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2.
Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality in the world. So far, there has been substantial progress toward understanding the pathophysiology and treatment of CVDs. There are multiple cell signaling cascades, some of which are beneficial or compensatory and others deleterious. The balance between these pathways determines the outcome as a diseased or non-diseased state. Protein phosphorylation, which is mediated by enzymes, called protein kinases, is a major mechanism for transducing external stimuli into intracellular signals. Electively targeting of signaling pathways using protein kinase inhibitors would have a potential advantage over receptor blockers. By now, there are types of protein kinase inhibitiors available for treating several diseases. The success of kinase inhibitors in cancer treatment has strongly supported application in the treatment of CVDs. Here, we will review several kinds of protein kinases as potential targets for CVDs and some difficulty in identifying a protein kinase as a putative therapeutic target for CVDs.  相似文献   

3.
AIM: To study the effects of protein kinase C (PKC) inhibitor， chelerythrine chloride (CH)， on nociceptive response, nitric oxide synthase (NOS) expression and nitric oxide (NO) content in spinal cord of rats with inflammatory pain. METHODS: Inflammatory pain was induced by formalin injection into right hind paw. NADPH-d histochemistry was used to investigate the changes of NOS expression. Nitrate/nitrite (NO2-/NO3-) was assayed to represent NO content. RESULTS: Compared with the control group, the number of NADPH-d positive cells increased significantly in the superficial layer (LaminaeⅠ-Ⅱ) of the spinal cord dorsal horn and the grey matter surrounding the central canal (Laminae Ⅹ) in rats with inflammatory pain, the reactive degree of NADPH-d positive soma and fibers and NO content of the lumbar enlargement of spinal cord also increased significantly. Intrathecal injection of CH inhibited the spontaneous pain response in the second phase induced by formalin injection, and prevented the increases in the number and reactive degree of NADPH-d positive cells, as well as NO content of the lumbar enlargement of spinal cord. CONCLUSION: It is suggested that the activation of PKC promotes NOS expression and NO production in the nociceptive neurons of spinal cord during formalin-induced inflammatory pain.  相似文献   

4.
AIM: The role of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) in the induction and maintenance of spinal long-term potentiation (LTP) was evaluated. METHODS: The C-fiber evoked field potentials were recorded at the superficial layers of spinal dorsal horn at the lumbar enlargement. RESULTS: (1) 8-Br-cAMP induced LTP of C-fiber evoked field potentials and 8-Br-cAMP-induced LTP occludes tetanus-induced LTP. (2) Rp-CPT-cAMPS, an inhibitor of PKA, blocked the induction of spinal LTP and reversed established LTP of C-fiber evoked field potentials in a time-dependent manner. (3) In the presence of anisomycin, a protein synthesis inhibitor, the potentiation induced by 8-Br-cAMP was completely blocked. (4) PD98059, a selective inhibitor of mitogen-activated protein kinase (MAPK),completely blocked the 8-Br-cAMP-induced LTP.CONCLUSION: Activation of PKA signal pathway in spinal dorsal horn may be crucial for the induction and the early-phase maintenance of LTP of C-fiber evoked field potentials.  相似文献   

5.
Pathological pain or clinical pain is caused by tissue and nerve injuries, and is usually chronic and mainly divided into inflammatory pain and neuropathic pain. Pathological pain is typically characterized by hyperalgesia (increased responsiveness to noxious stimuli) and allodynia (painful responses to normally innocuous stimuli). The mitogen-activated proteins kinases (MAPKs) are a family of evolutionally conserved molecules that play a critical role in cell signaling, consisting of extracellular signal regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), which play an important role in neural plasticity of pathological pain. Inhibition of MAPKs alleviates inflammatory pain and neuropathic pain in different animal models. It is very important to study the inhibition of MAPKs as a therapeutic approach to treat pathological pain.  相似文献   

6.
AIM: To investigate the effects of P2X4 receptor on peri-sciatic administration of recombinant rat TNF-α (rrTNF)-induced mechanical allodynia. METHODS: Male Sprague-Dawley rats (180~200 g) were used in the experiments. The levels of P2X4 receptor on day 3, day 7 and day 14 after peri-sciatic administration of rrTNF were examined by Western blot, and the location of P2X4 receptor in the spinal dorsal horn was observed by double immunofluorescence staining. The changes of 50% paw-withdrawal thresholds of the rat were detected by behavioral test, and the level of TNF-α in the spinal dorsal horn was also examined by Western blot when TNP-ATP was intrathecally injected before the administration of rrTNF. RESULTS: Compared with control group, the expression of P2X4 receptor in the spinal dorsal horn on the ipsilateral side significantly increased on day 3, day 7 and day 14 (P<0.01) after rrTNF (100 ng/L) administration. P2X4 receptor was co-localized only with microglia, but not with neurons or astrocytes. Intrathecal injection of TNP-ATP before rrTNF administration prevented mechanical allodynia induced by rrTNF and inhibited the upregulation of TNF-α in the spinal dorsal horn. CONCLUSION: P2X4 receptors in microglia may be involved in rrTNF-induced mechanical allodynia by the upregulation of TNF-α in the spinal dorsal horn.  相似文献   

7.
AIM: To observe the change of heme oxygenase(HO-1)expression in the spinal cord during formaldehyde-induced pathological pain and investigate the effect of HO-1 on neuronal apoptosis in the spinal cord induced by formaldehyde inflammatory pain.METHODS: The protein expression of HO-1 in the left and the right spinal dorsal horn was detected by Western blotting. The neuronal apoptosis rate of the spinal cord was determined by flow cytometry.RESULTS: Compared to control group, the protein expression of HO-1 was significantly up-regulated at different time points after the injection of formaldehyde, which was most obviously 24 h after the injection of formaldehyde and was still higher than that in control group at 72 h. Compared to control group, the neuronal apoptosis rate of spinal cord increased in the rats with formaldehyde inflammatory pain. No significant difference of the neuronal apoptosis rate was observed between formaldehyde group and solvent control group . Intrathecal injection of 100 μg ZnppIX, an inhibitor of HO-1, attenuated the degree of spontaneous pain response, but induced an increase in the rate of neuronal apoptosis in spinal cord in the rats with formaldehyde inflammatory pain. CONCLUSION: Formaldehyde inflammatory pain induces the increases in HO-1 expression and neuronal apoptosis in the rat spinal cord. HO-1 promotes the response of spontaneous pain and inhibits the process of neuronal apoptosis in spinal cord induced by formaldehyde inflammatory pain.  相似文献   

8.
ZHENG Chang-jian  HU Han  CAO Hong  LI Jun 《园艺学报》2014,30(11):1941-1945
AIM:To investigate the effect of JNK/MCP-1 signaling pathway on anti-diabetic neuropathic pain by curcumin in type 2 diabetic rats. METHODS:The male Sprague-Dawley rats were induced as the model of the type 2 diabetic neuropathic pain rats, they were randomly divided into 6 groups (n=27): type 2 diabetic neuropathic pain (DNP) group, type 2 diabetic neuropathic pain and intraperitoneal injection of curcumin (Cur) group, type 2 diabetic neuropathic pain and solvent control (DSC) group, type 2 diabetic neuropathic pain and JNK inhibitor (DJ) group, type 2 diabetic neuropathic pain and JNK inhibitor solvent control (DJS) group, type 2 diabetic neuropathic pain and monocyte chemoattractant protein 1 (MCP-1) agonist (DM) group. Another 27 normal SD rats were selected as control group. Mechanical withdrawal threshod and thermal withdrawal latency were measured at 3rd d, 7th d and 14th d after dosing, then the lumbar segment 4~6 of the spinal cord and L4~6 DRG were removed at the same time. ELISA was used to measure MCP-1 level. The expression of p-JNK was determined by Western blotting. RESULTS:Compared with DNP group, p-JNK was significantly decreased at 7th d and 14th d in Cur group, DJ group and DM group after treatment (P<0.05). Compared with C group, the MCP-1 was significantly declined in other 6 group after streptozotocin injection (P<0.05). Compared with DNP group, MCP-1 were significantly increased at 7th d and 14th d in Cur group and DJ group after treatment (P<0.05), and that in DM group was greatly decreased (P<0.05). CONCLUSION: The expression of p-JNK and MCP-1 was increased in DNP rats with spinal cord and dorsal root ganglion. The mechanism of curcumin reducing the neuropathic pain in type 2 diabetic rats might be through regulating the JNK/MCP-1 pathway.  相似文献   

9.
AIM: To investigate the role of interleukin-1β (IL-1β) in the long-term potentiation (LTP) of C-fiber-evoked field potentials in rats with neuropathic pain. METHODS: The rat model of neuropathic pain was produced by spared nerve injury (SNI) of sciatic nerve or the method of lumbar 5 ventral root transection (L5 VRT). The effect of exogenous IL-1β on C-fiber-evoked field potentials of spinal dorsal horn was tested in both intact rats and the rats with neuropathic pain. The roles of p38 MAPK and NF-κB in the process were also evaluated. RESULTS: IL-1β at concentration of 500 μg/L affected neither basal synaptic transmission mediated by C-fiber nor spinal LTP induced by high frequency stimulation in intact rats. However, low concentration (5 μg/L) of IL-1β induced LTP of C-fiber-evoked field potentials in the rats with neuropathic pain. Pretreatment with either p38 MAPK inhibitor (SB203580) or NF-κB inhibitor (PDTC) completely blocked LTP induced by IL-1β. CONCLUSION: Exogeneous IL-1β might induce spinal LTP of C-fiber-evoked field potentials in the rats with neuropathic pain. p38 MAPK and NF-κB may be involved in the process.  相似文献   

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11.
AIM: The role of protein kinase C (PKC) in the induction and maintenance of spinal long-term potentiation (LTP) was evaluated. METHODS: The C-fiber evoked field potentials were recorded at the superficial layers of spinal dorsal horn at the lumbar enlargement. RESULTS: (i) Chelerythrine （200 μmol/L） or G 6983 (100 μmol/L), a selective PKC inhibitor, completely blocked LTP induction. (ii) Chelerythrine or G 6983 reversed spinal LTP in a time-dependent manner. 15 min after LTP induction, chelerythrine （200 μmol/L） and G 6983 (100 μmol/L) depressed LTP to baseline in all tested rats. The same concentration of chelerythrine and G 6983, applied at 3 h after LTP induction, did not affect LTP. CONCLUSION: PKC in spinal dorsal horn may be crucial for the induction and the early-phase maintenance of LTP of C-fiber evoked field potentials.  相似文献   

12.
AIM：To investigate the effects of substance P (SP) on the modulation of H+-gated current in neurons. METHODS：Whole-cell patch-clamp technique was used to record the H+-gated current in the acutely isolated rat dorsal root ganglion (DRG) neurons at pH 4.0, pH 5.0, pH 6.0, and both SP and H+. The modulating action of SP on H+-gated current in the acutely isolated rat DRG neurons was studied by intracellular dialysis. RESULTS：H+-gated currents recorded at pH 5.0 were divided into 4 types: transient inward (T-type),sustained inward (S-type),biphasic inward (B-type) and opposite (O-type). SP exhibited obvious enhancing effect on the sustained component of S-type and B-type H+-gated currents, and the enhancing current amplitude was (85.53±22.93)%. However, the enhancing effect was not blocked by the SP receptor NK1 antagonist in about 81.8% DRG neurons. The enhancing effect was blocked by nonpeptidic SP receptor antagonist in about 75% DRG neurons. SP also exhibited obvious inhibitory effect on the sustained component of S-type and B-type H+-gated currents, and the inhibitory current amplitude was (48.46±4.45)%. However, the inhibitory effect was not blocked by the SP receptor antagonist in about 88.9% DRG neurons. After intracellular dialysis, GDP-β-S could not block the modulating action of SP on H+-gated currents. CONCLUSION：There are 4 types of H+-gated currents in acutely isolated rat DRG neurons: T-type, S-type, B-type and O-type. The modulating action of SP on H+-gated current exhibits both enhancement and inhibition. The regulatory mechanism includes G-protein-coupled receptor pathway and the binding of SP to a locus of H+-gated ion channels to exert modulating action on the H+-gated current.  相似文献   

13.
WANG Li-jun  TONG Lei 《园艺学报》2018,34(2):340-345
AIM: To investigate the anti-inflammatory action of resveratrol (Res) and its correlation with nuclear factor-κB (NF-κB) signaling pathway in a mouse model of inflammatory pain.METHODS: BALB/c mice (n=60) were randomly divided into 6 groups:normal control group, inflammatory pain model group, positive control (dexamethasone, 0.5 mg/kg) group and resveratrol (100, 50 and 25 mg/kg) groups (10 mice in each group). In order to observe the anti-inflammatory pain effects of reseratrol on mice, the paw withdrawal mechanical threshold, paw withdrawal thermal latency and cold withdrawal times were detected. In order to analyze the mechanism of analgesic effect of resveratrol, the expression levels of NF-κB, inhibitor of NF-κB (IκB) α, inhibitor of NF-κB kinase (IKK) β, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the spinal cord tissues (L4~L6) of the mice were determined by RT-PCR and Western blot.RESULTS: The resveratrol at 100 and 50 mg/kg increased the paw withdrawal mechanical threshold, prolonged the paw withdrawal thermal latency, and decreased the cold withdrawal times in the inflammatory pain mice (P<0.05 or P<0.01). The resveratrol at 100 mg/kg down-regulated the mRNA and protein expression levels of NF-κB, IκBα, IKKβ, TNF-α and IL-1β in the spinal cord tissues (L4~L6) of inflammatory pain mice (P<0.05 or P<0.01).CONCLUSION: Resveratrol ameliorates the inflammatory pain of the mice induced by complete Freund's adjuvant. The mechanism is related to the inhibition of NF-κB signaling pathway.  相似文献   

14.
AIM: To investigate the effects of immunoglobulin heavy chain-binding protein (BiP),an endoplasmic reticulum stress protein, on mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), spinal dorsal horn and dorsal root ganglion (DRG) in type Ⅱ diabetic neuropathic pain rats treated with curcumin. METHODS: The rats were fed with a high-fat and high-fructose diet for 8 weeks to induce insulin resistance, and then were intraperitoneally injected with streptozotocin (STZ, 35 mg/kg). Eighty-one rats were selected into experimental design as their blood glucose ≥ 16.7 mmol/L 3 d after STZ injection and their MWT and TWL were decreased to 85% of the baseline values 14 d after STZ injection. The rats were divided into 3 groups (n=27 each): DNP group: type 2 diabetic neuropathic pain; DCur group: type 2 diabetic neuropathic pain and intraperitonal injection of curcumin at a dose of 100 mg·kg-1·d-1; DSC group: type 2 diabetic neuropathic pain and intraperitonal injection of corn oil at a dose of 4 mL/kg. Another 27 normal SD male rats fed with normal forage were adopted as control group (C group). MWT and TWL were measured at the time points of 3 d, 7 d and 14 d after curcumin injection. The lumbar segment 4~6 of the spinal cord and the corresponding DRG were removed at the same time. The expression of BiP was determined by immunohistochemical staining and Western blotting. RESULTS: Compared with C group, the rats in DNP group developed hyperglycemia and a decrease in MWT and TWL, as well as an increase in the activity of BiP in spinal dorsal horn and DRG (P<0.05). Compared with DNP group, the rats in DCur group at the time point of 7 d significantly attenuated mechanical allodynia and thermal hyperalgesia, and these effects were correlated with the inhibition of BiP hyper-activation at the time point of 14 d after treatment with curcumin (P<0.05). No significant difference of MWT, TWL and the expression of BiP between DNP group and SC group was observed. CONCLUSION: BiP participates in the pathogenesis of type Ⅱ diabetic neuropathic pain. Curcumin attenuates the MWT and TWL in type 2 diabetic neuropathic pain rats. The mechanism may be involved in the inhibition of BiP expression by curcumin.  相似文献   

15.
AIM: To investigate the effect of mibefradil administered intrathecally on the pain threshold and the expression of neuron nitric oxide synthase (nNOS) in the spinal cord of the rats following chronic compression of dorsal root ganglion. METHODS: The chronic compression of dorsal root ganglion (CCD) model was adopted. Three different doses of mibefradil, a T-type calcium channel blocker, were administered singly intrathecally to the rats after CCD 5 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were determined with von Frey hair and thermal radiation apparatus before mibefradil administered and after mibefradil administered 30 min, 60 min, 120 min, 240 min, and 480 min. Changes of nNOS expression in neurons of the spinal dorsal horn were detected by immunohistochemistry method, and the number of the nNOS positive neurons was counted under microscope. RESULTS: MWT and TWL declined significantly from the first day to the 21st day after CCD. Mibefradil administered intrathecally attenuated significantly both mechanical and thermal hyperagesia of the rats, and markedly inhibited the increase in the nNOS expression. CONCLUSION: These data show that T type calcium channel plays a key role in the CCD-induced mechanical and thermal hyperalgesia and possibly involves in the nNOS expression in the spinal.  相似文献   

16.
薛鑫  石胜友  侯世奎 《园艺学报》2020,36(5):827-836
以龙眼‘蜀冠’ב大乌圆’的F1代65个单株为材料，对其果实的27个品质性状进行了连续3年的观测，应用SPSS19.0软件对各性状进行变异系数、Shannon-Weinner多样性指数和主成分分析。结果表明：65个单株果实品质性状存在着极显著差异，13个数量性状（单果质量、果实纵径、果实横径、可溶性固形物、可食率、果皮厚度、果皮质量、果肉厚、种子质量、维生素C含量、蔗糖含量、葡萄糖含量和果糖含量）变异系数在6.95% ~ 41.64%之间；多样性指数在1.33 ~ 2.02之间；14个描述性状（成熟期、果皮颜色、果形、果肩、果顶、龟裂纹、疣状突起、果肉颜色、果肉质地、果肉透明度、果肉离核难易度、果汁、化渣程度和果肉风味）多样性指数在0.56 ~ 1.28之间；主成分分析发现前5个性状（单果质量、可食率、可溶性固形物、成熟期和果实风味）的累积贡献率为87.50%；建立了‘蜀冠’ב大乌圆’杂交后代果实品质性状综合评价的方法，利用该方法在65个杂交后代中筛选出了5个优异的单株（SD7、SD11、SD36、SD53和SD120），结果与实际观测结果高度一致。  相似文献   

17.
DING Chang  YIN Ping  ZHAO Qi  SU Li 《园艺学报》2020,36(7):1230-1236
AIM To investigate the effect of nuciferine （NUF) on the formation of foam cells and its possible molecular mechanism. METHODS Human monocyte-macrophage cell line THP-1 was induced by oxidized low-density lipoprotein (Ox-LDL) to establish foam cell model, and simultaneously treated with NUF at 5, 10 or 20 μmol/L. Oil red O staining was used and total cholesterol content was measured to observe the effect of NUF on foam cell formation. Autophagy flow was detected by immunofluorescence, and autophagosomes were detected by transmission electron microscopy. The protein levels of microtubule-associated protein 1 light chain 3 (LC3), P62, phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) were determined by Western blot. 3-Methyladenine (3-MA), an autophagy inhibitor, was used to inhibit autophagy and to observe whether NUF inhibited foam cell formation by regulating autophagy. RESULTS Compared with control group, the intracellular lipid deposition and total cholesterol content in Ox-LDL group were increased. Compared with Ox-LDL group, the intracellular lipid deposition and total cholesterol content in NUF group were decreased, while autophagy flow and number of autophagosomes were increased. The inhibitory effect of NUF on cell foaming was weakened after 3-MA treatment. Moreover, NUF decreased the protein levels of p-mTOR and p-Akt. CONCLUSION Nuciferine may promote autophagy by inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway, thus reducing intracellular lipid deposition and formation of foam cells.  相似文献   

18.
AIM: To identify the correlation between intrapericardial injection of allogeneic chemicals and activation of the rat spinal trigeminal tract (STT) neurons.METHODS: Adult male Wistar rats were anesthetized with urethane and divided into 3 groups: inflammatory exudate solution (IES) group, receiving intrapericardial infusion of IES; negative control (saline) group, receiving intrapericardial infusion of saline; and sham group, undergoing the same surgical procedure without intrapericardial infusion. The expression of c-Fos in the neurons of the cervical spinal cord and brain stem, particularly in the region of the trigeminal sensory nuclear complex, including the principal sensory trigeminal nucleus (Pr5VL), subnucleus oralis (Sp5O), subnucleus interpolaris (Sp5I) and subnucleus caudalis (Sp5C), was analyzed by immunohistochemistry as an index of neuronal activation. RESULTS: Compared with saline group and sham group, the number of c-Fos-positive neurons in IES group increased significantly (P＜0.05). c-Fos-positive neurons were mainly found in the dorsal horns of laminae I-V at C2, as well as at the rostral edge of the Pr5VL, Sp5O, Sp5I, and Sp5C. The number of c-Fos-positive neurons gradually increased from bregma to interaural line at the pyramidal decussation. Interestingly, fewer c-Fos-positive neurons were observed on the right side than that on the left (P＜0.05).CONCLUSION: Intrapericardial injection of algogenic chemicals activates STT neurons, possibly underlying the phenomenon whereby cardiac ischemia causes craniofacial pain.  相似文献   

19.
AIM: To investigate the effects of Src family kinases (SFKs) on adenosine 5'-triphosphate (ATP)-induced long-term potentiation (LTP) in the spinal dorsal horn. METHODS: Male Sprague-Dawley rats (250-280 g) were used in the experiments. Western blotting, electrophysiological recording in spinal dorsal horn in vivo and immunohistochemistry were used in the study. The C-fiber-evoked field potentials were recorded at the superficial layers of spinal dorsal horn at the lumbar enlargement and the phosphorylation level and location of SFKs in spinal dorsal horn were examined by Western blotting and immunohistochemistry. RESULTS: Thirty min and 60 min after ATP application, the levels of phosphorylated SFKs (p-SFKs) were significantly increased.The p-SFKs were expressed in microglia, but not in astrocytes or neurons. Spinal application of SFK inhibitors prevented ATP-induced LTP. CONCLUSION: Microglial SFKs may play an important role in ATP-induced LTP of C-fiber evoked field potentials in the spinal dorsal horn.  相似文献   

20.
AIM: The role of external-signal regulated kinaseⅠ/Ⅱ(ERKⅠ/Ⅱ) in the induction and maintenance of spinal long-term potentiation (LTP) is evaluated.METHODS: The C-fiber evoked field potentials were recorded at the superficial layers of spinal dorsal horn at the lumbar enlargement.RESULTS: (1) PD98059 (100 μmol/L) or SL327 (200 μmol/L), a selective MEK inhibitor, completely blocked LTP induction when applied at 30 min prior to tetanic stimulation.(2) PD98059 or SL327 reversed spinal LTP in a time-dependent manner.At 15 min after LTP induction, PD98059 (100 μmol/L) or SL327 (200 μmol/L) reversed LTP completely, and at 30 min after LTP induction, the inhibitory rate of spinal LTP inhibited by PD98059 or SL327 was 62.5% and 75.0%， respectively.At 1 h after LTP induction, however, the same concentration of PD98059 or SL327 did not affect the spinal LTP.CONCLUSION: Activation of ERKⅠ/Ⅱ in spinal dorsal horn may be crucial for the induction and the early-phase maintenance of LTP of C-fiber evoked field potentials.  相似文献   

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