecular Structure; Organophosphates; Salicylates
PubMed: 36144714
DOI: 10.3390/molecules27185984 -
Asian Pacific Journal of Cancer... 2012Methyl isocyanate may have a role in cancer etiology, although the link is unclear. There is evidence in the literature that it can induce cancer in animals but the... (Review)
Review
Methyl isocyanate may have a role in cancer etiology, although the link is unclear. There is evidence in the literature that it can induce cancer in animals but the carcinogenic potency is weak. Pheochromocytoma of adrenal medulla and acinar cell tumors of pancreas have been observed in methyl isocyanate exposed animals. Conversely, emerging data from population-based epidemiological studies are contradictory since there is no evidence of such cancers in methyl isocyanate exposed humans. Recently, we reported a high prevalence of breast and lung cancers in such a population in Bhopal. In vitro findings appearing in the latest scientific literature suggest that genomic instability is caused by methyl isocyanate analogs in lung, colon, kidney, ovary epithelial cells, and that hepatocytes may undergo oncogenic transformation, have obvious implications. The conflicting information prompted us to present this update over the last three decades on methyl isocyanate-induced cancers after an extensive literature search using PubMed. While the pertinent literature remains limited, with a scarcity of strong laboratory analyses and field-epidemiological investigations, our succinct review of animal and human epidemiological data including in vitro evidences, should hopefully provide more insight to researchers, toxicologists, and public health professionals concerned with validation of the carcinogenicity of methyl isocyanate in humans.
Topics: Animals; Breast Neoplasms; Carcinoma, Acinar Cell; Cell Transformation, Neoplastic; Female; Genomic Instability; Humans; Isocyanates; Lung Neoplasms; Male; Neoplasms; Pheochromocytoma; Rats
PubMed: 22938400
DOI: 10.7314/apjcp.2012.13.6.2429 -
Journal of Translational Medicine May 2023Exosomes (EXOs), tiny extracellular vesicles that facilitate cell-cell communication, are being explored as a heart failure treatment, although the features of the cell...
BACKGROUND
Exosomes (EXOs), tiny extracellular vesicles that facilitate cell-cell communication, are being explored as a heart failure treatment, although the features of the cell source restrict their efficacy. Fibroblasts the most prevalent non-myocyte heart cells, release poor cardioprotective EXOs. A noninvasive method for manufacturing fibroblast-derived exosomes (F-EXOs) that target cardiomyocytes and slow cardiac remodeling is expected. As a cardioprotective isothiocyanate, sulforaphane (SFN)-induced F-EXOs (SFN-F-EXOs) should recapitulate its anti-remodeling properties.
METHODS
Exosomes from low-dose SFN (3 μM/7 days)-treated NIH/3T3 murine cells were examined for number, size, and protein composition. Fluorescence microscopy, RT-qPCR, and western blot assessed cell size, oxidative stress, AcH4 levels, hypertrophic gene expression, and caspase-3 activation in angiotensin II (AngII)-stressed HL-1 murine cardiomyocytes 12 h-treated with various EXOs. The uptake of fluorescently-labeled EXOs was also measured in cardiomyocytes. The cardiac function of infarcted male Wistar rats intramyocardially injected with different EXOs (1·10) was examined by echocardiography. Left ventricular infarct size, hypertrophy, and capillary density were measured.
RESULTS
Sustained treatment of NIH/3T3 with non-toxic SFN concentration significantly enhances the release of CD81 + EXOs rich in TSG101 (Tumor susceptibility gene 101) and Hsp70 (Heat Shock Protein 70), and containing maspin, an endogenous histone deacetylase 1 inhibitor. SFN-F-EXOs counteract angiotensin II (AngII)-induced hypertrophy and apoptosis in murine HL-1 cardiomyocytes enhancing SERCA2a (sarcoplasmic/endoplasmic reticulum Ca ATPase 2a) levels more effectively than F-EXOs. In stressed cardiomyocytes, SFN-F-EXOs boost AcH4 levels by 30% (p < 0.05) and significantly reduce oxidative stress more than F-EXOs. Fluorescence microscopy showed that mouse cardiomyocytes take in SFN-F-EXOs ~ threefold more than F-EXOs. Compared to vehicle-injected infarcted hearts, SFN-F-EXOs reduce hypertrophy, scar size, and improve contractility.
CONCLUSIONS
Long-term low-dose SFN treatment of fibroblasts enhances the release of anti-remodeling cardiomyocyte-targeted F-EXOs, which effectively prevent the onset of HF. The proposed method opens a new avenue for large-scale production of cardioprotective exosomes for clinical application using allogeneic fibroblasts.
Topics: Male; Rats; Mice; Animals; Myocytes, Cardiac; Exosomes; Angiotensin II; Rats, Wistar; Fibroblasts; Isothiocyanates; Antibodies
PubMed: 37161563
DOI: 10.1186/s12967-023-04155-x -
Molecules (Basel, Switzerland) May 2016Despite the major progress made in the field of cancer biology, cancer is still one of the leading causes of mortality, and prostate cancer (PCa) is one of the most... (Review)
Review
Despite the major progress made in the field of cancer biology, cancer is still one of the leading causes of mortality, and prostate cancer (PCa) is one of the most encountered malignancies among men. The effective management of this disease requires developing better anticancer agents with greater efficacy and fewer side effects. Nature is a large source for the development of chemotherapeutic agents, with more than 50% of current anticancer drugs being of natural origin. Isothiocyanates (ITCs) are degradation products from glucosinolates that are present in members of the family Brassicaceae. Although they are known for a variety of therapeutic effects, including antioxidant, immunostimulatory, anti-inflammatory, antiviral and antibacterial properties, nowadays, cell line and animal studies have additionally indicated the chemopreventive action without causing toxic side effects of ITCs. In this way, they can induce cell cycle arrest, activate apoptosis pathways, increase the sensitivity of resistant PCa to available chemodrugs, modulate epigenetic changes and downregulate activated signaling pathways, resulting in the inhibition of cell proliferation, progression and invasion-metastasis. The present review summarizes the chemopreventive role of ITCs with a particular emphasis on specific molecular targets and epigenetic alterations in in vitro and in vivo cancer animal models.
Topics: Animals; Anticarcinogenic Agents; Apoptosis; Brassicaceae; Cell Cycle Checkpoints; Disease Models, Animal; Humans; Isothiocyanates; Male; Prostatic Neoplasms
PubMed: 27187332
DOI: 10.3390/molecules21050626 -
Medicinal Research Reviews Mar 2019Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing... (Review)
Review
Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing protein-protein interaction inhibitors. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling." Beyond those strategies, there have been many recent advances in developing constrained peptides. The purpose of this review is to highlight recent advances in the development of new helix-stabilizing technologies, constraint diversification strategies, tether diversification strategies, and combination strategies that create new bicyclic helical peptides.
Topics: Animals; Chemistry, Pharmaceutical; Cross-Linking Reagents; Cysteine; Glucuronates; Humans; Hydrocarbons; Isocyanates; Lactams; Methionine; Nitrogen; Peptides; Permeability; Protein Conformation; Proteome; Pyrazoles; Selenocysteine; Sulfhydryl Compounds
PubMed: 30307621
DOI: 10.1002/med.21540