The versatile reactivity of isothiocyanate intermediates enabled the diversity-oriented synthesis (DOS) of N-heterocycles in a DNA-compatible manner. We first reported a mild in situ conversion of DNA-conjugated amines to isothiocyanates. Subsequently, a set of diverse transformations was successfully developed to construct 2-thioxo-quinazolinones, 1,2,4-thiadiazoles, and 2-imino thiazolines. Finally, the feasibility of these approaches in constructing DELs was further demonstrated through enzymatic ligation and mock pool preparation. This study demonstrated the advantages of combining in situ conversion strategies with DOS, which effectively broadened the chemical and structural diversity of DELs.

Abnormal glucose homeostasis is associated with metabolic syndromes including cardiovascular diseases, hypertension, type 2 diabetes mellitus, and obesity, highlighting the significance of maintaining a balanced glucose level for optimal biological function. This highlights the importance of maintaining normal glucose levels for proper biological functioning. Sulforaphane (SFN), the primary bioactive compound in broccoli from the Cruciferae or Brassicaceae family, has been shown to enhance glucose homeostasis effectively while exhibiting low cytotoxicity. This paper assesses the impact of SFN on glucose homeostasis in vitro, in vivo, and human trials, as well as the molecular mechanisms that drive its regulatory effects. New strategies have been proposed to enhance the bioavailability and targeted delivery of SFN in order to overcome inherent instability. The manuscript also covers the safety evaluations of SFN that have been documented for its production and utilization. Hence, a deeper understanding of the favorable influence and mechanism of SFN on glucose homeostasis, coupled with the fact that SFN is abundant in the human daily diet, may ultimately offer theoretical evidence to support its potential use in the food and pharmaceutical industries.

Human studies have shown the anticancer effects of dietary isothiocyanates (ITCs), but there are some inconsistencies, and more evidence supports that such anticancer effect is from higher doses of ITCs. The inconsistencies found in epidemiological studies may be due to many factors, including the biphasic dose-response (so called hormetic effect) of ITCs, which was found to be more profound under hypoxia conditions. In this comprehensive review, we aim to shed light on the intriguing synergistic interactions between dietary ITCs, focusing on sulforaphane (SFN) and various anticancer drugs. Our exploration is motivated by the potential of these combinations to enhance cancer management strategies. While the anticancer properties of ITCs have been recognized, our review delves deeper into understanding the mechanisms and emphasizing the significance of the hormetic effect of ITCs, characterized by lower doses stimulating both normal cells and cancer cells, whereas higher doses are toxic to cancer cells and inhibit their growth. We have examined a spectrum of studies unraveling the multifaceted interaction and combinational effects of ITCs with anticancer agents. Our analysis reveals the potential of these synergies to augment therapeutic efficacy, mitigate chemoresistance, and minimize toxic effects, thereby opening avenues for therapeutic innovation. The review will provide insights into the underlying mechanisms of action, for example, by spotlighting the pivotal role of Nrf2 and antioxidant enzymes in prevention. Finally, we glimpse ongoing research endeavors and contemplate future directions in this dynamic field. We believe that our work contributes valuable perspectives on nutrition and cancer and holds promise for developing novel and optimized therapeutic strategies.

Enhanced drug resistance poses a significant challenge in treating ovarian cancer (OC). Phenylethyl isothiocyanate (PEITC) is involved in drug resistance in OC, but the mechanism remains unclear. In this study, we investigated the molecular regulatory mechanism of carboplatin sensitivity in OC associated with PEITC, MAF BZIP Transcription Factor F (MAFF), and Zinc finger proteins (ZNF) 711. The carboplatin sensitivity was significantly increased in OC cells after PEITC treatment. Knockdown of MAFF significantly enhanced the carboplatin sensitivity of OC cells, promoted apoptosis, inhibited colony-forming efficiency in vitro, and suppressed tumor growth in vivo. The binding site of MAFF to the ZNF711 promoter was predicted, and the knockdown of MAFF significantly increased the ZNF711 expression. Results of the dual luciferase assay and ChIP-PCR confirmed the binding of MAFF to the ZNF711 promoter. Immunofluorescence and CoIP results demonstrated the colocalization and the binding of MAFF and its interacting protein, BZIP Transcription Factor ATF-like 3 (BATF3). Similarly, we confirmed the binding of BATF3 to the ZNF711 promoter. Knockdown of BATF3 alone and simultaneous knockdown of BATF3 and MAFF showed similar regulatory effects on ZNF711 transcription and apoptosis. These suggested that the binding of MAFF to BATF3 inhibited ZNF711 transcription and reduced carboplatin sensitivity in OC.

Despite recent advances in tumor diagnosis and treatment technologies, the number of cancer cases and deaths worldwide continues to increase yearly, creating an urgent need to find new methods to prevent or treat cancer. Sulforaphane (SFN), as a member of the isothiocyanates (ITCs) family, which is the hydrolysis product of glucosinolates (GLs), has been shown to have significant preventive and therapeutic cancer effects in different human cancers. Early studies have shown that SFN scavenges oxygen radicals by increasing cellular defenses against oxidative damage, mainly through the induction of phase II detoxification enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2). More and more studies have shown that the anticancer mechanism of SFN also includes induction of apoptotic pathway in tumor cells, inhibition of cell cycle progression, and suppression of tumor stem cells. Therefore, the application of SFN is expected to be a necessary new approach to treating cancer. In this paper, we review the multiple molecular mechanisms of SFN in cancer prevention and treatment in recent years, which can provide a new vision for cancer treatment.

UNASSIGNED: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. Phenethyl isothiocyanate (PEITC) is a bioactive substance present primarily in the cruciferous vegetables. PEITC has exhibited anti-cancer properties in various cancers, including lung, bile duct, and prostate cancers. It has been demonstrated that PEITC can inhibit the proliferation, invasion, and metastasis of SK-Hep1 cells, while effectively inducing apoptosis and cell cycle arrest in HepG2 cells. However, knowledge of its anti-carcinogenic effects on Huh7.5.1 cells and its underlying mechanism remains elusive. In the present study, we aim to evaluate the anti-carcinogenic effects of PEITC on human HCC Huh7.5.1 cells.
UNASSIGNED: MTT assay and colony formation assay was performed to investigate the anti-proliferative effects of PEITC against Huh7.5.1 cells. The pro-apoptosis effects of PEITC were determined by Annexin V-FITC/PI double staining assay by flow cytometry (FCM), mitochondrial transmembrane potential (MMP) measurement, and Caspase-3 activity detection. A DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was conducted to estimate the DNA damage in Huh7.5.1 cells induced by PEITC. Cell cycle progression was determined by FCM. Transwell invasion assay and wound healing migration assay were performed to investigate the impact of PEITC on the migration and invasion of Huh7.5.1 cells. In addition, transcriptome sequencing and gene set enrichment analysis (GSEA) were used to explore the potential molecular mechanisms of the inhibitory effects of PEITC on HCC. Quantitative real-time PCR (qRT-PCR) analysis was performed to verify the transcriptome data.
UNASSIGNED: MTT assay showed that treatment of Huh7.5.1 cells with PEITC resulted in a dose-dependent decrease in viability, and colony formation assay further confirmed its anti-proliferative effect. Furthermore, we found that PEITC could induce mitochondrial-related apoptotic responses, including a decrease of mitochondrial transmembrane potential, activation of Caspase-3 activity, and generation of intracellular reactive oxygen species. It was also observed that PEITC caused DNA damage and cell cycle arrest in the S-phase in Huh7.5.1 cells. In addition, the inhibitory effect of PEITC on the migration and invasion ability of Huh7.5.1 cells was assessed. Transcriptome sequencing analysis further suggested that PEITC could activate the typical MAPK, PI3K-Akt, and p53 signaling pathways, revealing the potential mechanism of PEITC in inhibiting the carcinogenic properties of Huh7.5.1 cells.
UNASSIGNED: PEITC exhibits anti-carcinogenic activities against human HCC Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways. Our results suggest that PEITC may be useful for the anti-HCC treatment.

Sulforaphane (SFN) has shown diverse effects on human health and diseases. SFN was administered daily to C57BL/6J mice at doses of 1 mg/kg (SFN1) and 3 mg/kg (SFN3) for 8 weeks. Both doses of SFN accelerated body weight increment. The cross-sectional area and diameter of Longissimus dorsi (LD) muscle fibers were enlarged in SFN3 group. Triglyceride (TG) and total cholesterol (TC) levels in LD muscle were decreased in SFN groups. RNA sequencing results revealed that 2455 and 2318 differentially expressed genes (DEGs) were found in SFN1 and SFN3 groups, respectively. Based on GO enrichment analysis, 754 and 911 enriched GO terms in the SFN1 and SFN3 groups, respectively. KEGG enrichment analysis shown that one KEGG pathway was enriched in the SFN1 group, while six KEGG pathways were enriched in the SFN3 group. The expressions of nine selected DEGs validated with qRT-PCR were in line with the RNA sequencing data. Furthermore, SFN treatment influenced lipid and protein metabolism related pathways including AMPK signaling, fatty acid metabolism signaling, cholesterol metabolism signalling, PPAR signaling, peroxisome signaling, TGFβ signaling, and mTOR signaling. In summary, SFN elevated muscle fibers size and reduced TG and TC content of in LD muscle by modulating protein and lipid metabolism-related signaling pathways.

Nutrition has been increasingly recognized for its use in mental health. Depression is commonly observed in patients with chronic liver disease (CLD). Building on our recent findings of depression-like behaviors in mice with hepatic ischemia/reperfusion (HI/R) injury, mediated by the gut-liver-brain axis, this study explored the potential influence of dietary sulforaphane glucosinolate (SGS) on these behaviors. Behavioral assessments for depression-like behaviors were conducted 7 days post either sham or HI/R injury surgery. Dietary intake of SGS significantly prevented splenomegaly, systemic inflammation, depression-like behaviors, and downregulation of synaptic proteins in the prefrontal cortex (PFC) of HI/R-injured mice. Through 16S rRNA analysis and untargeted metabolomic analyses, distinct bacterial profiles and metabolites were identified between control + HI/R group and SGS + HI/R group. Correlations were observed between the relative abundance of gut microbiota and both behavioral outcomes and blood metabolites. These findings suggest that SGS intake could mitigate depression-like phenotypes in mice with HI/R injury, potentially through the gut-liver-brain axis. Additionally, SGS, found in crucial vegetables like broccoli, could offer prophylactic nutritional benefits for depression in patients with CLD.

Cadmium (Cd) is a transition metal ion that is extremely harmful to human and animal biological systems. Cd is a toxic substance that can accumulate in the food chain and cause various health issues. Sulforaphane (SFN) is a natural bioactive compound with potent antioxidant properties. In our study, 80 1 day-old chicks were fed with Cd (140 mg/kg BW/day) and/or SFN (50 mg/kg BW/day) for 90 days. The blood-thymus barrier (BTB) is a selective barrier separating T-lymphocytes from blood and cortical capillaries in the thymus cortex. Our research revealed that Cd could destroy the BTB by downregulating Wnt/β-catenin signaling and induce immunodeficiency, leading to irreversible injury to the immune system. The study emphasizes the health benefits of SFN in the thymus. SFN could ameliorate Cd-triggered BTB dysfunction and pyroptosis in the thymus tissues. SFN modulated the PI3K/AKT/FOXO1 axis, improving the level of claudin-5 (CLDN5) in the thymus to alleviate BTB breakdown. Our findings indicated the toxic impact of Cd on thymus, and BTB could be the specific target of Cd toxicity. The finding also provides evidence for the role of SFN in maintaining thymic homeostasis for Cd-related health issues.

Myrosinase (Myr) catalyzes the hydrolysis of glucosinolates, yielding biologically active metabolites. In this study, glucoraphanin (GRA) extracted from broccoli seeds was effectively hydrolyzed using a Myr-obtained cabbage aphid (Brevicoryne brassicae) (BbMyr) to produce (R)-sulforaphane (SFN). The gene encoding BbMyr was successfully heterologously expressed in Escherichia coli, resulting in the production of 1.6 g/L (R)-SFN, with a remarkable yield of 20.8 mg/gbroccoli seeds, achieved using recombination E. coli whole-cell catalysis under optimal conditions (pH 4.5, 45 °C). Subsequently, BbMyr underwent combinatorial simulation-driven mutagenesis, yielding a mutant, DE9 (N321D/Y426S), showing a remarkable 2.91-fold increase in the catalytic efficiency (kcat/KM) compared with the original enzyme. Molecular dynamics simulations demonstrated that the N321D mutation in loopA of mutant DE9 enhanced loopA stability by inducing favorable alterations in hydrogen bonds, while the Y426S mutation in loopB decreased spatial resistance. This research lays a foundation for the environmentally sustainable enzymatic (R)-SFN synthesis.