Effects Of Diallyl Sulfide Research Articles

Diallyl trisulfide attenuates Pseudomonas aeruginosa virulence via inhibiting quorum sensing

Diallyl trisulfide (DATS), diallyl disulfide (DADS), and diallyl sulfide (DAS), three sulfur-rich compounds commonly found in garlic, can inhibit Pseudomonas aeruginosa quorum sensing (QS). We previously reported the inhibitory effects of DAS and DADS on the PAO1 QS system. To delineate any differences in QS inhibitory mechanisms among these three compounds and further verify their functional chemical groups, the QS-inhibitory effects and mechanism of DATS on P. aeruginosa PAO1 were investigated based on transcriptomic analysis, qRT-PCR, and physiological and chemical experiments in this study. The results indicated that DATS was mildly toxic to P. aeruginosa PAO1 and inhibited its growth slightly in a dose-dependent manner. Furthermore, DATS downregulated the transcriptional levels of all key genes involved in PAO1 QS systems, including lasI/lasR, rhlI/rhlR, and pqsABCDEH/pqsR, and downregulated the transcriptional levels of some related virulence genes, including the genes encoding exoprotease, elastase, lectin, and rhamnolipids, as well as those involved in PQS, pyocyanin biosynthesis, and biofilm formation. As a result, the production of related virulence factors by the PAO1 strain decreased upon DATS exposure. Therefore, DATS attenuated P. aeruginosa virulence and pathogenicity by inhibiting its QS systems. Through a comparative analysis of the QS-inhibitory effects of DATS, DADS, and DAS on the PAO1 strain, DATS was found to have the strongest QS-inhibitory activity, followed by DADS and DAS. In conclusion, the inhibitory activities of these sulfur compounds against P. aeruginosa QS and virulence were related to the thioether and disulfide groups, which increase with an increase in the number of sulfur atoms in the chemical formula. These findings are of great significance for the control of P. aeruginosa virulence and pathogenicity in the future.

Tobacco carcinogen 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone (NNK) drives metabolic rewiring and epigenetic reprograming in A/J mice lung cancer model and prevention with diallyl sulphide (DAS).

Early detection of biomarkers in lung cancer is one of the best preventive strategies. Although many attempts have been made to understand the early events of lung carcinogenesis including cigarette smoking (CS) induced lung carcinogenesis, the integrative metabolomics and next-generation sequencing approaches are lacking. In this study, we treated the female A/J mice with CS carcinogen 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone (NNK) and naturally occurring organosulphur compound, diallyl sulphide (DAS) for 2 and 4 weeks after NNK injection and examined the metabolomic and DNA CpG methylomic and RNA transcriptomic profiles in the lung tissues. NNK drives metabolic changes including mitochondrial tricarboxylic acid (TCA) metabolites and pathways including Nicotine and its derivatives like nicotinamide and nicotinic acid. RNA-seq analysis and Reactome pathway analysis demonstrated metabolism pathways including Phase I and II drug metabolizing enzymes, mitochondrial oxidation and signaling kinase activation pathways modulated in a sequential manner. DNA CpG methyl-seq analyses showed differential global methylation patterns of lung tissues from week 2 versus week 4 in A/J mice including Adenylate Cyclase 6 (ADCY6), Ras-related C3 botulinum toxin substrate 3 (Rac3). Oral DAS treatment partially reversed some of the mitochondrial metabolic pathways, global methylation and transcriptomic changes during this early lung carcinogenesis stage. In summary, our result provides insights into CS carcinogen NNK's effects on driving alterations of metabolomics, epigenomics and transcriptomics and the chemopreventive effect of DAS in early stages of sequential lung carcinogenesis in A/J mouse model.

Estrogen receptor-α36 is involved in diallyl sulfide-induced inhibition of malignant growth of HepG2 and Huh7 hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly malignant disease that currently lacks effective treatment. Epidemiological studies have suggested the preventive role of raw garlic intake in different tumors, such as HCC. Although diallyl sulfide (DAS), the main component of garlic extracts, has been reported to inhibit the growth of HCC cells, the underlying mechanism remains elusive. This study aimed to investigate the inhibitory effect of DAS on the growth of HepG2 and Huh7 hepatocellular carcinoma cells and its underlying mechanism. HepG2 and Huh7 cells were treated with DAS and nude mice were intrahepatically injected with human HCC HepG2 cells and maintained with or without DAS administration for 28 days. MTS and clonogenic assays revealed that DAS inhibited the growth and clonogenicity of HepG2 and Huh7 hepatocellular carcinoma cells. Furthermore, DAS inhibited the growth of xenograft tumors accompanied by a decreased rate of pathological karyomitosis as observed by H&E staining. The expression levels of estrogen receptor-α36 (ER-α36) and epidermal growth factor receptor (EGFR) in HepG2 and Huh7 cells and in xenograft tumors derived from HepG2 cells after DAS treatment were detected by immunohistochemistry and western blotting. We found that DAS disrupted the positive regulatory loop between ER-α36 and EGFR, and decreased the phosphorylation of AKT at Ser 473 both in vivo and in vitro. DAS also induced cell apoptosis, as evidenced by Hoechst and TUNEL staining. Western blotting revealed activation of caspase3, increased BAX and decreased Bcl-2 expression. However, the ER-α36 expression knockdown attenuated DAS-induced ERK and AKT phosphorylation in HCC cells. DAS was also able to inhibit ER-α36-mediated activation of the MAPK/ERK signaling induced by estrogen. Thus, our results indicate that ER-α36 signaling is involved in DAS-induced inhibition of HCC cell growth both in vitro and in vivo.

Diallyl sulfide protects against dilated cardiomyopathy via inhibition of oxidative stress and apoptosis in mice

Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnTR141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS-induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria-dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin-converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.

Diallyl Sulfide Attenuation of Carcinogenesis in Mammary Epithelial Cells through the Inhibition of ROS Formation, and DNA Strand Breaks.

Garlic has long been used medicinally for many diseases, including cancer. One of the active garlic components is diallyl sulfide (DAS), which prevents carcinogenesis and reduces the incidence rate of several cancers. In this study, non-cancerous MCF-10A cells were used as a model to investigate the effect of DAS on Benzo (a)pyrene (BaP)-induced cellular carcinogenesis. The cells were evaluated based on changes in proliferation, cell cycle arrest, the formation of peroxides, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, the generation of DNA strand breaks, and DNA Polymerase β (Pol β) expression. The results obtained indicate that when co-treated with BaP, DAS inhibited BaP-induced cell proliferation (p < 0.05) to levels similar to the negative control. BaP treatment results in a two-fold increase in the accumulation of cells in the G2/M-phase of the cell cycle, which is restored to baseline levels, similar to untreated cells and vehicle-treated cells, when pretreated with 6 μM and 60 μM DAS, respectively. Co-treatment with DAS (60 μM and 600 μM) inhibited BaP-induced reactive oxygen species (ROS) formation by 132% and 133%, respectively, as determined by the accumulation of H2O2 in the extracellular medium and an increase in 8-OHdG levels of treated cells. All DAS concentrations inhibited BaP-induced DNA strand breaks through co-treatment and pre-treatment methods at all time points evaluated. Co-Treatment with 60 μM DAS increased DNA Pol β expression in response to BaP-induced lipid peroxidation and oxidative DNA damage. These results indicate that DAS effectively inhibited BaP-induced cell proliferation, cell cycle transitions, ROS, and DNA damage in an MCF-10A cell line. These results provide more experimental evidence for garlic’s antitumor abilities and corroborate many epidemiological studies regarding the association between the increased intake of garlic and the reduced risk of several types of cancer.

The effect of diallyl sulfide on the lung tissue of rats poisoned by paraquat

Objective: To investigate the mechanism of diallyl sulfide (DAS) on paraquat (PQ) - induced acute lung injury in rats. Methods: In May 2016, 32 adult male Wistar rats were randomly divided into control group, model (PQ) group, DAS treatment group and dexamethasone (DXM) treatment group, with 8 rats in each group. PQ poisoning model was established by intragastric administration of PQ solution (70 mg/kg) . 100 mg/kg DAS (DAS treatment group) , normal saline (control group and PQ group) and 1 mg/kg DXM (DXM treatment group) were injected intraperitoneally before and after modeling. After 24 hours, the rats were killed and the degree of lung injury was observed. The expression of inducible nitric oxide synthase (iNOS) in lung tissue was measured. Alveolar macrophages were isolated and cultured. The supernatant was taken to determine the content of NO, and the expressions of iNOS mRNA in alveolar macrophages were detected. Results: Compared with the control group, the pathological injury score and the expression of iNOS in the lung tissue of PQ group were significantly increased, and the content of NO secreted by alveolar macrophages and the expression of iNOS mRNA were significantly increased (P<0.05) . Compared with PQ group, the pathological injury scores and the expressions of iNOS in lung tissue of rats in DAS treatment group and DXM treatment group were significantly decreased, and the contents of NO secreted by alveolar macrophages and the expressions of iNOS mRNA were significantly decreased (P<0.05) . There was no significant difference between DXM group and DAS group (P>0.05) . Conclusion: DAS may have protective effect on acute lung injury induced by PQ in rats.

Diallyl sulfide from garlic suppresses quorum‐sensing systems of Pseudomonas aeruginosa and enhances biosynthesis of three B vitamins through its thioether group

Diallyl sulfide (DAS) and diallyl disulfide (DADS), two constituents of garlic, can inhibit quorum sensing (QS) systems of Pseudomonas aeruginosa. However, the differences in the mechanism of QS inhibition between DAS and DADS, and the functional chemical groups of these sulfides that contribute in QS inhibition have not been elucidated yet. We assumed that the sulfide group might play a key role in QS inhibition. To prove this hypothesis and to clarify these unsolved problems, in this study, we synthesized diallyl ether (DAE), and compared and investigated the effects of DAS and DAE on the growth and production of virulence factors, including Pseudomonas quinolone signal (PQS), elastase and pyocyanin, of P. aeruginosa PAO1. Transcriptome analysis and qRT-PCR were used to compare and analyse the differentially expressed genes between the different treatment groups (DAS, DAE and control). The results indicated that DAS did not affect the growth dynamics of P. aeruginosa PAO1; however, DAS inhibited transcription of most of the QS system genes, including lasR, rhlI/rhlR and pqsABCDE/pqsR; thus, biosynthesis of the signal molecules C4 -HSL (encoded by rhlI) and PQS (encoded by pqsABCDE) was inhibited. Furthermore, DAS inhibited the transcription of virulence genes regulated by the QS systems, including rhlABC, lasA, lasB, lecA and phzAB, phzDEFG, phzM and phzS that encode for rhamnolipid, exoprotease, elastase, lectin and pyocyanin biosynthesis respectively. DAS also enhanced the expression of the key genes involved in the biosynthesis of three B vitamins: folate, thiamine and riboflavin. In conclusion, DAS suppressed the production of some virulence factors toxic to the host and enhanced the production of some nutrition factors beneficial to the host. These actions of DAS may be due to its thioether group. These findings would be significant for development of an effective drug to control the virulence and pathogenesis of the opportunistic pathogen P. aeruginosa.

Relaxant effect of diallyl sulfide on nonpregnant rat uterus: Involvement of voltage-dependent calcium channels.

We aimed to determine the effect and mechanism of action of diallyl sulfide (DAS), an active component of sulfur-containing foods such as garlic on rat uterine activity. Isometric tension changes in longitudinal uterine strips obtained from 20 female Sprague-Dawley rats (250-300 g) in estrus stage of estrous cycle were studied in isolated organ baths containing Krebs-Henseleit solution. Diallyl sulfide (10-8 -10-6 M) caused a concentration-dependent relaxation on KCl (60 mM)-induced contractions and inhibited spontaneous peristaltic activity of uterine strips (P < 0.05). None of the following antagonists significantly changed the inhibitory effect of DAS on both KCl-precontracted uterine strips and spontaneous peristaltic activity of the uterus (P > 0.05): nitric oxide synthase inhibitor L-NAME (10-4 M), hydrogen sulfide-producing enzymes cystation β synthase and cystation γ-lyase inhibitors, aminooxyacetic acid (10-4 M) and propargylglycine (10-3 M) and nonselective cyclooxygenase inhibitor indomethacin (10-4 M). However, in calcium-free Krebs solution containing high KCl (30 mM), DAS significantly inhibited CaCl2 (10-5 -10-2 M)-induced uterine contractions in a concentration-dependent manner (P < 0.05). Diallyl sulfide has a relaxing effect on KCl-contracted rat uterus strips and an inhibitory effect on spontaneous uterine activity, possibly by decreasing the calcium influx into the cytoplasm of uterine smooth muscle cells.

Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats

Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.

Inhibitory effects of diallyl sulfide on the activation of Kupffer cell in lipopolysaccharide/d-galactosamine-induced acute liver injury in mice

Abstract Diallyl sulfide (DAS) is an effective bioactive organosulfur compound extracted from garlic. This study aimed to explore whether the protective effect of DAS on lipopolysaccharide (LPS)/ d -galactosamine ( d -GalN) induced acute liver injury was associated with the regulation of Kupffer cell (KC) activation. The results indicated that DAS administration protected mice from LPS/D-GalN-induced histopathological damage and serum aminotransferase elevation and also showed more pronounced beneficial effects than GdCl3 administration. The F4/80+ or CD11b+ KC immunohistochemistry results showed that DAS administration suppressed LPS/D-GalN-induced KC activation. DAS administration also suppressed LPS/D-GalN-triggered production of TNF-α, IL-1β, MCP-1 and NO in the liver or serum, which was in line with the mRNA expression of TNF-α, IL-1β, IL-6, MCP-1 and iNOS in the liver. Taken together, these findings reveal that the protective effects of DAS on LPS/D-GalN-induced acute liver injury may be achieved by inhibiting the activation of KC, thereby suppressing the secretion of various proinflammatory mediators.

The Protective Effect of DAS and DADS Against Doxorubicin Induced Toxicity

PurposeCancer survival rates are increasing but the mechanisms involved in the adverse effects of cancer therapy such as doxorubicin are still being investigated along with treatment for these effects. Doxorubicin, an established chemotherapeutic agent used for various cancers, has limited use due to cardiotoxicity. The objective of this study, is to determine how garlic constituents, Diallyl sulfide (DAS) and Diallyl disulfide (DADS) may decrease the adverse effects of doxorubicin exposure.With a S. cerevisiae deletion library, a genome wide screen was conducted to detect mutants sensitive to doxorubicin exposure. A mutant deleted for the gene enconding for Mac1, a copper sensing transcription factor, was found to be highly sensitive. In S. cerevisiae the MAC1 gene is activated upon copper deficiency, resulting in the induction of copper transporters. Other doxorubicin sensitive strains included the sod1 mutant and its copper chaperone ccs1 mutant, both of which are associated with MAC1. The sensitivity of the mutant strains to doxorubicin, was in part due to the drug's capacity to generate reactive oxygen species (ROS). To test if garlic constituents, DAS and DADS could reduce the sensitivity of the mutants to ROS, the viability of the sensitive yeast strains were determined by exposing them to doxorubicin in the presence or absence of DAS and DADS.MethodsYeast survival assays were completed to determine the sensitivity of wt, mac1, ccs1, and sod1 strains to doxorubicin, menadione and etoposide, co‐treated with DAS and DADS. Statistical significance was set at p&lt;0.05.Resultsmac1 shows sensitivity to doxorubicin and etoposide but not menadione. Menadione contains a quinone ring like doxorubicin, and acts through the induction of reactive oxygen species. Etoposide, a chemotherapeutic agent acts only through inhibition of DNA topoisomerase II. The sensitivity of mac1 to both etoposide and doxorubicin, shows that doxorubicin's sensitivity to mac1 is through its action on topoisomerase II. Unlike DAS, DADS was able to decrease the sensitivity of mac1 to doxorubicin and etoposide. Menadione has greater toxicity to ccs1 and sod1 than doxorubicin and etoposide, with DAS and DADS both increasing the survival of all chemicals to ccs1 and sod1.ConclusionGarlic constituents, das and dads may decrease the adverse effects of doxorubicin exposure, improving the quality of life of patients expose to doxorubicin.Support or Funding InformationResearch supported by National Institutes of Health (NIH) under Award Number G12MD007582This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diallyl sulfide protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice

The effects of diallyl sulfide (DAS) and the potential mechanisms were investigated on lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced acute liver injury in mice. DAS (50, 100, 200 μmol/kg) were orally given 1 h prior to LPS (10 μg/kg)/D-GalN (500 mg/kg) intraperitoneal injection. Serum and liver were collected at 8 h after LPS/D-GalN treatment. DAS Pretreatment reduced the activities of serum aminotransferase and attenuated histopathological damage in LPS/D-GalN-induced liver injury. Additionally, LPS/D-GalN-induced liver oxidative stress was ameliorated by DAS pretreatment, as evidenced by the decreased content of MDA and increased level of GSH, SOD, CAT in liver. Moreover, LPS/D-GalN-induced the excessive levels of TNF-α, IL-1β and MCP-1 in serum and liver was decreased by DAS pretreatment. Furthermore, DAS pretreatment attenuated LPS/D-GalN-induced hepatocyte apoptosis, as evidenced by TUNEL staining and protein expression of cleaved caspase3, Bax and Bcl-2 in liver. DAS also up-regulated the expression of p-PI3K p85 and p-Akt in a dose-dependent manner, and Akt inhibitor MK-2206 weakened the inhibitory effect of DAS on hepatocyte apoptosis induced by LPS/D-GalN. In conclusion, the results suggest that DAS exerts the protective effect on LPS/GalN-induced acute liver injury, and this effects possibly by suppressing oxidative stress, inflammation and regulating hepatocyte apoptosis via the PI3K/Akt pathway.

Thymoquinone and diallyl sulfide protect against fipronil-induced oxidative injury in rats.

Fipronil (FPN) is a phenylpyrazole insecticide, widely used for agricultural and veterinary activities. Early reports indicated that FIP organ toxicity is primarily mediated by the induction of oxidative stress. Both thymoquinone (TQ) and diallyl sulfide (DAS) are natural antioxidants with established health benefits. This study investigated the potential ameliorative effects of DAS and TQ against FPN-induced toxicity in rats. Thirty-two male Wistar rats (150-180g) were randomized into four treatment groups, receiving (I) saline, (II) FPN (10mg/kg bw), (III) FPN with DAS (200mg/kg bw), and (IV) FPN with TQ (10mg/kg bw). All treatments were administered once daily for 28days. The results showed that compared to the control rats, FPN-treated rats had significantly increased (p < 0.05) serum levels of uric acid, urea, creatinine, cholesterol, aspartate transferase, alanine transferase, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transferase. Moreover, FPN significantly reduced (p < 0.05) the serum levels of total proteins, albumin, and triglycerides. In addition, compared with the control group, FPN-treated rats had significantly elevated (p < 0.05) malondialdehyde and nitric oxide levels, as well as significantly reduced glutathione concentration and activities of glutathione peroxidase, superoxide dismutase, and catalase enzymes in the hepatic, renal, and brain tissues. Cotreatment with DAS or TQ significantly ameliorated (p < 0.05) the FPN-induced alterations in all the previously mentioned parameters with more frequent restoration of normal control ranges in the TQ group. In conclusion, both DAS and TQ alleviated the oxidative injury of FPN, probably by enhancing tissue antioxidant defenses.

Diallyl sulfide alleviates cisplatin-induced nephrotoxicity in rats via suppressing NF-κB downstream inflammatory proteins and p53/Puma signalling pathway.

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo-sulfide, present in garlic, in cisplatin-induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno-protective effect of DAS in cisplatin-induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100mg/kg, orally for 4 consecutive days, starting 1hour after administration of single dose of cisplatin (3.5mg/kg, intraperitoneally [i.p.]). The Cis-induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co-treated with DAS. In addition, DAS significantly restored Cis-depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis-elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis-increased renal expression of nuclear factor kappa B (NF-κB) and subsequent pro-inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co-treatment with DAS significantly inhibited Cis-increased caspase-8 and -9 levels. Additionally, DAS significantly mitigated Cis-induced protein expression of p53, Puma, and Bax while, it significantly restored Cis-reduced protein expression of Bcl-xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin-induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.

Evaluating the effect of diallyl sulfide on regulation of inflammatory mRNA expression in 3T3L1 adipocytes and RAW 264.7 macrophages during ethanol treatment

Diallyl sulfide (DAS) has been studied extensively for its alleged role as an anticancer and protective agent. Alcohol influences and effects on human health have been extensively studied. However, investigations toward developing and testing therapeutic agents that can reduce the tissue injury caused by ethanol are scarce. In this backdrop, this study was designed to explore the potential effect of DAS in reducing alcohol induced damage of 3T3L1 adipocytes and RAW 264.7 macrophages. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed to determine the DAS effect on cell viability. Reactive oxygen species (ROS) production was assessed by flow cytometer. Expression of inflammatory genes was studied by the qRT-PCR method. Our study results showed that DAS at concentrations less than 200 μM was not toxic to the cells and the viability of ethanol-exposed 3T3L1 adipocyte cells was found to be significantly increased when ethanol-exposed cells were treated with DAS. Further, treatment of ethanol-exposed 3T3L1 cells with 100 μM DAS for 24 h was found to reduce ethanol induced ROS production, expression of pro-inflammatory cytokines, and enhance anti-inflammatory cytokine production in the cells. Also, 100 μM DAS was found to increase the expression of M2 phenotype-specific genes in ethanol-exposed RAW 264.7 macrophage cells. Further, 100 μM DAS also improved the levels of lipid accumulation in 3T3L1 adipocytes that was down-regulated by ethanol exposure. Taken together, our study results imply that DAS may be effective in reducing ethanol induced injury of cells thereby suggesting its potential to be used in drug formulations.

Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis, and decreases breast cancer metastasis.

Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1α (HIF-1α) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1α protein due to von Hippel-Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1α target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1α transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells. It reduced the protein expression of HIF-1α, which did not involve inhibition of HIF-1α mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1α expression was required for DATS to resist breast cancer.

Study on the Combined Effects of Diallyl Sulfide, Cisplatin, and Celecoxib on Cervical Carcinoma HeLa Cells

Study on the Combined Effects of Diallyl Sulfide, Cisplatin, and Celecoxib on Cervical Carcinoma HeLa Cells

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells invitro and invivo, suggesting it to be a novel therapeutic agent for the treatment of PEL.

Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide.

Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125-150 g were given a single dose of Fe-NTA (9 mg kg(-1) body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg(-1) DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2-2.5-fold. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of DAS. DAS protected against hepatic lipid peroxidation, hydrogen peroxide generation, preserved GSH levels, and GSH metabolizing enzymes to 60-80% as compared to Fe-NTA alone-treated group. Present data suggest that DAS can ameliorate the toxic effects of Fe-NTA and suppress oxidant-induced tissue injury and hepatotoxicity in rats.

Pretreatment with diallylsulphide modulates mercury-induced neurotoxicity in male rats.

Many studies have reported on the toxicity and related oxidative stress of mercury. Antioxidants play an important role in counteracting metal-induced neurotoxicity under in vivo conditions. In this study, the effect of diallylsulphide (DAS) was evaluated on mercuric chloride induced activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione content in brains of rats. Pretreatment of rats with DAS in the Hg-treated group also inhibited an increase in lipid peroxidation and elevated acetyl cholinesterase and glutathione content. Activities of antioxidant enzymes were also restored concomitantly when compared to the control rats after DAS administration. DAS also caused a decrease in tumor necrosis factor-α level which was higher in HgCl2-treated group. The results indicate that DAS augments antioxidant defense with anti-inflammatory response against HgCl2-induced neurotoxicity. The increased level of antioxidant enzymes enhances the antioxidant potential of the organ to reduce oxidative stress.