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Yogeshwer Shukla - One of the best experts on this subject based on the ideXlab platform.

  • Diallyl Sulfide and its role in chronic diseases prevention
    Advances in Experimental Medicine and Biology, 2016
    Co-Authors: Shankar Suman, Yogeshwer Shukla
    Abstract:

    Diallyl Sulfide (C6H10S, DAS) is one of the novel natural organosulfur compounds, which is mostly obtained from the genus Allium plants. Numerous studies have revealed several unique properties of DAS in terms of its health-promoting effects. DAS has proved to be anticancer, antimicrobial, anti-angiogenic, and immunomodulatory like unique functions as demonstrated by the multiple investigations. Diallyl Sulfide can also impede oxidative stress and chronic inflammation as suggested by the literature. Studies also explored that DAS could thwart the development of chronic diseases like cancer, neuronal, cardiovascular disease through modulating mechanistic pathways involved in pathogenesis. In this book chapter, we have attempted to give the comprehensive view on DAS about the physiochemical and biological properties, and its preventive role in chronic diseases with a mechanistic overview.

  • synergistic growth inhibition of mouse skin tumors by pomegranate fruit extract and Diallyl Sulfide evidence for inhibition of activated mapks nf κb and reduced cell proliferation
    Food and Chemical Toxicology, 2011
    Co-Authors: Jasmine George, Madhulika Singh, Amit Kumar Srivastava, Kulpreet Bhui, Yogeshwer Shukla
    Abstract:

    Limited outcomes from earlier chemopreventive studies have necessitated that some modifications be made to get better efficacy. It is proposed that cancer prevention is more feasible than treatment, and this could be achieved effortlessly with use of multiple agents competent of targeting multiple targets. This study was initiated to examine the chemopreventive efficacy of pomegranate fruit extract (PFE) and Diallyl Sulfide (DAS), alone and in combination, using 2-stage mouse skin tumorigenesis model. PFE and DAS alone delayed onset and tumor incidence by ∼55% and ∼45%, respectively, while their combination at low doses synergistically decreased tumor incidence more potentially (∼84%, p<0.01). In addition, regression in tumor volume was seen with continuous combinatorial treatment (p<0.01). Mechanistic studies revealed that this inhibition was associated with decreased expression of phosphorylated ERK1/2, JNK1 and activated NF-κB/p65, IKKα, IκBα phosphorylation and degradation in skin tissue/tumor. Histological and cell death analysis also confirmed that combined PFE and DAS inhibit cellular proliferation and markedly induce apoptosis than the single agents. Altogether, our results suggest that PFE and DAS in combination impart better suppressive activity than either of these agents alone and provide support that development of novel combination therapies/chemoprevention using dietary agents will be more beneficial against cancer.

  • regulation of oxidative stress mediated apoptosis by Diallyl Sulfide in dmba exposed swiss mice
    Human & Experimental Toxicology, 2008
    Co-Authors: Sahdeo Prasad, Neetu Kalra, Satya P Srivastava, Yogeshwer Shukla
    Abstract:

    Diallyl Sulfide, a sulfur-containing volatile compound present in garlic (Allium sativum), exerts anticarcinogenic activity in various rodent tumor models. In the present study, apoptosis-inhibiting effects of Diallyl Sulfide against a carcinogenic polycyclic aromatic hydrocarbon, 7,12-dimethyl benz(a)anthracene (DMBA), in Swiss albino mice were observed. The animals were given either 250 microg/mouse or 500 mug/mouse of Diallyl Sulfide for 1 week after a single intragastric dose of 7,12-dimethyl benz(a)anthracene (50 mg/kg body weight). Results showed that Diallyl Sulfide supplementation effectively protects against 7,12-dimethyl benz(a)anthracene-induced oxidative stress, characterized by restored antioxidant enzyme levels (up to 64%) and lipid peroxidation (up to 25%). Flow cytometric analysis showed a reduction in apoptotic cell population in hypodiploid region in Diallyl Sulfide-supplemented animals. Inhibition of apoptosis was preceded by decrease in reactive oxygen species levels and restoration of mitochondrial transmembrane potential followed by decreased DNA fragmentation. In 7,12-dimethyl benz(a)anthracene-exposed animals, downregulation approximately 30%) of antiapoptotic Bcl-2 and upregulation (approximately 60%) of pro-apoptotic Bax proteins were observed. These alterations were restored significantly by Diallyl Sulfide supplementation, indicating inhibition of apoptosis. Thus, these results show that Diallyl Sulfide provides protection against oxidative damage induced by 7,12-dimethyl benz(a)anthracene in mouse liver and may be an effective chemopreventive and therapeutic agent by modulating expression of cell-growth regulatory proteins.

  • preventive effects of Diallyl Sulfide on 7 12 dimethylbenz a anthracene induced dna alkylation damage in mouse skin
    Molecular Nutrition & Food Research, 2007
    Co-Authors: Nidhi Nigam, Yogeshwer Shukla
    Abstract:

    Mutations that occur through DNA strand breaks are the prerequisites for the development of tumors, which ultimately leads to various genetic disorders including cancer. A number of naturally occurring compounds including certain dietary constituents play an important role in causation and prevention of a number of genetic diseases. Diallyl Sulfide (DAS), a volatile organosulfur compound present in garlic has been shown to possess various pharmacological effects including cancer preventive properties. Now we are reporting the antimutagenic properties of DAS on 7,12- dimethylbenz[a]anthracene (DMBA), a carcinogenic polycyclic aromatic hydrocarbon, induced DNA strand breaks in mouse skin, using an alkaline unwinding assay. DAS (2.5-10 mg/kg body-weight) was applied topically, prior and post to DMBA (5 mg/kg body-weight) at the sampling time of 24, 48, 72 and 96 h. DAS application resulted in a significant (p < 0.001) protection in DMBA-induced DNA strand breaks. The pre-treatment of DAS (10 mg/kg body-weight) showed 68.35% protection and post-treatment showed 59.49% protection, at an intermittent period of 48 h, against DMBA-induced DNA strand breakage. These findings suggest that DAS can effectively check the mutations induced by environmental toxicants.

  • Potential of Diallyl Sulfide bearing pH-sensitive liposomes in chemoprevention against DMBA-induced skin papilloma.
    Molecular Medicine, 2007
    Co-Authors: Arif Khan, Yogeshwer Shukla, Neetu Kalra, Maroof Alam, Manzoor Ahmad, Seema Hakim, Mohammad Owais
    Abstract:

    Diallyl Sulfide (DAS), an active component of garlic, possesses strong anti-neoplastic properties against various forms of cancer. In the present study, we have evaluated chemo-preventive effects of liposomized DAS (conventional egg PC and pH-sensitive liposomes) against DMBA-induced skin papilloma. Various liposome-based novel formulations of DAS (250 µg/mouse) were applied topically, after one hour of exposure to DMBA (52 µg/mouse/dose), to the animals. The animals were treated thrice weekly for the total period of 12 weeks. The efficacy of the various liposomal formulations of DAS was evaluated on the basis of parameters such as incidence of tumorogenesis and total numbers and sizes of induced tumor nodules. The liposomized DAS formulations also were assessed for their effect on the expression of p53wt, p53mut, and p21/Waf1. The results of the present study showed that liposomized DAS could effectively delay the onset of tumorogenesis and reduce the cumulative numbers and sizes of tumor papillomas in treated mice. Treatment of DMBA-exposed animals with the liposomal formulation of DAS ensued in up-regulation of p53wt and p21/Waf1, while levels of p53mut expression reduced down. The promising chemo-preventive nature of liposomal DAS may form the basis for establishing effective means of controlling various forms of cancer, including skin papilloma.

Annu Arora - One of the best experts on this subject based on the ideXlab platform.

  • regulation of p21 ras protein expression by Diallyl Sulfide in dmba induced neoplastic changes in mouse skin
    Cancer Letters, 2006
    Co-Authors: Annu Arora, Neetu Kalra, Yogeshwer Shukla
    Abstract:

    Diallyl Sulfide (DAS), a naturally occurring organoSulfide, present in garlic, is known to possess pleiotropic biological effects. DAS is known to inhibit chemically induced tumors in a number of animal models. The chemopreventive properties of DAS seem to occur through a number of mechanisms, but its role on primary events on oncogenic activation is not well understood. In the present study, we demonstrated the modulatory effect of DAS on the expression of H-ras gene product, p21/ras protein as one of the mechanisms of its chemopreventive action in chemically induced mouse skin tumors. Our results showed that DAS administration leads to modulation of the DMBA-induced levels of p21/ras oncoprotein as early as 24 h after the DMBA application, suggesting down-regulation of the p21/ras by DAS. Furthermore, the modulatory effects of DAS were also evident in DMBA-induced mouse skin tumors. DAS administration led to increase in the levels of cytosolic p21/ras and decrease in the levels of p21/ras in membrane fractions. DAS administration was also found to down regulate the DMBA-induced H-ras mRNA level in mouse skin tumors. The immunohistochemical staining of the skin/tumor showed 55.82 and 46.86% decrease in the area positive for p21/ras expression levels in DAS pre- and post-supplemented groups, respectively. Flow-cytometric analysis, further confirms our results as indicated by a shift in the mean fluorescence intensity (MFI) towards lower fluorescence in DAS administered groups in comparison to the DMBA treated group. Thus, one mechanism of the growth inhibitory properties of DAS is through the suppression of development of tumors that harbor ras mutations by inhibiting the membrane association of oncogenic p21/ras protein.

  • involvement of multiple signaling pathways in Diallyl Sulfide mediated apoptosis in mouse skin tumors
    Asian Pacific Journal of Cancer Prevention, 2006
    Co-Authors: Neetu Kalra, Annu Arora, Yogeshwer Shukla
    Abstract:

    Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of neoplastic conversion selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in pre-malignant cells, in which these pathways are still relatively intact, may be an effective module of cancer prevention. Diallyl Sulfide (DAS), a naturally occurring organoSulfide, present in garlic, is reported to have pleiotropic biological effects. DAS is known to inhibit chemically induced tumors in a number of in vivo and in vitro studies. The aberration of tumor suppressor gene, p53 and the ras oncogene have been linked to the induction of multiple signaling pathways and to the resistance offered by cancer cells to the apoptosis. Therefore, the present study was carried out to investigate the role of DAS on modulation of multiple p53 and ras-induced signaling pathways in 7,12-dimethylbenathacene (DMBA) induced skin carcinogenesis. The results showed that DAS up regulates expression of tumor suppressor protein p53 (wt p53) and its downstream target molecule p21/waf1. Proapoptotic protein, bax was upregulated by DAS supplementation. An opposite trend was observed in DMBA induced antiapoptotic proteins expressions, survivin and bcl-2, which were significantly downregulated by DAS supplementation. In the present study we also demonstrated that DAS supplementation significantly reduces the expression of ras oncoprotein and to modulate expression of its signaling molecules including PI3K/Akt and MAPKs. Western blot analysis demonstrated that DAS significantly reduced the DMBA induced protein expressions of PI3K/Akt and p38MAPK. However, DAS supplementation did not alter the expression JNK1 and ERK1/2. Thus, our results confirm that DAS can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of DMBA induced skin tumors in Swiss albino mice. Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in cancer chemoprevention by naturally occurring compounds.

  • modulation of p53 in 7 12 dimethylbenz a anthracene induced skin tumors by Diallyl Sulfide in swiss albino mice
    Molecular Cancer Therapeutics, 2004
    Co-Authors: Annu Arora, Imtiaz A Siddiqui, Yogeshwer Shukla
    Abstract:

    Allium vegetables have been shown to have beneficial health effects against several chronic diseases including cancer. Diallyl Sulfide (DAS), an organosulfur compound present in garlic, is well known for its chemopreventive properties in several tumor models. The pharmacologic role of DAS in prevention and treatment of cancer is well documented in the literature, but its molecular mechanism of action is not yet well defined. In the present study, modulation in p53 expression by topical application of DAS was recorded in 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumors in Swiss albino mice. Western blot analysis and immunohistochemical protein detection, combined with multivariable flow cytometry, show that DAS application induces the expression of the wild-type (wt) p53 and down-regulates the expression of mutant (mut) p53. Immunoblotting analysis of tumors showed significant increase in levels of wtp53 by DAS application, whereas for mutp53 the DMBA-induced levels of protein were found to reduce to near normal levels with DAS application. The quantitative analysis of immunostained skin/tumor sections using image analysis and quantitative stereology showed 66.6% and 54.2% increases in wtp53 levels and 53.4% and 44.3% decreases in mutp53 levels in animals where DAS was applied 1 hour prior to or 1 hour after DMBA application, respectively. Flow cytometric analysis further confirmed modulation of wtp53 and mutp53 protein in DAS-supplemented tumors. The increase in the expression of wt tumor suppressor gene protein p53 was accompanied by elevation of the levels of cyclin-dependent kinase inhibitor p21/waf1. The percentage increase in the levels of p21/waf1 was found to be 72.9% and 61.3%, respectively, in DAS-supplemented groups before and after administration. These results thus show that DAS is a potential chemopreventive agent capable of modulating and regulating the tumor suppressor p53 along with its downstream effective molecule, p21/waf1. Thus, DAS can be a potential chemopreventive agent against skin tumor development.

  • reversal of p glycoprotein mediated multidrug resistance by Diallyl Sulfide in k562 leukemic cells and in mouse liver
    Carcinogenesis, 2004
    Co-Authors: Annu Arora, Kavita Seth, Yogeshwer Shukla
    Abstract:

    Multidrug resistance (MDR) mediated by the overexpression of drug efflux protein P-glycoprotein (P-gp) is one of the major obstacles to successful cancer chemotherapy. P-gp acts as an energy-dependent drug efflux pump, reducing the intracellular concentration of structurally unrelated drugs. Modulators of P-gp function can restore the sensitivity of multidrug-resistant cells to such drugs. In the present study, we evaluated the P-gp modulatory potential of Diallyl Sulfide (DAS), a volatile organosulfur compound present in garlic, known to possess many medicinal properties, including antimutagenic and anticarcinogenic activities. For in vitro studies, K562 leukemic cells were made resistant (K562/R) to the cytotoxicity of vinblastine (VBL) by progressive adaptation of the sensitive K562 parental cells to VBL. Cross-resistance of K562/R was found between vincristine (VCR), doxorubicin and other antineoplastic agents. A non-toxic concentration of DAS (8.75 x 10(-3) M) enhanced the cytotoxic effects of VBL and another vinca alkaloid, VCR, time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on the parent (K562/S) cells. The results show that DAS decreased the induced levels of P-gp in resistant cells back to the normal levels as analyzed both qualitatively and quantitatively by western blotting and immunocytochemistry. Furthermore, in vivo combination studies showed that DAS effectively inhibited vinca alkaloid-induced P-gp overexpression in mouse hepatocytes. Quantitation of immunostained tissue sections with image analysis showed that the reduction in P-gp levels was up to 73% for VBL- and 65% for VCR-induced drug resistance. The above features thus indicate that DAS can serve as a novel, non-toxic modulator of MDR and can be used as a dietary adjuvant.

  • antitumorigenic potential of Diallyl Sulfide in ehrlich ascites tumor bearing mice
    Biomedical and Environmental Sciences, 2002
    Co-Authors: Yogeshwer Shukla, Annu Arora, Alka Singh
    Abstract:

    OBJECTIVE To study the effects of Diallyl Sulfide (DAS), an organosulfur compound present in garlic (Allium sativum), on the life span of ehrlich ascites (EA) tumor bearing Swiss albino mice, cytotoxicity and angiogenesis. METHODS EA tumor cells were maintained by serial transplantation in peritoneal cavity of male Swiss albino mice. EA tumor cells were inoculated at concentrations of 1 x 10(6) EA cells, 2.5 x 10(6) EA cells and 5 x 10(6) EA cells. DAS was given in 0.2 ml normal saline i.p., daily for seven days followed one hour later by inoculation with EA cells in respective groups. RESULTS The results revealed that administration of DAS increased the life span of EA tumor bearing animals by more than 25 percent. A significant dose dependant cytotoxic response of DAS was also observed on EA tumor cells. DAS was also found to inhibit the angiogenesis in EA tumor bearing mice in a dose dependent manner. CONCLUSION It is suggested that DAS may exert its anticarcinogenic effects by more than one mechanism and is a useful chemopreventive and chemotherapeutic agent.

Keqin Xie - One of the best experts on this subject based on the ideXlab platform.

  • Diallyl Sulfide induced attenuation of n hexane induced peripheral nerve impairment is associated with metabolic inhibition of n hexane
    Food and Chemical Toxicology, 2020
    Co-Authors: Shuo Wang, Qiong Wang, Zhidan Liu, Keqin Xie
    Abstract:

    Abstract Chronic exposure to n-hexane could induced serious peripheral nerve impairments. It has been well documented that the metabolic activation from n-hexane to 2,5-hexanedione (2,5-HD) is vital in the pathogenesis. Diallyl Sulfide (DAS) is an extract of garlic and able to block the bioactivation of xenobiotic. The current study was designed to investigate whether DAS can attenuate n-hexane induced neuropathy. Male Wistar rats were pretreated with DAS (50 or 100 mg/kg.bw) and then n-hexane (3 g/kg.bw) for 7 weeks. Behavioral performance, biomarker measurement and toxicokinetic studies were performed. Enzymatic methods and western blotting analyses were also conducted to investigate the hepatic phase I enzymes (including cytochrome P450(CYP)2E1, CYP1A1 and CYP2B1) and phase II enzymes (including glutathione S transferase theta 1 (GSTT1) and NA(D)PH dehydrogenase quinone 1 (NQO1)). The results showed that DAS improved the behavioral performance while reducing the toxic metabolite: 2,5-HD and pyrrole adducts. Besides, DAS reduced the expression of CYP2E1 with a proportional decrease in activity, which largely decreased the bioactivation of n-hexane in vivo. The results suggested that DAS decreased the toxic metabolites of n-hexane to attenuate n-hexane-induced peripheral neuropathy.

  • study on the effect of Diallyl Sulfide on peripheral nerve injury in n hexane intoxicated rats
    Chinese Journal of Industrial Hygiene and Occupational Diseases, 2020
    Co-Authors: Qi Wang, Z D Liu, N Zhao, Keqin Xie
    Abstract:

    Objective To investigate the antagonistic effect of Diallyl Sulfide (DAS) against peripheral nerve injury induced by n-hexane in rats. Methods A total of 68 adult male Wistar rats were selected, among which 50 were randomly selected and divided into blank control group, DAS control group (100 mg/kg·bw) , n-hexane model group, low-dose DAS intervention group (50 mg/kg·bw) , and high-dose DAS intervention group (100 mg/kg·bw) . A rat model of peripheral nerve injury was established by n-hexane exposure, and the rats were treated with DAS at different doses. The changes in pyrrole adducts and behavior were observed, a metabolic analysis was performed for serum pyrrole adducts, and the intervention effect was evaluated. The remaining 18 rats were randomly assigned to the n-hexane model group, the low-dose DAS intervention group, and the high-dose DAS intervention group, with 6 rats in each group, as satellite groups used for the toxicokinetic analysis of serum pyrrole adducts. Results Compared with the blank control group, the n-hexane model group and low-and high-dose DAS intervention groups had a significant reduction in body weight since week 2 (P 0.05) . The n-hexane model group developed gait abnormality at week 2 of poisoning, while the low-and high-dose DAS intervention groups developed gait abnormality at weeks 3 and 5 of poisoning, respectively. At the end of the experiment, the n-hexane model group and the low-and high-dose DAS intervention groups had a significantly higher gait score than the blank control group (P 0.05) . Compared with the n-hexane model group, the low-and high-dose DAS intervention groups had a significant increase in latency in rotarod test (P 0.05) , and compared with the n-hexane model group, the low-and high-dose DAS intervention groups had a significant increase in nerve conduction velocity (P 0.05) , and the high-dose DAS intervention group had a significantly lower concentration of pyrrole adducts in serum, urine, and hair than the low-dose DAS intervention group (P<0.05) . Serum pyrrole adducts reached the peak level at 9-12 hours and then started to decrease. Compared with the n-hexane model group, the high-and low-dose DAS intervention groups had a significantly shorter half-life period of serum pyrrole adducts (P<0.01) . Compared with the n-hexane model group, the high-and low-dose DAS intervention groups had a significant reduction in the area under the curve of serum pyrrole adducts (P<0.05) . Conclusion DAS can antagonize peripheral nerve injury induced by n-hexane. Key words: N-hexane; Poisoning; Rats; Diallyl Sulfide; Pyrrole adducts; Peripheral nerves; Nerve injury

  • inhibitory effects of Diallyl Sulfide on the activation of kupffer cell in lipopolysaccharide d galactosamine induced acute liver injury in mice
    Journal of Functional Foods, 2019
    Co-Authors: Shuo Wang, Qiong Wang, Zhidan Liu, Ruirui Kou, Keqin Xie
    Abstract:

    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 effects of Diallyl Sulfide das on benzene induced leukopenia in mice
    Chinese Journal of Industrial Hygiene and Occupational Diseases, 2019
    Co-Authors: Qi Wang, Z D Liu, Keqin Xie
    Abstract:

    Objective: To study the protective effects of Diallyl Sulfide (DAS) on leukopenia induced by benzene. Methods: 90 Healthy male ICR mice, adaptive feeding 5 days later, 15 were randomly divided into blank control group、model group、low、middle、high dose DAS intervention groups and DAS control group. Mice in intervention groups and DAS control group were orally given DAS at 40, 80, 160, 160 mg/kg·bw, while mice in the other two groups received an equal volume of corn oil. After 2 hours, model group and the other three intervention groups were given benzene, corn oil suspension (1.3 g/kg·bw) , the two control groups treated with the same volume of corn oil, Benzene and DAS are dissolved in corn oil. one time for each day. 4 weeks later, Anesthesia at 14/29, make blood routine examination and count organ index and observe pathological examinations of spleen and thymus. Results: On day 14, the counts of peripheral blood white blood cells (WBC) , lymphocytes, monocytes in the model group decreased to 68.99%, 71.72%, 53.19% (P<0.05) ; On day 29, the counts of peripheral blood lymphocytes, monocytes, neutrophils in the model group decreased to 83.00%, 81.03%, 89.37%, 20.84%, 19.25% (P<0.05) ; spleen weight, spleen index, white pulp area ratio of spleen, thymus weight, thymus index, thymic cortex area ratio of mice in the model group decreased (P<0.05) . On day 14, the counts of peripheral blood monocytes and lymphocytes in the DAS high dose intervention group increased by 136.36%, 260.00% (P<0.05) ; On day 29, the counts of White blood cells, lymphocytes, red blood cells, platelets, hemoglobin in the DAS low, middle and high dose intervention groups increased (P<0.05) ; spleen weight, spleen index, white pulp area ratio of spleen, thymus weight, thymus index, thymic cortex area ratio of mice in the DAS high dose intervention groups increased (P<0.05) . Conclusion: DAS can effectively suppress benzene-induced leucopenia in mice.

  • Diallyl Sulfide treatment protects against acetaminophen carbon tetrachloride induced acute liver injury by inhibiting oxidative stress inflammation and apoptosis in mice
    Toxicology Research, 2019
    Co-Authors: Shuo Wang, Qiong Wang, Ruirui Kou, Xujing Wang, Ning Zhao, Tao Zeng, Keqin Xie
    Abstract:

    The purpose of the present study was to investigate the effects and underlying mechanisms of Diallyl Sulfide (DAS), an organosulfur compound extracted from garlic, on drug-induced or chemical-induced liver injury caused by acetaminophen (APAP) or carbon tetrachloride (CCl4) in mice. DAS (100, 200, or 400 μmol kg-1) was orally administered 1 hour before APAP or CCl4 intraperitoneal injection, and the serum and liver tissue were collected 24 hours after APAP or CCl4 exposure. The serum aminotransferase activities and liver histopathological examination showed that DAS exhibited obvious hepatoprotective effects against acute liver injury induced by APAP or CCl4. In addition, exposure to APAP or CCl4 resulted in an increased content of malonaldehyde as well as a decreased ratio of reduced to oxidized glutathione, and a decreased level of superoxide dismutase and catalase activity in the liver (p < 0.05); however, pretreatment with DAS restored the perturbations of the antioxidant system in the liver. Beyond that, DAS pretreatment reduced the APAP-/CCl4-induced increase in phosphorylation of inhibitor of kappa B alpha (IκBα) and p65 subunit of nuclear factor kappa B (NF-κB) expression in the cytoplasm and nucleus in the liver. DAS pretreatment also decreased the excessive level of TNF-α caused by APAP or CCl4 in serum (p < 0.05). Moreover, DAS pretreatment regulated the expression of cleaved caspase 3, Bax and Bcl-2 in the liver and suppressed APAP-/CCl4-induced hepatocyte apoptosis. In conclusion, DAS exhibits hepatoprotective effects against drug-induced and chemical-induced liver injuries induced by APAP or CCl4 in mice, probably due to its ability to reduce hepatic oxidative stress and inhibit inflammatory injury and hepatocyte apoptosis.

Neetu Kalra - One of the best experts on this subject based on the ideXlab platform.

  • regulation of oxidative stress mediated apoptosis by Diallyl Sulfide in dmba exposed swiss mice
    Human & Experimental Toxicology, 2008
    Co-Authors: Sahdeo Prasad, Neetu Kalra, Satya P Srivastava, Yogeshwer Shukla
    Abstract:

    Diallyl Sulfide, a sulfur-containing volatile compound present in garlic (Allium sativum), exerts anticarcinogenic activity in various rodent tumor models. In the present study, apoptosis-inhibiting effects of Diallyl Sulfide against a carcinogenic polycyclic aromatic hydrocarbon, 7,12-dimethyl benz(a)anthracene (DMBA), in Swiss albino mice were observed. The animals were given either 250 microg/mouse or 500 mug/mouse of Diallyl Sulfide for 1 week after a single intragastric dose of 7,12-dimethyl benz(a)anthracene (50 mg/kg body weight). Results showed that Diallyl Sulfide supplementation effectively protects against 7,12-dimethyl benz(a)anthracene-induced oxidative stress, characterized by restored antioxidant enzyme levels (up to 64%) and lipid peroxidation (up to 25%). Flow cytometric analysis showed a reduction in apoptotic cell population in hypodiploid region in Diallyl Sulfide-supplemented animals. Inhibition of apoptosis was preceded by decrease in reactive oxygen species levels and restoration of mitochondrial transmembrane potential followed by decreased DNA fragmentation. In 7,12-dimethyl benz(a)anthracene-exposed animals, downregulation approximately 30%) of antiapoptotic Bcl-2 and upregulation (approximately 60%) of pro-apoptotic Bax proteins were observed. These alterations were restored significantly by Diallyl Sulfide supplementation, indicating inhibition of apoptosis. Thus, these results show that Diallyl Sulfide provides protection against oxidative damage induced by 7,12-dimethyl benz(a)anthracene in mouse liver and may be an effective chemopreventive and therapeutic agent by modulating expression of cell-growth regulatory proteins.

  • Potential of Diallyl Sulfide bearing pH-sensitive liposomes in chemoprevention against DMBA-induced skin papilloma.
    Molecular Medicine, 2007
    Co-Authors: Arif Khan, Yogeshwer Shukla, Neetu Kalra, Maroof Alam, Manzoor Ahmad, Seema Hakim, Mohammad Owais
    Abstract:

    Diallyl Sulfide (DAS), an active component of garlic, possesses strong anti-neoplastic properties against various forms of cancer. In the present study, we have evaluated chemo-preventive effects of liposomized DAS (conventional egg PC and pH-sensitive liposomes) against DMBA-induced skin papilloma. Various liposome-based novel formulations of DAS (250 µg/mouse) were applied topically, after one hour of exposure to DMBA (52 µg/mouse/dose), to the animals. The animals were treated thrice weekly for the total period of 12 weeks. The efficacy of the various liposomal formulations of DAS was evaluated on the basis of parameters such as incidence of tumorogenesis and total numbers and sizes of induced tumor nodules. The liposomized DAS formulations also were assessed for their effect on the expression of p53wt, p53mut, and p21/Waf1. The results of the present study showed that liposomized DAS could effectively delay the onset of tumorogenesis and reduce the cumulative numbers and sizes of tumor papillomas in treated mice. Treatment of DMBA-exposed animals with the liposomal formulation of DAS ensued in up-regulation of p53wt and p21/Waf1, while levels of p53mut expression reduced down. The promising chemo-preventive nature of liposomal DAS may form the basis for establishing effective means of controlling various forms of cancer, including skin papilloma.

  • modulatory effects of Diallyl Sulfide against testosterone induced oxidative stress in swiss albino mice
    Asian Journal of Andrology, 2006
    Co-Authors: Sahdeo Prasad, Neetu Kalra, Yogeshwer Shukla
    Abstract:

    Aim: To investigate the protective effect of Diallyl Sulfide (DAS), a constituent of garlic, against testosterone-induced oxidative stress in male Swiss albino mice. Methods: The animals were given low (250 mg/animal) and high dose (500 mg/animal) of DAS in corn oil for 7 days along with testosterone (5 mg/kg body weight, i.p.). At the end of the study period, the prostate and the liver were dissected to determine various antioxidant enzyme levels (catalase, superoxide dismutase, glutathione reductase, glutathione-s-transferase) and lipid peroxidation. Results: In testosterone treated mice, depleted antioxidant enzyme level was accompanied with enhancement in lipid peroxidation in prostate and liver. DAS significantly restored the testosterone-induced antioxidant enzymes and lipid peroxidation in the both organs. These changes appear to be mediated by the antioxidant-enhancing effects of DAS. Conclusion: The results of the present study suggest that DAS is effective in exerting antioxidant effects by inhibiting testosterone-induced oxidative stress and might be helpful in preventing prostate cancer. Edited by Anna-Maria Andersson

  • regulation of p21 ras protein expression by Diallyl Sulfide in dmba induced neoplastic changes in mouse skin
    Cancer Letters, 2006
    Co-Authors: Annu Arora, Neetu Kalra, Yogeshwer Shukla
    Abstract:

    Diallyl Sulfide (DAS), a naturally occurring organoSulfide, present in garlic, is known to possess pleiotropic biological effects. DAS is known to inhibit chemically induced tumors in a number of animal models. The chemopreventive properties of DAS seem to occur through a number of mechanisms, but its role on primary events on oncogenic activation is not well understood. In the present study, we demonstrated the modulatory effect of DAS on the expression of H-ras gene product, p21/ras protein as one of the mechanisms of its chemopreventive action in chemically induced mouse skin tumors. Our results showed that DAS administration leads to modulation of the DMBA-induced levels of p21/ras oncoprotein as early as 24 h after the DMBA application, suggesting down-regulation of the p21/ras by DAS. Furthermore, the modulatory effects of DAS were also evident in DMBA-induced mouse skin tumors. DAS administration led to increase in the levels of cytosolic p21/ras and decrease in the levels of p21/ras in membrane fractions. DAS administration was also found to down regulate the DMBA-induced H-ras mRNA level in mouse skin tumors. The immunohistochemical staining of the skin/tumor showed 55.82 and 46.86% decrease in the area positive for p21/ras expression levels in DAS pre- and post-supplemented groups, respectively. Flow-cytometric analysis, further confirms our results as indicated by a shift in the mean fluorescence intensity (MFI) towards lower fluorescence in DAS administered groups in comparison to the DMBA treated group. Thus, one mechanism of the growth inhibitory properties of DAS is through the suppression of development of tumors that harbor ras mutations by inhibiting the membrane association of oncogenic p21/ras protein.

  • involvement of multiple signaling pathways in Diallyl Sulfide mediated apoptosis in mouse skin tumors
    Asian Pacific Journal of Cancer Prevention, 2006
    Co-Authors: Neetu Kalra, Annu Arora, Yogeshwer Shukla
    Abstract:

    Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of neoplastic conversion selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in pre-malignant cells, in which these pathways are still relatively intact, may be an effective module of cancer prevention. Diallyl Sulfide (DAS), a naturally occurring organoSulfide, present in garlic, is reported to have pleiotropic biological effects. DAS is known to inhibit chemically induced tumors in a number of in vivo and in vitro studies. The aberration of tumor suppressor gene, p53 and the ras oncogene have been linked to the induction of multiple signaling pathways and to the resistance offered by cancer cells to the apoptosis. Therefore, the present study was carried out to investigate the role of DAS on modulation of multiple p53 and ras-induced signaling pathways in 7,12-dimethylbenathacene (DMBA) induced skin carcinogenesis. The results showed that DAS up regulates expression of tumor suppressor protein p53 (wt p53) and its downstream target molecule p21/waf1. Proapoptotic protein, bax was upregulated by DAS supplementation. An opposite trend was observed in DMBA induced antiapoptotic proteins expressions, survivin and bcl-2, which were significantly downregulated by DAS supplementation. In the present study we also demonstrated that DAS supplementation significantly reduces the expression of ras oncoprotein and to modulate expression of its signaling molecules including PI3K/Akt and MAPKs. Western blot analysis demonstrated that DAS significantly reduced the DMBA induced protein expressions of PI3K/Akt and p38MAPK. However, DAS supplementation did not alter the expression JNK1 and ERK1/2. Thus, our results confirm that DAS can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of DMBA induced skin tumors in Swiss albino mice. Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in cancer chemoprevention by naturally occurring compounds.

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  • mechanisms of inhibition of chemical toxicity and carcinogenesis by Diallyl Sulfide das and related compounds from garlic
    Journal of Nutrition, 2001
    Co-Authors: Chung S Yang, Jun-yan Hong, Saranjit K Chhabra, Theresa J Smith
    Abstract:

    Diallyl Sulfide (DAS) is a flavor compound derived from garlic and is sequentially converted to Diallyl sulfoxide (DASO) and Diallyl sulfone (DASO(2)) by cytochrome P(450) 2E1 (CYP2E1). These compounds have been shown to reduce the incidence of a multitude of chemically induced tumors in animal models. The impediment of phase I activation of these carcinogens is hypothesized to be accountable for the reduction in tumor incidence. Indeed, DAS, DASO and DASO(2) are competitive inhibitors of CYP2E1. DASO(2), in addition, is a suicide inhibitor of CYP2E1. These compounds have been shown to reduce carbon tetrachloride-, N-nitrosodimethylamine- and acetaminophen-induced toxicity in rodents. All three chemicals are substrates for CYP2E1. The protective effect was observed when the organosulfur compounds were given before, during or soon after chemical treatment. DAS and DASO(2) inhibited the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related lung tumorigenesis in A/J mice. Because CYP2E1 does not play a key role in NNK activation, the inhibition of other CYP enzymes active in NNK metabolism is likely. DAS also has been shown to induce other CYP and phase II enzymes as well as decrease hepatic catalase activity. All of these effects are observed at concentrations much higher than what is normally ingested by humans. The biological activities of garlic and its related compounds at lower concentrations that mimic human consumption remain to be studied further.

  • decrease of hepatic catalase level by treatment with Diallyl Sulfide and garlic homogenates in rats and mice
    Journal of Biochemical and Molecular Toxicology, 1999
    Co-Authors: Laishun Chen, Jun-yan Hong, Abas Hj Hussin, Wufeng Cheng, Chung S Yang
    Abstract:

    Diallyl Sulfide (DAS) is a flavor compound derived from garlic and is active in the inhibition of chemically induced cytotoxicity and carcinogenicity in animal models. This study was conducted to examine the effects of the treatment of DAS and garlic homogenates on the activities of catalase, glutathione peroxidase, and superoxide dismutase. Male Sprague-Dawley rats were treated with DAS i.g. at daily doses of 50 or 200 mg/kg for 8 days, causing the hepatic catalase activity to decrease by 55 and 95%, respectively. Such a decrease in hepatic catalase activity was also observed when the DAS treatment was extended to 29 days. Western blot analysis showed that the DAS treatments resulted in corresponding decreases in the liver catalase protein level. No significant change in the catalase activity in the kidney, lung, and brain was observed with the treatments, but a slight decrease in heart catalase activity was observed. These treatments did not cause significant changes in superoxide dismutase and glutathione peroxidase activities in these tissues. Treatment with DAS at a daily dose of 200 mg/kg for 1-7 days resulted in a gradual decrease in the liver catalase activity to 5% of the control level, but it did not decrease the erythrocyte catalase activity. Treatment of rats with fresh garlic homogenates (2 or 4 g/kg, i.g., daily for 7 days) caused a 35% decrease in liver catalase activity. A/J mice treated with DAS and garlic homogenates also showed a decrease in the liver catalase activity. Diallyl sulfone (DASO2), a DAS metabolite, however, did not effectively decrease catalase activity in mice. The catalase activity was not inhibited by either DAS or DASO2 in vitro. The present results demonstrate that treatment with DAS and garlic homogenates decrease the hepatic catalase level in rats and mice.

  • protective effects of Diallyl Sulfide on acetaminophen induced toxicities
    Food and Chemical Toxicology, 1996
    Co-Authors: J S H Yoo, M Lin, Erjia Wang, Chung S Yang
    Abstract:

    Diallyl Sulfide (DAS), a major flavour component of garlic, is known to modulate drug metabolism and may protect animals from chemically induced toxicity and carcinogenesis. In this study the effects of DAS on the oxidative metabolism and hepatotoxicity induced by acetaminophen (APAP) in rats were investigated. In the hepatotoxicity evaluation of Fischer 344 rats there was a dose-dependent increase in the odds of mortality rate by APAP (P = 0.009); DAS treatment significantly protected rats from APAP-related mortality (P = 0.026). Liver toxicity determined by lactate dehydrogenase activity was significantly increased by APAP treatment (0.75 g/kg). Pretreatment with DAS protected animals from APAP-induced liver toxicity in a time- and dose-dependent fashion. Treatment of DAS (50 mg/kg) 3 hr after APAP dosing significantly (P < 0.05) protected rats from APAP-induced liver toxicity. The metabolism of APAP (50 microM) in vitro was significantly inhibited by DAS (0.3-1 mM) in liver microsomes isolated from F344 rats. As the effect of DAS on APAP-induced hepatotoxicity in vivo was observed only when DAS was administered before or shortly after (< 3 hr) APAP dosing, data suggested that the protective effect of DAS is mainly at the metabolic activation step of APAP. However, the possibility that DAS may also have effects on other drug metabolism systems, such as glutathione (GSH) and glutathione S-transferases, cannot be ruled out.

  • inhibition of cytochrome p 450 2e1 by Diallyl Sulfide and its metabolites
    Chemical Research in Toxicology, 1991
    Co-Authors: John F Brady, Hiroyuki Ishizaki, Jon M Fukuto, Marie C Lin, Addi Fadel, Jeanne M Gapac, Chung S Yang
    Abstract:

    Diallyl Sulfide, a major flavor ingredient from garlic, was previously shown to inhibit chemically induced carcinogenesis and cytotoxicity in animal model systems. It modulated cytochrome P-450 compositions by inactivating P-450 2E1 and inducing P-450 2B1. The present studies examined the inhibition of P-450 2E1 mediated p-nitrophenol hydroxylase activity by Diallyl Sulfide and its putative metabolites Diallyl sulfoxide and Diallyl sulfone (DASO2). Each compound displayed competitive inhibition of p-nitrophenol hydroxylase activity in incubations using liver microsomes from acetone-pretreated male Sprague-Dawley rats. Preincubation of the microsomes with DASO2 inactivated p-nitrophenol hydroxylase activity in a process that was time- and NADPH-dependent and saturable, exhibited pseudo-first-order kinetics, was protected by alternate substrate, was accompanied by a loss of microsomal P-450-CO binding spectrum, and was unaffected by exogenous nucleophile. The Ki value for DASO2 was 188 microM and the maximal rate of inactivation was 0.32 min-1. DASO2 was ineffective in the inactivation of ethoxyresorufin dealkylase, pentoxyresorufin dealkylase, or benzphetamine demethylase activity. Purified P-450 2E1 in a reconstituted system was inactivated in a time- and NADPH-dependent manner by DASO2. The metabolic conversion of Diallyl Sulfide to the sulfoxide and sulfone was observed in vivo and in vitro. The results suggest that Diallyl Sulfide inhibits the metabolism of P-450 2E1 substrates by competitive inhibition mechanisms and by inactivating P-450 2E1 via a suicide-inhibitory action of DASO2.

  • modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by Diallyl Sulfide
    Toxicology and Applied Pharmacology, 1991
    Co-Authors: John F Brady, Jun-yan Hong, Shu M. Ning, Jon M Fukuto, Jeanne M Gapac, Mongheng Wang, Fang Xiao, Jeong Sook H Yoo, Mao Jung Lee, Chung S Yang
    Abstract:

    Diallyl Sulfide (DAS) and other organosulfur compounds inhibit chemically induced carcinogenic and toxic responses in rodent model systems. A possible mechanism of action is the inhibition of the hepatic cytochrome P450IIE1-dependent bioactivation of the procarcinogens and protoxicants. Previous work showed competitive inhibition by DAS of N-nitrosodimethylamine (NDMA) demethylase activity in vitro, and a reduction in the microsomal level of P450IIE1 after in vivo treatment with DAS. The present studies demonstrated a time- and dose-dependent decrease of hepatic microsomal P450IIE1 activity, induction of P450IIB1 and pentoxyresorufin dealkylase activity, and moderate induction of ethoxyresorufin dealkylase activity by oral DAS treatment. DAS treatment elevated P450IIB1 mRNA but had no effect on P450IIE1 mRNA. Treatment with putative metabolites of DAS, Diallyl sulfoxide and Diallyl sulfone, led to similar modulations in monooxygenase activities, but the decrease of P450IIE1 activity by the sulfone occurred more rapidly. In studies in vitro, Diallyl sulfone caused a metabolism-dependent inactivation of P450IIE1, but such inactivation was not observed with DAS or Diallyl sulfoxide. The profile of microsomal testosterone metabolism after DAS treatment indicated an enhancement of P450IIB1-dependent 16β-hydroxylase activity, and a decrease in 6β-hydroxytestosterone production possibly related to a lower level of P450IIIA1 or IIIA2. When rats were subjected to a 48-hr fast and DAS treatment, the starvation-induced microsomal P450IIE1 level was decreased by DAS. Inhibition of hepatotoxicity due to exposure to P450IIE1 substrates, CCl4 and NDMA, by DAS was observed under a variety of treatment schedules.