OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and his...OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.展开更多
Pain is unfortunately a quite common symptom for cancer patients. Normally pain starts as an episodic experience at early cancer phases to become chronic in later stages. In order to improve the quality of life of onc...Pain is unfortunately a quite common symptom for cancer patients. Normally pain starts as an episodic experience at early cancer phases to become chronic in later stages. In order to improve the quality of life of oncological patients, anti-cancer treatments are often accompanied by analgesic therapies. The P2 X receptor are adenosine triphosphate(ATP) gated ion channels expressed by several cells including neurons, cancer and immune cells. Purinergic signaling through P2 X receptors recently emerged as possible common pathway for cancer onset/growth and pain sensitivity. Indeed, tumor microenvironment is rich in extracellular ATP, which has a role in both tumor development and pain sensation. The study of the different mechanisms by which P2 X receptors favor cancer progression and relative pain, represents an interesting challenge to design integrated therapeutic strategies for oncological patients. This review summarizes recent findings linking P2 X receptors and ATP to cancer growth, progression and related pain. Special attention has been paid to the role of P2X2, P2X3, P2X4 and P2X7 in the genesisof cancer pain and to the function of P2X7 in tumor growth and metastasis. Therapeutic implications of the administration of different P2 X receptor blockers to alleviate cancer-associated pain sensations contemporarily reducing tumor progression are also discussed.展开更多
基金Supported by the China Academy of Chinese Medical Sciences Innovation Fund:Multicenter Randomized Controlled Study on the Intervention of Yiqi Huoxue Huatan Tongluo decoction in Post-Stent Restenosis of Vertebral Arteries(No.CI2021A01308)In-Hospital Mentorship Program of Xiyuan Hospital,China Academy of Chinese Medical Sciences-Zhou Shaohua(No.0203055)。
文摘OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.
基金Supported by Grants to Elena Adinolfi from the Italian association for Cancer research(MFAG11630)from the Region Emilia Romagna(Young researchers funds,Bando Alessandro Liberati)
文摘Pain is unfortunately a quite common symptom for cancer patients. Normally pain starts as an episodic experience at early cancer phases to become chronic in later stages. In order to improve the quality of life of oncological patients, anti-cancer treatments are often accompanied by analgesic therapies. The P2 X receptor are adenosine triphosphate(ATP) gated ion channels expressed by several cells including neurons, cancer and immune cells. Purinergic signaling through P2 X receptors recently emerged as possible common pathway for cancer onset/growth and pain sensitivity. Indeed, tumor microenvironment is rich in extracellular ATP, which has a role in both tumor development and pain sensation. The study of the different mechanisms by which P2 X receptors favor cancer progression and relative pain, represents an interesting challenge to design integrated therapeutic strategies for oncological patients. This review summarizes recent findings linking P2 X receptors and ATP to cancer growth, progression and related pain. Special attention has been paid to the role of P2X2, P2X3, P2X4 and P2X7 in the genesisof cancer pain and to the function of P2X7 in tumor growth and metastasis. Therapeutic implications of the administration of different P2 X receptor blockers to alleviate cancer-associated pain sensations contemporarily reducing tumor progression are also discussed.
