Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Metho...Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.展开更多
Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pai...Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.展开更多
TRPA1 channels are non-selective cation channels that could be activated by plant-derived pungent products, including gingerol, a main active constituent of ginger. Ginger could improve the digestive function; however...TRPA1 channels are non-selective cation channels that could be activated by plant-derived pungent products, including gingerol, a main active constituent of ginger. Ginger could improve the digestive function; however whether ginger improves the digestive function through activating TRPA1 receptor in gastrointestinal tract has not been investigated. In the present study, gingerol was used to stimulate cell lines(RIN14B or STC-1) while depletion of extracellular calcium.TRPA1 inhibitor(rethenium red) and TRPA1 gene silencing via TRPA1-specific si RNA were also used for mechanistic studies. The intracellular calcium and secretion of serotonin or cholecystokinin were measured by fura-2/AM and ELISA. Stimulation of those cells with gingerol increased intracellular calcium levels and the serotonin or cholecystokinin secretion. The gingerol-induced intracellular calcium increase and secretion(serotonin or cholecystokinin) release were completely blocked by ruthenium red, EGTA, and TRPA1-specific si RNA. In summary, our results suggested that gingerol derived from ginger might improve the digestive function through secretion releasing from endocrine cells of the gut by inducing TRPA1-mediated calcium influx.展开更多
Itch（pruritus） is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the e...Itch（pruritus） is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-Lcysteine（NAC） and N-tert-butyl-a-phenylnitrone（PBN）were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetonediethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80-and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin.Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.展开更多
Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive,abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potent...Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive,abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential(TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion,TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular,activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective antimigraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.展开更多
基金supported by grants from the US National Institutes of Health (R01-DE17794,R01-NS54362 and R01-NS67686)
文摘Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.
基金supported by the National Natural Science Foundation of China,No.81671891
文摘Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.
基金supported by the Opening Program of Shanghai Key Laboratory of Complex Prescription(No.10DZ2270900)the Program of Shanghai Leading Academic Discipline,Shanghai Education Committee,China(No.J50305,J50301)
基金supported by the National Natural Science Foundation of China(Nos.30973003&30901993)Administration of TCM of Jiangsu province(No.LZ11093)
文摘TRPA1 channels are non-selective cation channels that could be activated by plant-derived pungent products, including gingerol, a main active constituent of ginger. Ginger could improve the digestive function; however whether ginger improves the digestive function through activating TRPA1 receptor in gastrointestinal tract has not been investigated. In the present study, gingerol was used to stimulate cell lines(RIN14B or STC-1) while depletion of extracellular calcium.TRPA1 inhibitor(rethenium red) and TRPA1 gene silencing via TRPA1-specific si RNA were also used for mechanistic studies. The intracellular calcium and secretion of serotonin or cholecystokinin were measured by fura-2/AM and ELISA. Stimulation of those cells with gingerol increased intracellular calcium levels and the serotonin or cholecystokinin secretion. The gingerol-induced intracellular calcium increase and secretion(serotonin or cholecystokinin) release were completely blocked by ruthenium red, EGTA, and TRPA1-specific si RNA. In summary, our results suggested that gingerol derived from ginger might improve the digestive function through secretion releasing from endocrine cells of the gut by inducing TRPA1-mediated calcium influx.
基金supported by grants from the National Natural Science Foundation of China(31371179 and 81300968)the Natural Science Foundation of Jiangsu Province,China(BK20140372)+3 种基金supported by funding from Jiangsu Province,China(2015-JY-029)supported by a grant from Jiangsu Province,China(201310285096X)subject to the second affiliated hospital of Soochow University Preponderant Clinic Discipline Group Project Funding(XKQ2015007)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Itch（pruritus） is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-Lcysteine（NAC） and N-tert-butyl-a-phenylnitrone（PBN）were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetonediethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80-and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin.Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.
基金supported by the Japan Society for the Promotion of Science KAKENHI(26460706 and 19K07849)a Japan-China Sasakawa Medical Fellowship(2017816)a State Scholarship Fund of the China Scholarship Council(201908500072)。
文摘Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive,abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential(TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion,TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular,activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective antimigraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.
