Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY: This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS: A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS: Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1ß, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS: In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.

Predicting sulforaphane-induced adverse effects in colon cancer patients via in silico investigation.

Colorectal cancer (CRC) is a significant global health burden that ranks as the third most diagnosed and second most common cause of cancer related deaths worldwide. New therapeutic strategies include chemoprevention and use of molecules which could prevent, suppress or reverse CRC progression such as sulforaphane (SFN). However, evidences about its safety in CRC patients are still lacking. The aim of this in silico investigation was to predict SFN-induced adverse effects in CRC patients by computational analysis. The study showed that 334 genes were consistently dysregulated in CRC (223 downregulated and 111 upregulated), while 38 were recognized as significant and might be used as predictive biomarkers for overall survival and metastasis (TCGA, GEO, R studio). Among them, SFN interacted with 86 genes, out of which 11 were marked as significant (correlate with overall prognosis and metastasis). Sulforaphane potentiates the overexpression of TIMP1, AURKA, and CEP55, and promotes inhibition of CRYAB, PLCE1, and MMP28, that might lead to the progression of CRC (CTD). Pathway enrichment analysis revealed that SFN stimulated Transcriptional activation of RUNX2, AURKA activation by TPX2, IL-10 signaling, while inhibited Differentiation of White and Brown Adipocyte process, an underlying pathway which inactivation led to obesity (Cytoscape ClueGo + CluePedia, DAVID). Thus, genome signature of CRC patients could serve as important factor when addressing the risk-to-benefit profile of SFN. Patients with colon cancer and increased expression of TIMP1, CCL20, SPP1, AURKA, CEP55, NEK2, SOX9 and CDK1, or downregulation of CRYAB, PLCE1, MMP28, BMP2 and PLAC8 may not be ideal candidates for SFN chemoprevention.

Efficacy and safety of sulforaphane for treatment of mild to moderate depression in patients with history of cardiac interventions: A randomized, double-blind, placebo-controlled clinical trial.

AIM: Depression has been recognized as one of the disorders associated with cardiac interventions such as percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In the present study, we evaluated the efficacy and safety of sulforaphane in treatment of depression induced by cardiac interventions. METHODS: After initial screening, 66 patients with previous history of at least one cardiac intervention and current mild to moderate depression were randomly assigned to two parallel groups receiving either sulforaphane (n = 33) or placebo (n = 33) for six successive weeks. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D) at baseline and week 2, 4, and 6. Safety of the treatments was checked during the trial period. RESULTS: Sixty participants completed the clinical trial (n = 30 in each group). Baseline demographic and clinical parameters were all similar among groups. Repeated measures analysis indicated that the sulforaphane group exhibited greater improvement in HAM-D scores throughout the trial (P < 0.001). Response to treatment (≥50% reduction in the HAM-D score) rate was higher in the sulforaphane group at trial endpoint (30% vs 6.67%, P = 0.042). Remission (HAM-D score ≤ 7) rate was also higher in the sulforaphane group; however, the difference was not significant (23.33% vs 3.33%, P = 0.052). Finally, no significant difference was observed between the two groups in terms of frequency of side effects. CONCLUSIONS: Sulforaphane could safely improve depressive symptoms induced by cardiac interventions. Further clinical trials with larger sample sizes and longer follow-up periods are warranted to confirm our results.

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder.

BACKGROUND: Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD. METHODS: We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3-12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD. RESULTS: Data from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF (Cohen's d 0.21; 95% CI - 0.46, 0.88 and 0.10; 95% CI - 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks (Cohen's d - 0.96; 95% CI - 1.73, - 0.15), but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell. LIMITATIONS: The sample size was limited to 45 children with ASD and we did not impute missing data. We were unable to document significant changes in clinical assessments during clinical visits in those taking SF compared to PL. The clinical results were confounded by placebo effects during the open-label phase. CONCLUSIONS: SF led to small yet non-statistically significant changes in the total and all subscale scores of the primary outcome measure, while for secondary outcome measures, caregivers' assessments of children taking SF showed statistically significant improvements compared to those taking PL on the ABC but not the SRS-2. Clinical effects of SF were less notable in children compared to our previous trial of a SF-rich preparation in young men with ASD. Several of the effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures. TRIAL REGISTRATION: This study was prospectively registered at clinicaltrials.gov (NCT02561481) on September 28, 2015. Funding was provided by the U.S. Department of Defense.

The rodent model of impaired gastric motility induced by allyl isothiocyanate, a pungent ingredient of wasabi, to evaluate therapeutic agents for functional dyspepsia.

Functional dyspepsia (FD) is thought to be mainly based on gastric motility dysfunction and chronic hypersensitivity, yet FD animal models has been reported a few. We studied to establish the mouse model of impaired gastric motility induced by a pungent ingredient of wasabi allyl isothiocyanate (AITC), which is reliable to evaluate prokinetic agents. Male ddY mice were used. Gastric motility was measured by 13C-acetic acid breath test in conscious mice. AITC (80 mM) was given 60 min before the measurement of motility. Prokinetic agents including itopride (30, 100 mg/kg), mosapride (0.1-1 mg/kg), neostigmine (30 µg/kg), acotiamide (10-100 mg/kg), and daikenchuto (100-1000 mg/kg) were given 40 min before the measurement. AITC impaired gastric motility without mucosal damages, which reverted 24 h after AITC treatment. The decreased motility induced by AITC was restored by prokinetic agents such as itopride, mosapride, neostigmine, and acotiamide. In separate experiment, daikenchuto recovered the decreased motility induced by AITC, although daikenchuto had no effect on motility in normal condition. In conclusion, it is considered that the AITC-induced impaired gastric motility mouse model is useful to develop new prokinetic agents for treatment of FD, and to re-evaluate traditional Japanese herbal medicines.

[ALLERGIC CONTACT DERMATITIS DUE TO NITRILE RUBBER GLOVES: ETHYL ISOTHIOCYANATE AND BUTYL ISOTHIOCYANATE AS POSSIBLE CAUSATIVE CHEMICALS].

BACKGROUND: The causative chemicals responsible for nitrile rubber glove-induced allergic contact dermatitis have not been fully elucidated. SUBJECT: This case involved a 36-year-old female, who developed an erythematous rash on her hands after one and a half months of wearing nitrile rubber gloves at her workplace. METHODS: Patch tests were performed using the gloves as is, and the Japanese standard allergen 2008 and their components. The gloves were chemically analyzed and several detected substances were subjected to further patch testing. RESULTS: The patient exhibited positive patch test reactions to nitrile rubber gloves as is, as well as to the dithiocarbamate mix and thiuram mix in the Japanese standard allergen 2008. Further patch testing revealed positive reactions to zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD) and weak positive reactions to zinc dimethyldithiocarbamate (ZDMC) and tetramethylthiuram monosulfide (TMTM). Chemical analysis revealed that ethyl isothiocyanate (EITC) and butyl isothiocyanate (BITC), which might have been produced from dithiocarbamate-type accelerators (DTCs) or thiuram-type accelerators (thiurams) during the vulcanization process, were present in the nitrile rubber gloves the patient used at her workplace, as was ZDBC. No other DTCs or thiurams were detected. Patch testing of the detected materials produced positive reactions to EITC and BITC, but not to ZDBC. CONCLUSION: We diagnosed the patient with allergic contact dermatitis due to the EITC and BITC present in nitrile rubber gloves, and considered that alkyl isothiocyanate might also have played a causative role. We propose that nitrile rubber gloves should be produced without using vulcanization accelerators.

The efficacy and safety of sulforaphane as an adjuvant in the treatment of bipolar depressive disorder: Study protocol for a randomized, double-blinded, placebo-controlled, parallel-group clinical trial.

BACKGROUND: Bipolar disorder (BD) is a chronic and disabling psychiatric disorder. The treatment of BD still remains a significant clinical challenge due to the complex nature of the disease. Nutraceutical therapy as adjunctive role is a promising therapy for BD. Sulforaphane (SFN), a broccoli extract, was reported to be effective for emotional problems and cognitive impairment. However, clinical research of SFN in the treatment of BD was rare. Therefore, this study is designed to evaluate the adjuvant role of SFN in the treatment of BD. METHODS: This is a randomized, double-blinded, placebo-controlled, parallel-group clinical trial. A total of 100 patients who meet inclusion criteria will be assigned to receive quetiapine plus SFN or quetiapine plus placebo in a 1:1 ratio. The total duration of the study will be 12 weeks including 5 follow ups. The primary outcome is in the Montgomery-Asberg depression rating scale. The secondary outcomes are the quick inventory of depressive symptomatology-self report, Hamilton anxiety rating scale, young mania rating scale, cognitive function, inflammatory factors, and intestinal flora. Any adverse events will be recorded throughout the trial. DISCUSSION: This trial will provide evidences to evaluate the efficacy and safety of SFN combined with quetiapine in the treatment of BD patients, as well as the adjuvant role of SFN in combination. TRIAL REGISTRATION: This study protocol was registered at the Chinese clinical trial registry (ChiCTR2000028706).

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms.

OBJECTIVE: The P2Y6 receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y6 receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE-/-) mice by using its selective antagonist. METHODS: Male apoE-/- mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. RESULTS: Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0.05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0.05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0.05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. CONCLUSIONS: The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y12 receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate.

Alcohol-Related Dermatitis: A Review.

: Wine, beer, liquor, and spirits are widely consumed in many cultures across the globe, and for some individuals, ingestion, cutaneous contact, or other exposure can lead to dermatologic findings. However, there currently exist no comprehensive reviews on alcohol-related dermatitis. Herein, we will provide an overview of alcohol-related dermatitis and contact urticaria, including the epidemiology and clinical manifestations, potential allergens found in alcoholic beverages, testing approaches, and strategies for allergen avoidance.

Molecular Mechanisms of the Anti-Cancer Effects of Isothiocyanates from Cruciferous Vegetables in Bladder Cancer.

Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds-allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate-in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

Phenylethyl isothiocyanate induces oxidative damage of porcine kidney cells mediated by reactive oxygen species.

The aim of this study is to confirm the toxic effect of phenylethyl isothiocyanate (PEITC) on porcine kidney cells (PK-15) and explore the effect of oxidative damage mediated by reactive oxygen species (ROS) induced by PEITC in PK-15 cells. Porcine kidney cell line (PK-15) was treated with PEITC (2, 5, and 10 µM) for 24 hours, and the oxidative damage mediated by PEITC through ROS was investigated. The survival rate of PK-15 cells decreased in a dose-dependent manner after the treatment of PEITC in a dose-dependent manner. A high concentration of PEITC (10 µM) can change cell morphology, increase the content of malondialdehyde, ROS, and lactate dehydrogenase, and decrease the activity of SOD, CAT, GSH-PX, and GSH. PEITC has a toxic effect on PK-15 cells by inducing oxidative stress in PK-15 cells through the generation of ROS.

Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough.

BACKGROUND: The differential sensitivity of cough to antitussive therapies implies the existence of heterogeneity in cough hypersensitivity, but how such heterogeneity is expressed across individual patients is poorly understood. We investigated the phenotypes of cough hypersensitivity by examining transient receptor potential ankyrin 1 (TRPA1)- and transient receptor potential vanilloid 1 (TRPV1)-mediated cough sensitivity in patients with chronic refractory cough. METHODS: Using a selective TRPA1 agonist, allyl isothiocyanate (AITC), we established an AITC cough challenge as a measure of TRPA1-mediated cough sensitivity. The AITC cough challenge and the widely used capsaicin (a selective TRPV1 agonist) cough challenge were performed with 250 patients with chronic refractory cough and 56 healthy subjects. The concentration of AITC or capsaicin solution causing at least two (C2) and five coughs (C5) was recorded. Cough sensitivity was expressed as the mean (95% confidence interval) of log C5, and cough hypersensitivity was defined as a log C5 value lower than that of healthy subjects. RESULTS: A distinct concentration-response effect of inhaled AITC was identified both in patients with chronic refractory cough and in healthy subjects. Cough sensitivity to AITC and capsaicin was significantly higher in patients than in healthy subjects (AITC: 2.42 [2.37-2.48] vs 2.72 [2.66-2.78] mM, p = 0.001; capsaicin: 1.87 [1.75-1.98] vs 2.53 [2.36-2.70] µM, p = 0.001) and was higher in females than in males for both healthy subjects and patients (all p < 0.05). Among the 234 patients who completed both challenges, 25 (10.7%) exhibited hypersensitivity to both AITC and capsaicin, 44 (18.8%) showed hypersensitivity to AITC only, 28 (11.9%) showed hypersensitivity to capsaicin only, and 137 (58.6%) exhibited hypersensitivity to neither. Those with TRPA1- and/or TRPV1-mediated hypersensitivity were predominantly female, while those without TRPA1- and TRPV1-mediated hypersensitivity were mainly male. CONCLUSIONS: Four phenotypes of cough hypersensitivity were identified by the activation of TRPV1 and TRPA1 channels, which supports the existence of heterogeneity in cough pathways and provides a new direction for personalized management of chronic refractory cough. TRIAL REGISTRATION: ClinicalTrials.gov NCT02591550 .

Sulforaphane as anticancer agent: A double-edged sword? Tricky balance between effects on tumor cells and immune cells.

Sulforaphane (SFN) is a naturally occurring isothiocyanate derived from cruciferous vegetables such as broccoli. It has been reported to inhibit the growth of a variety of cancers, such as breast, prostate, colon, skin, lung, gastric or bladder cancer. SFN is supposed to act primarily as an antioxidant due to the activation of the Nrf2-Keap1 signaling pathway. This enhances the activity of phase II detoxifying enzymes and the trapping of free radicals. Finally, SFN induces cell cycle arrest or apoptosis of tumor cells. Here, we discuss effects of SFN on the immune defense system. In contrast to the situation in tumor cells, SFN acts pro-oxidatively in primary human T cells. It increases intracellular ROS levels and decreases GSH, resulting in inhibition of T cell activation and T cell effector functions. Regarding the use of SFN as an "anticancer agent" we conclude that SFN could act as a double-edged sword. On the one hand it reduces carcinogenesis, on the other hand it blocks the T cell-mediated immune response, the latter being important for immune surveillance of tumors. Thus, SFN could also interfere with the successful application of immunotherapy by immune checkpoint inhibitors (e.g. CTLA-4 antibodies and PD-1/PD-L1 antibodies) or CAR T cells. Therefore, a combination of SFN with T cell-mediated cancer immunotherapies does not seem advisable.

Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury.

The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulated by siRNA targeting NRF2 and upregulated by siRNA targeting KEAP1 in PHH. Applying weighted gene co-expression network analysis (WGCNA) to transcriptomic data from the Open TG-GATES toxicogenomics repository (representing PHH exposed to 158 compounds) revealed four co-expressed gene sets or 'modules' enriched for these and other NRF2-associated genes. By classifying the 158 TG-GATES compounds based on published evidence, and employing the four modules as network perturbation metrics, we found that the activation of NRF2 is a very good indicator of the intrinsic biochemical reactivity of a compound (i.e. its propensity to cause direct chemical stress), with relatively high sensitivity, specificity, accuracy and positive/negative predictive values. We also found that NRF2 activation has lower sensitivity for the prediction of clinical DILI risk, although relatively high specificity and positive predictive values indicate that false positive detection rates are likely to be low in this setting. Underpinned by our comprehensive analysis, activation of the NRF2 network is one of several mechanism-based components that can be incorporated into holistic systems toxicology models to improve mechanistic understanding and preclinical prediction of DILI in man.

Combination of garlic essential oil, allyl isothiocyanate, and nisin Z as bio-preservatives in fresh sausage.

The effects of natural antimicrobial compounds (garlic essential oil [GO], allyl isothiocyanate [AITC], and nisin Z [NI]) on microbiological, physicochemical and sensory characteristics of fresh sausage were assessed. The minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) towards Escherichia coli O157:H7 and Lactobacillus plantarum were determined in vitro. Sausages inoculated with E. coli O157:H7, were treated with different combinations of antimicrobials and assessed for microbiological and physicochemical parameters during storage (6C for 20 d). Treatments that presented the greatest antimicrobial effects were subjected to sensory evaluation. Combinations of 20 mg/kg NI + 125 µL/kg GO + 62.5 µL/kg AITC or 20 mg/kg NI + 62.5 µL/kg GO + 125 µL/kg AITC were effective in reducing E. coli O157H7 and spoilage lactic acid bacteria, and maintained the physicochemical characteristics of fresh sausage. Combinations of NI, GO and AITC were effective to improve the safety and the shelf life of fresh sausage, with no impact on its sensory acceptance.

Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi.

Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 µmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 µmol, 206 ng/mL for 100 µmol, and 655 ng/mL for 200 µmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 µmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 µmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 µmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429-38. ©2018 AACR.

Isothiocyanates are important as haptens in contact allergy to chloroprene rubber.

BACKGROUND: Contact allergy to chloroprene rubber products is well known. Thiourea compounds are considered the cause of allergy. Diethylthiourea commonly occurs in this type of product and can decompose to the sensitizer ethyl isothiocyanate. OBJECTIVES: To investigate the clinical importance of degradation products and metabolites from organic thioureas in contact allergy to chloroprene rubber with a focus on isothiocyanates and isocyanates. METHODS: Patients with contact allergy to diphenylthiourea were patch tested with phenyl isothiocyanate and phenyl isocyanate. Patients with known contact allergy to diethylthiourea were retested with diethylthiourea, while chemical analyses of their chloroprene rubber products were performed. The stability of diethylthiourea, diphenylthiourea and dibutylthiourea in patch-test preparations was investigated. Liquid chromatography/mass spectrometry and solid-phase microextraction/gas chromatography were used for determination of organic thioureas and isothiocyanates. RESULTS: All patients allergic to diphenylthiourea reacted to phenyl isothiocyanate, two of eight reacted to phenyl isocyanate and six of eight reacted to diphenylthiourea. Four patients allergic to diethylthiourea reacted at retest; diethylthiourea was detected in all chloroprene rubber samples, with levels of 2-1200 nmol cm-2 . At 35 °C, ethyl isothiocyanate was emitted from all samples. Patch-test preparations of diethylthiourea, diphenylthiourea and dibutylthiourea all emitted the corresponding isothiocyanate, with diethylthiourea showing the highest rate of isothiocyanate emission. CONCLUSIONS: Thiourea compounds are degraded to isothiocyanates, which are generally strong or extreme sensitizers, thus acting as prehaptens. This process occurs in both chloroprene rubber products and patch-test preparations. Positive reactions to phenyl isocyanate indicate cutaneous metabolism, as the only known source of exposure to phenyl isocyanate is through bioactivation of diphenylthiourea.

Concentrations of thiocyanate and goitrin in human plasma, their precursor concentrations in brassica vegetables, and associated potential risk for hypothyroidism.

Brassica vegetables are common components of the diet and have beneficial as well as potentially adverse health effects. Following enzymatic breakdown, some glucosinolates in brassica vegetables produce sulforaphane, phenethyl, and indolylic isothiocyanates that possess anticarcinogenic activity. In contrast, progoitrin and indolylic glucosinolates degrade to goitrin and thiocyanate, respectively, and may decrease thyroid hormone production. Radioiodine uptake to the thyroid is inhibited by 194 µmol of goitrin, but not by 77 µmol of goitrin. Collards, Brussels sprouts, and some Russian kale (Brassica napus) contain sufficient goitrin to potentially decrease iodine uptake by the thyroid. However, turnip tops, commercial broccoli, broccoli rabe, and kale belonging to Brassica oleracae contain less than 10 µmol of goitrin per 100-g serving and can be considered of minimal risk. Using sulforaphane plasma levels following glucoraphanin ingestion as a surrogate for thiocyanate plasma concentrations after indole glucosinolate ingestion, the maximum thiocyanate contribution from indole glucosinolate degradation is estimated to be 10 µM, which is significantly lower than background plasma thiocyanate concentrations (40-69 µM). Thiocyanate generated from consumption of indole glucosinolate can be assumed to have minimal adverse risks for thyroid health.

Protective role of sulphoraphane against vascular complications in diabetes.

Context Diabetes is a global health challenge. Although large prospective clinical trials have shown that intensive control of blood glucose or blood pressure reduces the risk for development and progression of vascular complications in diabetes, a substantial number of diabetic patients still experience renal failure and cardiovascular events, which could account for disabilities and high mortality rate in these subjects. Objective Sulphoraphane is a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, such as broccoli, cabbage and Brussels sprouts, and an inducer of phase II antioxidant and detoxification enzymes with anticancer properties. We reviewed here the protective role of sulphoraphane against diabetic vascular complications. Methods In this review, literature searches were undertaken in Medline and in CrossRef. Non-English language articles were excluded. Keywords [sulphoraphane and (diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, diabetic complications, vascular, cardiomyocytes, heart or glycation)] have been used to select the articles. Results There is accumulating evidence that sulphoraphane exerts beneficial effects on vascular damage in both cell culture and diabetic animal models via antioxidative properties. Furthermore, we have recently found that sulphoraphane inhibits in vitro formation of advanced glycation end products (AGEs), suppresses the AGE-induced inflammatory reactions in rat aorta by reducing receptor for AGEs (RAGE) expression and decreases serum levels of AGEs in humans. Conclusion These findings suggest that blockade of oxidative stress and/or the AGE-RAGE axis by sulphoraphane may be a novel therapeutic strategy for preventing vascular complications in diabetes.

Characterization of cardiovascular reflexes evoked by airway stimulation with allylisothiocyanate, capsaicin, and ATP in Sprague-Dawley rats.

Acute inhalation of airborne pollutants alters cardiovascular function and evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the effect of capsaicin [transient receptor potential (TRP) vanilloid 1 (TRPV1) agonist], AITC [TRP ankyrin 1 (TRPA1) agonist], and ATP (P2X2/3 agonist) on bronchopulmonary sensory activity and cardiovascular responses of conscious Sprague-Dawley (SD) rats. Single fiber recordings show that allyl isothiocyanate (AITC) and capsaicin selectively activate C fibers, whereas subpopulations of both A and C fibers are activated by stimulation of P2X2/3 receptors. Inhalation of the agonists by conscious rats caused significant bradycardia, atrioventricular (AV) block, and prolonged PR intervals, although ATP-induced responses were lesser than those evoked by AITC or capsaicin. Responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine. AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase. Atropine accentuated the hypertensive phase, while preventing the hypotension. AITC-evoked bradycardia was not abolished by terazosin, the α1-adrenoceptor inhibitor, which prevented the hypertensive response. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine, and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following precollicular decerebration. In conclusion, we provide evidence that activation of ion channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in conscious SD rats via reflex modulation of the autonomic nervous system.