The Experts below are selected from a list of 8091 Experts worldwide ranked by ideXlab platform
Rajesh Agarwal - One of the best experts on this subject based on the ideXlab platform.
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clinically relevant cutaneous lesions by nitrogen mustard useful biomarkers of vesicants Skin Injury in skh 1 hairless and c57bl 6 mice
PLOS ONE, 2013Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, Skin Injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry Skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry Skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous Injury endpoints in screening and optimization of therapies for Skin injuries by vesicating agents.
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silibinin attenuates sulfur mustard analog induced Skin Injury by targeting multiple pathways connecting oxidative stress and inflammation
PLOS ONE, 2012Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Chapla Agarwal, Rajesh AgarwalAbstract:Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating Skin injuries. To identify effective countermeasures against HD-induced Skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced Injury biomarkers in Skin cells and SKH-1 hairless mouse Skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced Skin Injury and oxidative stress. In Skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p 90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD Skin toxicity model to develop a novel effective therapy for Skin injuries by vesicants.
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sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury involves dna damage and induction of inflammatory mediators in part via oxidative stress in skh 1 hairless mouse Skin
Toxicology Letters, 2011Co-Authors: Anil K Jain, Neera Tewarisingh, Mallikarjuna Gu, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous Injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse Skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, Skin samples from mice exposed to 2 mg or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced Skin Injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced Skin Injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing Skin Injury in humans by SM.
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inflammatory biomarkers of sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury in skh 1 hairless mice
Toxicological Sciences, 2009Co-Authors: Neera Tewarisingh, Mallikarjuna Gu, Carl W White, Sumeet Rana, David J Orlicky, Rajesh AgarwalAbstract:Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe Skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused Skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal Skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced Skin Injury in dose- (0.05–2 mg) and time- (3–168 h) response experiments, and developed a CEES-induced Skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in Skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated Skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed Skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of Skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced Skin toxicity.
Neera Tewarisingh - One of the best experts on this subject based on the ideXlab platform.
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clinically relevant cutaneous lesions by nitrogen mustard useful biomarkers of vesicants Skin Injury in skh 1 hairless and c57bl 6 mice
PLOS ONE, 2013Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, Skin Injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry Skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry Skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous Injury endpoints in screening and optimization of therapies for Skin injuries by vesicating agents.
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silibinin attenuates sulfur mustard analog induced Skin Injury by targeting multiple pathways connecting oxidative stress and inflammation
PLOS ONE, 2012Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Chapla Agarwal, Rajesh AgarwalAbstract:Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating Skin injuries. To identify effective countermeasures against HD-induced Skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced Injury biomarkers in Skin cells and SKH-1 hairless mouse Skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced Skin Injury and oxidative stress. In Skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p 90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD Skin toxicity model to develop a novel effective therapy for Skin injuries by vesicants.
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sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury involves dna damage and induction of inflammatory mediators in part via oxidative stress in skh 1 hairless mouse Skin
Toxicology Letters, 2011Co-Authors: Anil K Jain, Neera Tewarisingh, Mallikarjuna Gu, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous Injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse Skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, Skin samples from mice exposed to 2 mg or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced Skin Injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced Skin Injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing Skin Injury in humans by SM.
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inflammatory biomarkers of sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury in skh 1 hairless mice
Toxicological Sciences, 2009Co-Authors: Neera Tewarisingh, Mallikarjuna Gu, Carl W White, Sumeet Rana, David J Orlicky, Rajesh AgarwalAbstract:Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe Skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused Skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal Skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced Skin Injury in dose- (0.05–2 mg) and time- (3–168 h) response experiments, and developed a CEES-induced Skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in Skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated Skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed Skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of Skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced Skin toxicity.
Carl W White - One of the best experts on this subject based on the ideXlab platform.
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clinically relevant cutaneous lesions by nitrogen mustard useful biomarkers of vesicants Skin Injury in skh 1 hairless and c57bl 6 mice
PLOS ONE, 2013Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, Skin Injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry Skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry Skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous Injury endpoints in screening and optimization of therapies for Skin injuries by vesicating agents.
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silibinin attenuates sulfur mustard analog induced Skin Injury by targeting multiple pathways connecting oxidative stress and inflammation
PLOS ONE, 2012Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Chapla Agarwal, Rajesh AgarwalAbstract:Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating Skin injuries. To identify effective countermeasures against HD-induced Skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced Injury biomarkers in Skin cells and SKH-1 hairless mouse Skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced Skin Injury and oxidative stress. In Skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p 90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD Skin toxicity model to develop a novel effective therapy for Skin injuries by vesicants.
-
sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury involves dna damage and induction of inflammatory mediators in part via oxidative stress in skh 1 hairless mouse Skin
Toxicology Letters, 2011Co-Authors: Anil K Jain, Neera Tewarisingh, Mallikarjuna Gu, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous Injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse Skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, Skin samples from mice exposed to 2 mg or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced Skin Injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced Skin Injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing Skin Injury in humans by SM.
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inflammatory biomarkers of sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury in skh 1 hairless mice
Toxicological Sciences, 2009Co-Authors: Neera Tewarisingh, Mallikarjuna Gu, Carl W White, Sumeet Rana, David J Orlicky, Rajesh AgarwalAbstract:Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe Skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused Skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal Skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced Skin Injury in dose- (0.05–2 mg) and time- (3–168 h) response experiments, and developed a CEES-induced Skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in Skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated Skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed Skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of Skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced Skin toxicity.
Anil K Jain - One of the best experts on this subject based on the ideXlab platform.
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clinically relevant cutaneous lesions by nitrogen mustard useful biomarkers of vesicants Skin Injury in skh 1 hairless and c57bl 6 mice
PLOS ONE, 2013Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, Skin Injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry Skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry Skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous Injury endpoints in screening and optimization of therapies for Skin injuries by vesicating agents.
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silibinin attenuates sulfur mustard analog induced Skin Injury by targeting multiple pathways connecting oxidative stress and inflammation
PLOS ONE, 2012Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Chapla Agarwal, Rajesh AgarwalAbstract:Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating Skin injuries. To identify effective countermeasures against HD-induced Skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced Injury biomarkers in Skin cells and SKH-1 hairless mouse Skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced Skin Injury and oxidative stress. In Skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p 90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD Skin toxicity model to develop a novel effective therapy for Skin injuries by vesicants.
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sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury involves dna damage and induction of inflammatory mediators in part via oxidative stress in skh 1 hairless mouse Skin
Toxicology Letters, 2011Co-Authors: Anil K Jain, Neera Tewarisingh, Mallikarjuna Gu, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous Injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse Skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, Skin samples from mice exposed to 2 mg or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced Skin Injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced Skin Injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing Skin Injury in humans by SM.
Swetha Inturi - One of the best experts on this subject based on the ideXlab platform.
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clinically relevant cutaneous lesions by nitrogen mustard useful biomarkers of vesicants Skin Injury in skh 1 hairless and c57bl 6 mice
PLOS ONE, 2013Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, Skin Injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry Skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry Skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous Injury endpoints in screening and optimization of therapies for Skin injuries by vesicating agents.
-
silibinin attenuates sulfur mustard analog induced Skin Injury by targeting multiple pathways connecting oxidative stress and inflammation
PLOS ONE, 2012Co-Authors: Neera Tewarisingh, Anil K Jain, Swetha Inturi, Carl W White, Chapla Agarwal, Rajesh AgarwalAbstract:Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating Skin injuries. To identify effective countermeasures against HD-induced Skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced Injury biomarkers in Skin cells and SKH-1 hairless mouse Skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced Skin Injury and oxidative stress. In Skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p 90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD Skin toxicity model to develop a novel effective therapy for Skin injuries by vesicants.
-
sulfur mustard analog 2 chloroethyl ethyl sulfide induced Skin Injury involves dna damage and induction of inflammatory mediators in part via oxidative stress in skh 1 hairless mouse Skin
Toxicology Letters, 2011Co-Authors: Anil K Jain, Neera Tewarisingh, Mallikarjuna Gu, Swetha Inturi, Carl W White, Rajesh AgarwalAbstract:Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous Injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse Skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, Skin samples from mice exposed to 2 mg or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced Skin Injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced Skin Injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing Skin Injury in humans by SM.
