[Involvement of miR-199a in cisplatin resistance of ovarian cancer cell through modulating expression of mTOR].

OBJECTIVE: To study the effect of miR-199a on the sensitivity of OV2008 and C13* cells to cisplatin and investigate its mechanism of action. METHODS: Real-time polymerase chain reaction(PCR) and Western blot were applied to detect the expression level changes of mammalian target of rapamycin (mTOR) in OV2008 and C13* cells before and after transfecting the cells with the mimics and inhibitor of miR-199a with Lipofectamine 2000.We constructed luciferase reporter vectors of mTOR and then transfected OV2008 cells with the mimics of miR-199a with Lipofectamine 2000 to study the regulation of miR-199a's downstream target genes. RESULTS: The expression level of mTOR was significantly higher in C13* than OV2008 cells (P<0.05). After OV2008 and C13* cells were transfected with the mimics and inhibitor of miR-199a, real-time PCR and Western blot showed that the mimics of miR-199a repressed the expression of mTOR; and the inhibitor of miR-199a promoted the expression of mTOR. After transfecting OV2008 cells with the mimics of miR-199a and luciferase reporter vectors of mTOR, renillaluciferase reporter gene analysis indicated the expression level of mTOR was negatively regulated by miR-199a. CONCLUSION: miR-199a regulates the sensitivity of ovarian cancer cells to cisplatin through modulating expression of mTOR, and involves in the cisplatin resistance process of ovarian cancer cells.

Prognostic significance of integrating total metabolic tumor volume and EGFR mutation status in patients with lung adenocarcinoma.

Background: The objective of this study was to investigate the prognostic significance of total metabolic tumor volume (TMTV) derived from baseline 18F-2-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), in conjunction with epidermal growth factor receptor (EGFR) mutation status, among patients with lung adenocarcinoma (LUAD). Methods: We performed a retrospective analysis on 141 patients with LUAD (74 males, 67 females, median age 67 (range 34-86)) who underwent 18F-FDG PET/CT and had their EGFR mutation status determined. Optimal cutoff points for TMTV were determined using time-dependent receiver operating characteristic curve analysis. The survival difference was compared using Cox regression analysis and Kaplan‒Meier curves. Results: The EGFR mutant patients (n = 79, 56.0%) exhibited significantly higher 2-year progression-free survival (PFS) and overall survival (OS) rates compared to those with EGFR wild-type (n = 62, 44.0%), with rates of 74.2% vs 69.2% (P = 0.029) and 86.1% vs 67.7% (P = 0.009), respectively. The optimal cutoff values of TMTV were 36.42 cm3 for PFS and 37.51 cm3 for OS. Patients with high TMTV exhibited significantly inferior 2-year PFS and OS, with rates of 22.4% and 38.1%, respectively, compared to those with low TMTV, who had rates of 85.8% and 95.0% (both P < 0.001). In both the EGFR mutant and wild-type groups, patients exhibiting high TMTV demonstrated significantly inferior 2-year PFS and OS compared to those with low TMTV. In multivariate analysis, EGFR mutation status (hazard ratio, HR, 0.41, 95% confidence interval, CI [0.18-0.94], P = 0.034) and TMTV (HR 8.08, 95% CI [2.34-28.0], P < 0.001) were independent prognostic factors of OS, whereas TMTV was also an independent prognosticator of PFS (HR 2.59, 95% CI [1.30-5.13], P = 0.007). Conclusion: Our study demonstrates that the integration of TMTV on baseline 18F-FDG PET/CT with EGFR mutation status improves the accuracy of prognostic evaluation for patients with LUAD.

Identification of EGFR mutation status in male patients with non-small-cell lung cancer: role of 18F-FDG PET/CT and serum tumor markers CYFRA21-1 and SCC-Ag.

BACKGROUND: The high incidence of epidermal growth factor receptor (EGFR) mutations is usually found in female patients with lung adenocarcinoma who have never-smoked. However, reports concerning male patients are scarce. Thus, this study aimed to explore a novel approach based on 18F-fluoro-2-deoxy-2-deoxyglucose (18F-FDG) PET/CT and serum tumor markers (STMs) to determine EGFR mutation status in male patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 121 male patients with NSCLC were analyzed between October 2019 and March 2022. All patients underwent 18F-FDG PET/CT scan before treatment and monitored 8 STMs (cytokeratin 19 fragment [CYFRA21-1], squamous cell carcinoma-related antigen [SCC-Ag], carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], carbohydrate antigen [CA] 50, CA125, CA72-4, and ferritin). A comparison was done between EGFR mutant and wild-type patients in terms of the maximum standardized uptake value of primary tumors (pSUVmax) and 8 STMs. We performed receiver operating characteristic (ROC) curve and multiple logistic regression analyses to determine predictors for EGFR mutation status. RESULTS: EGFR mutations were detected in 39 patients (32.2%). Compared with patients with EGFR wild-type, EGFR-mutant patients had lower concentrations of serum CYRFA21-1 (2.65 vs. 4.01, P = 0.002) and SCC-Ag (0.67 vs. 1.05, P = 0.006). No significant differences of CEA, NSE, CA 50, CA125, CA72-4 and ferritin were found between the two groups. The presence of EGFR mutations was significantly associated with low pSUVmax (< 8.75), low serum SCC-Ag (< 0.79 ng/mL) and CYFRA21-1 (< 2.91 ng/mL) concentrations. The area under ROC curve values were 0.679, 0.655, 0.685 and 0.754, respectively, for low CYFRA21-1, SCC-Ag, pSUVmax and the combination of these three factors. CONCLUSIONS: We demonstrated that low concentrations of CYFRA21-1 and SCC-Ag, as well as low pSUVmax, were associated with EGFR mutations, and that the combination of these factors resulted in a higher differentiation of EGFR mutation status in male patients with NSCLC.

Metabolic phenotypes, serum tumor markers, and histopathological subtypes in predicting bone metastasis: analysis of 695 patients with lung cancer in China.

Background: Patients with lung cancer who develop bone metastasis (BM) generally have an adverse prognosis. Although several clinical models have been used to predict BM in patients with lung cancer, the results are unsatisfactory. In this retrospective study, we investigated the role of 18F-2-fluoro-2-deoxyglucose (FDG) metabolic activity, serum tumor markers, and histopathological subtypes in predicting BM in patients with lung cancer. Methods: This study included 695 consecutive patients with lung cancer who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) and in whom serum tumor markers were detected prior to treatment. The maximum standardized uptake value of primary tumors (pSUVmax), metastatic lymph nodes (nSUVmax) and distant metastases (mSUVmax), 8 serum tumor markers [carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), squamous cell carcinoma-related antigen (SCCA), cytokeratin 19 fragment (CYFRA21-1), carbohydrate antigen (CA) 125, CA50, CA72-4, and ferritin], and histopathological subtypes were compared between patients with and without BM. Receiver operating characteristic (ROC) curve and multiple logistic regression analyses were performed to identify predictors of BM in patients with lung cancer. Results: BM was identified in 133 (19.1%) patients and not in 562 (80.9%). Patients with BM had significantly higher pSUVmax, nSUVmax, and mSUVmax than did those without BM. High concentrations of 6 serum tumor markers (i.e., CEA, ferritin, NSE, CA50, CA125, and CYFRA21-1) were significantly associated with BM. There were significant differences in the proportion of histopathological subtypes between patients with and without BM (χ2=32.35; P<0.001). The area under ROC-derived curve based on metabolic parameters was 0.737 (95% CI: 0.644-0.829) and 0.884 (95% CI: 0.825-0.943) when combined with the 6 serum tumor markers and histopathological subtypes, respectively. Conclusions: High pSUVmax, nSUVmax, and mSUVmax favor the presence of BM in patients with lung cancer, and serum tumor markers and histopathological subtypes are important factors for predicting BM in these patients.

Association between cigarette smoking history, metabolic phenotypes, and EGFR mutation status in patients with non-small cell lung cancer.

Background: Cigarette smoking exerts a significant impact on metabolic phenotypes and epidermal growth factor receptor (EGFR) mutation status; however, their correlation remains insufficiently established. Therefore, the aim of this study was to investigate the association between cigarette smoking history, metabolic phenotypes, and EGFR mutation status in patients with non-small cell lung cancer (NSCLC). Methods: We retrospectively analyzed 198 consecutive patients with NSCLC who underwent 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) before treatment and were tested for EGFR mutation status between September 2019 and March 2022. Metabolic phenotypes, including the maximum standardized uptake value (SUVmax) of the primary tumors (pSUVmax), metastatic lymph nodes (nSUVmax), and distant metastases (mSUVmax) were assessed. Patients were classified into never-smokers and smokers based on detailed smoking history. The correlations between smoking status, metabolic parameters, and EGFR mutation status were evaluated in patients with NSCLC. Results: We observed EGFR mutations in 73 (60.3%) of 121 never-smokers and 18 (23.4%) of 77 smokers (P<0.001). EGFR-mutant NSCLC had a lower pSUVmax than that of EGFR wild-type (WT; 8.9±4.5 vs. 12.7±6.9, P<0.001). Smokers had a higher pSUVmax than never-smokers (12.5±6.4 vs. 9.9±5.9, P=0.004). With the increase of cumulative smoking dose, the pSUVmax increased significantly (r=0.198, P=0.005). There was no significant difference between nSUVmax and mSUVmax in patients with or without EGFR mutation and smoking history. Cumulative smoking dose, pSUVmax, and their combination predicted EGFR mutation status with areas under the receiver operating characteristic (ROC) curves (AUCs) 0.688, 0.673, and 0.753, respectively. Conclusions: Our findings indicate that cigarette smoking may be one of the triggers for increased pSUVmax and decreased EGFR mutations, further suggesting that EGFR mutations are associated with low pSUVmax, which may guide clinicians in risk stratification and treatment strategy selection for patients with NSCLC.

Anti-OJ antibody-positive anti-synthetase syndrome with repeated arthritis, fever, and recurrent liver cancer: a case report.

Background: Anti-isoleucyl-transfer RNA synthetase (anti-OJ) autoantibody-positive anti-synthetase syndrome (ASS) is a rare systemic autoimmune disease that manifests as an inflammatory myopathy and interstitial lung disease. We present a case of an anti-OJ antibody-positive ASS, with recurrent joint pain and fever, significantly elevated inflammatory markers, occult myositis but no interstitial pneumonia. This clinical presentation of an anti-OJ antibody-positive ASS has not been reported before. Case Description: A 75-year-old male, was admitted to our hospital complaining of recurrent joint pain for more than 1 year, recurrent fever for 6 months, and recurrence of joint pain and fever for 1 week. The patient had a history of chronic viral hepatitis B, hepatocellular carcinoma (HCC) surgery 11 years ago, hypertension and type 2 diabetes. In the past year, the patient visited Departments of orthopedics, Infectious Medicine and rheumatology for many times, and has undergone positron emission tomography-computed tomography (PET-CT), bone marrow puncture and other examinations, but the cause was still unknown. On admission, physical examination showed that the temperature was 39.6 ℃, and there was tenderness in multiple joints and muscles, such as the left ankle, the right shoulder, the left wrist, biceps brachii and quadriceps femoris, and so on. The laboratory results showed white blood cell (WBC) count of 30,500/µL (neutrophils: 90.1%), C-reactive protein (CRP): 140.79 mg/dL, Creatine Kinase and creatine kinase-MB were normal. Because of the muscle tenderness, myositis antibody tests were performed and the anti-OJ autoantibody was positive. Asking the medical history in detail, the patient had myasthenia, which was covered up due to prominent joint pain and fever. The patient had no interstitial pneumonia and mechanic's hand. Recurrent hepatocellular carcinoma was confirmed 1 year after the diagnosis of ASS, and the clinical symptoms were relieved after surgical resection. Conclusions: We report this rare case of anti-OJ antibody-positive ASS with atypical manifestations to raise awareness of the disease for clinicians. For patients with recurrent unexplained arthritis with fever, we should consider ASS, and myositis antibody tests should be performed if necessary. Patients with a history of tumours should be monitored for tumour recurrence.

Effects of cigarette smoking on metabolic activity of lung cancer on baseline 18F-FDG PET/CT.

Background: Never-smokers with lung cancer usually have a higher survival rate than that of smokers. The high metabolic activity of lung cancer on 18F-2-Fluoro-2-deoxyglucose (18F-FDG) PET/CT generally indicates a poor outcome. However, there is a lack of reports on the association between cigarette smoking and 18F-FDG metabolic activity in patients with lung cancer. In this study, we aimed to investigate the effects of cigarette smoking on metabolic activity of lung cancer on 18F-FDG PET/CT. Materials and Methods: A total of 338 patients (230 males, 108 females; mean age: 66.3, range 34-86) with pathologically diagnosed lung cancer were enrolled from September 2019 to April 2021. All patients underwent baseline 18F-FDG PET/CT and the maximum standard uptake value (SUVmax) of the primary tumor (pSUVmax), lymph node (nSUVmax) and distant metastasis (mSUVmax) were measured. The associations between cigarette smoking status, clinical stage, pathological subtypes and metabolic parameters on 18F-FDG PET/CT were analyzed. Results: Of the 338 patients, cigarette smoking was identified in 153 patients (45.3%) and the remaining 185 (54.7%) were never-smokers. Smoking was found more frequently in males, squamous cell carcinoma (SCC) and stage III-IV diseases. The pSUVmax in smokers was significantly higher than that in never-smokers (t = 3.386, P < 0.001), but the nSUVmax and mSUVmax revealed no statistically significant differences (t = 0.399, P = 0.690 and t = 0.057, P = 0.955; respectively). With the increase of cumulative smoking dose, pSUVmax increased significantly (r = 0.217, P < 0.001). In addition, the pSUVmax in patients with stage III-IV was significantly higher than that in stage I-II (t = 8.509, P < 0.001). Smokers showed a higher pSUVmax than never-smokers for patients with stage I-II (t = 3.106, P = 0.002), but not in stage III-IV (t = 0.493, P = 0.622). The pSUVmax was significantly different among patients with different pathological subtypes of lung cancer (F = 11.45, P < 0.001), while only the adenocarcinoma (ADC) and SCC groups showed a difference in pSUVmax (t = 6.667, P < 0.001). Smokers with ADC showed a higher pSUVmax when compared to never-smokers, but not in SCC. There were no significant differences of pSUVmax between smokers and never-smokers at stage I-II ADC or SCC and stage III-IV ADC or SCC. Conclusions: This study demonstrated a close association between cigarette smoking and the metabolic activity of lung cancer and suggests that smoking may be a potential risk factor of higher pSUVmax in early lung cancer on 18F-FDG PET/CT.

A Review of the Correlation Between Epidermal Growth Factor Receptor Mutation Status and 18F-FDG Metabolic Activity in Non-Small Cell Lung Cancer.

PET/CT with 18F-2-fluoro-2-deoxyglucose (18F-FDG) has been proposed as a promising modality for diagnosing and monitoring treatment response and evaluating prognosis for patients with non-small cell lung cancer (NSCLC). The status of epidermal growth factor receptor (EGFR) mutation is a critical signal for the treatment strategies of patients with NSCLC. Higher response rates and prolonged progression-free survival could be obtained in patients with NSCLC harboring EGFR mutations treated with tyrosine kinase inhibitors (TKIs) when compared with traditional cytotoxic chemotherapy. However, patients with EGFR mutation treated with TKIs inevitably develop drug resistance, so predicting the duration of resistance is of great importance for selecting individual treatment strategies. Several semiquantitative metabolic parameters, e.g., maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), measured by PET/CT to reflect 18F-FDG metabolic activity, have been demonstrated to be powerful in predicting the status of EGFR mutation, monitoring treatment response of TKIs, and assessing the outcome of patients with NSCLC. In this review, we summarize the biological and clinical correlations between EGFR mutation status and 18F-FDG metabolic activity in NSCLC. The metabolic activity of 18F-FDG, as an extrinsic manifestation of NSCLC, could reflect the mutation status of intrinsic factor EGFR. Both of them play a critical role in guiding the implementation of treatment modalities and evaluating therapy efficacy and outcome for patients with NSCLC.

[Electroacupuncture of Multiple Acupoints Is Significantly Superior to That of Single Acupoint in Improving Sleep by Regulating Serum Sleep-promoting and Awakening-promoting Factors in Insomnia Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of single and multiple acupoints on sleep and concentrations of interlukin-1 ß(IL-1 ß), brain-derived neurotrophic factor (BDNF), prostaglandin D2(PGD2) and melatonin (MLT, sleep-promoting factors) and corticosterone (CORT, awakening-promoting factor) in the serum in insomnia rats, so as to explore its efficacy difference and the mechanism underlying improving sleep. METHODS: Fifty-four male SD rats were randomly divided into control, model, EA-Baihui (GV 20), EA-Shenmen (HT 7), EA-Sanyinjiao (SP 6) and EA-GV 20＋HT 7＋SP 6 groups (n＝9 rats in each group). The insomnia model was established by intraperitoneal injection of para-chlorophenylalanine (PCPA, 300 mg/kg) once daily for 2 days. In the EA-GV 20, EA-HT 7, EA-SP 6 and EA-GV 20＋HT 7＋SP 6 groups, EA stimulation was administrated for 30 min, once a day for 4 days. The sleep onset latency and sleep duration were measured after intraperitoneal injection of pentobarbital sodium (35 mg/kg). The concentrations of IL-1 ß， BDNF, MLT, PGD2and CORT in the serum were detected by ELISA. RESULTS: After EA stimulation of GV 20, HT 7, SP 6 and GV 20＋HT 7＋SP 6, the sleep latency was significantly shortened (P<0.05, P<0.01, except SP 6), and the sleep duration was remarkably prolonged in comparison with the model group (P<0.05, P<0.01), and the therapeutic effects of EA-GV 20＋HT 7＋SP 6 were significantly superior to those of EA-GV 20, EA-HT 7 and EA-SP 6 in shortening the sleep latency and lengthening the sleep duration (P<0.05). Following modeling, the concentrations of IL-1 ß， BDNF, PGD2 and MLT were significantly down-regulated, and the CORT level was markedly up-regulated in the model group relevant to the control group (P<0.05). Following EA，modeling induced dramatic decrease of serum IL-1 ß， BDNF, PGD2 and MLT was considerably up-regulated, and the increased CORT level markedly down-regulated in the EA-GV 20, EA-HT 7, EA-SP 6 and EA-GV 20＋HT 7＋SP 6 groups (P<0.05). The effects of EA-GV 20＋HT 7＋SP 6 were evidently superior to those of EA-GV 20 and EA-SP 6 in up-regulating serum IL-1 ß， BDNF and PGD2levels, and to those of HT 7, GV 20 and SP 6 in up-regulating serum MLT level, and significantly superior to those of EA-ST 7 and EA-SP 6 in down-regulating serum CORT (P<0.05). CONCLUSION: EA stimulation of HT 7, GV 20, SP 6 and GV 20＋HT 7＋ SP 6 can significantly improve the sleep in insomnia rats, which is closely associated with its effects in regulating serum sleep-promoting factors and awakening-promoting factor. Joint administration of EA of GV 20＋HT 7＋ SP 6 has a better effect than the single acupoint mentioned above.

[Transcutaneous Electrostimulation of Auricular Otopoints Reduces Epileptic Attack Possibly by Suppressing Hippocampal Gliocyte Proliferation and Regulating IL-6 and IL-10 Expression in Chronic Temporal Lobe Epilepsy Rats].

OBJECTIVE: To observe the effect of transcutaneous otopoint electrostimulaiton (TCOES) on seizure frequency, immunoreactivity of hippocampal gliocytes and expression of proinflammatory cytokine interleukin-6(IL-6) and anti-inflammatory cytokine IL-10 in chronic temporal lobe epilepsy (CTLE) rats, so as to investigate its antiepileptic mechanism. METHODS: Thirty-six SD rats were randomly divided into control, model and TCOES groups (n=12 in each group). The CTLE model was established by intraperitoneal injection (i.p.i.) of lithium chloride (127.2 mg/kg), scopolamine (1 mg/kg, 20 h after the 1st injection) and pilocarpine (10 mg/kg, 30 min after scopolamine injection). Rats of the control group were treated by i.p.i. of normal saline. TCOES (1 mA, 20 Hz) was applied to bilateral otopoint "Heart"-"Lung"-"Subcortex" region for 20 min, once daily for 6 weeks. The epileptic attack was observed by a video monitoring system. The numbers of ionized calcium-binding adapter molecule-1 (Iba 1)-labeled microgliacytes and glial fibrillary acidic protein (GFAP)-labeled astrocytes in the CA 1 and CA 3 regions of hippocampus were counted under light microscope after immunostaining, and the expression levels of hippocampal IL-6 and IL-10 proteins and genes were determined by immunofluorescence and quantitative real-time PCR, respectively. RESULTS: After TCOES intervention, the seizure frequency was significantly decreased in comparison with pre-treatment(P<0.05), modeling-induced dramatic increase of the numbers of microgliacytes and astrocytes,IL-6 immunoactivity in the hippocampal CA 1 and CA 3 regions, and IL-6 mRNA expression in the hippocampus were significantly suppressed (P<0.05), and hippo-campal IL-10 immunoactivity and mRNA expression were considerably up-regulated in comparison with the model group (P<0.05). CONCLUSIONS: TCOES intervention has an antiepileptic effect in CTLE rats, which may be associated with its effects in suppressing gliocyte proliferation, suppressing the expression of proinflammatory cytokine IL-6, and up-regulaiting the expression of anti-inflammatory cytokine IL-10 in the hippocampus.

[Effects of Electroacupuncture on Activities of Satellite Glial Cells of Dorsal Root Ganglia in Rats with Neck Incision Pain].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Futu"(LI 18), etc. on activities of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) in rats with neck-incision pain so as to explore its mechanism underlying reduction of post-surgical pain of thyroidectomy. METHODS: Male SD rats were randomly divided into control, model, EA-Futu (LI 18), EA-Hegu (LI 4)-Neiguan (PC 6), and EA-Zusanli (ST 36)-Yanglingquan (GB 34) groups, with 20 rats in each group. The neck-incision pain model was established by making a longitudinal incision and repeated mechanical stimulation. In the EA-LI 18, EA-LI 4-PC 6 and EA-ST 36-GB 34 groups, EA stimulation was administrated for 30 min, once a day,continuously for 3 days. The thermal pain threshold (PT) of the neck-incision region was detected. The immunoactivity of glial fibrillary acidic protein (GFAP,a specific marker for SGCs) and connexin 43 (Cx 43) of DRGs (C 2-C 6) was determined by fluorescent immunohistochemistry. The expression levels of GFAP, IL-1 ß, IL-6, and TNF-α mRNAs were determined by quantitative Real-time PCR, and the contents of IL-1 ß,IL-6,TNF-α assayed by enzyme linked immunosorbent assay (ELISA) and the expression of Cx 43 protein was detected by Western blot. RESULTS: After EA intervention at LI 18 and LI 4-PC 6 (but not ST 36-GB 34), neck incision-induced reduction of the thermal PT was obviously prolonged in comparison with the model group (P<0.05),suggesting a pain relief. The expression levels of GFAP, IL-1 ß, IL-6 and TNF-α mRNAs and Cx 43 protein, and the contents of IL-1 ß, IL-6 and TNF-α in C 2-C 6 DRGs were all significantly up-regulated in the model group relevant to those of the control group (P<0.05). Following EA, modeling induced dramatic increase of expression of GFAP, IL-1 ß, IL-6 and TNF-α mRNAs and Cx 43 protein in both EA-LI 18 and EA-LI 4-PC 6 groups, and the contents of IL-1 ß and TNF-α in the EA-LI 18 group, IL-6 in the EA-LI 4-PC 6 group was considerably down-regulated (P<0.05). In comparison with the model group, no significant changes were found in all the abovementioned indexes of EA-ST 36 -GB 34 group except the down-regulated IL-1 ß and TNF-α mRNAs, in the contents of IL-1 ß and TNF-α of the EA-LI 4-PC 6 group, and in the IL-6 content of the EA-LI 18 group (P>0.05). CONCLUSIONS: EA stimulation of LI 18 and LI 4-PC 6 can significantly suppress pain reaction of neck incision in the rat, which is closely associated with its effects in down-regulating the activity of SGCs, decreasing the release of pro-inflammatory cytokines and in weakening the expression of Cx 43 in the cervical DRGs.