AIM To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. METHODS Ten weeks after the onset of type 1 diabetes samp...AIM To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. METHODS Ten weeks after the onset of type 1 diabetes samples were taken from the duodenum, ileum and colon of streptozotocin-induce diabetic, insulin-treated diabetic and sex-and age-matched control rats. Whole-mount preparations of submucous plexus were prepared from the different gut segments for quantitative fluorescent immunohistochemistry. The following double-immunostainings were performed: neuronal nitric oxide synthase(n NOS) and Hu C/D, heme oxygenase(HO) 1 and peripherin, as well as HO2 and peripherin. The density of n NOS-, HO1-and HO2-immunoreactive(IR) neurons was determined as a percentage of the total number of submucous neurons. RESULTS The total number of submucous neurons and the proportion of n NOS-, HO1-and HO2-IR subpopulations were not affected in the duodenal ganglia of control, diabetic and insulin-treated rats. While the total neuronal number did not change in either the ileum or the colon, the density of nitrergic neurons exhibited a 2-and 3-fold increase in the diabetic ileum and colon, respectively, which was further enhanced after insulin replacement. The presence of HO1-and HO2-IR submucous neurons was robust in the colon of controls(38.4%-50.8%), whereas it was significantly lower in the small intestinal segments(0.0%-4.2%, P < 0.0001). Under pathophysiological conditions the only alteration detected was an increase in the ileum and a decrease in the colon of the proportion of HO-IR neurons in insulin-treated diabetic animals. CONCLUSION Diabetes and immediate insulin replacement induce the most pronounced region-specific alterations of n NOS-, HO1-and HO2-IR submucous neuronal density in the distal parts of the gut.展开更多
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in re...Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.展开更多
Objective: The content of saikosaponins in genus Bupleurum is increased with numbers of lateral root, but the genetic mechanisms are largely unknown. This study aims to identify the heme oxygenase(HO) gene family memb...Objective: The content of saikosaponins in genus Bupleurum is increased with numbers of lateral root, but the genetic mechanisms are largely unknown. This study aims to identify the heme oxygenase(HO) gene family members of B. chinense and B. scorzonerifolium, and assess their role in the root development in Bupleurum.Methods: The gene sequences of HO family were selected from iso-seq full-length transcriptome data of B. chinense and B. scorzonerifolium, and were analyzed in physicochemical properties, conserved domains,motifs and phylogenetic relationship. In addition, the expression patterns of HO gene in different parts of roots were compared via transcriptome sequencing and qRT-PCR in the two species.Results: Five Bupleurum HO genes(BcHO1-BcHO5) belonging to the HO1 subfamily were identified from the transcriptome data, whereas the HO_(2) subfamily member was not identified. The expression levels of BcHO1 and BcHO_(2) were significantly higher than those of other three HO members in the transcriptome analysis. In addition, the expression profile of BcHO1 showed consistency with lateral root development in B. chinense and B. scorzonerifolium.Conclusion: Hos might participate in the auxin-induced morphogenesis of lateral roots. The yield of saikosaponin may be improved by manipulating expression of these genes.展开更多
As a leading cause of respiratory disease, influenza A virus(IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement f...As a leading cause of respiratory disease, influenza A virus(IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement for new drugs. Compound Yi-Zhi-Hao pellet(CYZH) is a famous traditional Chinese medicine(TCM) used in the clinic, whose formula has been recorded in Complication of National Standard for Traditional Chinese Medicine to treat common cold. In this study, we found that CYZH exhibited a broad-spectrum anti-influenza activity and inhibited the expression of viral RNA and proteins in vitro. Mechanistically, CYZH had no inhibitory activities against viral protein hemagglutinin and IAV RNA-dependent RNA polymerase. Instead, it induced activation of erythroid 2-related factor 2(Nrf2) and nuclear factor kappa B(NF-κB), which subsequently upregulated heme oxygenase-1(HO-1) expression.Also, CYZH protected cells from oxidative damage induced by reactive oxygen series. In conclusions,CYZH inhibits IAV replication in vitro, at least partly by activating expression of the Nrf2/HO-1 pathway.展开更多
Hemin can improve the stress resistance of plants through the heme oxygenase system.Additionally,substances contained in plants,such as secondary metabolites,can improve stress resistance.However,few studies have expl...Hemin can improve the stress resistance of plants through the heme oxygenase system.Additionally,substances contained in plants,such as secondary metabolites,can improve stress resistance.However,few studies have explored the effects of hemin on secondary metabolite content.Therefore,the effects of hemin on saponin synthesis and the mechanism of plant injury relief by hemin in Conyza blinii were investigated in this study.Hemin treatment promoted plant growth and increased the antioxidant enzyme activity and saponin content of C.blinii under osmotic stress and cold stress.Further study showed that hemin could provide sufficient precursors for saponin synthesis by improving the photosynthetic capacity of C.blinii and increasing the gene expression of key enzymes in the saponin synthesis pathway,thus increasing the saponin content.Moreover,the promotion effect of hemin on saponin synthesis is dependent on heme oxygenase-1 and can be reversed by the inhibitor Zn-protoporphyrin-IX(ZnPPIX).This study revealed that hemin can increase the saponin content of C.blinii and alleviate the damage caused by abiotic stress,and it also broadened the understanding of the relationship between hemin and secondary metabolites in plant abiotic stress relief.展开更多
Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord ...Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.展开更多
CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebr...CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.展开更多
AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide(HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal mo...AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide(HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous(sc)], zinc protoporphyrin IX [Zn PPIX, 50 μg/kg/intraperitoneal(ip)] and hemin(50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation(EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine(ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron(3 μmol/L, 15 min), Zn PPIX(10 μmol/L, 60 min) or CO-releasing molecule-3(CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment withor without atropine(3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine(L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTS Administration of granisetron(50, 75 μg/kg) in vivo significantly increased the time to first defecation(P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of Zn PPIX or hemin alone had no effect on this gastrointestinal motility parameter, Zn PPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone(3 μmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with Zn PPIX alone(10 μmol/L) significantly reduced the colon's contractile response to EFS(P = 0.016) but had no effect on contractile response to ACh. Co-administration of Zn PPIX and atropine(3 μmol/L) abolished the Zn PPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3(400 μmol/L) alone increased both the contractile response to EFS at 10 Hz(10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh(100 μmol/L)(P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnP PIX, the ZnP PIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3(400 μmol/L) further increased the colon's contractile response to EFS(at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh(ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFSinduced and ACh-induced contractile response.CONCLUSION Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.展开更多
Objective:To investigate the effect of Huangqin Decoction(HQD)on nuclear factor erythroid 2 related-factor 2(Nrf2)/heme oxygenase(HO-1)signaling pathway by inducing the colitis-associated carcinogenesis(CAC)model mice...Objective:To investigate the effect of Huangqin Decoction(HQD)on nuclear factor erythroid 2 related-factor 2(Nrf2)/heme oxygenase(HO-1)signaling pathway by inducing the colitis-associated carcinogenesis(CAC)model mice with azoxymethane(AOM)/dextran sodium sulfate(DSS).Methods:The chemical components of HQD were analyzed by liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF-MS/MS)to determine the molecular constituents of HQD.Totally 48 C57BL/6J mice were randomly divided into 6 groups by a random number table,including control,model(AOM/DSS),mesalazine(MS),low-,medium-,and high-dose HQD(HQD-L,HQD-M,and HQD-H)groups,8 mice in each group.Except for the control group,the mice in the other groups were intraperitoneally injected with AOM(10 mg/kg)and administrated with 2.5%DSS orally for 1 week every two weeks(totally 3 rounds of DSS)to construct a colitis-associated carcinogenesis mouse model.The mice in the HQD-L,HQD-M and HQD-H groups were given HQD by gavage at doses of 2.925,5.85,and 11.7 g/kg,respectively;the mice in the MS group was given a suspension of MS at a dose of 0.043 g/kg(totally 11 weeks).The serum levels of malondialdehyde(MDA)and superoxide dismutase(SOD)were measured by enzyme-linked immunosorbent assay.The mRNA and protein expression levels of Nrf2,HO-1,and inhibitory KELCH like ECH-related protein 1(Keap1)in colon tissue were detected by quantitative real-time PCR,immunohistochemistry,and Westem blot,respectively.Results:LC-Q-TOF-MS/MS analysis revealed that the chemical constituents of HQD include baicalin,paeoniflorin,and glycyrrhizic acid.Compared to the control group,significantly higher MDA levels and lower SOD levels were observed in the model group(P<0.05),whereas the expressions of Nrf2 and HO-1 were significantly decreased,and the expression of Keap1 increased(P<0.01).Compared with the model group,serum MDA level was decreased and SOD level was increased in the HQD-M,HQD-H and MS groups(P<0.05).Higher expressions of Nrf2 and HO-1 were observed in the HQD groups.Conclusion:HQD may regulate the expression of Nrf2 and HO-1 in colon tissue,reduce the expression of MDA and increase the expression of SOD in serum,thus delaying the progress of CAC in AOM/DSS mice.展开更多
Background: The antioxidant effects of bilirubin in Parkinson’s disease (PD) have recently gained much attention from the research community. However, results from these studies have been conflicting. This meta-analy...Background: The antioxidant effects of bilirubin in Parkinson’s disease (PD) have recently gained much attention from the research community. However, results from these studies have been conflicting. This meta-analysis is conducted to assess the relationship between the serum bilirubin concentration and the risk of PD.Methods: Two reviewers performed a systematic literature search across five databases (MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials). The case-control studies regarding bilirubin levels in PD patients published up to April 2020 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the standard mean difference (SMD) and the 95% confidence interval (CI), which were analyzed using the Stata V.12.0 statistical software.Results: A total of eight studies which included 1463 PD cases and 1490 controls were incorporated into our meta-analysis. SMD analysis showed that there was a higher total bilirubin (TBIL) and direct bilirubin (DBIL) levels in PD patients compared with controls (for TBIL, SMD: 0.300, 95% CI: 0.050-0.549,P = 0.018;for DBIL, SMD: 0.395, 95% CI: 0.102-0.688,P = 0.008). However, no significant relationship was found between the serum indirect bilirubin and PD patients (SMD: -0.223, 95% CI: -0.952-0.505,P = 0.548). A subgroup analysis based on ethnicity indicated that the serum TBIL was higher in PD patients of Caucasian descent in contrast to matched healthy controls (SMD: 0.511, 95% CI: 0.324-0.698,P = 0.000,I2 = 58.0%).Conclusion: Higher serum bilirubin levels in PD patients suggest that bilirubin might play a role in the pathogenesis of PD and have the potential to be utilized as a biochemical marker for PD diagnosis and treatment.展开更多
Cytochrome P450 reductase(POR)is an essential electron transfer protein located on the endoplasmic reticulum of most cell types,and has long been appreciated for its role in cytochrome P450-mediated drug metabolism.Ad...Cytochrome P450 reductase(POR)is an essential electron transfer protein located on the endoplasmic reticulum of most cell types,and has long been appreciated for its role in cytochrome P450-mediated drug metabolism.Additional roles and electron acceptors for POR have been described,but it is largely with the recent availability of POR-null tissues that these supplemental roles for POR have been able to be explored.These studies have confirmed POR as the principal redox partner for the microsomal P450s responsible for drug and xenobiotic metabolism as well as cholesterol and bile acid synthesis,and for heme oxygenase,which catalyzes the initial step in the breakdown of heme.Surprisingly,these studies have revealed that squalene monooxygenase,an enzyme essential to cholesterol synthesis,has a second unknown redox partner in addition to POR,and that 7-dehydrocholesterol reductase,previously proposed to require POR as an electron donor,functions fully independently of POR.These studies have also helped define the role of cytochrome b5 in P450 catalysis,and raise the question as to the extent to which POR contributes to b5-dependent redox pathways.展开更多
Inflammation links neurodegenerative,neuropsychiatric and other neurological diseases(NDs)with acute brain events.It is responsible for the alteration of neurotransmission and circuity,brain architecture,and cell fate...Inflammation links neurodegenerative,neuropsychiatric and other neurological diseases(NDs)with acute brain events.It is responsible for the alteration of neurotransmission and circuity,brain architecture,and cell fate,affecting mood and personality(anxiety,depression and schizophrenia)and behavior(decline in cognitive,motor and speech abilities,altered sleep,fatigue,pain sensitivity and dementia).Inflammation is also a key component in systemic chronic diseases(cardiovascular disease,cancer,diabetes,and metabolic syndrome),in which bilirubin has been demonstrated to improve the diseases by acting as a multi-target antiinflammatory molecule,and where the evaluation of pharmacological modulation of the pigment level as a therapeutic approach has already started.While altered serum bilirubin levels have been reported in ND patients,the potential activity of bilirubin in the brain is vague.This review summarizes the available fragmentary information on the interplay of bilirubin with neuroinflammation,aiming to elucidate the pigment's role in the central nervous system environment.展开更多
Objective: To study the protective effect of anthocyanins extracted from Vaccinium Uliginosum(VU)on retinal 661W cells against microwave radiation induced retinal injury. Methods: 661W cells were divided into 6 groups...Objective: To study the protective effect of anthocyanins extracted from Vaccinium Uliginosum(VU)on retinal 661W cells against microwave radiation induced retinal injury. Methods: 661W cells were divided into 6 groups, including control, model [661W cells radiated by microwave(30 mW/cm2, 1 h)] and VU groups [661W cells pretreated with anthocyanins extracted from VU(25, 50, 100 and 200 μg/mL, respectively) for 48 h, and radiated by microwave 30 mW/cm2, 1 h]. After treatment with different interventions, the cell apoptosis index(AI)was determined using Heochst staining;contents of malonaldehyde(MDA), glutataione(GSH), and activity of superoxide dismutase(SOD) were measured. mRNA expressions of nuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase 1(HO-1) were detected by real time quantitative polymerase chain reaction, and the expression of HO-1 protein was examined by Western blot analysis. Nucleus and cytoplasm were separated and Nrf2 protein expression was further verified by Western blot analysis. Results: There was significant difference in AI among the groups(F=322.83, P<0.05). Compared with the control group, AI was significantly higher in the model group and was lower in 4 VU-pretreated groups(P<0.05). Linear regression analysis showed the decline of AI was in a dose-dependent manner with VU treatment(r=0.8419, P<0.05). The MDA and GSH contents of 661W cells in VU-treated groups were significantly lower than the model group(P<0.05). Compared with the model group, the SOD activity in the VU-treated groups(50, 100 and 200 μg/mL) was significantly higher(all P<0.05). The Nrf2 and HO-1 mRNA expressions were slightly increased after irradiation, and obviously increased in 100 μg/mL VU-treated group. After irradiation, the relative expressions of HO-1 and Nrf2 proteins in nucleus were slightly increased(P<0.05), and the changes in cytoplasm were not obvious,whereas it was significantly increased in both nucleus and cytoplasm in the VU treatment groups. Conclusions:Anthocyanins extracted from VU could reduce apoptosis, stabilize cell membrane, and alleviate oxidant injury of mouse retinal photoreceptor 661W cells. The mechanism might be through activating Nrf2/HO-1 signal pathway and inducing HO-1 transcription and translation.展开更多
Ferroptosis is a recently emerging non-apoptotic mode of cell death involving the production of iron-dependent reactive oxygen species(ROS).Here we described a mitochondria-targeted iridium(III)complex Ir FN that exhi...Ferroptosis is a recently emerging non-apoptotic mode of cell death involving the production of iron-dependent reactive oxygen species(ROS).Here we described a mitochondria-targeted iridium(III)complex Ir FN that exhibited potent antiproliferative activity against a variety of cancer cells,especially the A2780 human ovarian cancer cells,through the ferroptosis pathways.Mechanistic studies by label-free quantitative proteomics profiling indicated that heme oxygenase 1(HMOX1)-mediated ferroptosis process was activated by Ir FN.The study on iron-dependent cell death,ROS accumulation,lipid peroxidation,and over released iron further confirmed the ferroptosis processes.m RNA transcription quantification,in vitro over-expression of HMOX1,and RNAi-mediated knock-down experiments suggested that Ir FN activated the over-expression of HMOX1.Our report revealed the first case of anticancer iridium complex leading to ferroptosis,highlighting ferroptosis as a promising approach in future design of metallodrugs.展开更多
基金Supported by the Hungarian Scientific Research Fund,OTKA grant,No.PD 108309(Nikolett Bódi)by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences(Mária Bagyánszki)by the Stipendium Hungaricum Scholarship,No.2015-SH-500041,Tempus Public Foundation(Lalitha Chandrakumar)
文摘AIM To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. METHODS Ten weeks after the onset of type 1 diabetes samples were taken from the duodenum, ileum and colon of streptozotocin-induce diabetic, insulin-treated diabetic and sex-and age-matched control rats. Whole-mount preparations of submucous plexus were prepared from the different gut segments for quantitative fluorescent immunohistochemistry. The following double-immunostainings were performed: neuronal nitric oxide synthase(n NOS) and Hu C/D, heme oxygenase(HO) 1 and peripherin, as well as HO2 and peripherin. The density of n NOS-, HO1-and HO2-immunoreactive(IR) neurons was determined as a percentage of the total number of submucous neurons. RESULTS The total number of submucous neurons and the proportion of n NOS-, HO1-and HO2-IR subpopulations were not affected in the duodenal ganglia of control, diabetic and insulin-treated rats. While the total neuronal number did not change in either the ileum or the colon, the density of nitrergic neurons exhibited a 2-and 3-fold increase in the diabetic ileum and colon, respectively, which was further enhanced after insulin replacement. The presence of HO1-and HO2-IR submucous neurons was robust in the colon of controls(38.4%-50.8%), whereas it was significantly lower in the small intestinal segments(0.0%-4.2%, P < 0.0001). Under pathophysiological conditions the only alteration detected was an increase in the ileum and a decrease in the colon of the proportion of HO-IR neurons in insulin-treated diabetic animals. CONCLUSION Diabetes and immediate insulin replacement induce the most pronounced region-specific alterations of n NOS-, HO1-and HO2-IR submucous neuronal density in the distal parts of the gut.
基金Supported by Grant SFB547 A8 from the Deutsche Forschun-gsgemeinschaft (to Immenschuh S)
文摘Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.
基金financially supported by China Agriculture Research System of MOF and MARA,the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2016-I2M-2-003)Opening Project Fund of Key Laboratory of Rubber Biology and Genetic Resource Utilization,Ministry of Agriculture/State Key Laboratory Breeding Base of Cultivation&Physiology for Tropical Crops/Danzhou Investigation&Experiment Station of Tropical Crops,Ministry of Agriculture(No.RRL-KLOF202201)。
文摘Objective: The content of saikosaponins in genus Bupleurum is increased with numbers of lateral root, but the genetic mechanisms are largely unknown. This study aims to identify the heme oxygenase(HO) gene family members of B. chinense and B. scorzonerifolium, and assess their role in the root development in Bupleurum.Methods: The gene sequences of HO family were selected from iso-seq full-length transcriptome data of B. chinense and B. scorzonerifolium, and were analyzed in physicochemical properties, conserved domains,motifs and phylogenetic relationship. In addition, the expression patterns of HO gene in different parts of roots were compared via transcriptome sequencing and qRT-PCR in the two species.Results: Five Bupleurum HO genes(BcHO1-BcHO5) belonging to the HO1 subfamily were identified from the transcriptome data, whereas the HO_(2) subfamily member was not identified. The expression levels of BcHO1 and BcHO_(2) were significantly higher than those of other three HO members in the transcriptome analysis. In addition, the expression profile of BcHO1 showed consistency with lateral root development in B. chinense and B. scorzonerifolium.Conclusion: Hos might participate in the auxin-induced morphogenesis of lateral roots. The yield of saikosaponin may be improved by manipulating expression of these genes.
基金supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (2012ZX10004501-004-001) The Science & Technology project of Urumqi of Xinjiang Uygur Autonomous Region (Y151310010): Study on the mechanism of anti-influenza virus effect of compound Yi-Zhi-Hao Pellets
文摘As a leading cause of respiratory disease, influenza A virus(IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement for new drugs. Compound Yi-Zhi-Hao pellet(CYZH) is a famous traditional Chinese medicine(TCM) used in the clinic, whose formula has been recorded in Complication of National Standard for Traditional Chinese Medicine to treat common cold. In this study, we found that CYZH exhibited a broad-spectrum anti-influenza activity and inhibited the expression of viral RNA and proteins in vitro. Mechanistically, CYZH had no inhibitory activities against viral protein hemagglutinin and IAV RNA-dependent RNA polymerase. Instead, it induced activation of erythroid 2-related factor 2(Nrf2) and nuclear factor kappa B(NF-κB), which subsequently upregulated heme oxygenase-1(HO-1) expression.Also, CYZH protected cells from oxidative damage induced by reactive oxygen series. In conclusions,CYZH inhibits IAV replication in vitro, at least partly by activating expression of the Nrf2/HO-1 pathway.
基金supported by the Sichuan Science and Technology Program(No.2020YFH0136),China。
文摘Hemin can improve the stress resistance of plants through the heme oxygenase system.Additionally,substances contained in plants,such as secondary metabolites,can improve stress resistance.However,few studies have explored the effects of hemin on secondary metabolite content.Therefore,the effects of hemin on saponin synthesis and the mechanism of plant injury relief by hemin in Conyza blinii were investigated in this study.Hemin treatment promoted plant growth and increased the antioxidant enzyme activity and saponin content of C.blinii under osmotic stress and cold stress.Further study showed that hemin could provide sufficient precursors for saponin synthesis by improving the photosynthetic capacity of C.blinii and increasing the gene expression of key enzymes in the saponin synthesis pathway,thus increasing the saponin content.Moreover,the promotion effect of hemin on saponin synthesis is dependent on heme oxygenase-1 and can be reversed by the inhibitor Zn-protoporphyrin-IX(ZnPPIX).This study revealed that hemin can increase the saponin content of C.blinii and alleviate the damage caused by abiotic stress,and it also broadened the understanding of the relationship between hemin and secondary metabolites in plant abiotic stress relief.
基金supported by the National Natural Science Foundation of China,Nos.LY20H090018(to XL)and LY20H060008(to HS).
文摘Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.
基金supported by the National Natural Science Foundation of China,No.81402930Natural Science Foundation of Universities in Anhui Province,No.KJ2021A0688+2 种基金National College Students Innovation and Entrepreneurship Program,No.202110367071Key projects of science and technology projects of Bengbu Medical College,No.2020byzd017512 Talents Training Program of Bengbu Medical College,No.BY51201104(all to SYD).
文摘CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.
基金Supported by Universitàdegli Studi di Bari,protocol No.10110 tit-VIII/2
文摘AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide(HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous(sc)], zinc protoporphyrin IX [Zn PPIX, 50 μg/kg/intraperitoneal(ip)] and hemin(50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation(EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine(ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron(3 μmol/L, 15 min), Zn PPIX(10 μmol/L, 60 min) or CO-releasing molecule-3(CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment withor without atropine(3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine(L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTS Administration of granisetron(50, 75 μg/kg) in vivo significantly increased the time to first defecation(P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of Zn PPIX or hemin alone had no effect on this gastrointestinal motility parameter, Zn PPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone(3 μmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with Zn PPIX alone(10 μmol/L) significantly reduced the colon's contractile response to EFS(P = 0.016) but had no effect on contractile response to ACh. Co-administration of Zn PPIX and atropine(3 μmol/L) abolished the Zn PPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3(400 μmol/L) alone increased both the contractile response to EFS at 10 Hz(10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh(100 μmol/L)(P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnP PIX, the ZnP PIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3(400 μmol/L) further increased the colon's contractile response to EFS(at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh(ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFSinduced and ACh-induced contractile response.CONCLUSION Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.
基金Supported by the Natural Science Foundation Project of Nanjing University of Traditional Chinese Medicine(No.XZR2020030)Jiangsu Famous Traditional Chinese Medicine Inheritance Studio Project(Jiangsu Traditional Chinese Medicine Science and Education(No.20SGzs003)。
文摘Objective:To investigate the effect of Huangqin Decoction(HQD)on nuclear factor erythroid 2 related-factor 2(Nrf2)/heme oxygenase(HO-1)signaling pathway by inducing the colitis-associated carcinogenesis(CAC)model mice with azoxymethane(AOM)/dextran sodium sulfate(DSS).Methods:The chemical components of HQD were analyzed by liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF-MS/MS)to determine the molecular constituents of HQD.Totally 48 C57BL/6J mice were randomly divided into 6 groups by a random number table,including control,model(AOM/DSS),mesalazine(MS),low-,medium-,and high-dose HQD(HQD-L,HQD-M,and HQD-H)groups,8 mice in each group.Except for the control group,the mice in the other groups were intraperitoneally injected with AOM(10 mg/kg)and administrated with 2.5%DSS orally for 1 week every two weeks(totally 3 rounds of DSS)to construct a colitis-associated carcinogenesis mouse model.The mice in the HQD-L,HQD-M and HQD-H groups were given HQD by gavage at doses of 2.925,5.85,and 11.7 g/kg,respectively;the mice in the MS group was given a suspension of MS at a dose of 0.043 g/kg(totally 11 weeks).The serum levels of malondialdehyde(MDA)and superoxide dismutase(SOD)were measured by enzyme-linked immunosorbent assay.The mRNA and protein expression levels of Nrf2,HO-1,and inhibitory KELCH like ECH-related protein 1(Keap1)in colon tissue were detected by quantitative real-time PCR,immunohistochemistry,and Westem blot,respectively.Results:LC-Q-TOF-MS/MS analysis revealed that the chemical constituents of HQD include baicalin,paeoniflorin,and glycyrrhizic acid.Compared to the control group,significantly higher MDA levels and lower SOD levels were observed in the model group(P<0.05),whereas the expressions of Nrf2 and HO-1 were significantly decreased,and the expression of Keap1 increased(P<0.01).Compared with the model group,serum MDA level was decreased and SOD level was increased in the HQD-M,HQD-H and MS groups(P<0.05).Higher expressions of Nrf2 and HO-1 were observed in the HQD groups.Conclusion:HQD may regulate the expression of Nrf2 and HO-1 in colon tissue,reduce the expression of MDA and increase the expression of SOD in serum,thus delaying the progress of CAC in AOM/DSS mice.
基金National Natural Science Foundation of China(No.81971192)。
文摘Background: The antioxidant effects of bilirubin in Parkinson’s disease (PD) have recently gained much attention from the research community. However, results from these studies have been conflicting. This meta-analysis is conducted to assess the relationship between the serum bilirubin concentration and the risk of PD.Methods: Two reviewers performed a systematic literature search across five databases (MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials). The case-control studies regarding bilirubin levels in PD patients published up to April 2020 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the standard mean difference (SMD) and the 95% confidence interval (CI), which were analyzed using the Stata V.12.0 statistical software.Results: A total of eight studies which included 1463 PD cases and 1490 controls were incorporated into our meta-analysis. SMD analysis showed that there was a higher total bilirubin (TBIL) and direct bilirubin (DBIL) levels in PD patients compared with controls (for TBIL, SMD: 0.300, 95% CI: 0.050-0.549,P = 0.018;for DBIL, SMD: 0.395, 95% CI: 0.102-0.688,P = 0.008). However, no significant relationship was found between the serum indirect bilirubin and PD patients (SMD: -0.223, 95% CI: -0.952-0.505,P = 0.548). A subgroup analysis based on ethnicity indicated that the serum TBIL was higher in PD patients of Caucasian descent in contrast to matched healthy controls (SMD: 0.511, 95% CI: 0.324-0.698,P = 0.000,I2 = 58.0%).Conclusion: Higher serum bilirubin levels in PD patients suggest that bilirubin might play a role in the pathogenesis of PD and have the potential to be utilized as a biochemical marker for PD diagnosis and treatment.
文摘Cytochrome P450 reductase(POR)is an essential electron transfer protein located on the endoplasmic reticulum of most cell types,and has long been appreciated for its role in cytochrome P450-mediated drug metabolism.Additional roles and electron acceptors for POR have been described,but it is largely with the recent availability of POR-null tissues that these supplemental roles for POR have been able to be explored.These studies have confirmed POR as the principal redox partner for the microsomal P450s responsible for drug and xenobiotic metabolism as well as cholesterol and bile acid synthesis,and for heme oxygenase,which catalyzes the initial step in the breakdown of heme.Surprisingly,these studies have revealed that squalene monooxygenase,an enzyme essential to cholesterol synthesis,has a second unknown redox partner in addition to POR,and that 7-dehydrocholesterol reductase,previously proposed to require POR as an electron donor,functions fully independently of POR.These studies have also helped define the role of cytochrome b5 in P450 catalysis,and raise the question as to the extent to which POR contributes to b5-dependent redox pathways.
基金Jayanti S was supported in part by a fellowship from the Lembaga Pengelola Dana Pendidikan of Ministry of Finance of Indonesia and an internal grant from the Italian Liver Foundation.The funders had no role in data analysis and interpretation and also writing of the manuscript
文摘Inflammation links neurodegenerative,neuropsychiatric and other neurological diseases(NDs)with acute brain events.It is responsible for the alteration of neurotransmission and circuity,brain architecture,and cell fate,affecting mood and personality(anxiety,depression and schizophrenia)and behavior(decline in cognitive,motor and speech abilities,altered sleep,fatigue,pain sensitivity and dementia).Inflammation is also a key component in systemic chronic diseases(cardiovascular disease,cancer,diabetes,and metabolic syndrome),in which bilirubin has been demonstrated to improve the diseases by acting as a multi-target antiinflammatory molecule,and where the evaluation of pharmacological modulation of the pigment level as a therapeutic approach has already started.While altered serum bilirubin levels have been reported in ND patients,the potential activity of bilirubin in the brain is vague.This review summarizes the available fragmentary information on the interplay of bilirubin with neuroinflammation,aiming to elucidate the pigment's role in the central nervous system environment.
文摘Objective: To study the protective effect of anthocyanins extracted from Vaccinium Uliginosum(VU)on retinal 661W cells against microwave radiation induced retinal injury. Methods: 661W cells were divided into 6 groups, including control, model [661W cells radiated by microwave(30 mW/cm2, 1 h)] and VU groups [661W cells pretreated with anthocyanins extracted from VU(25, 50, 100 and 200 μg/mL, respectively) for 48 h, and radiated by microwave 30 mW/cm2, 1 h]. After treatment with different interventions, the cell apoptosis index(AI)was determined using Heochst staining;contents of malonaldehyde(MDA), glutataione(GSH), and activity of superoxide dismutase(SOD) were measured. mRNA expressions of nuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase 1(HO-1) were detected by real time quantitative polymerase chain reaction, and the expression of HO-1 protein was examined by Western blot analysis. Nucleus and cytoplasm were separated and Nrf2 protein expression was further verified by Western blot analysis. Results: There was significant difference in AI among the groups(F=322.83, P<0.05). Compared with the control group, AI was significantly higher in the model group and was lower in 4 VU-pretreated groups(P<0.05). Linear regression analysis showed the decline of AI was in a dose-dependent manner with VU treatment(r=0.8419, P<0.05). The MDA and GSH contents of 661W cells in VU-treated groups were significantly lower than the model group(P<0.05). Compared with the model group, the SOD activity in the VU-treated groups(50, 100 and 200 μg/mL) was significantly higher(all P<0.05). The Nrf2 and HO-1 mRNA expressions were slightly increased after irradiation, and obviously increased in 100 μg/mL VU-treated group. After irradiation, the relative expressions of HO-1 and Nrf2 proteins in nucleus were slightly increased(P<0.05), and the changes in cytoplasm were not obvious,whereas it was significantly increased in both nucleus and cytoplasm in the VU treatment groups. Conclusions:Anthocyanins extracted from VU could reduce apoptosis, stabilize cell membrane, and alleviate oxidant injury of mouse retinal photoreceptor 661W cells. The mechanism might be through activating Nrf2/HO-1 signal pathway and inducing HO-1 transcription and translation.
基金supported by the National Natural Science Foundation of China(21622103,21671099,91753121)Shenzhen Basic Research Program(JCYJ20170413150538897,JCYJ20180508182240106)+1 种基金the Fundamental Research Funds for the Central Universities(020814380109)the International Postdoctoral Exchange Fellowship Program of China
文摘Ferroptosis is a recently emerging non-apoptotic mode of cell death involving the production of iron-dependent reactive oxygen species(ROS).Here we described a mitochondria-targeted iridium(III)complex Ir FN that exhibited potent antiproliferative activity against a variety of cancer cells,especially the A2780 human ovarian cancer cells,through the ferroptosis pathways.Mechanistic studies by label-free quantitative proteomics profiling indicated that heme oxygenase 1(HMOX1)-mediated ferroptosis process was activated by Ir FN.The study on iron-dependent cell death,ROS accumulation,lipid peroxidation,and over released iron further confirmed the ferroptosis processes.m RNA transcription quantification,in vitro over-expression of HMOX1,and RNAi-mediated knock-down experiments suggested that Ir FN activated the over-expression of HMOX1.Our report revealed the first case of anticancer iridium complex leading to ferroptosis,highlighting ferroptosis as a promising approach in future design of metallodrugs.
