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1.
Pharmaceutics ; 15(9)2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37765278

ABSTRACT

The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or a combination of multiple therapeutics. By utilizing nanoformulations, the solubility of analgesics can be increased. Meanwhile, controlled drug release and targeted delivery can be realized. These not only improve the pharmacokinetics and biodistribution of analgesics but also lead to improved pain relief effects with fewer side effects. Additionally, combination therapy is frequently applied to anesthesia and analgesia. The co-encapsulation of multiple therapeutics into a single nanoformulation for drug co-delivery has garnered significant interest. Numerous approaches using nanoformulation-based combination therapy have been developed and evaluated for pain management. These methods offer prolonged analgesic effects and reduced administration frequency by harnessing the synergy and co-action of multiple targets. However, it is important to note that these nanomaterial-based pain treatment methods are still in the exploratory stage and require further research to be effectively translated into clinical practice.

2.
Int J Mol Sci ; 24(12)2023 Jun 15.
Article in English | MEDLINE | ID: mdl-37373296

ABSTRACT

Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.


Subject(s)
Neuralgia , Peripheral Nerve Injuries , Animals , Mice , Ganglia, Spinal/metabolism , Hyperalgesia/genetics , Hyperalgesia/metabolism , Neuralgia/etiology , Neuralgia/metabolism , Peripheral Nerve Injuries/metabolism , Potassium/metabolism , RNA, Small Interfering/metabolism , Sensory Receptor Cells/metabolism , Shal Potassium Channels/metabolism
3.
Neurosci Bull ; 37(4): 550-562, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33355900

ABSTRACT

Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.


Subject(s)
Neuralgia , Toll-Like Receptor 8 , Trigeminal Neuralgia , Animals , Hyperalgesia , Mice , Trigeminal Ganglion
4.
Neurosci Bull ; 37(3): 339-352, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33196963

ABSTRACT

Chemokines and receptors have been implicated in the pathogenesis of chronic pain. Here, we report that spinal nerve ligation (SNL) increased CXCR3 expression in dorsal root ganglion (DRG) neurons, and intra-DRG injection of Cxcr3 shRNA attenuated the SNL-induced mechanical allodynia and heat hyperalgesia. SNL also increased the mRNA levels of CXCL9, CXCL10, and CXCL11, whereas only CXCL10 increased the number of action potentials (APs) in DRG neurons. Furthermore, in Cxcr3-/- mice, CXCL10 did not increase the number of APs, and the SNL-induced increase of the numbers of APs in DRG neurons was reduced. Finally, CXCL10 induced the activation of p38 and ERK in ND7-23 neuronal cells and DRG neurons. Pretreatment of DRG neurons with the P38 inhibitor SB203580 decreased the number of APs induced by CXCL10. Our data indicate that CXCR3, activated by CXCL10, mediates p38 and ERK activation in DRG neurons and enhances neuronal excitability, which contributes to the maintenance of neuropathic pain.


Subject(s)
Ganglia, Spinal , Neuralgia , Animals , Hyperalgesia , Mice , Rats , Rats, Sprague-Dawley , Spinal Nerves
5.
Article in English | WPRIM (Western Pacific) | ID: wpr-878361

ABSTRACT

Objective@#This study was designed to conduct a retrospective and systematic occupational health risk assessment (OHRA) of enterprises that used benzene, toluene, and xylene (BTX) in Shanghai, China.@*Methods@#All data for the study were obtained from 1,705 occupational health examination and evaluation reports from 2013 to 2017, and a semiquantitative model following Chinese OHRA guidelines (GBZ/T 298-2017) was applied for the assessment.@*Results@#The selected enterprises using BTX were mainly involved in manufacturing of products. Using the exposure level method, health risk levels associated with exposure to BTX were classified as medium, negligible, or low. However, the risk levels associated with benzene and toluene were significantly different according to job types, with gluers and inkers exhibiting greater health risks. For the same job type, the health risk levels assessed using the comprehensive index method were higher than those using the exposure level method.@*Conclusion@#Our OHRA reveals that workers who are exposed to BTX still face excessive health risk. Additionally, the risk level varied depending on job categories and exposure to specific chemicals. Therefore, additional control measures recommended by OHRA guidelines are essential to reduce worker exposure levels.


Subject(s)
Humans , Air Pollutants, Occupational/analysis , Benzene/analysis , China , Occupational Exposure/adverse effects , Retrospective Studies , Risk Assessment , Toluene/analysis , Xylenes/analysis
6.
Brain Res Bull ; 139: 235-242, 2018 05.
Article in English | MEDLINE | ID: mdl-29550454

ABSTRACT

Visceral pain, observed in inflammatory bowel disease (IBD) patients, is a challenging medical problem and remains poorly understood because the mechanisms underlying it are unclear. Emerging evidence indicates that microRNAs (miRNAs) play a crucial role in the pathogenesis of acute and chronic pain. In this study, we aimed to explore the potential role of miR-146a-5p (the mature form of miR-146a) in a mouse model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). We found that induction of colitis resulted in visceral hyperalgesia manifested by a decreased pain threshold to colorectal distension and upregulation of miR-146a-5p expression in the lumbosacral spinal cord. In situ hybridization and immunohistochemistry results showed that miR-146a-5p was colocalized with neuronal marker NeuN, but not with astrocytic marker GFAP or microglial marker IBA-1. Dual-luciferase reporter assay showed that miR-146a-5p directly targeted the 3'-untranslated region (UTR) of CCL8, which was previously identified as an important regulator of visceral pain. In cultured Neuro-2a cells, TNF-α-induced CCL8 upregulation was decreased by transfection of miR-146a-5p mimic dose-dependently. In vivo, exogenous supplementation of miR-146a-5p by intrathecal miR-146a-5p agomir significantly alleviated visceral pain and decreased CCL8 expression in colitis mice. Furthermore, inhibition of CCL8 expression by CCL8 siRNA relieved colitis-induced visceral nociception. Finally, in naïve mice intrathecal miR-146a-5p antagomir upregulated CCL8 expression and induced visceral pain hypersensitivity, which could be partially rescued by neutralization of CCL8. Taken together, the present findings indicate that miR-146a-5p may be an endogenous suppressor of visceral pain and exogenous supplementation of miR-146a-5p could exert an analgesic effect at least partly by targeting spinal CCL8 expression. Thus, miR-146a-5p may serve as a novel therapeutic target for visceral pain intervention in the context of colitis.


Subject(s)
Chemokine CCL8/metabolism , Colitis/complications , Gene Expression Regulation/genetics , MicroRNAs/therapeutic use , Spinal Cord/metabolism , Visceral Pain , Animals , Antagomirs/therapeutic use , Antibodies/therapeutic use , Cells, Cultured , Chemokine CCL8/chemistry , Chemokine CCL8/genetics , Chemokine CCL8/immunology , Colitis/chemically induced , Colitis/pathology , Disease Models, Animal , Gene Expression Regulation/drug effects , Humans , Hyperalgesia/metabolism , Male , Mice , Mice, Inbred C57BL , MicroRNAs/chemistry , MicroRNAs/metabolism , Peroxidase/metabolism , RNA, Small Interfering/therapeutic use , Spinal Cord/drug effects , Trinitrobenzenesulfonic Acid/toxicity , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation/drug effects , Visceral Pain/etiology , Visceral Pain/pathology , Visceral Pain/therapy
7.
Brain Res Bull ; 135: 170-178, 2017 Oct.
Article in English | MEDLINE | ID: mdl-29037608

ABSTRACT

Visceral hypersensitivity induced by inflammatory bowel disease (IBD) is a clinical challenge since the underlying mechanisms remain elusive. Chemokines and their receptors have been suggested to modulate inflammatory pain and neuropathic pain. However, the exact chemokines involved in visceral pain remain to be determined. Here, we investigated the effects of spinal chemokine CCL8 and its major receptor CCR5 on the development of visceral hyperalgesia. We showed that intracolonic injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice produced significant colonic inflammation and visceral hypersensitivity to colorectal distension. Moreover, the mRNA and protein expression of CCL8 and CCR5 in the lumbosacral spinal cord were significantly upregulated. Both of CCL8 and CCR5 were expressed in spinal neurons. Furthermore, TNBS induced the activation of extracellular signal-regulated kinase (ERK) in the spinal cord. The induction of visceral pain by TNBS was attenuated by injection of ERK upstream kinase (MEK) inhibitor PD98059. Finally, intrathecal CCL8 neutralizing antibody or CCR5 antagonist DAPTA dose-dependently suppressed TNBS-evoked visceral hyperalgesia and spinal ERK activation. Taken together, these data demonstrated that CCL8 and CCR5, expressed and upregulated in spinal neurons after colonic inflammation, are involved in the maintenance of visceral hyperalgesia via the activation of spinal ERK. Targeting CCL8/CCR5/ERK pathway in the spinal cord might provide a novel treatment for the relief of visceral pain.


Subject(s)
Chemokine CCL8/metabolism , Colitis/physiopathology , Visceral Pain/metabolism , Animals , Chemokine CCL8/physiology , Colitis/chemically induced , Disease Models, Animal , Gene Expression Regulation/genetics , Hyperalgesia/metabolism , Hyperalgesia/pathology , Male , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinases/metabolism , Neuralgia/metabolism , Neurons/metabolism , Receptors, CCR5/metabolism , Receptors, CCR5/physiology , Spinal Cord/metabolism , Spinal Cord/physiopathology , Up-Regulation , Visceral Pain/physiopathology
8.
Sci Rep ; 6: 34836, 2016 10 06.
Article in English | MEDLINE | ID: mdl-27708397

ABSTRACT

CXCL13 is a B lymphocyte chemoattractant and activates CXCR5 receptor in the immune system. Here we investigated whether CXCL13/CXCR5 mediates inflammatory pain in dorsal root ganglia (DRG) and the underlying mechanisms. Peripheral injection of complete Freund's Adjuvant (CFA) increased the expression of CXCL13 and CXCR5 in DRG neurons. In Cxcr5-/- mice, CFA-induced pain hypersensitivity were attenuated. Whole-cell patch-clamp recording showed that the excitability of dissociated DRG neurons was increased after CFA injection or CXCL13 incubation from wild-type (WT) mice, but not from Cxcr5-/- mice. Additionally, sodium channel Nav1.8 was co-expressed with CXCR5 in dissociated DRG neurons, and the increased neuronal excitability induced by CFA or CXCL13 was reduced by Nav1.8 blocker. Intrathecal injection of Nav1.8 blocker also attenuated intrathecal injection of CXCL13-induced pain hypersensitivity. Furthermore, CXCL13 increased Nav1.8 current density in DRG neurons, which was inhibited by p38 MAP kinase inhibitor. CFA and CXCL13 increased p38 phosphorylation in the DRG of WT mice but not Cxcr5-/- mice. Finally, intrathecal p38 inhibitor alleviated CXCL13-induced pain hypersensitivity. Taken together, these results demonstrated that CXCL13, upregulated by peripheral inflammation, acts on CXCR5 on DRG neurons and activates p38, which increases Nav1.8 current density and further contributes to the maintenance of inflammatory pain.


Subject(s)
Inflammation/metabolism , NAV1.8 Voltage-Gated Sodium Channel/metabolism , Pain/metabolism , Receptors, CXCR5/metabolism , Sensory Receptor Cells/metabolism , Animals , Cell Count , Chemokine CXCL13/genetics , Chemokine CXCL13/metabolism , Disease Models, Animal , Freund's Adjuvant/toxicity , Ganglia, Spinal/cytology , Ganglia, Spinal/metabolism , Inflammation/physiopathology , Male , Mice, Inbred ICR , Mice, Knockout , NAV1.8 Voltage-Gated Sodium Channel/genetics , Receptors, CXCR5/genetics , Sensory Receptor Cells/pathology , p38 Mitogen-Activated Protein Kinases/metabolism
9.
Nat Commun ; 7: 12531, 2016 08 19.
Article in English | MEDLINE | ID: mdl-27538456

ABSTRACT

Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of ß-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1.8. Loss of Arrb2 also results in prolongation of inflammatory pain and neuropathic pain and enhancement of GluN2B-mediated NMDA currents in spinal lamina IIo not lamina I neurons. Finally, spinal over-expression of Arrb2 reverses chronic neuropathic pain after nerve injury. Thus, spinal Arrb2 may serve as an intracellular gate for acute to chronic pain transition via desensitization of NMDAR.


Subject(s)
Chronic Pain/pathology , Neuralgia/pathology , Neurons/metabolism , Peripheral Nerve Injuries/pathology , Receptors, N-Methyl-D-Aspartate/metabolism , Substantia Gelatinosa/metabolism , beta-Arrestin 2/metabolism , Analgesics, Opioid/pharmacology , Animals , Chronic Pain/etiology , Disease Models, Animal , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Humans , Hyperalgesia/chemically induced , Hyperalgesia/pathology , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Mice, Knockout , N-Methylaspartate/pharmacology , Neuralgia/etiology , Neurons/drug effects , Peripheral Nerve Injuries/etiology , Receptors, Opioid, mu/antagonists & inhibitors , Spinal Cord Dorsal Horn/cytology , Spinal Cord Dorsal Horn/metabolism , Substantia Gelatinosa/cytology , Time Factors , beta-Arrestin 2/genetics
10.
Pain ; 157(4): 806-817, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26645545

ABSTRACT

Increasing evidence suggests that Toll-like receptor 4 (TLR4) contributes importantly to spinal cord glial activation and chronic pain sensitization; however, its unique role in acute and chronic itch is unclear. In this study, we investigated the involvement of TLR4 in acute and chronic itch models in male mice using both transgenic and pharmacological approaches. Tlr4 mice exhibited normal acute itch induced by compound 48/80 and chloroquine, but these mice showed substantial reductions in scratching in chronic itch models of dry skin, induced by acetone and diethylether followed by water (AEW), contact dermatitis, and allergic contact dermatitis on the neck. Intrathecal (spinal) inhibition of TLR4 with lipopolysaccharide Rhodobacter sphaeroides did not affect acute itch but suppressed AEW-induced chronic itch. Compound 48/80 and AEW also produced robust alloknesis, a touch-elicited itch in wild-type mice, which was suppressed by intrathecal lipopolysaccharide R sphaeroides and Tlr4 deletion. Acetone and diethylether followed by water induced persistent upregulation of Tlr4 mRNA and increased TLR4 expression in GFAP-expressing astrocytes in spinal cord dorsal horn. Acetone and diethylether followed by water also induced TLR4-dependent astrogliosis (GFAP upregulation) in spinal cord. Intrathecal injection of astroglial inhibitor L-α-aminoadipate reduced AEW-induced chronic itch and alloknesis without affecting acute itch. Spinal TLR4 was also necessary for AEW-induced chronic itch in the cheek model. Interestingly, scratching plays an essential role in spinal astrogliosis because AEW-induced astrogliosis was abrogated by putting Elizabethan collars on the neck to prevent scratching the itchy skin. Our findings suggest that spinal TLR4 signaling is important for spinal astrocyte activation and astrogliosis that may underlie alloknesis and chronic itch.


Subject(s)
Astrocytes/metabolism , Posterior Horn Cells/physiology , Pruritus/metabolism , Spinal Cord Dorsal Horn/metabolism , Toll-Like Receptor 4/metabolism , Animals , Astrocytes/immunology , Chronic Disease , Disease Models, Animal , Hyperalgesia/chemically induced , Male , Mice, Knockout , Pruritus/chemically induced , Spinal Cord Dorsal Horn/immunology , Toll-Like Receptor 4/deficiency
11.
Cell Mol Neurobiol ; 36(1): 143-9, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26115624

ABSTRACT

Ligustilide is a major component of Radix Angelica Sinensis and reported to have anti-inflammatory and anti-nociceptive effects. Toll-like receptor 4 (TLR4) has been shown to be expressed in the spinal cord and be involved in inflammatory pain and neuropathic pain. Whether ligustilide can inhibit spinal TLR4 expression in inflammatory pain is still unknown. In the present study, we intravenously injected ligustilide daily for 4 days, with the first injection given at 1 h before complete Freund's adjuvant (CFA) injection. We tested the analgesic effect of ligustilide by behavioral test and checked the expression and distribution of TLR4 in the spinal cord by real-time quantitative PCR, Western blot, and immunofluorescence. Our data showed that repeated daily intravenous treatment with ligustilide alleviated CFA-induced heat hyperalgesia and mechanical allodynia. The same treatment also inhibited CFA-induced TLR4 mRNA and protein increase in the spinal cord. Immunofluorescence double staining showed that TLR4 was predominantly expressed in spinal astrocytes. In primary cultured astrocytes, ligustilide dose-dependently reduced lipopolysaccharide-induced upregulation of TLR4 mRNA expression. These data indicate that ligustilide treatment reduces TLR4 expression in spinal astrocytes and is an effective therapy for inflammatory pain.


Subject(s)
4-Butyrolactone/analogs & derivatives , Astrocytes/metabolism , Inflammation/drug therapy , Pain/drug therapy , Spinal Cord/pathology , Toll-Like Receptor 4/genetics , Up-Regulation/drug effects , 4-Butyrolactone/pharmacology , 4-Butyrolactone/therapeutic use , Animals , Astrocytes/drug effects , Cells, Cultured , Freund's Adjuvant/administration & dosage , Hot Temperature , Hyperalgesia/complications , Hyperalgesia/drug therapy , Hyperalgesia/genetics , Inflammation/genetics , Inflammation/pathology , Male , Mice, Inbred ICR , Pain/complications , Pain/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Toll-Like Receptor 4/metabolism
12.
Sci Rep ; 5: 10278, 2015 May 19.
Article in English | MEDLINE | ID: mdl-25988362

ABSTRACT

Curcumin is a major component of turmeric and reportedly has anti-inflammatory and anti-oxidant effects. Neuroinflammation has been recognized to play an important role in the pathogenesis of various diseases in the central nervous system. Here we investigated the anti-nociceptive and anti-neuroinflammatory effect of curcumin on arthritic pain in rats. We found that repeated oral treatment with curcumin, either before or after complete Freund's adjuvant (CFA) injection, dose-dependently attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, but had no effect on joint edema. Repeated intrathecal injection of curcumin reversed CFA-induced pain hypersensitivity. Furthermore, such a curcumin treatment reduced CFA-induced activation of glial cells and production of inflammatory mediators [interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 (MCP-1), and monocyte inflammatory protein-1 (MIP-1α)] in the spinal cord. Curcumin also decreased lipopolysaccharide-induced production of IL-1ß, tumor necrosis factor-α, MCP-1, and MIP-1α in cultured astrocytes and microglia. Our results suggest that intrathecal curcumin attenuates arthritic pain by inhibiting glial activation and the production of inflammatory mediators in the spinal cord, suggesting a new application of curcumin for the treatment of arthritic pain.


Subject(s)
Analgesics/therapeutic use , Arthritis, Experimental/drug therapy , Curcumin/therapeutic use , Hyperalgesia/drug therapy , Pain/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Arthritis, Experimental/chemically induced , Astrocytes/drug effects , Astrocytes/pathology , Cells, Cultured , Chemokine CCL2/biosynthesis , Chemokine CCL3/biosynthesis , Curcumin/administration & dosage , Inflammation/drug therapy , Inflammation/immunology , Injections, Spinal , Interleukin-1beta/biosynthesis , Lipopolysaccharides , Male , Microglia/drug effects , Microglia/pathology , Rats , Rats, Sprague-Dawley , Spinal Cord/drug effects , Spinal Cord/metabolism , Spine/pathology
13.
Brain Res Bull ; 109: 54-60, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25305342

ABSTRACT

Ligustilide is the main component of Danggui essential oil, and recently reported to have anti-inflammatory and neuroprotective effect. Increasing evidence suggests that glia-mediated neuroinflammation in the spinal cord plays a vital role in the pathogenesis of chronic pain. In the present study, we investigated the anti-inflammatory and anti-nociceptive effect of ligustilide both in vitro and in vivo. In microglial cell line BV2 cells, lipopolysaccharide (LPS) time-dependently increased the mRNA expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6), which was decreased by pretreatment with ligustilide in a dose-dependent manner. Ligustilide also decreased LPS-induced proinflammatory cytokines production in primary cultured microglia. In vivo, intrathecal injection of LPS induced mechanical allodynia in mice. Intravenous injection of ligustilide prevented LPS-induced mechanical allodynia, and decreased LPS-induced TNF-α, IL-1ß, and IL-6 up-regulation in the spinal cord. In addition, repetitive intravenous injection of ligustilide attenuated intraplantar injection of complete Freund's adjuvant (CFA)-induced mechanical allodynia and thermal hyperalgesia. The same treatment of ligustilide also inhibited CFA-induced TNF-α, IL-1ß, and IL-6 up-regulation and microglial activation in the spinal cord. Taken together, our data suggest that ligustilide can alleviate inflammatory pain partly through inhibition of microglial activation and proinflammatory cytokines production, which indicates a possible benefit from the use of ligustilide in the treatment of inflammatory pain and neuroinflammation-associated disorders.


Subject(s)
4-Butyrolactone/analogs & derivatives , Anti-Inflammatory Agents/pharmacology , Cytokines/metabolism , Inflammation/complications , Microglia/drug effects , Pain , 4-Butyrolactone/pharmacology , 4-Butyrolactone/therapeutic use , Animals , Anti-Inflammatory Agents/therapeutic use , Calcium-Binding Proteins/metabolism , Cell Line, Transformed , Cytokines/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Freund's Adjuvant/toxicity , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Male , Mice , Microfilament Proteins/metabolism , Pain/drug therapy , Pain/etiology , Pain/pathology , Pain Measurement , Pain Threshold/drug effects , RNA, Messenger/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism , Time Factors
14.
Eur J Neurosci ; 39(8): 1391-402, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24521480

ABSTRACT

Ligustilide (LIG) is a major component of Radix Angelica Sinensis, and reportedly has neuroprotective and anti-inflammatory effects. Recent studies have demonstrated that spinal astrocyte-mediated neuroinflammation plays an important role in the pathogenesis of chronic pain. Here we investigated the anti-nociceptive effect of systemic treatment with LIG on chronic inflammatory pain and explored possible mechanisms. Unilateral hindpaw injection of complete Freund's adjuvant (CFA) induced persistent pain hypersensitivity. Repeated daily intravenous treatment with LIG, either before or after CFA injection, attenuated CFA-induced thermal hyperalgesia and mechanical allodynia. The same treatment also inhibited CFA-induced keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein increases in astrocytes of the spinal cord. In vitro study showed LIG dose-dependently reduced lipopolysaccharide (LPS)-induced upregulation of KC and MCP-1 mRNA in astrocyte cultures. Interestingly, LIG treatment did not affect CFA- or LPS-induced glial fibrillary acidic protein upregulation, but did inhibit CFA-induced phosphorylated nuclear factor-κB (p-NFκB) upregulation in spinal astrocytes. Furthermore, intrathecal injection of NFκB inhibitor attenuated CFA-induced pain hypersensitivity and upregulation of KC and MCP-1 in the spinal cord. Finally, single intravenous injection of LIG attenuated intrathecal injection of LPS-induced mechanical allodynia. The same treatment also decreased LPS-induced NFκB activation and KC and MCP-1 upregulation in the spinal cord. These data indicate that LIG attenuates chronic inflammatory pain potentially via inhibiting NFκB-mediated chemokines production in spinal astrocytes. These results provide direct evidence of the anti-nociceptive and anti-inflammatory effects of LIG, suggesting a new application of LIG for the treatment of chronic inflammatory pain.


Subject(s)
4-Butyrolactone/analogs & derivatives , Astrocytes/drug effects , Chemokine CCL2/metabolism , Chemokines/metabolism , NF-kappa B/metabolism , Nociceptive Pain/drug therapy , Spinal Cord/metabolism , 4-Butyrolactone/pharmacology , 4-Butyrolactone/therapeutic use , Angelica sinensis/chemistry , Animals , Astrocytes/metabolism , Cells, Cultured , Chemokine CCL2/genetics , Chemokines/genetics , Hyperalgesia/drug therapy , Male , Mice , Mice, Inbred ICR , NF-kappa B/genetics , Nociception/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Spinal Cord/drug effects , Spinal Cord/pathology
15.
Cell Mol Neurobiol ; 32(6): 1003-10, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22410671

ABSTRACT

The important role of neuroinflammation in many chronic and acute pathological conditions of the central nervous system is widely recognized. Curcumin is a major component of turmeric and reportedly has anti-inflammatory and anti-oxidant effects. This study investigated the inhibitory effect of curcumin on lipopolysacharide (LPS)-induced chemokine CCL2 (or monocyte chemoattractant protein-1, MCP-1) production and whether the effect is mediated by mitogen-activated protein kinases (MAPKs) in the rat astrocytoma cell C6. We observed that LPS (1 µg/ml) induced the upregulation of CCL2 mRNA and protein in C6. Treatment with curcumin (2.5, 10, and 25 µM) decreased the expression of CCL2 mRNA and protein in a dose-dependent manner under treatment with LPS. Additionally, the c-jun N-terminal kinase (JNK) inhibitor (SP600125) dose-dependently inhibited LPS-induced CCL2 upregulation, whereas the MAPK kinase (MEK) inhibitor (PD98059) only had a mild effect and the p38 MAPK inhibitor (SB203580) had no effect. Finally, western blot showed that LPS induced rapid JNK activation and curcumin reduced LPS-induced phosphoJNK (pJNK) expression at 30 min after LPS stimulation. These data suggest that the anti-neuroinflammatory effect of curcumin relates to the downregulation of CCL2 expression through the JNK pathway in astrocytoma cells, which indicates a possible benefit from the use of curcumin in the treatment of neuroinflammation-associated disorders.


Subject(s)
Astrocytoma/enzymology , Chemokine CCL2/metabolism , Curcumin/pharmacology , Lipopolysaccharides/pharmacology , MAP Kinase Signaling System/drug effects , Animals , Astrocytoma/genetics , Astrocytoma/pathology , Cell Line, Tumor , Chemokine CCL2/genetics , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , JNK Mitogen-Activated Protein Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Up-Regulation/drug effects , Up-Regulation/genetics
16.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-242768

ABSTRACT

<p><b>OBJECTIVE</b>To discuss the urine biomarkers in 1,3-butadiene exposed workers, and to provide basement for establishing biological limit value.</p><p><b>METHODS</b>44 BD exposed workers as exposure group and 25 BD non-exposed people as control group including 12 workers in boiler workshop in the same factory and 13 people in one public institute, we collected their in-end-of shift urine, then detected urine BD-derived mercapturic metabolites [3,4-dihydroxybutyl mercapturic acid (DHBMA),1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA)] concentrations using UPLC-MS/MS method. Meanwhile, we detected air BD concentration with GC-FID in the workplace, and compared their relationship.</p><p><b>RESULTS</b>lgDHBMA and lg (MHBMA + DHBMA) levels in exposed group (lgDHBMA: 2.51 ± 0.44) µg/L, lg [MHBMA + DHBMA: (2.68 ± 0.27) µg/L] were higher than which in control group (lgDHBMA: (2.20 ± 0.25) µg/L, lg(MHBMA + DHBMA: (2.49 ± 0.34) µg/L), and the differences were significant (P < 0.01). Urine DHBMA was obviously influenced by air BD concentrations (r = 0.539, P = 0.001). The equation of Multiple Regression Analysis was y = 2.417 + 0.520x (x represents air BD dose, and represents urinary DHBMA level). Adjusted R(2) of this model was 0.262. Urinary MHBMA was not affected by smoking, alcohol and years of works.</p><p><b>CONCLUSION</b>Urine metabolite DHBMA in BD-exposed workers might be major biological exposure indice.</p>


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Biomarkers , Urine , Butadienes , Occupational Exposure , Surveys and Questionnaires
17.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-324268

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the reliability and validity of musculoskeletal questionnaire.</p><p><b>METHODS</b>A self-administered modified musculoskeletal questionnaire was used to investigate 12 098 workers from eight occupations, i.e. coal mining, petroleum, metallurgical, mechanical manufacturing, chemical, garment and railroad transportation industries and education. The Cronbach's α coefficient, analysis of covariance and multiple logistic regression were used to assess the reliability and validity of musculoskeletal questionnaire.</p><p><b>RESULTS</b>The consistent test between total items of Musculoskeletal Questionnaire and each factor showed that the range of Cronbach's α was 0.52 ∼ 0.92, except from vibration factor, other Cronbach's α was more than 0.7. All 55 items of Musculoskeletal Questionnaire were subjected to factor analysis, and ten latent factors were identified, which explained 55.17% of the total variance. The potentially hazardous working conditions could be categorized into seven dimensions (force, dynamic load, static load, repetitive load, climate factors, vibration exposure and environmental ergonomic factor), which consisted with the theory model. The results of covariance analysis indicated that there were significant difference among 7 dimension indices in different jobs (P < 0.01).</p><p><b>CONCLUSION</b>The modified Musculoskeletal Questionnaire is a valid and reliable tool for measuring musculoskeletal workload.</p>


Subject(s)
Humans , Factor Analysis, Statistical , Musculoskeletal Diseases , Occupational Health , Surveys and Questionnaires
18.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-324234

ABSTRACT

<p><b>OBJECTIVE</b>To explore the relationship between the polymorphisms of DNA repair gene (XRCC1 194, 280 and 399) and the chromosomal damage induced by benzene.</p><p><b>METHODS</b>The chromosomal damage of the peripheral lymphocytes in 459 workers occupationally exposed to benzene and 88 non-exposed controls were detected with cytokinesis-block micronucleus (CBMN) assay. PCR-RFLP technique was used to measure polymorphisms in XRCC1 194, 280 and 399.</p><p><b>RESULTS</b>It was found that the MN frequency (2.12‰ ± 1.88‰) of the exposed group was significantly higher than that (1.19‰ ± 1.68‰) of the control group (P < 0.05), in the exposed group, the MN frequency (3.00‰ ± 2.76‰) of older workers (> 35 years) was significantly higher than that (2.02‰ ± 1.71‰) of younger workers (≤ 35 years) (P < 0.05). The effect of genetic polymorphisms of XRCC1 on CBMN was not found. The haplotypes AAA/BAA, AAB/AAB, ABA/ABA, ABB/ABB could associated with the increased frequencies of total micronucleus (P < 0.05).</p><p><b>CONCLUSION</b>Benzene exposure could result in chromosome damage. Age of workers and diplotypes of XRCC1 could associated with chromosomal damage induced by benzene.</p>


Subject(s)
Adult , Humans , Young Adult , Benzene , DNA Damage , Genetics , DNA-Binding Proteins , Genetics , Micronuclei, Chromosome-Defective , Micronucleus Tests , Occupational Exposure , Polymorphism, Single Nucleotide , X-ray Repair Cross Complementing Protein 1
19.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-282569

ABSTRACT

<p><b>OBJECTIVE</b>To explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design.</p><p><b>METHODS</b>152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene-environment interactions.</p><p><b>RESULTS</b>Based on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3-order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840.</p><p><b>CONCLUSION</b>Gene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP.</p>


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Benzene , Poisoning , Case-Control Studies , Cytochrome P-450 CYP1A1 , Genetics , Cytochrome P-450 CYP2D6 , Genetics , Cytochrome P-450 CYP2E1 , Genetics , Epoxide Hydrolases , Genetics , Gene-Environment Interaction , Genetic Predisposition to Disease , Genotype , Logistic Models , Multifactor Dimensionality Reduction , Occupational Exposure , Polymorphism, Single Nucleotide
20.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-282539

ABSTRACT

<p><b>OBJECTIVE</b>To explore the association between chromosomal damage induced by vinyl chloride monomer (VCM) and polymorphisms of xenobiotic metabolism genes and DNA repair genes.</p><p><b>METHODS</b>Cytokinesis-block micronucleus (CBMN) test was performed to detect chromosomal damage in peripheral lymphocytes of 402 VCM-exposed workers. Multiplex PCR was used to simultaneously amplify GSTM1 and GSTT1 genes, other genetic polymorphisms were performed using a PCR-RFLP technique.</p><p><b>RESULTS</b>Multiple (adjusted) Poisson regression analysis showed that mean MN frequencies were significantly elevated for the intermediate (4000-40000 mg) and high (> 40000 mg) exposure groups as compared with the low exposure group (P = 0.003 and 0.03, respectively). For genetic polymorphisms, the exposed workers with CYP2E1 or XRCC1 Arg280His variance showed a higher CBMN frequency than their wild-type homozygous counterparts (P = 0.02); so did the workers with GSTP1 105Val/Val genotype or ALDH2 504Glu/Glu genotype than those with a combination of other genotypes (P = 0.01 and 0.003, respectively).</p><p><b>CONCLUSION</b>Our findings reveal that cumulative exposure dose of VCM and common genetic variants in genes, such as GSTP1, CYP2E1, ALDH2, XRCC1 Arg280His genotypes, are the major factors that modulate MN induction in VCM- exposed workers. Further study to investigate the relationship between individual characteristics and genetic susceptibility to VCM-caused chromosome damage is warranted, it is helpful for us to understand the mechanism of VCM metabolism, to find the biomarkers of susceptibility and to recognize the susceptible individuals in the primary prevention of VCM-caused damage.</p>


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Chromosome Aberrations , DNA Damage , DNA Repair , Genetic Predisposition to Disease , Genotype , Micronucleus Tests , Occupational Exposure , Vinyl Chloride , Toxicity
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