Escin, as an internally applied anti-inflammatory agent, has been widely used in the treatment of inflammation and edema resulting from trauma or operation in the clinic. However, the effect of its external use on cut...Escin, as an internally applied anti-inflammatory agent, has been widely used in the treatment of inflammation and edema resulting from trauma or operation in the clinic. However, the effect of its external use on cutaneous inflammation and edema remains unexplored. In the present study, the anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats, paraxylene-induced ear swelling in mice, and cotton pellet-induced granuloma in rats. Effects of external use of escin gel on prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α), and interleukin-1β(IL-1β) were determined by ELISA. The anti-inflammatory mechanism was explored by detecting the expression of glucocorticoid receptor(GR) with Western blotting and Real-time PCR analyses, with further exploration of nuclear factor-κB(NF-κB), p38 mitogen-activated protein kinase(P38 MAPK) and activator protein-1(AP-1) expressions. We demonstrated that external use of escin showed significant anti-inflammatory effects on acute and chronic inflammation in different animal models and its anti-inflammatory effects might be related to down-regulation of PGE2, TNF-α, and IL-1β. The results also showed that escin exerted its anti-inflammatory effects by promoting the expression of GR, with the possible mechanism being inhibition of the expressions of GR-related signaling molecules such as NF-κB and AP-1.展开更多
A new triterpenoid saponin named escin IV e was isolated from the seeds of Aesculus chinensis. Its structure was established as 28-tigloylprotoaescigenin-3 beta-O- [beta-D-glucopyranosyl (1-2)] [beta-D-glucopyranosyl ...A new triterpenoid saponin named escin IV e was isolated from the seeds of Aesculus chinensis. Its structure was established as 28-tigloylprotoaescigenin-3 beta-O- [beta-D-glucopyranosyl (1-2)] [beta-D-glucopyranosyl (1-4)] -beta-D-glucopyranosiduronic acid.展开更多
AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o...AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o t h e ra p y o n C C A c e l l s. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells(QBC939, Sk-Ch A-1, and MZ-Ch A-1). Immunocytochemistry was used to detect the expression of P-glycoprotein(P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, p S9-GSK3β, p T216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting.RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil(5-FU) cells to 5-FU, vincristine sulfate(VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone(P < 0.05). In addition, the combination of β-escin(20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the m RNA and protein expression of P-gp was downregulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3 a resulted in upregulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner.CONCLUSION: β-escin was a potent reverser of P-gpdependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.展开更多
OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injure...OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.展开更多
The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of esci...The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of escin on inflammation and edema have been confirmed in various models.In a study in 1961,intravenous administration of escin was found to reduce acute edema in a rat paw.In the same study,escin was found to inhibit the increase in vascular permeability induced by egg white injection.Escin dose-dependently reduced the capillary permeability in chloroform-induced local inflammation in the abdominal skin surface of rabbits.The anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats.Escin gel decreased the contents of PGE2,TNF-α,and IL^(-1)β,and reduced the raw edema and capillary permeability.The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to investigate the anti-inflammatory effects of escin and glucocorticoid alone or combined.Co-administration of escin with cortisone significantly reduced the volume of exudates and the number of white blood cells of exudates.The findings suggest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect.The anti-inflammatory effect of escin was investigated in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice.Escin showed an anti-inflammatory effect,which is similar to that seen with dexamethasone treatment.However,escin showed a longer duration of the anti-inflammatory response than that of dexamethasone.Furthermore,escin had no significant effects on spleen index,thymus index,proliferative capacity of splenocytes,lymphocyte count,and phagocytic rate.The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects without any immunosuppressive effects.Traditionally the mechanism of anti-inflammatory effect of escin is supposed to be relative to release of PGF2αand corticosterone.The early studies showed that escin might promote the release of PGF2αand affect the pituitary adrenal system,stimulate the release of adrenocorticotropic hormone(ACTH)and glucocorticoid,which may explain its anti-inflammatory and anti-edema effects.Escin has glucocorticoid-like anti-inflammatory effect.However,escin did not exhibit an anti-inflammatory effect in low dose.Combination of suboptimal concentrations of escin with corticosterone inhibited the release of inflammatory factors including NO,TNF-αand IL^(-1)βin the LPS-stimulated macrophage cells.Previous studies demonstrate that escin combined with glucocorticoid produced synergistic anti-inflammatory effects.The potential synergistic mechanisms may be associated with the property which escin regulates the glucocorticoid receptor(GR)signaling pathway.Escin can upregulate the expression of GR,promote the combination of glucocorticoid and GR,then promote the activated GR transfer into the nucleus.Activated GR will inhibit the activation of NF-κB directly,thus further inhibiting the expression of TNF-αand IL^(-1)βand other inflammatory factors.Escin could inhibit 11β-HSD2 but not 11β-HSD1,thus decrease the metabolism of glucocorticoid.Escin and glucocorticoids have similar chemical structures.This indicate that one of the anti-inflammatory mechanisms of escin may be due to its stimulating GR by binding to it.Eacin might be a partial agonist of GR.A good many of researches have demonstrated the anti-inflammatory properties of escin,and shed light on the underlying mechanisms by which escin exerts these effects.Escin,as an oral or intravenous formulation,or a topical gel,inhibits inflammation,producing measurable improvements in edema and acute lung injury.Further clinical studies of escin are needed to demonstrate these properties in larger patient populations.展开更多
Escin is a natural mixture of triterpenoid as- ponin isolated from the seed of the horse chestnut and demonstrates anti-oedematous and anti-inflammatory effects. As yet, the pre-cise mechanisms by which escin exerts i...Escin is a natural mixture of triterpenoid as- ponin isolated from the seed of the horse chestnut and demonstrates anti-oedematous and anti-inflammatory effects. As yet, the pre-cise mechanisms by which escin exerts its anti- inflammatory effects remain unclear. The data from current studies indicate that the anti-in-flammatory properties of escin were attributed to its ability to reduce the adhesiveness of neu-trophils and the associated release of inflam-matory mediators;its ability to decrease hista-minic and serotoninergic activities;its ability to inhibit phospholipase A2;its ability to decrease nuclear factor-κ B activation and down-regulate the expression of tumor necrosis factor-α. All these effects are similar to glucocorticoids. Mo- reover, escin depends on adrenal glands to ex-ert its anti-inflammatory effects. Also, our recent research showed that the serum corticosterone level in mice did not increase after a 7-day in-travenous injection of escin. The results sup-port the hypothesis that escin may exert a syn-ergistic anti-inflammatory effect with glucocor-ticoids. Confirming this hypothesis will play a role in elucidating the anti-inflammatory mech- anisms of escin.展开更多
With protoescigenin as starting material and through orchestrated application of Yu and Schmidt glycosylation protocols,the synthesis of acyl group-free escin derivatives was achieved for the first time.As the undesir...With protoescigenin as starting material and through orchestrated application of Yu and Schmidt glycosylation protocols,the synthesis of acyl group-free escin derivatives was achieved for the first time.As the undesired non-specific toxicity,originating from the existence of acyl groups on aglycone,prohibits the wide application of escins,the established strategies toward non-acylated protoescigenin-type saponins would dramatically ease the access to escin derivatives dispense of acyl groups,thereby speeding up the pace of pharmaceutical use of these valuable compounds.展开更多
Aim To study the saponin constituents of the seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang. Methods Compounds were separated and purified by macroreticular resin column chromatography and high...Aim To study the saponin constituents of the seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang. Methods Compounds were separated and purified by macroreticular resin column chromatography and high-performance liquid chromatography. Their structures were elucidated by spectroscopic and hydrolysis analysis. Results Six compounds were isolated from the 70% ethanolic extracts. They were identified as escins IVc, IVd, Ia, Ib, isoescins Ia and Ib, respectively. Conclusion The above compounds were obtained from the seeds of Aesculus chinensis Bunge var.chekiangensis (Hu et Fang) Fang for the first time.展开更多
Three new triterpenoid saponins, escins IVg (1), IVh (2) and VIb (3) were isolatedfrom the seeds of Aesculus chinensis along with two known saponins, escin IIIa (4) anddesacylescin I (5). Their structures were elucida...Three new triterpenoid saponins, escins IVg (1), IVh (2) and VIb (3) were isolatedfrom the seeds of Aesculus chinensis along with two known saponins, escin IIIa (4) anddesacylescin I (5). Their structures were elucidated by spectroscopic analysis and chemicalhydrolysis.展开更多
基金supported by the National Natural Science Foundation of China(No.81602108)
文摘Escin, as an internally applied anti-inflammatory agent, has been widely used in the treatment of inflammation and edema resulting from trauma or operation in the clinic. However, the effect of its external use on cutaneous inflammation and edema remains unexplored. In the present study, the anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats, paraxylene-induced ear swelling in mice, and cotton pellet-induced granuloma in rats. Effects of external use of escin gel on prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α), and interleukin-1β(IL-1β) were determined by ELISA. The anti-inflammatory mechanism was explored by detecting the expression of glucocorticoid receptor(GR) with Western blotting and Real-time PCR analyses, with further exploration of nuclear factor-κB(NF-κB), p38 mitogen-activated protein kinase(P38 MAPK) and activator protein-1(AP-1) expressions. We demonstrated that external use of escin showed significant anti-inflammatory effects on acute and chronic inflammation in different animal models and its anti-inflammatory effects might be related to down-regulation of PGE2, TNF-α, and IL-1β. The results also showed that escin exerted its anti-inflammatory effects by promoting the expression of GR, with the possible mechanism being inhibition of the expressions of GR-related signaling molecules such as NF-κB and AP-1.
文摘A new triterpenoid saponin named escin IV e was isolated from the seeds of Aesculus chinensis. Its structure was established as 28-tigloylprotoaescigenin-3 beta-O- [beta-D-glucopyranosyl (1-2)] [beta-D-glucopyranosyl (1-4)] -beta-D-glucopyranosiduronic acid.
基金Supported by National Nature Science Foundation of China,No.81101502the National Science Foundation for Fostering Talents in Basic Research of the National Natural Science Foundation of China,No.J1310027
文摘AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o t h e ra p y o n C C A c e l l s. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells(QBC939, Sk-Ch A-1, and MZ-Ch A-1). Immunocytochemistry was used to detect the expression of P-glycoprotein(P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, p S9-GSK3β, p T216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting.RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil(5-FU) cells to 5-FU, vincristine sulfate(VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone(P < 0.05). In addition, the combination of β-escin(20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the m RNA and protein expression of P-gp was downregulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3 a resulted in upregulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner.CONCLUSION: β-escin was a potent reverser of P-gpdependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.
基金National Natural Science Foundation of China(8187303981973547)Natural Science Foundation of Shandong Province(ZR2017MH068)
文摘OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.
文摘The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of escin on inflammation and edema have been confirmed in various models.In a study in 1961,intravenous administration of escin was found to reduce acute edema in a rat paw.In the same study,escin was found to inhibit the increase in vascular permeability induced by egg white injection.Escin dose-dependently reduced the capillary permeability in chloroform-induced local inflammation in the abdominal skin surface of rabbits.The anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats.Escin gel decreased the contents of PGE2,TNF-α,and IL^(-1)β,and reduced the raw edema and capillary permeability.The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to investigate the anti-inflammatory effects of escin and glucocorticoid alone or combined.Co-administration of escin with cortisone significantly reduced the volume of exudates and the number of white blood cells of exudates.The findings suggest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect.The anti-inflammatory effect of escin was investigated in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice.Escin showed an anti-inflammatory effect,which is similar to that seen with dexamethasone treatment.However,escin showed a longer duration of the anti-inflammatory response than that of dexamethasone.Furthermore,escin had no significant effects on spleen index,thymus index,proliferative capacity of splenocytes,lymphocyte count,and phagocytic rate.The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects without any immunosuppressive effects.Traditionally the mechanism of anti-inflammatory effect of escin is supposed to be relative to release of PGF2αand corticosterone.The early studies showed that escin might promote the release of PGF2αand affect the pituitary adrenal system,stimulate the release of adrenocorticotropic hormone(ACTH)and glucocorticoid,which may explain its anti-inflammatory and anti-edema effects.Escin has glucocorticoid-like anti-inflammatory effect.However,escin did not exhibit an anti-inflammatory effect in low dose.Combination of suboptimal concentrations of escin with corticosterone inhibited the release of inflammatory factors including NO,TNF-αand IL^(-1)βin the LPS-stimulated macrophage cells.Previous studies demonstrate that escin combined with glucocorticoid produced synergistic anti-inflammatory effects.The potential synergistic mechanisms may be associated with the property which escin regulates the glucocorticoid receptor(GR)signaling pathway.Escin can upregulate the expression of GR,promote the combination of glucocorticoid and GR,then promote the activated GR transfer into the nucleus.Activated GR will inhibit the activation of NF-κB directly,thus further inhibiting the expression of TNF-αand IL^(-1)βand other inflammatory factors.Escin could inhibit 11β-HSD2 but not 11β-HSD1,thus decrease the metabolism of glucocorticoid.Escin and glucocorticoids have similar chemical structures.This indicate that one of the anti-inflammatory mechanisms of escin may be due to its stimulating GR by binding to it.Eacin might be a partial agonist of GR.A good many of researches have demonstrated the anti-inflammatory properties of escin,and shed light on the underlying mechanisms by which escin exerts these effects.Escin,as an oral or intravenous formulation,or a topical gel,inhibits inflammation,producing measurable improvements in edema and acute lung injury.Further clinical studies of escin are needed to demonstrate these properties in larger patient populations.
文摘Escin is a natural mixture of triterpenoid as- ponin isolated from the seed of the horse chestnut and demonstrates anti-oedematous and anti-inflammatory effects. As yet, the pre-cise mechanisms by which escin exerts its anti- inflammatory effects remain unclear. The data from current studies indicate that the anti-in-flammatory properties of escin were attributed to its ability to reduce the adhesiveness of neu-trophils and the associated release of inflam-matory mediators;its ability to decrease hista-minic and serotoninergic activities;its ability to inhibit phospholipase A2;its ability to decrease nuclear factor-κ B activation and down-regulate the expression of tumor necrosis factor-α. All these effects are similar to glucocorticoids. Mo- reover, escin depends on adrenal glands to ex-ert its anti-inflammatory effects. Also, our recent research showed that the serum corticosterone level in mice did not increase after a 7-day in-travenous injection of escin. The results sup-port the hypothesis that escin may exert a syn-ergistic anti-inflammatory effect with glucocor-ticoids. Confirming this hypothesis will play a role in elucidating the anti-inflammatory mech- anisms of escin.
基金supported by the National Natural Science Foundation of China(22177042 and 22307048)The generous support from Beijing Municipal Commission of Science and Technology(L212015)was also highly appreciated.
文摘With protoescigenin as starting material and through orchestrated application of Yu and Schmidt glycosylation protocols,the synthesis of acyl group-free escin derivatives was achieved for the first time.As the undesired non-specific toxicity,originating from the existence of acyl groups on aglycone,prohibits the wide application of escins,the established strategies toward non-acylated protoescigenin-type saponins would dramatically ease the access to escin derivatives dispense of acyl groups,thereby speeding up the pace of pharmaceutical use of these valuable compounds.
文摘Aim To study the saponin constituents of the seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang. Methods Compounds were separated and purified by macroreticular resin column chromatography and high-performance liquid chromatography. Their structures were elucidated by spectroscopic and hydrolysis analysis. Results Six compounds were isolated from the 70% ethanolic extracts. They were identified as escins IVc, IVd, Ia, Ib, isoescins Ia and Ib, respectively. Conclusion The above compounds were obtained from the seeds of Aesculus chinensis Bunge var.chekiangensis (Hu et Fang) Fang for the first time.
文摘Three new triterpenoid saponins, escins IVg (1), IVh (2) and VIb (3) were isolatedfrom the seeds of Aesculus chinensis along with two known saponins, escin IIIa (4) anddesacylescin I (5). Their structures were elucidated by spectroscopic analysis and chemicalhydrolysis.
