Four sulfur-containing compounds with anti-colon cancer effect from marine-derived fungus Aspergillus terreus.

Sulfur-containing natural products possess a variety of biological functions including antitumor, antibacterial, anti-inflammatory and antiviral activities. In this study, four previously undescribed sulfur-containing compounds asperteretals L and M, terreins A and B, together with 17 known compounds were obtained from a culture of marine fungus A. terreus supplemented with inorganic sulfur source Na2SO4. Their planar structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD experiments. The in vitro cytotoxicities of compounds 1-21 against HCT-116 and Caco-2 were evaluated by SRB assay. Asperteretal M (2) exhibited activity against HCT-116 with the IC50 value at 30µM. The antiproliferative effect of asperteretal M was confirmed by colony formation assay and cell death staining. Furthermore, the preliminary study on the anti-colon cancer mechanism of asperteretal M was performed by RNA-seq analysis. Western blotting validated that asperteretal M significantly decreased the expression of cell-cycle regulatory proteins CDK1, CDK4, and PCNA in a concentration-dependent manner.

Comprehensive metabolite and biological profile of "Sulmona Red Garlic" ecotype's aerial bulbils.

"Sulmona Red Garlic" is a well-known Italian traditional product. Bulbs, used for culinary purposes, have been largely investigated for their medicinal properties whereas aerial bulbils are usually removed as waste material. Here, for the first time, chemical composition and biological properties of the hydroalcoholic extract from aerial bulbils were investigated. Complementary information on metabolite composition were obtained using both NMR based untargeted and HPLC-DAD targeted methodologies. The NMR analysis revealed the presence of sugars, organic acids, amino acids, organosulphur compounds (methiin, alliin, allicin and cycloalliin), and other secondary metabolites. In particular, methiin and alliin were identified for the first time in the NMR spectra of aerial bulbil garlic extracts. Polyphenol content was determined by HPLC-DAD analysis: catechin, chlorogenic acid, and gallic acid turned out to be the most abundant phenolics. Hydroalcoholic extract blocked cell proliferation of colon cancer cell line HCT116 with an IC50 of 352.07 µg/mL, while it was non-toxic to myoblast cell line C2C12. In addition, it caused seedling germination reduction of two edible and herbaceous dicotyledon species, namely Cichorium intybus and C. endivia. Moreover, the same extract reduced the gene expression of TNF-α (tumor necrosis factor), HIF1-α (hypoxia-inducible factor), VEGFA (vascular endothelial growth factor), and transient receptor potential (TRP) M8 (TRPM8) indicating the ability to contrast cancer development through the angiogenic pathway. Final, in silico experiments were also carried out supporting the biological effects of organosulphur compounds, particularly alliin, which may directly interact with TRPM8. The results here reported suggest the potential use of garlic aerial bulbils often considered a waste product as a source in phytotherapeutic remedies.

Improving endothelial health with food-derived H2S donors: an in vitro study with S-allyl cysteine and with a black-garlic extract enriched in sulfur-containing compounds.

A healthy vascular endothelium plays an essential role in modulating vascular tone by producing and releasing vasoactive factors such as nitric oxide (NO). Endothelial dysfunction (ED), the loss of the endothelium physiological functions, results in the inability to properly regulate vascular tone, leading to hypertension and other cardiovascular risk factors. Alongside NO, the gasotransmitter hydrogen sulfide (H2S) has emerged as a key molecule with vasodilatory and antioxidant activities. Since a reduction in H2S bioavailability is related to ED pathogenesis, natural H2S donors are very attractive. In particular, we focused on the sulfur-containing amino acid S-allyl cysteine (SAC), a bioactive metabolite, of which black garlic is particularly rich, with antioxidant activity and, among others, anti-diabetic and anti-hypertensive properties. In this study, we analyzed the protective effect of SAC against ED by evaluating reactive oxygen species level, H2S release, eNOS phosphorylation, and NO production (by fluorescence imaging and western blot analysis) in Bovine Aortic Endothelial cells (BAE-1). Furthermore, we chemically characterized a Black Garlic Extract (BGE) for its content in SAC and other sulfur-containing amino acids. BGE was used to carry out an analysis on H2S release on BAE-1 cells. Our results show that both SAC and BGE significantly increase H2S release. Moreover, SAC reduces ROS production and enhances eNOS phosphorylation and the consequent NO release in our cellular model. In this scenario, a natural extract enriched in SAC could represent a novel therapeutic approach to prevent the onset of ED-related diseases.

Long term exposure of cigarette smoke condensate (CSC) mediates transcriptomic changes in normal human lung epithelial Beas-2b cells and protection by garlic compounds.

Chronic cigarette smoke condensate (CSC) exposure is one of the preventable risk factors in the CS-induced lung cancer. However, understanding the mechanism of cellular transformation induced by CS in the lung remains limited. We investigated the effect of long term exposure of CSC in human normal lung epithelial Beas-2b cells, and chemopreventive mechanism of organosulphur garlic compounds, diallyl sulphide (DAS) and diallyl disulphide (DADS) using Next Generation Sequencing (NGS) transcriptomic analysis. CSC regulated 1077 genes and of these 36 genes are modulated by DAS while 101 genes by DADS. DAS modulated genes like IL1RL1 (interleukin-1 receptor like-1), HSPA-6 (heat shock protein family A, member 6) while DADS demonstrating ADTRP (Androgen-Dependent TFPI Regulating Protein), ANGPT4 (Angiopoietin 4), GFI1 (Growth Factor-Independent 1 Transcriptional Repressor), TBX2 (T-Box Transcription Factor 2), with some common genes like NEURL-1 (Neuralized E3-Ubiquitin Protein Ligase 1), suggesting differential effects between these two garlic compounds. They regulate genes by influencing pathways including HIF-1alpha, STAT-3 and matrix metalloproteases, contributing to the chemoprotective ability of organosulfur garlic compounds against CSC-induced cellular transformation. Taken together, we demonstrated CSC induced global gene expression changes pertaining to cellular transformation which potentially can be delayed with dietary chemopreventive phytochemicals like DS and DADS influencing alterations at the transcriptomic level.

Role of Sulfur Compounds in Garlic as Potential Therapeutic Option for Inflammation and Oxidative Stress in Asthma.

Asthma is a chronic inflammatory disease in the airways with a multifactorial origin but with inflammation and oxidative stress as related pathogenic mechanisms. Garlic (Allium sativum) is a nutraceutical with different biological properties due to sulfur-containing natural compounds. Studies have shown that several compounds in garlic may have beneficial effects on cardiovascular diseases, including those related to the lungs. Therefore, it is possible to take advantage of the compounds from garlic as nutraceuticals for treating lung diseases. The objective of this article is to review the biological properties of the sulfur compounds present in garlic for the treatment of asthma, as well as the cellular mechanisms involved. Here, we discuss the potential therapeutic effects of garlic compounds in the modulation of inflammation and oxidative stress, as well as its antibiotic and antiviral activities for identifying and testing potential treatment options for asthma management.

Sustained Delivery of Methylsulfonylmethane from Biodegradable Scaffolds Enhances Efficient Bone Regeneration.

Introduction: As a popular dietary supplement containing sulfur compound, methylsulfonylmethane (MSM) has been widely used as an alternative oral medicine to relieve joint pain, reduce inflammation and promote collagen protein synthesis. However, it is rarely used in developing bioactive scaffolds in bone tissue engineering. Methods: Three-dimensional (3D) hydroxyapatite/poly (lactide-co-glycolide) (HA/PLGA) porous scaffolds with different doping levels of MSM were prepared using the phase separation method. MSM loading efficiency, in vitro drug release as well as the biological activity of MSM-loaded scaffolds were investigated by incubating mouse pre-osteoblasts (MC3T3-E1) in the uniform and interconnected porous scaffolds. Results: Sustained release of MSM from the scaffolds was observed, and the total MSM release from 1% and 10% MSM/HA/PLGA scaffolds within 16 days was up to 64.9% and 68.2%, respectively. Cell viability, proliferation, and alkaline phosphatase (ALP) activity were significantly promoted by incorporating 0.1% of MSM in the scaffolds. In vivo bone formation ability was significantly enhanced for 1% MSM/HA/PLGA scaffolds indicated by the repair of rabbit radius defects which might be affected by a stimulated release of MSM by enzyme systems in vivo. Discussion: Finding from this study revealed that the incorporation of MSM would be effective in improving the osteogenesis activity of the HA/PLGA porous scaffolds.

Effects of sulfated polysaccharides from Laminaria japonica on regularating the gut microbiotan and alleviating intestinal inflammation in obese mice.

Due to their known health-enhancing properties, Laminaria japonica polysaccharides (LJP) may alleviate obesity via unknown mechanisms. This study aimed to investigate beneficial LJP effects and mechanism(s) of action using an animal obesity model (ICR mice fed a high-fat diet). First, LJP were confirmed to consist of sulfated polysaccharides via infrared spectroscopy. Next, LJP administration to mice was found to induce weight loss, reduce liver fat accumulation, and support healthy obesity-related blood serum indicator levels. Notably, LJP treatment significantly reduced TC and LDL levels and significantly increased HDL, LPL, UCP-2, and PPAR-α levels. Furthermore, examinations of tissues of LJP-treated mice revealed significantly reduced intestinal tissue inflammation as compared to corresponding results obtained for untreated obese controls. Additionally, LJP treatment relieved colonic shortening and reduced colonic levels of inflammatory factors TNF-α and IL-6. Further exploration of LJP treatment effects on mouse gut microbiota conducted via fecal 16S rRNA gene sequence-based gut microbiome profiling analysis revealed that LJP treatment increased the Bacteroidetes/Firmicutes ratio and increased gut abundances of probiotics Bacteroides acidifaciens, s_Lactobacillus intestinalis, and s_Lactobacillus murinus. In conclusion, these results collectively suggest that LJP use as a food supplement may alleviate obesity and related gut microbiota dysbiosis and intestinal inflammatory disorders.

Antinociceptive effect of garlic, garlic preparations and derivative compounds.

BACKGROUND AND OBJECTIVE: The antinociceptive effects of garlic have shown promise in treating different chronic diseases in humans, such as knee osteoarthritis, rheumatoid arthritis and peripheral arterial occlusive disease stage II. The most common garlic products are garlic powder (dried garlic), steam distilled garlic oils, garlic oil macerate and aged garlic extract. These commercial products contain organosulphur compounds (OSCs) that have been extensively evaluated in preclinical models and some clinical assays to treat different diseases against pain. In this review, we describe the importance of some bioactive compounds found in garlic and their role in treating pain. MATERIALS & METHODS: A systematic search of the literature in Dimensions, PubMed, Scopus, and Web of Science was performed. Terms and preselected keywords relating to garlic, its derivatives and organusulphure compounds in acute, chronic and neuropathic pain, were used to perform a systematic literature search. Two independent reviewers screened the papers for inclusion and assessed the methodological quality. RESULTS & DISCUSSION: The antinociceptive activity of garlic and its OSC is related to its antioxidant and anti-inflammatory properties, which may be explained by the ability to block the synthesis of PGs, pro-inflammatory cytokines and interferon-γ, by the reduction COX-2 activity and increasing the levels of anti-inflammatory cytokines. Besides, garlic extract is an activator of TRPA1 and TRPV1, where the principal responsible for this activation are OSC. CONCLUSION: The relationship between these pathways allows a better understanding how garlic and its derivates could be carrying out its pharmacological action over the management of acute and chronic pain and provide a base by further investigations. SIGNIFICANCE: Antinociceptive effect of garlic and its OSCs has been extensively evaluated in preclinical models and clinical assays to treat different diseases, contributing to the modulation of inflammation as an essential factor in reducing pain. The current review emphasizes the potential therapeutic effect of garlic and its derivatives in treatment of pain and related mechanisms of action. Moreover, it provides information about the potential clinical use in patients with painful conditions.

Construction of sulfur-containing compounds with anti-cancer stem cell activity using thioacrolein derived from garlic based on nature-inspired scaffolds.

Sulfur-containing compounds, such as cyclic compounds with a vinyl sulfane structure, exhibit a wide range of biological activities including anticancer activity. Therefore, the development of efficient strategies to synthesize such compounds is a remarkable achievement. We have developed a unique approach for the rapid and modular preparation of nature-inspired cyclic and acyclic sulfur-containing compounds using thioacrolein, a naturally occurring chemically unstable intermediate. We constructed thiopyranone derivatives through the regioselective sequential double Diels-Alder reaction of thioacrolein produced by allicin, a major component in garlic, and two molecules of silyl enol ether as the diene partner. The cytotoxicity toward cancer stem cells of the thiopyranones was equal to or higher than that of (Z)-ajoene (positive control) derived from garlic, and the thiopyranones had higher chemical stability than (Z)-ajoene.

Methylgerambullin derived from plant Glyccsmis pentaphylla (Retz) correa. Mediates anti-hepatocellular carcinoma cancer effect by activating mitochondrial and endoplasmic reticulum stress signaling and inhibiting AKT and STAT3 pathways.

Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors. Glycosmis pentaphylla is used by traditional medical practitioners worldwide to treat various diseases. We isolated and identified a chemical component with potential anti-hepatocellular carcinoma (HCC) effects. Methylgerambullin is a sulfur containing amine and has significant antihepatoma activity in vitro and in vivo. Methylgerambullin was significantly cytotoxic to HCC cells and induces apoptosis in HCC cells. In addition, methylgerambullin is able to inhibit the growth of transplanted tumors in nude mice without significant toxicity. Regarding the anti-cancer mechanism of methylgerambullin, treatment with methylgerambullin increased the expression of caspase-3, caspase-9 and Bax in vitro and in vivo and reduce the expression of B-cell lymphoma-2 (Bcl-2). Simultaneously, methylgerambullin can also affect ERS-related proteins, inhibit Protein Kinase B (Akt) activity, cause dephosphorylation of downstream Bad, and inhibit the expression of the Signal Transducer and Activator of Transcription 3 (STAT3) protein to inhibit HCC cells proliferation. Overall, these results suggest that methylgerambullin can inhibit HCC cells proliferation by inducing mitochondrial apoptosis, activating ERS signaling pathways and inhibiting the Akt and STAT3 pathways.

Regulation of Selenium/Sulfur Interactions to Enhance Chemopreventive Effects: Lessons to Learn from Brassicaceae.

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living systems. Se-containing compounds have been found to reduce carcinogenesis of animal models, and dietary supplemental Se might decrease cancer risk. Se is mainly taken up by plant roots in the form of selenate via high-affinity sulfate transporters. Consequently, owing to the chemical similarity between Se and sulfur (S), the availability of S plays a key role in Se accumulation owing to competition effects in absorption, translocation, and assimilation. Moreover, naturally occurring S-containing compounds have proven to exhibit anticancer potential, in addition to other bioactivities. Therefore, it is important to understand the interaction between Se and S, which depends on Se/S ratio in the plant or/and in the growth medium. Brassicaceae (also known as cabbage or mustard family) is an important family of flowering plants that are grown worldwide and have a vital role in agriculture and populations' health. In this review we discuss the distribution and further interactions between S and Se in Brassicaceae and provide several examples of Se or Se/S biofortifications' experiments in brassica vegetables that induced the chemopreventive effects of these crops by enhancing the production of Se- or/and S-containing natural compounds. Extensive further research is required to understand Se/S uptake, translocation, and assimilation and to investigate their potential role in producing anticancer drugs.

Potentiation of Differentiation and Apoptosis in a Human Promyelocytic Leukemia Cell Line by Garlic Essential Oil and Its Organosulfur Compounds.

BACKGROUND/AIM: The clinical course of acute leukemia is complicated, and it is often necessary to combine or change treatment methods due to the rapid increase and spread of malignant cells. In this study, the potential anti-leukemia activities of prepared garlic essential oil (GEO) and some organosulfur compounds contained therein were examined. MATERIALS AND METHODS: Garlic essential oil component identification by gas chromatography-mass spectrometry (GC-MS). MTT assay evaluated cytotoxicity of tested samples. Leukemia cell differentiation was determined by NBT assay. Apoptosis and related mechanisms were investigated by western blotting. RESULTS: GC-MS analysis confirmed that the two most abundant constituents, diallyl disulfide (DADS) and diallyl trisulfide (DATriS), constituted 80% of the composition. GEO and DADS exhibited the best effects in terms of significant production of intracellular reactive oxygen species (ROS), induction apoptosis and potentiation differentiation of human promyelocytic leukemia cell line HL-60 cells. The GEO-mediated apoptosis was alleviated by the free radical scavenger N-acetyl-L-cysteine (NAC). CONCLUSION: The anti-leukemia activity of GEO and organosulfur compound DADS through the action of ROS elevation was herein confirmed.

SiO2@Cu7S4 nanotubes for photo/chemodynamic and photo-thermal dual-mode synergistic therapy under 808 nm laser irradiation.

Photodynamic therapy (PDT) is a light-based modality for tumor treatment that involves the generation of reactive oxygen species (ROS) by the combination of light, a photosensitizer, and molecular oxygen. Nevertheless, the therapeutic effects of PDT are limited by hypoxic conditions that worsen with oxygen consumption during the PDT process. Photo/chemodynamic therapy (PCDT) based on the Fenton reaction is one strategy to improve ROS generation, provided a highly effective Fenton reagent is developed. In this research, SiO2@Cu7S4 nanotubes (NTs) were synthesized as a PCDT agent. This double-valence metal-sulfide composite material can react with H2O2 at the tumor site. SiO2@Cu7S4 NTs can produce more ROS than the traditional PDT agents, and besides, they can also be used as a photothermal therapy (PTT) agent. SiO2@Cu7S4 NTs will trigger the PTT effect under 808 nm irradiation and generate a large amount of heat to eradicate cancer cells. This heat will also promote the PCDT effect by increasing the reaction rate. Thus, the SiO2@Cu7S4 NT is a suitable material for PCDT and PTT synergistic oncotherapy. The 808 nm laser is selected as the appropriate excitation source, providing adequate penetration and minimal harm to normal cells. The experimental data presented herein demonstrate the promising photosensitive, Fenton-like, and photothermal performance of SiO2@Cu7S4 NTs. Furthermore, the findings could promote the development of PCDT and PTT synergistic therapy. Thus, this research provides a feasible method to design a single, multifunctional material for cancer treatment.

Hairy Garlic (Allium subhirsutum) from Sicily (Italy): LC-DAD-MSn Analysis of Secondary Metabolites and In Vitro Biological Properties.

Allium subhirsutum, known as hairy garlic, is a bulbous plant widespread in the Mediterranean area and locally used as a food and spice. In the present study, the chemical profile of the ethanolic extracts from bulbs (BE) and aerial parts (APE) were analyzed by HPLC-ESI-MSn, and antioxidant properties were evaluated by DPPH, ABTS and TEAC assays. The traditional use in the diet, and the well documented biological activity of Allium species suggest a potential as a new nutraceutical. For this reason, the potential usefulness of this food can be considered in the treatment and prevention of degenerative Alzheimer disease. For this reason, acetylcholinesterase inhibitory property was investigated. Furthermore, due to the observed presence of sulfur-containing and phenolic constituents, the cytotoxicity on tumor cells line was investigated. Results revealed significant AChE inhibitory activity for BE and APE. Both extracts exhibited also moderate antioxidant properties in the in vitro assays. Finally, limited cytotoxic activity was observed towards Human colon carcinoma and adenocarcinoma cell line, with differences between the individual parts tested. HPLC-ESI-MSn analysis showed that hairy garlic is a good source of sulphur compounds, flavonoids and phenylpropanoids derivatives, thus being a valid alternative to the common garlic (A. sativum). This work opens new opportunities for the application of A. subhirsutum as a health-promoting food.

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs.

Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H2S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H2S/SS in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H2S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H2S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H2S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H2S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H2S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new "supramolecular tuning" paradigm.

Photo-inactivation of bacteria in hospital effluent via thiolated iron-doped nanoceria.

Hospital wastewater is a major contributor of disease-causing microbes and the emergence of antibiotic resistant bacteria. In this study, thiolated iron-doped nanoceria was synthesised and tested for killing of microbes from hospital effluent. These particles were designed to inhibit the efflux pumps of the bacteria found in hospital effluent with further ability to activate in visible light via iron doping thus generating tunable amount of reactive oxygen species (ROS). The quantum yield of the ROS generated by the nanoceria was 0.67 while the ROS types produced were singlet oxygen (36%), hydroxyl radical (31%) and hydroxyl ions (32%), respectively. The particles were initially synthesised through green route using Foeniculum vulgare seeds extract and were annealed at 200°C and further coated with thiolated chitosan to enhance the solubility and efflux pump inhibition. X-ray diffraction confirmed the polycrystalline nature of nanoparticles and uniform spherical shape with 30 nm size, confirmed by scanning electron microscope. The nanoparticles exhibited 100% bactericidal activity at 100 µg/mL against all the isolated bacteria. The enhanced bactericidal effect of iron-doped nanoceria could be attributed to efflux inhibition via thiolated chitosan as well as the production of ROS upon illumination in visible light, causing oxidative stress against microbes found in hospital effluent.

Activity of methylgerambullin from Glycosmis species (Rutaceae) against Entamoeba histolytica and Giardia duodenalis in vitro.

Entamoeba histolytica and Giardia duodenalis are widespread intestinal protozoan parasites which both spread via cysts that have to be ingested to infect a new host. Their environment, the small intestine for G. duodenalis and the colon for E. histolytica, contains only very limited amounts of oxygen, so both parasites generate energy by fermentation and substrate level phosphorylation rather than by oxidative phosphorylation. They both contain reducing agents able to reduce and activate nitroimidazole drugs such as metronidazole which is the gold standard drug to treat Entamoeba or Giardia infections. Although metronidazole works well in the majority of cases, it has a number of drawbacks. In animal models, the drug has carcinogenic activity, and concerns about a possible teratogenic activity remain. In addition, the treatment of G. duodenalis infections is hampered by emerging metronidazole resistance. Plant-derived drugs play a dominant role in human medicine, therefore we tested the activity of 14 isolated plant compounds belonging to seven different classes in vitro against both parasites. The tests were performed in a new setting in microtiter plates under anaerobic conditions. The compound with the highest activity was methylgerambullin, a sulphur-containing amide found in Glycosmis species of the family Rutaceae with an EC50 of 14.5 µM (6.08 µg/ml) after 24 h treatment for E. histolytica and 14.6 µM (6.14 µg/ml) for G. duodenalis. The compound was successfully synthesised in the laboratory which opens the door for the generation of new derivatives with higher activity.

Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds.

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/ß (GSK-3α/ß), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.

An overview of organosulfur compounds from Allium spp.: From processing and preservation to evaluation of their bioavailability, antimicrobial, and anti-inflammatory properties.

The use of Allium species and their extracts has been known since immemorial times due to their health beneficial properties. It is known that functional properties of Allium genus come from the high content of bioactive compounds. The biological activity of Allium extracts will be conditioned by the type of Allium variety, agricultural conditions, and specific extraction process used since all these factors affect the content and the profile of bioactive compounds. Innovative extraction techniques in comparison to conventional processes could be considered as a promising tool to recover bioactive compounds from Allium spp. with antimicrobial and anti-inflammatory properties. Trying to fill the gap in the literature, this paper reviews the chemical composition, the effects of processing on the nutritional and bioactive composition of Allium species and their extracts. Moreover, the antimicrobial and anti-inflammatory effects, as well as the bioavailability of bioactive compounds of edible members from the Allium genus is discussed.

Organosulfur compounds induce cytoprotective autophagy against apoptosis by inhibiting mTOR phosphorylation activity in macrophages.

Organosulfur compounds (OSCs) are the bioactive components of garlic. Some OSCs have apoptotic or autophagy-inducing effects. Autophagy plays roles in both cytoprotection and apoptosis-related cell death, and the interaction between autophagy and apoptosis is important in the modulation of immune responses. The mechanism of an OSC-mediated effect via the interaction of autophagy and apoptosis is unknown. In this study, the effects of five OSC compounds on autophagy in the macrophage cell line RAW264.7 and primary macrophages were investigated. We found that S-allylcysteine (SAC), diallyl disulde (DADS) and diallyl tetrasulfide (DTS) treatment increased the number of autophagosomes of RAW264.7 cells, inhibited the phosphorylation of ribosomal protein S6 kinase beta-1 (p70S6K/S6K1) which is a substrate of mammalian target of rapamycin (mTOR), and significantly enhanced autophagy flux. The induction of autophagy by SAC, DADS and DTS was inhibited by stably knocking down the expression of autophagy-related gene 5 (ATG5) with short hairpin RNA (shRNA). Further experiments confirmed that SAC, DADS and DTS also induced apoptosis in RAW264.7 cells. The induction of apoptosis and Caspase 3 activity by SAC, DADS and DTS were increased by stably knocking down of ATG5 expression with shRNA in RAW264.7 cells or treating with 5 mM 3-MA in primary macrophages. Our results suggest that SAC, DADS and DTS induce both autophagy and apoptosis. The autophagy induction protects macrophages from apoptosis by inhibiting mTOR phosphorylation activity to maintain the mass of immune cells.