Isothiocyanates in medicine: A comprehensive review on phenylethyl-, allyl-, and benzyl-isothiocyanates.

In recent years, isothiocyanates (ITCs), bioactive compounds primarily derived from Brassicaceae vegetables and herbs, have gained significant attention within the biomedical field due to their versatile biological effects. This comprehensive review provides an in-depth exploration of the therapeutic potential and individual biological mechanisms of the three specific ITCs phenylethyl isothiocyanate (PEITC), allyl isothiocyanate (AITC), and benzyl isothiocyanate (BITC), as well as their collective impact within the formulation of ANGOCIN® Anti-Infekt N (Angocin). Angocin comprises horseradish root (Armoracia rusticanae radix, 80 mg) and nasturtium (Tropaeoli majoris herba, 200 mg) and is authorized for treating inflammatory diseases affecting the respiratory and urinary tract. The antimicrobial efficacy of this substance has been confirmed both in vitro and in various clinical trials, with its primary effectiveness attributed to ITCs. PEITC, AITC, and BITC exhibit a wide array of health benefits, including potent anti-inflammatory, antioxidant, and antimicrobial properties, along with noteworthy anticancer potentials. Moreover, we highlight their ability to modulate critical biochemical pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription (STAT) pathways, shedding light on their involvement in cellular apoptosis and their intricate role to guide immune responses.

The Immunomodulatory Effects of Sulforaphane in Exercise-Induced Inflammation and Oxidative Stress: A Prospective Nutraceutical.

Sulforaphane (SFN) is a promising molecule for developing phytopharmaceuticals due to its potential antioxidative and anti-inflammatory effects. A plethora of research conducted in vivo and in vitro reported the beneficial effects of SFN intervention and the underlying cellular mechanisms. Since SFN is a newly identified nutraceutical in sports nutrition, only some human studies have been conducted to reflect the effects of SFN intervention in exercise-induced inflammation and oxidative stress. In this review, we briefly discussed the effects of SFN on exercise-induced inflammation and oxidative stress. We discussed human and animal studies that are related to exercise intervention and mentioned the underlying cellular signaling mechanisms. Since SFN could be used as a potential therapeutic agent, we mentioned briefly its synergistic attributes with other potential nutraceuticals that are associated with acute and chronic inflammatory conditions. Given its health-promoting effects, SFN could be a prospective nutraceutical at the forefront of sports nutrition.

Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m6A modification.

N6-methyladenosine (m6A) modification is a prevalent RNA epigenetic modification, which plays a crucial role in tumor progression including metastasis. Isothiocyanates (ITCs) are natural compounds and inhibit the tumorigenesis of various cancers. Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells, and have synergistic effects with chemotherapy drugs. In this study, we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer cell metastasis. We showed that phenethyl isothiocyanate (PEITC) dose-dependently inhibited the cell viability of both NSCLC cell lines H1299 and H226 with IC50 values of 17.6 and 15.2 µM, respectively. Furthermore, PEITC dose-dependently inhibited the invasion and migration of H1299 and H226 cells. We demonstrated that PEITC treatment dose-dependently increased m6A methylation levels and inhibited the expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in H1299 and H226 cells. Knockdown of FTO significantly increased m6A methylation in H1299 and H226 cells, impaired their abilities of invasion and migration in vitro, and enhanced the inhibition of PEITC on tumor growth in vivo. Overexpression of FTO promoted the migration of NSCLC cells, and also mitigated the inhibitory effect of PEITC on migration of NSCLC cells. Furthermore, we found that FTO regulated the mRNA m6A modification of a transcriptional co-repressor Transducin-Like Enhancer of split-1 (TLE1) and further affected its stability and expression. TCGA database analysis revealed TLE1 was upregulated in NSCLC tissues compared to normal tissues, which might be correlated with the metastasis status. Moreover, we showed that PEITC suppressed the migration of NSCLC cells by inhibiting TLE1 expression and downstream Akt/NF-κB pathway. This study reveals a novel mechanism underlying ITC's inhibitory effect on metastasis of lung cancer cells, and provided valuable information for developing new therapeutics for lung cancer by targeting m6A methylation.

Sulforaphane attenuates irradiation induced testis injury in mice.

OBJECTIVE: The testis is vulnerable to ionizing radiation, sexual dysfunction and male infertility are common problems after local radiation or whole-body exposure. Currently, there are no approved drugs for the prevention or treatment of radiation testicular injury. Sulforaphane (SFN) is an indirect antioxidant that induces phase II detoxification enzymes and antioxidant genes. Herein, we investigated the radiation protective effect of SFN on testicular injury in mice and its potential mechanism. MATERIALS AND METHODS: Mice were randomly divided into blank control group (Ctrl), radiation + no pretreatment group (IR), and radiation + SFN groups (IRS). In the radiation + SFN groups, starting from 72 h before radiation, SFN solution was intraperitoneally injected once a day until they were sacrificed. Mice in the blank control group and the radiation + no pretreatment group were simultaneously injected intraperitoneally with an equal volume of the solvent used to dissolve SFN (PBS with a final concentration of 0.1%DMSO) until they were sacrificed. They were subjected to 6Mev-ray radiation to the lower abdominal testis area (total dose 2Gy). Twenty-four hours after radiation, six mice in each group were randomly sacrificed. Seventy-two hours after radiation, the remaining mice were sacrificed. RESULTS: The results showed that the harmful effects of ionizing radiation on testes were manifested as damage to histoarchitecture, increased oxidative stress, and apoptosis, and thus impaired male fertility. SFN injections can reverse these symptoms. CONCLUSIONS: The results showed that SFN can improve the damage of mouse testis caused by irradiation. Furthermore, SFN prevents spermatogenesis dysfunction caused by ionizing radiation by activating Nrf2 and its downstream antioxidant gene.

Ethyl Isothiocyanate as a Novel Antifungal Agent Against Candida albicans.

In the recent years, occurrence of candidiasis has increased drastically which leads to significant mortality and morbidity mainly in immune compromised patients. Glucosinolate (GLS) derivatives are reported to have antifungal activities. Ethyl isothiocyanate (EITC) and its antifungal activity and mechanism of action is still unclear against Candida albicans. The present work was designed to get a mechanistic insight in to the anti-Candida efficacy of EITC through in vitro and in vivo studies. EITC inhibited C. albicans planktonic growth at 0.5 mg/ml and virulence factors like yeast to hyphal form morphogenesis (0.0312 mg/ml), adhesion to polystyrene surface (0.0312 mg/ml) and biofilm formation (developing biofilm at 2 mg/ml and mature biofilm at 0.5 mg/ml) effectively. EITC blocked ergosterol biosynthesis and arrested C. albicans cells at S-phase. EITC caused ROS-dependent cellular death and nuclear or DNA fragmentation. EITC at 0.0312 mg/ml concentration regulated the expression of genes involved in the signal transduction pathway and inhibited yeast to hyphal form morphogenesis by upregulating TUP1, MIG1, and NRG1 by 3.10, 5.84 and 2.64-fold, respectively and downregulating PDE2 and CEK1 genes by 15.38 and 2.10-fold, respectively. EITC has showed haemolytic activity at 0.5 mg/ml concentration. In vivo study in silk worm model showed that EITC has toxicity to C. albicans at 0.5 mg/ml concentration. Thus, from present study we conclude that EITC has antifungal activity and to reduce its MIC and toxicity, combination study with other antifungal drugs need to be done. EITC and its combinations might be used as alternative therapeutics for the prevention and treatment of C. albicans infections.

Benefits of Wasabi Supplements with 6-MSITC (6-Methylsulfinyl Hexyl Isothiocyanate) on Memory Functioning in Healthy Adults Aged 60 Years and Older: Evidence from a Double-Blinded Randomized Controlled Trial.

BACKGROUND: Cognitive functions decline with age. Declined cognitive functions negatively affect daily behaviors. Previous studies showed the positive effect of spices and herbs on cognition. In this study, we investigated the positive impact of wasabi, which is a traditional Japanese spice, on cognitive functions. The main bioactive compound of wasabi is 6-MSITC (6 methylsulfinyl hexyl isothiocyanate), which has anti-oxidant and anti-inflammatory functions. Anti-oxidants and anti-inflammatories have an important role in cognitive health. Therefore, 6-MSITC is expected to have positive effects on cognitive function. Previous studies showed the beneficial effects on cognitive functions in middle-aged adults. However, it is unclear that 6-MSITC has a positive effect on cognitive functions in healthy older adults aged 60 years and over. Here, we investigated whether 12 weeks' 6-MSITC intervention enhances cognitive performance in older adults using a double-blinded randomized controlled trial (RCT). METHODS: Seventy-two older adults were randomly assigned to 6-MSITC or placebo groups. Participants were asked to take a supplement (6-MSITC or a placebo) for 12 weeks. We checked a wide range of cognitive performances (e.g., executive function, episodic memory, processing speed, working memory, and attention) at the pre- and post-intervention periods. RESULTS: The 6-MSITC group showed a significant improvement in working and episodic memory performances compared to the placebo group. However, we did not find any significant improvements in other cognitive domains. DISCUSSION: This study firstly demonstrates scientific evidence that 6-MSITC may enhance working memory and episodic memory in older adults. We discuss the potential mechanism for improving cognitive functions after 6-MSITC intake.

A mechanistic overview of sulforaphane and its derivatives application in diabetes and its complications.

Sulforaphane (SFN) is a type of phytochemical found in many cruciferous vegetables that has been shown to positively benefit the control of Type 2 Diabetes Mellitus (T2DM). The search was done from 2000 until December 2022 using PubMed, Scopus, Web of Sciences, and Google Scholar databases. We included all in vitro, in vivo, and clinical trials. Sulforaphane has been demonstrated to activate the PI3K/AKT and AMP-activated protein kinase pathways and the glucose transporter type 4 to increase insulin production and reduce insulin resistance. Interestingly, SFN possesses protective effects against diabetes complications, such as diabetic-induced hepatic damage, vascular inflammation and endothelial dysfunction, nephropathy, and neuropathy via nuclear factor erythroid 2-related factor 2 activation that leads to the translation of several anti-oxidant enzymes and regulation glycolysis, pentose phosphate pathway, fatty acid metabolism, glutamine metabolism, and glutathione metabolism. Furthermore, multiple clinical trial studies emphasized the ameliorating effects of SFN on T2DM patients. This review provides sufficient evidence for further research and development of sulforaphane as a hypoglycemic drug.

Glucosinolates in cancer prevention and treatment: experimental and clinical evidence.

Glucosinolates are naturally occurring ß-d-thioglucosides that mainly exist in the Brassicaceae family. The enzyme myrosinase hydrolyzes glucosinolates to form isothiocyanates, which are chemical protectors. Phenethyl isothiocyanate, sulforaphane, and benzyl isothiocyanate are potential isothiocyanate with efficient anti-cancer effects as a protective or treatment agent. Glucosinolate metabolites exert the cancer-preventive activity through different mechanisms, including induction of the Nrf2 transcription factor, inhibition of expression of tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß), induction of apoptosis through inhibiting phase I enzymes and inducting phase II enzymes, interruption of caspase pathways, STAT1/STAT2, inhibition of sulfotransferases. Moreover, glucosinolates and their metabolites are effective in cancer treatment by inhibiting angiogenesis, upregulating natural killers, increasing expression of p53, p21, caspase 3 and 9, and modulating NF-κB. Despite the mentioned cancer-preventing effects, some isothiocyanates can increase the risk of tumors. So, further studies are needed to obtain an accurate and effective dose for each glucosinolates to treat different types of tumors.

The Effect of Moringa Isothiocyanate-1 on Renal Damage in Diabetic Nephropathy.

INTRODUCTION: Diabetic nephropathy (DN) is the most common clinical complication of diabetes mellitus. Moringa isothiocyanate-1 (MIC-1) is effective in the treatment of diabetes mellitus, but its mechanism of action in DN remains obscure. This research specifically probed the role of MIC-1 in modulating renal injury in DN. METHODS: Six db/m mice were assigned to control group and twelve db/db mice were randomly allocated to the db/db and db/db + MIC-1 groups. The body and kidney weights of the mice were monitored. Renal function indicators and oxidative stress-related markers were assessed by automatic biochemical analyzer and ELISA method. The pathological changes, apoptosis of renal tissues, extracellular regulated protein kinases (ERK) 1/2/ Nuclear factor erythroid2-related factor 2 (Nrf2) pathway-related markers, and the positive expressions of podocalyxin (Pod) and synaptopodin (Syn) were measured by H&E, PAS, and TUNEL staining, Western blot, and IHC assay. RESULTS: MIC-1 reduced the body and kidney weights, and increased the kidney organ index (calculated as 100*kidney weight/ body weight) in db/db mice. In addition, MIC-1 improved renal function, kidney tissue injury, and apoptosis of db/db mice. MIC1 noticeably repressed the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) and enhanced the contents of (glutathione) GSH, superoxide dismutase (SOD), and catalase (CAT) in db/db mice. At molecular level, db/db mice showed a decrease in p-ERK/ERK, Nrf2, SOD-1, heme oxygenase 1 (HO-1), and CAT and an increase in p- inhibitor kappa B alpha (IKBα) and p-Nuclear factor-kappa B (P65/P65), which were reversed when MIC-1 was administered. Furthermore, MIC-1 facilitated the positive expressions of Pod and Syn of the kidney tissues in db/db mice. CONCLUSION: MIC-1 reduces oxidative stress and renal injury by activating the ERK/Nrf2/HO-1 signaling and repressing the NFκB signaling in db/db mice.  DOI: 10.52547/ijkd.7515.

The preventive effects of broccoli bioactives against cancer: Evidence from a validated rat glioma model.

The aggressive and incurable diffuse gliomas constitute 80% of malignant brain tumors, and patients succumb to recurrent surgeries and drug resistance. Epidemiological research indicates that substantial consumption of fruits and vegetables diminishes the risk of developing this tumor type. Broccoli consumption has shown beneficial effects in both cancer and neurodegenerative diseases. These effects are partially attributed to the isothiocyanate sulforaphane (SFN), which can regulate the Keap1/Nrf2/ARE signaling pathway, stimulate detoxifying enzymes, and activate cellular antioxidant defense processes. This study employs a C6 rat glioma model to assess the chemoprotective potential of aqueous extracts from broccoli seeds, sprouts, and inflorescences, all rich in SFN, and pure SFN as positive control. The findings reveal that administering a dose of 100 mg/kg of broccoli sprout aqueous extract and 0.1 mg/kg of SFN to animals for 30 days before introducing 1 × 104 cells effectively halts tumor growth and progression. This study underscores the significance of exploring foods abundant in bioactive compounds, such as derivatives of broccoli, for potential preventive integration into daily diets. Using broccoli sprouts as a natural defense against cancer development might seem idealistic, yet this investigation establishes that administering this extract proves to be a valuable approach in designing strategies for glioma prevention. Although the findings stem from a rat glioma model, they offer promising insights for subsequent preclinical and clinical research endeavors.

Sulforaphane's Multifaceted Potential: From Neuroprotection to Anticancer Action.

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.

Restoring glomerular filtration rate by sulforaphane modulates ERK1/2/JNK/p38MAPK, IRF3/iNOS, Nrf2/HO-1 signaling pathways against folic acid-induced acute renal injury in rats.

BACKGROUND: Folic acid (FA)-induced acute renal injury (AKI) is a commonly and highly reproducible model used to study AKI. The current study aims to evaluate the possible protective effects of sulforaphane (SFN) against FA-induced renal damage and explore the underlying molecular mechanism. METHODS: The animals were divided into four groups (6 rats/group) as follows: normal group (received vehicle, p.o.), FA group (received 250 mg/kg, i.p.), SFN low dose group (received 15 mg/kg, p.o. plus FA 250 mg/kg, i.p.), SFN high dose group (30 mg/kg, p.o. plus FA 250 mg/kg, i.p.). At the end of the experiment, serum samples and kidney tissues were obtained to perform biochemical, molecular, and histopathological investigations. RESULTS: The present study showed that FA-caused AKI was confirmed by a significant elevation of kidney function biomarkers serum levels accompanied by an observation of histopathologic changes. Interestingly, SFN-administration significantly improved kidney function, reduced oxidative stress markers; MDA, NADPH oxidase, MPO, iNOS with up-regulation of GSH, GCLM, GPX4, SOD, NQO1, HO-1 and Nrf2 levels. SFN also downregulated proinflammatory markers. The results also demonstrated the anti-apoptotic effect of SFN through its ability to increase the antiapoptotic Bcl-2 protein and to decrease caspase-3. Moreover, SFN significantly decreased the relative expression of JNK, ERK-1/2, IRF3, and p38MAPK as compared to the FA-nephrotoxic group. CONCLUSION: The present study revealed that SFN possess an antioxidant, anti-inflammatory and antiapoptotic activity by modulating caspase-3, Bcl-2, ERK1/2, JNK, GCLM, NQO1, GPX4, Nrf2, HO-1 and P38 signaling pathways in a dose dependent manner which provides a potential therapeutic strategy for preventing FA-induced AKI.

Allyl isothiocyanate mitigates airway inflammation and constriction in a house dust mite-induced allergic asthma model via upregulation of tight junction proteins and the TRPA1 modulation.

Asthma is a chronic inflammatory disease that has been associated with insufficient vegetable intake. Allyl Isothiocyanate (AITC) is a natural isothiocyanate found in cruciferous plants with anti-inflammatory and antioxidant abilities. Our study aimed to investigate the potential effect of AITC on tracheal constriction in a house dust mite (HDM)-induced asthma animal model, and explore the underlying mechanisms. To investigate the effects of AITC on HDM-induced allergic asthma model, established by intranasally administering extracts of HDM and AITC or DEX was given orally for four weeks. Flexivent SCIREQ, H&E staining, ELISA were employed to evaluate the lung function and the cytokine secretion. Possible mechanisms were determined by Western blot. Rat tracheae contraction was measured by Labscribe. We utilized lung epithelial cells (BEAS-2B) to assess the adhesion response to the combination of inflammatory factors TNF-α and IL-4. The results of the study showed that AITC significantly reduced tracheal constriction in ex vivo experiments and improved lung function in in vivo experiments compared to HDM-induced mice. Additionally, AITC decreased cytokine secretion, inflammatory cell infiltration in the lung, and constriction-related proteins expression in both lung and tracheae. Moreover, AITC increased tight junction-related protein expression in lung tissues. In vitro experiments showed that AITC had a protective effect through TRPA1 channel without affecting cell viability. Our results demonstrate that AITC has potential anti-asthma effects in HDM-induced asthma models by alleviating airway inflammation and airway constriction through increasing tight junction-related protein expression and suppressing Ca2+ signaling. These findings suggest that AITC may be a beneficial adjuvant therapy in asthma treatment.

Allyl-isothiocyanate against colorectal cancer via the mutual dependent regulation of p21 and Nrf2.

Allyl-isothiocyanate (AITC) is a common Isothiocyanates (ITC) and its chemo-preventive and anti-tumor effects are believed to be related to the activation of NF-E2 p45-related Factor 2 (Nrf2). However, its anti-tumor effects on colorectal cancer (CRC) are not well elucidated. Here, we investigated the therapeutic in vitro and/or in vivo effects and mechanisms of action (MOA) for AITC on CRC cell line HCT116 (human) and MC38 (mouse). AITC treatment in a low concentration range (1 mg/kg in vivo) significantly inhibited the tumor cell growth and increased the expression of p21 and Nrf2. The AITC-mediated induction of p21 was dependent on Nrf2 but independent on p53 in vitro and in vivo at low dose. In contrast, the high dose of AITC (5 mg/kg in vivo) failed to increase substantial levels of p21/MdmX, and impaired the total antioxidant capacity of tumors and subsequent anti-tumor effect in vivo. These results suggest that an optimal dose of AITC is important and required for the proper Nrf2 activation and its anti-CRC effects and thus, providing insights into the potential applications of AITC for the prevention and treatment of CRC.

Effects of Sulforaphane on SARS­CoV­2 infection and NF­κB dependent expression of genes involved in the COVID­19 'cytokine storm'.

Since its spread at the beginning of 2020, the coronavirus disease 2019 (COVID­19) pandemic represents one of the major health problems. Despite the approval, testing, and worldwide distribution of anti­severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) vaccines, the development of specific antiviral agents targeting the SARS­CoV­2 life cycle with high efficiency, and/or interfering with the associated 'cytokine storm', is highly required. A recent study, conducted by the authors' group indicated that sulforaphane (SFN) inhibits the expression of IL­6 and IL­8 genes induced by the treatment of IB3­1 bronchial cells with a recombinant spike protein of SARS­CoV­2. In the present study, the ability of SFN to inhibit SARS­CoV­2 replication and the expression of pro­inflammatory genes encoding proteins of the COVID­19 'cytokine storm' was evaluated. SARS­CoV­2 replication was assessed in bronchial epithelial Calu­3 cells. Moreover, SARS­CoV­2 replication and expression of pro­inflammatory genes was evaluated by reverse transcription quantitative droplet digital PCR. The effects on the expression levels of NF­κB were assessed by western blotting. Molecular dynamics simulations of NF­kB/SFN interactions were conducted with Gromacs 2021.1 software under the Martini 2 CG force field. Computational studies indicated that i) SFN was stably bound with the NF­κB monomer; ii) a ternary NF­kB/SFN/DNA complex was formed; iii) the SFN interacted with both the protein and the nucleic acid molecules modifying the binding mode of the latter, and impairing the full interaction between the NF­κB protein and the DNA molecule. This finally stabilized the inactive complex. Molecular studies demonstrated that SFN i) inhibits the SARS­CoV­2 replication in infected Calu­3 cells, decreasing the production of the N­protein coding RNA sequences, ii) decreased NF­κB content in SARS­CoV­2 infected cells and inhibited the expression of NF­kB­dependent IL­1ß and IL­8 gene expression. The data obtained in the present study demonstrated inhibitory effects of SFN on the SARS­CoV­2 life cycle and on the expression levels of the pro­inflammatory genes, sustaining the possible use of SFN in the management of patients with COVID­19.

Preclinical investigations on broccoli-derived sulforaphane for the treatment of ophthalmic disease.

Vision loss causes a significant burden on individuals and communities on a financial, emotional and social level. Common causes include age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and retinitis pigmentosa (RP; also known as 'rod-cone dystrophy'). As the population continues to grow and age globally, an increasing number of people will experience vision loss. Hence, there is an urgent need to develop therapies that can curb early pathological events. The broccoli-derived compound, sulforaphane (SFN), is reported to have multiple health benefits and modes of action. In this review, we outline the preclinical findings on SFN in ocular diseases and discuss the future clinical testing of this compound.

Design and Synthesis of Brefeldin A-Isothiocyanate Derivatives with Selectivity and Their Potential for Cervical Cancer Therapy.

Brefeldin A has a wide range of anticancer activity against a variety of tumor cells. Its poor pharmacokinetic properties and significant toxicity seriously hinder its further development. In this manuscript, 25 brefeldin A-isothiocyanate derivatives were designed and synthesized. Most derivatives showed good selectivity between HeLa cells and L-02 cells. In particular, 6 exhibited potent antiproliferative activity against HeLa cells (IC50 = 1.84 µM) with no obvious cytotoxic activity to L-02 (IC50 > 80 µM). Further cellular mechanism tests indicated that 6 induced HeLa cell cycle arrest at G1 phase. Cell nucleus fragmentation and decreased mitochondrial membrane potential suggested 6 could induce apoptosis in HeLa cells through the mitochondrial-dependent pathway.

Cardiomyocyte-targeting exosomes from sulforaphane-treated fibroblasts affords cardioprotection in infarcted rats.

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 (1·1012) 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 Ca2+ 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.

Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis.

AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases. MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect. KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P < 0.0001, I2 = 0 %) and decreased the plasma creatinine (SMD -1.24, [-1.59; -0.88], P < 0.0001, I2 = 36.0 %) and urea (SMD -3.22 [-4.42, -2.01], P < 0.0001, I2 = 72.4 %) levels. SFN administration (median dose: 2.5 mg/kg, median duration: 3 weeks) significantly decreased urinary protein excretion (SMD -2.20 [-2.68; -1.73], P < 0.0001, I2 = 34.1 %). It further improved two kidney lesion histological indices namely kidney fibrosis (SMD -3.08 [-4.53; -1.63], P < 0.0001, I2 = 73.7 %) and glomerulosclerosis (SMD -2.24 [-2.96; -1.53], P < 0.0001, I2 = 9.7 %) and decreased kidney injury molecular biomarkers (SMD -1.51 [-2.00; -1.02], P < 0.0001, I2 = 0 %). SIGNIFICANCE: These findings provide new insights concerning preclinical strategies for treating kidney disease or kidney failure with SFN supplements and should stimulate interest in clinical evaluations of SFN in patients with kidney disease.

Novel nanoparticles prepared from isothiocyanate derivatives for phototherapy of tumor.

Phototherapy is a new method to treat tumor, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, the GSH in tumor cells could deplete ROS produced by photosensitizers, resulting in inadequate PDT. Isothiocyanate not only is a new type of anti-tumor drug, but also may combine with GSH, increasing the content of intracellular ROS and improving PDT effect. Here we synthesized a kind of water-soluble nanoparticles (BN NPs) parceling BODIPY-I-35 up with mPEG-ITC and lecithin. mPEG-ITC can react with GSH in tumor cells to reduce the consumption of ROS. BN NPs can be used as vectors to deliver drugs to tumor sites. Under 808 nm laser irradiation, BN NPs solution increased 13 °C within 10 min, indicating that BN NPs had superb photothermal performance. In vitro experiments, low dose BN NPs showed satisfactory PDT and PTT effects, and the cell viability of MCF-7 cell was only 13%. In vivo, BN NPs with excellent biocompatibility showed favorable phototherapy effect and tumor was effectively inhibited. Fluorescence imaging could present the long retention effect of BN NPs in tumor locations. In conclusion, the BN NPs showed the effect of enhancing phototherapy and provided a remarkable application prospect in the phototherapy of tumor cells.