Biliverdin,a bile pigment hydrolyzed from heme by heme oxygenase(HO),serves multiple functions in the human body,including antioxidant,anti-inflammatory,and immune response inhibitory activities.Biliverdin has great p...Biliverdin,a bile pigment hydrolyzed from heme by heme oxygenase(HO),serves multiple functions in the human body,including antioxidant,anti-inflammatory,and immune response inhibitory activities.Biliverdin has great potential as a clinical drug;however,no economic and efficient production method is available currently.Therefore,the production of biliverdin by the biotransformation of exogenous heme using recombinant HO-expressing yeast cells was studied in this research.First,the heme oxygenase-1 gene(HO1)encoding the inducible plastidic isozyme from Arabidopsis thaliana,with the plastid transport peptide sequence removed,was recombined into Pichia pasto-ris GS115 cells.This resulted in the construction of a recombinant P.pastoris GS115-HO1 strain that expressed active HO1 in the cytoplasm.After that,the concentration of the inducer methanol,the induction culture time,the pH of the medium,and the concentration of sorbitol supplied in the medium were optimized,resulting in a significant improvement in the yield of HO1.Subsequently,the whole cells of GS115-HO1 were employed as catalysts to convert heme chloride(hemin)into biliverdin.The results showed that the yield of biliverdin was 132 mg/L when hemin was added to the culture of GS115-HO1 and incubated for 4 h at 30°C.The findings of this study have laid a good foundation for future applications of this method for the economical production of biliverdin.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug...Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.展开更多
Biliverdin（BV） has long been thought to be a cytotoxic metabolic waste product. It has also been demonstrated to have important cytoprotective functions during oxidative stress. The present study aimed to examine th...Biliverdin（BV） has long been thought to be a cytotoxic metabolic waste product. It has also been demonstrated to have important cytoprotective functions during oxidative stress. The present study aimed to examine the cytoprotective effect of BV on NRK-52 E cells, a proximal tubular cell line derived from rat kidney. Cells were treated with 50 μmol/L cisplatin for 24 h（cisplatin group） or pre-treated with BV for 30 min, then with 50 μmol/L cisplatin for 24 h（cisplatin＋BV group）. Those given no treatment served as a control. Cell apoptosis was evaluated by flow cytometry and cell viability by Cell Counting Kit-8（CCK-8）. The protein expressions of cleaved caspase3, Bax and Bcl-2 were assessed by Western blotting. Reactive oxygen species（ROS） levels were measured using carboxydichlorodihydrofluorescein diacetate（H2DCF）. The results showed that cisplatin induced the apoptosis of NRK-52 E cells, decreased cell viability, and increased the formation of ROS by upregulating the expression of cleaved caspase3 and Bax and decreasing Bcl-2 protein expression. These effects could be significantly reversed by pretreatment with BV. It was concluded that BV can protect against cisplatin-induced cell apoptosis through the anti-oxidative effects.展开更多
Monolayer formation and LB film fabrication of amphiphilic derivative of biliverdin 1, diododecyl biliverdinamide [B(CONHC12H25)(2), 2] at an air-water interface on pure water subphase and subphase containing calcium ...Monolayer formation and LB film fabrication of amphiphilic derivative of biliverdin 1, diododecyl biliverdinamide [B(CONHC12H25)(2), 2] at an air-water interface on pure water subphase and subphase containing calcium ion were investigated and compared with 1. The coordination in ordered molecular films is much different from that in bulk solution. The formation of ligand-calcium complex was confirmed by X-ray photoelectron spectroscopy.展开更多
As one of the biological endogenous pigments,biliverdin(BV)and its dimethyl ester(BVE)have extremely weak uorescence in solution with quantum yield less than 0.01%.However,the situation reverses with the addition of z...As one of the biological endogenous pigments,biliverdin(BV)and its dimethyl ester(BVE)have extremely weak uorescence in solution with quantum yield less than 0.01%.However,the situation reverses with the addition of zinc ions.The strength for uorescence of BVE-Zn^2+ complex is greatly enhanced and uorescence quantum yield can increase to5%.Herein,we studied ultrafast excited state dynamics of BVE-Zn^2+ complex in ethanol,npropanol,and DMSO solutions in order to reveal the mechanism of uorescence quantum yield enhancement.The results show that BVE can form a stable coordination complex with zinc with 1:1 stoichiometry in solution.BVE is structurally and energetically more stable in the complex.Using picosecond time-resolve uorescence and femtosecond transient absorption spectroscopy,we show that smaller non-radiative rate constant of BVE-Zn^2+ complex in DMSO is the key to increasing its uorescence quantum yield and the excited state decay mechanism is also revealed.These results provide valuable information about the uorescence property change after BVE binding to metal ions and may provide a guidance for the study of phytochromes or other uorescence proteins in which BV/BVE acts as chromophores.展开更多
Summary:Sodium bisulfite could add to the central methine bridge of biliver- din in methanol,and give sodium bilirubin-10-sulfonate,however no bilirubin was formed.
Treatment of biliverdin IXα dimethyl ester(2)with silver nitrate in alkaline solution gave two violin-like tripyrrione carbaldehydes,one de- graded at C15-C16,other at C4-C5.Biliverdin IXα(1),bilirubin IXα(3)and it...Treatment of biliverdin IXα dimethyl ester(2)with silver nitrate in alkaline solution gave two violin-like tripyrrione carbaldehydes,one de- graded at C15-C16,other at C4-C5.Biliverdin IXα(1),bilirubin IXα(3)and its dimethyl ester(4)gave the same results.展开更多
Background：Biliverdin （BV） has a protective role against ischemia-reperfusion injury （IRI）.However,the protective role and potential mechanisms of BV on lung IRI （LIRI） remain to be elucidated.Thus,we aimed to ...Background：Biliverdin （BV） has a protective role against ischemia-reperfusion injury （IRI）.However,the protective role and potential mechanisms of BV on lung IRI （LIRI） remain to be elucidated.Thus,we aimed to investigate the protective role and potential mechanisms of BV on LIRI.Methods：Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model.After an initial 15 min stabilization period,the isolated lungs were subjected to ischemia for 60 min,followed by 90 min ofreperfusion with or without BV treatment.Results：Lungs in the I/R group exhibited significant decrease in tidal volume （1.44 ± 0.23 ml/min in I/R group vs.2.41 ± 0.31 ml/min in sham group;P 〈 0.001）,lung compliance （0.27 ± 0.06 ml/cmH2O in I/R group vs.0.44 ± 0.09 ml/cmH2O in sham group;P 〈 0.001;1 cmH2O=0.098 kPa）,and oxygen partial pressure （PaO2） levels （64.12 ± 12 mmHg in FR group vs.114 ± 8.0 mmHg in sham group;P 〈 0.001;1 mmHg =0.133 kPa）.In contrast,these parameters in the BV group （2.27 ± 0.37 ml/min of tidal volume,0.41 ± 0.10 ml/ cmH2O of compliance,and 98.7 ± 9.7 mmHg of PaO2） were significantly higher compared with the I/R group （P =0.004,P 〈 0.001,and P 〈 0.001,respectively）.Compared to the I/R group,the contents of superoxide dismutase were significantly higher （47.07 ± 7.91 U/mg protein vs.33.84 ± 10.15 U/mg protein;P =0.005） while the wet/dry weight ratio （P 〈 0.01）,methane dicarboxylic aldehyde （1.92 ± 0.25 nmol/mg protein vs.2.67 ± 0.46 nmol/mg protein;P 〈 0.001）,and adenosine triphosphate contents （297.05 ± 47.45 nmol/mg protein vs.208.09 ± 29.11 nmol/mg protein;P =0.005） were markedly lower in BV-treated lungs.Histological analysis revealed that BV alleviated LIRI.Furthermore,the expression of inflammatory cytokines （interleukin-1 β,interleukin-6,and tumor necrosis factor-α） was downregulated and the expression of cyclooxygenase-2,inducible nitric oxide synthase,and Jun N-terminal kinase was significantly reduced in BV group （all P 〈 0.01 compared to I/R group）.Finally,the apoptosis index in the BV group was significantly decreased （P 〈 0.01 compared to I/R group）.Conclusion：BV protects lung IRI through its antioxidative,anti-inflammatory,and anti-apoptotic effects.展开更多
The electrochemical redox behavior of bilirubin(BR Ⅳ_α),biliverdin(BV Ⅳ_α)and their oxidized product bile-purpurin(Bi-Pu)have been studied by in situ spectroelectrochemical techniques,which reveals that the transf...The electrochemical redox behavior of bilirubin(BR Ⅳ_α),biliverdin(BV Ⅳ_α)and their oxidized product bile-purpurin(Bi-Pu)have been studied by in situ spectroelectrochemical techniques,which reveals that the transformation of BR Ⅳ_α■BV Ⅳ_α■Bi-Pu can be achieved by controlling poten- tials.The kinetic investigation has shown that the heterogeneous electron transfer reactions of the couples of Ⅰ/Ⅱ and Ⅳ/Ⅲ were quasi-reversible and irreversible at a clean platinum electrode with the formal heteroge- neous electron transfer rate constants 1.5×10^(-4)cm·s^(-1)and 4.8×10^(-5)cm·s^(-1),respectively.展开更多
基金financially supported by the Key Research and Development Program of Zhejiang Province(2021C03088-2).
文摘Biliverdin,a bile pigment hydrolyzed from heme by heme oxygenase(HO),serves multiple functions in the human body,including antioxidant,anti-inflammatory,and immune response inhibitory activities.Biliverdin has great potential as a clinical drug;however,no economic and efficient production method is available currently.Therefore,the production of biliverdin by the biotransformation of exogenous heme using recombinant HO-expressing yeast cells was studied in this research.First,the heme oxygenase-1 gene(HO1)encoding the inducible plastidic isozyme from Arabidopsis thaliana,with the plastid transport peptide sequence removed,was recombined into Pichia pasto-ris GS115 cells.This resulted in the construction of a recombinant P.pastoris GS115-HO1 strain that expressed active HO1 in the cytoplasm.After that,the concentration of the inducer methanol,the induction culture time,the pH of the medium,and the concentration of sorbitol supplied in the medium were optimized,resulting in a significant improvement in the yield of HO1.Subsequently,the whole cells of GS115-HO1 were employed as catalysts to convert heme chloride(hemin)into biliverdin.The results showed that the yield of biliverdin was 132 mg/L when hemin was added to the culture of GS115-HO1 and incubated for 4 h at 30°C.The findings of this study have laid a good foundation for future applications of this method for the economical production of biliverdin.
基金Funding for the canine atorvastatin study was through the Alzheimer's Association IIRG-03-5673 to Elizabeth Head
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
文摘Biliverdin（BV） has long been thought to be a cytotoxic metabolic waste product. It has also been demonstrated to have important cytoprotective functions during oxidative stress. The present study aimed to examine the cytoprotective effect of BV on NRK-52 E cells, a proximal tubular cell line derived from rat kidney. Cells were treated with 50 μmol/L cisplatin for 24 h（cisplatin group） or pre-treated with BV for 30 min, then with 50 μmol/L cisplatin for 24 h（cisplatin＋BV group）. Those given no treatment served as a control. Cell apoptosis was evaluated by flow cytometry and cell viability by Cell Counting Kit-8（CCK-8）. The protein expressions of cleaved caspase3, Bax and Bcl-2 were assessed by Western blotting. Reactive oxygen species（ROS） levels were measured using carboxydichlorodihydrofluorescein diacetate（H2DCF）. The results showed that cisplatin induced the apoptosis of NRK-52 E cells, decreased cell viability, and increased the formation of ROS by upregulating the expression of cleaved caspase3 and Bax and decreasing Bcl-2 protein expression. These effects could be significantly reversed by pretreatment with BV. It was concluded that BV can protect against cisplatin-induced cell apoptosis through the anti-oxidative effects.
文摘Monolayer formation and LB film fabrication of amphiphilic derivative of biliverdin 1, diododecyl biliverdinamide [B(CONHC12H25)(2), 2] at an air-water interface on pure water subphase and subphase containing calcium ion were investigated and compared with 1. The coordination in ordered molecular films is much different from that in bulk solution. The formation of ligand-calcium complex was confirmed by X-ray photoelectron spectroscopy.
基金the National Nature Science Foundation of China(No.11674101,No.21873030 and No.91850202)。
文摘As one of the biological endogenous pigments,biliverdin(BV)and its dimethyl ester(BVE)have extremely weak uorescence in solution with quantum yield less than 0.01%.However,the situation reverses with the addition of zinc ions.The strength for uorescence of BVE-Zn^2+ complex is greatly enhanced and uorescence quantum yield can increase to5%.Herein,we studied ultrafast excited state dynamics of BVE-Zn^2+ complex in ethanol,npropanol,and DMSO solutions in order to reveal the mechanism of uorescence quantum yield enhancement.The results show that BVE can form a stable coordination complex with zinc with 1:1 stoichiometry in solution.BVE is structurally and energetically more stable in the complex.Using picosecond time-resolve uorescence and femtosecond transient absorption spectroscopy,we show that smaller non-radiative rate constant of BVE-Zn^2+ complex in DMSO is the key to increasing its uorescence quantum yield and the excited state decay mechanism is also revealed.These results provide valuable information about the uorescence property change after BVE binding to metal ions and may provide a guidance for the study of phytochromes or other uorescence proteins in which BV/BVE acts as chromophores.
基金This work was supported by the Natural Science Funda-tion of China(86020219)
文摘Summary:Sodium bisulfite could add to the central methine bridge of biliver- din in methanol,and give sodium bilirubin-10-sulfonate,however no bilirubin was formed.
文摘Treatment of biliverdin IXα dimethyl ester(2)with silver nitrate in alkaline solution gave two violin-like tripyrrione carbaldehydes,one de- graded at C15-C16,other at C4-C5.Biliverdin IXα(1),bilirubin IXα(3)and its dimethyl ester(4)gave the same results.
文摘Background：Biliverdin （BV） has a protective role against ischemia-reperfusion injury （IRI）.However,the protective role and potential mechanisms of BV on lung IRI （LIRI） remain to be elucidated.Thus,we aimed to investigate the protective role and potential mechanisms of BV on LIRI.Methods：Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model.After an initial 15 min stabilization period,the isolated lungs were subjected to ischemia for 60 min,followed by 90 min ofreperfusion with or without BV treatment.Results：Lungs in the I/R group exhibited significant decrease in tidal volume （1.44 ± 0.23 ml/min in I/R group vs.2.41 ± 0.31 ml/min in sham group;P 〈 0.001）,lung compliance （0.27 ± 0.06 ml/cmH2O in I/R group vs.0.44 ± 0.09 ml/cmH2O in sham group;P 〈 0.001;1 cmH2O=0.098 kPa）,and oxygen partial pressure （PaO2） levels （64.12 ± 12 mmHg in FR group vs.114 ± 8.0 mmHg in sham group;P 〈 0.001;1 mmHg =0.133 kPa）.In contrast,these parameters in the BV group （2.27 ± 0.37 ml/min of tidal volume,0.41 ± 0.10 ml/ cmH2O of compliance,and 98.7 ± 9.7 mmHg of PaO2） were significantly higher compared with the I/R group （P =0.004,P 〈 0.001,and P 〈 0.001,respectively）.Compared to the I/R group,the contents of superoxide dismutase were significantly higher （47.07 ± 7.91 U/mg protein vs.33.84 ± 10.15 U/mg protein;P =0.005） while the wet/dry weight ratio （P 〈 0.01）,methane dicarboxylic aldehyde （1.92 ± 0.25 nmol/mg protein vs.2.67 ± 0.46 nmol/mg protein;P 〈 0.001）,and adenosine triphosphate contents （297.05 ± 47.45 nmol/mg protein vs.208.09 ± 29.11 nmol/mg protein;P =0.005） were markedly lower in BV-treated lungs.Histological analysis revealed that BV alleviated LIRI.Furthermore,the expression of inflammatory cytokines （interleukin-1 β,interleukin-6,and tumor necrosis factor-α） was downregulated and the expression of cyclooxygenase-2,inducible nitric oxide synthase,and Jun N-terminal kinase was significantly reduced in BV group （all P 〈 0.01 compared to I/R group）.Finally,the apoptosis index in the BV group was significantly decreased （P 〈 0.01 compared to I/R group）.Conclusion：BV protects lung IRI through its antioxidative,anti-inflammatory,and anti-apoptotic effects.
基金the National Natural Science Foundation of China
文摘The electrochemical redox behavior of bilirubin(BR Ⅳ_α),biliverdin(BV Ⅳ_α)and their oxidized product bile-purpurin(Bi-Pu)have been studied by in situ spectroelectrochemical techniques,which reveals that the transformation of BR Ⅳ_α■BV Ⅳ_α■Bi-Pu can be achieved by controlling poten- tials.The kinetic investigation has shown that the heterogeneous electron transfer reactions of the couples of Ⅰ/Ⅱ and Ⅳ/Ⅲ were quasi-reversible and irreversible at a clean platinum electrode with the formal heteroge- neous electron transfer rate constants 1.5×10^(-4)cm·s^(-1)and 4.8×10^(-5)cm·s^(-1),respectively.
