Neuroprotective Effects of Dexmedetomidine Preconditioning on Oxygen-glucose Deprivation-reoxygenation Injury in PC12 Cells via Regulation of Ca2+-STIM1/Orai1 Signaling.

Dexmedetomidine (DEX), a potent and highly selective agonist for α2-adrenergic receptors (α2AR), exerts neuroprotective effects by reducing apoptosis through decreased neuronal Ca2+ influx. However, the exact action mechanism of DEX and its effects on oxygen-glucose deprivation-reoxygenation (OGD/R) injury in vitro are unknown. We demonstrate that DEX pretreatment reduced OGD/R injury in PC12 cells, as evidenced by decreased oxidative stress, autophagy, and neuronal apoptosis. Specifically, DEX pretreatment decreased the expression levels of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1), and reduced the concentration of intracellular calcium pools. In addition, variations in cytosolic calcium concentration altered apoptosis rate of PC12 cells after exposure to hypoxic conditions, which were modulated through STIM1/Orai1 signaling. Moreover, DEX pretreatment decreased the expression levels of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3), hallmark markers of autophagy, and the formation of autophagosomes. In conclusion, these results suggested that DEX exerts neuroprotective effects against oxidative stress, autophagy, and neuronal apoptosis after OGD/R injury via modulation of Ca2+-STIM1/Orai1 signaling. Our results offer insights into the molecular mechanisms of DEX in protecting against neuronal ischemia-reperfusion injury.

Risk factors for Mallory-Weiss Tear during endoscopic submucosal dissection of superficial esophageal neoplasms.

BACKGROUND: Adverse events during endoscopic submucosal dissection (ESD) of superficial esophageal neoplasms, such as perforation and bleeding, have been well-documented. However, the Mallory-Weiss Tear (MWT) during esophageal ESD remains under investigation. AIM: To investigate the incidence and risk factors of the MWT during esophageal ESD. METHODS: From June 2014 to July 2017, patients with superficial esophageal neoplasms who received ESD in our institution were retrospectively analyzed. The clinicopathological characteristics of the patients were collected. Patients were divided into an MWT group and non-MWT group based on whether MWT occurred during ESD. The incidence of MWTs was determined, and the risk factors for MWT were then further explored. RESULTS: A total of 337 patients with 373 lesions treated by ESD were analyzed. Twenty patients developed MWTs during ESD (5.4%). Multivariate analysis identified that female sex (OR = 5.36, 95%CI: 1.47-19.50, P = 0.011) and procedure time longer than 88.5 min (OR = 3.953, 95%CI: 1.497-10.417, P = 0.005) were independent risk factors for an MWT during ESD. The cutoff value of the procedure time for an MWT was 88.5 min (sensitivity, 65.0%; specificity, 70.8%). Seven of the MWT patients received endoscopic hemostasis. All patients recovered satisfactorily without surgery for the laceration. CONCLUSION: The incidence of MWTs during esophageal ESD was much higher than expected. Although most cases have a benign course, fatal conditions may occur. We recommend inspection of the stomach during and after the ESD procedure for timely management in cases of bleeding MWTs or even perforation outside of the procedure region.

Efficacy and safety of endoscopic submucosal tunnel dissection for superficial esophageal squamous cell carcinoma and precancerous lesions.

AIM: To evaluate the clinical outcomes of patients who underwent endoscopic submucosal tunnel dissection (ESTD) for esophageal squamous cell carcinoma (ESCC) and precancerous lesions. METHODS: ESTD was performed in 289 patients. The clinical outcomes of the patients and pathological features of the lesions were retrospectively reviewed. RESULTS: A total of 311 lesions were included in the analysis. The en bloc rate, complete resection rate, and curative resection rate were 99.04%, 81.28%, and 78.46%, respectively. The ESTD procedure time was 102.4 ± 35.1 min, the mean hospitalization time was 10.3 ± 2.8 d, and the average expenditure was 3766.5 ± 846.5 dollars. The intraoperative bleeding rate was 6.43%, the postoperative bleeding rate was 1.61%, the perforation rate was 1.93%, and the postoperative infection rate was 9.65%. Esophageal stricture and positive margin were severe adverse events, with an incidence rate of 14.79% and 15.76%, respectively. No tumor recurrence occurred during the follow-up period. CONCLUSION: ESTD for ESCC and precancerous lesions is feasible and relatively safe, but for large mucosal lesions, the rate of esophageal stricture and positive margin is high.

[The Expression and Biological Function of claudin-23 in Colorectal Cancer].

OBJECTIVE: To determine the expression of claudin-23 in colorectal cancer and paracarcinoma tissues,and its effects on the proliferation and migration of colorectal cancer cells. METHODS: Six pairs of samples of colorectal cancer and corresponding paracarcinoma tissues were collected from the West China Hospital of Sichuan University. Quantitative real time PCR was performed to determine the expression of claudin-23 in the tissue samples. Colorectal cancer cell lines with stable overexpression of claduin-23 were constructed using lentivirus. CCK-8 and migration assays were conducted to identify the effects of claudin-23 on cell proliferation and migration. RESULTS: The expression of claudin-23 in colorectal cancer tissues decreased compared with their adjacent normal tissues (P<0.05). claudin-23 decreased cell adhesion and increased cell proliferation in HCT15 cells. RKO and HCT15 cells with over expressed claudin-23 had increased ability of migration. CONCLUSION: claudin-23 facilitates the migration ability of colorectal cancer cells and may participate in the metastasis of colorectal cancer.

[Efficacy of Oral Corticosteroids in Preventing Esophageal Stenosis after Large Area Endoscopic Submucosal Tunnel Dissection].

OBJECTIVE: To evaluate the efficacy of oral corticosteroids in preventing esophageal stenosis after large area esophageal endoscopic submucosal tunnel dissection (ESTD). METHODS: The patients undertook esophageal ESTD were included from January 2014 to January 2018. The inclusion criteria was single lesion of esophageal early esophagus cancer with the extent more than 3/4 of circumferential degree. According to the inclusion time, the patients were divided into the trial group (ESTD + oral corticosteroids) and the control group (simple ESTD). The incidence of the total esophageal stenosis, intractable esophageal stenosis, the remission rate of dysphagia and the period from the dysphagia present were observed and compared in the two groups. RESULTS: A total of 101 cases of esophageal ESTD patients were included. There were 48 cases in the trial group, 28 cases of male and 20 cases of female, with an average age of (62.98±7.52) years; 53 cases in the control group, 28 cases of male and 25 cases of female, with an average age of (62.67±8.04) years. The rate of intractable esophageal stenosis in the trial group was lower than that in the control group (6.25% vs. 20.75%, P<0.05). The average endoscopic treatment times in the non-refractory stenosis patients in the trial group were significantly less than those in the control group 〔(1.85±0.27) times vs. (3.24±0.49) times, P<0.05〕, and the occurrence time of esophageal stenosis in the trial group was 51.06 d after ESTD, significantly later than that in the control group (29.12 d, P<0.05). CONCLUSIONS: Oral corticosteroids can effectively reduce the degree of esophageal stenosis after large area ESTD, as well as the incidence of intractable esophageal stenosis and the number of endoscopic treatment in non-refractory esophageal stenosis patients.

[Risk Factors for Missed Diagnosis of Esophageal Low-grade Intraepithelial Neoplasia in Endoscopic Forceps Biopsy Compared with Endoscopic Submucosal Dissection].

OBJECTIVE: To investigate the risk factors for pathological upgrading after endoscopic treatment of esophageal lesions which confirmed to be low-grade intraepithelial neoplasia (LGIN) by preoperative biopsy. METHODS: A total of 148 patients who were confirmed to be LGIN in preoperative forceps underwent further endoscopic resection between November 2013 and July 2018. According to the final pathological results after endoscopic treatment, they were divided into pathological upgrading group and pathological non-upgrading group, and their clinicopathological characteristics were analyzed and compared through univariate and multivariate analysis. RESULTS: The average age of the patients was (59.95±7.75) years old and the percent of male patients was 67.57% (100/148). Most lesions were located in the middle esophagus (99 cases) and lower esophagus (38 cases). Endoscopic gross type was mainly depressed type (72 cases). The en-bloc resection rate was 99.32% (147/148). Among the patients (77, 52.03%) who had pathological upgrading, 33 (22.3%) cases were HGIN, 25 (16.9%) cases were in-situ cancer, and 19 (12.8%) cases were superficial esophageal squamous cell carcinoma. Univariate analysis showed that circumferential extent (≥1/2), longitudinal diameter (≥3 cm), submucosa involvement found by endoscopic ultrasongraphy, depressed gross type and redness of lesion mucosa were risk factors for postoperative pathological upgrading. Multivariate analysis indicated that the redness of the lesion mucosa and longitudinal diameter (≥3 cm) of the lesion were independent risk factors for pathological upgrading. CONCLUSIONS: For esophageal lesions diagnosed by biopsy as LGIN, clinicians should be highly alert to the pathological underestimate if the lesion surface is reddened and its longitudinal diameter is greater than 3 cm.

LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway.

The radiotherapy as a local and regional modality is widely applied in treatment of glioma, but most glioblastomas are commonly resistant to irradiation treatment. It remains challengeable to seek out efficient strategies to conquer the resistance of human glioblastoma cells to radiotherapy. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a newly discovered tumor suppressor which involved in regulation of chemosensitivity in various human cancer cells. In the present study, we established a radioresistant U251 cell line (U251R) to investigate the role of LRIG1 in regulation of radiosensitivity in human glioblastoma cells. Significantly decreased expression level of LRIG1 and enhanced expression of EGFR and phosphorylated Akt were detected in U251R cells compared with the parental U251 cells. U251R cells exhibited an advantage in colony formation ability, which accompanied by remarkably reduced X-ray-induced γ-H2AX foci formation and cell apoptosis. LRIG1 overexpression significantly inhibited the colony formation ability of U251R cells and obviously enhanced X-ray-inducedγ-H2AX foci formation and cell apoptosis. In addition, up-regulated expression of LRIG1 suppressed the expression level of EGFR and phosphorylated Akt protein. Our results demonstrated that LRIG1 expression was related to the radiosensitivity of human glioblastoma cells and may play an important role in the regulation of cellular radiosensitivity of human glioblastoma cells through the EGFR/Akt signaling pathway.

Photodynamic therapy mediated by 5-aminolevulinic acid suppresses gliomas growth by decreasing the microvessels.

Although 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) has been demonstrated to be a novel and effective therapeutic modality for some human malignancies, its effect and mechanism on glioma are still controversial. Previous studies have reported that 5-ALA-PDT induced necrosis of C6 rat glioma cells in vitro. The aim of this study was to further investigate the effect and mechanism of 5-ALA-PDT on C6 gliomas implanted in rats in vivo. Twenty-four rats bearing similar size of subcutaneously implanted C6 rat glioma were randomly divided into 3 groups: receiving 5-ALA-PDT (group A), laser irradiation (group B), and mock procedures but without any treatment (group C), respectively. The growth, histology, microvessel density (MVD), and apoptosis of the grafts in each group were determined after the treatments. As compared with groups B and C, the volume of tumor grafts was significantly reduced (P<0.05), MVD was significantly decreased (P<0.001), and the cellular necrosis was obviously increased in group A. There was no significant difference in apoptosis among the three groups. The in vivo studies confirmed that 5-ALA-PDT may be an effective treatment for gliomas by inhibiting the tumor growth. The mechanism underlying may involve increasing the cellular necrosis but not inducing the cellular apoptosis, which may result from the destruction of the tumor microvessels.

A mini review: Tau transgenic mouse models and olfactory dysfunction in Alzheimer's Disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment (MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss (1) the function of Tau physiologically and pathologically; (2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice; (3) the structural and molecule basis of olfaction; (4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.

Hypermethylation of Cox5a promoter is associated with mitochondrial dysfunction in skeletal muscle of high fat diet-induced insulin resistant rats.

High-fat diet (HFD) is an environmental factor that contributes to the pathogenesis of obesity and type 2 diabetes. A number of genes influencing oxidative phosphorylation (OXPHOS) were found to be downregulated in skeletal muscle of humans and rats treated with HFD and have been implicated in mitochondrial dysfunction, insulin resistance, and consequent type 2 diabetes. In this study, we hypothesized that DNA methylation plays a crucial role in the regulation of OXPHOS genes in skeletal muscle of rats exposed to HFD. Using whole genome promoter methylation analysis of skeletal muscle followed by qPCR and bisulfite sequencing analysis, we identified hypermethylation of Cox5a in HFD rats. Furthermore, we found that Cox5a hypermethylation was associated with downregulation of Cox5a expression at the mRNA and protein level, and a reduction in mitochondrial complex IV activity and ATP content in HFD-induced insulin resistant rats compared to controls. Moreover, we found that while exposure to palmitate resulted in hypermethylation of the Cox5a promoter in rat myotubes, demethylation with 5-aza-2'-deoxycytidine was associated with preserved Cox5a expression, as well as restoration of complex IV activity and cellular ATP content. These novel observations indicate that Cox5a hypermethylation is associated with mitochondrial dysfunction in skeletal muscle of HFD-induced insulin resistant rats.

Ursolic acid suppresses growth and adrenocorticotrophic hormone secretion in AtT20 cells as a potential agent targeting adrenocorticotrophic hormone-producing pituitary adenoma.

Adrenocorticotrophic hormone (ACTH)-producing pituitary adenoma leads to excess ACTH secretion, which is associated with significant mortality and impaired quality of life. Thus far, the first line therapy is the transphenoidal microsurgery. Considering the high recurrence rate and complications of surgery, novel agents, which directly target on pituitary ACTH-producing adenoma and suppress ACTH secretion are urgently required. In the present study, the effect of ursolic acid (UA) as a candidate agent targeting ACTH-producing AtT20 cells was investigated. It was demonstrated that UA inhibited the viability and induced apoptosis of AtT20 cells and decreased ACTH secretion. The process of apoptosis involved a decrease of the B cell lymphoma 2 (Bcl-2)/Bcl2-associated X protein ratio followed by a release of mitochondrial cytochrome c into the cytosol with subsequent activation of caspase-9, -3/7 and -8. The potential signaling pathway involved the activation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinases1/2 and p38 mitogen-activated protein kinase. The JNK pathway participated in UA-induced mitochondrial apoptotic signaling transduction via increasing the phosphorylation and degradation of Bcl-2, which may be partly attenuated by the JNK inhibitor SP600125. In conclusion, the present study indicates that UA may be a promising candidate agent for the management of ACTH-producing pituitary adenoma.

[Generation of Tau/App/PS1 triple-transgenic mouse model and the study of its biological characteristics].

OBJECTIVE: To establish the triple-transgenic mouse model and study their biological characteristics by molecular biology, behavior and pathology. METHODS: Hybrid the Tau and amyloid precursor protein (APP)/presenilins (PS1) transgenic mouse, the genotype of offspring mice were identified by PCR. Transcribed target genes were detected by RT-PCR. The protein expression of exogenous genes was detected by Western-blot. The pathological change of neurofibrillary tangles and senile plaque were observed by Bielschowsky silver staining and ABC immunohistochemical method. The changes time of learning and memory were observed by Morris water maze. RESULTS: APP, PS1 and Tau genes were transcript in Tau/APP/PS1 mice. In 6 to 8 months old Tau/APP/PS1 mice, the neurofibrillary tangles and senile plaque could be found in cortex and hippocampus. In 6 months old Tau/APP/PS1 mice, the learning and memory abilities were worse. CONCLUSION: With the behavior change and pathological changes in Tau and beta-amyloid protein (AP), the Tau/APP/PS1 triple-transgenic mice can be used as a further study animal model of AD's pathogenesis and the target of drug treatment.

[Differential expressions of microRNA between young and senescent endothelial cells].

OBJECTIVE: To explore the differential expressions of microRNA (miRNA) between young and senescent endothelial cells. METHODS: Young and senescent aorta endothelial cells (EC) were isolated and cultured in young and old male C57BL/6J mice. Immunostaining of VIII factor was performed to identify the endothelial cells. The method of diphenyl tetrazolium bromide (MTT) was employed to compare the cell growth. Microarray was used to detect the differential expression of microRNA between young and senescent endothelial cells and the microarray results were confirmed by real-time polymerase chain reaction (PCR). The expression of endothelial nitric oxide synthase (eNOS) was detected by Western blot. RESULTS: Primarily cultured endothelial cells were confirmed by the VIII immunostaining factor. Senescent ECs grew more rapidly than young ECs in lower serum ex vivo. Excluding gender difference, miR-135a, miR-182, miR-96, miR-31, miR-126-3p and miR-362-5p were up-regulated over 2 folds in young ECs, and miR-335-3p and miR-335-5p up-regulated over 2 folds in senescent ECs by miRNA microarray and RT-PCR. The up-regulation of miR335-3p in old ECs and the up-regulation of miR-135a, miR-96 in the young ECs might contribute to a lower expression of eNOS in senescent ECs. CONCLUSION: The expression of miRNAs changes with advancing age and may result in differential expressions of downstream genes.

[Association of the tumor necrosis factor-alpha -1031T/C and its combination with interleukin-6 -634C/G gene polymorphisms with susceptibility to endometriosis].

OBJECTIVE: To investigate the association of tumor necrosis factor-alpha (TNF-α) gene promoter region -1031T/C and its combination with interleukin-6 (IL-6) gene promoter region -634C/G single nucleotide polymorphisms (SNP) with the genetic susceptibility to endometriosis. METHODS: Total of 432 endometriosis patients and 499 non-endometriosis women who had received an operation due to tubal ligation, tubal recanalization, laparoscopic hydrotubation, ovarian simple cyst and teratoma were collected and separated into endometriosis group and control group, that all cases were confirmed by operation and pathology. A case-control study was performed in endometriosis and control group to evaluate the association of these SNP with the susceptibility to endometriosis by using a fluorescent quantitative PCR-based high resolution melting (HRM) method. RESULTS: (1) TNF-α -1031T/C genotype:the T and C of TNF-α -1031T/C allele frequencies in the endometriosis group and control group were 79.2% (684/864), 20.8% (180/864) and 81.8% (816/998), 18.2% (182/998), respectively. The TT, TC and CC of TNF-α -1031T/C genotype frequencies in the two groups were 63.7% (275/432), 31.0% (134/432), 5.3% (23/432) and 66.5% (332/499), 30.5% (152/499), 3.0% (15/499), respectively. There were no statistical significances in the TNF-α -1031T/C alleles and genotypes distributions between the two groups (P = 0.158, P = 0.186). (2) TNF-α -1031T/C and IL-6 -634C/G conjoint genotypes: to research on the TNF-α -1031T/C and IL-6 -634C/G genotypes for conjoint analysis, the TT+CC, TC+CC, CC+CC, TT+CG, TC+CG, CC+CG, TT+GG, TC+GG and CC+GG combination genotype frequencies in the two groups were 39.4% (170/432), 19.4% (84/432), 4.6% (20/432), 20.6% (89/432), 8.8% (38/432), 0.9% (4/432), 3.5% (15/432), 2.3% (10/432), 0.5% (2/432) and 36.7% (183/499), 17.4% (87/499), 1.4% (7/499), 26.1% (130/499), 10.4% (52/499), 1.2% (6/499), 3.8% (19/499), 2.6% (13/499), 0.4% (2/499), respectively. There were no statistical significances in the combination genotypes distributions between the two groups (P = 0.107). As compared with carriers of TT+CC combination genotype, the endometriosis risk of carriers of CC+CC combination genotype enhanced 3.076 times (95%CI: 1.268 - 7.457, P = 0.009), and the endometriosis risk of carriers of other combination genotypes were no statistical significances (all P > 0.05). CONCLUSIONS: The study demonstrates that there are no significant association between the SNP of TNF-α -1031T/C and genetic susceptibility to endometriosis. However the results indicate that there are significant association between genetic susceptibility to endometriosis and the combination polymorphisms of TNF-α -1031T/C and IL-6 -634C/G.

[Improvement of universal salt iodization program on the intelligence quotient among children in Linxia Hui Autonomous Prefecture of Gansu].

OBJECTIVE: To assess the improvement of intelligence quotient through an Universal Salt Iodization Supply Program, among children. METHODS: 3518 and 1611 children were selected from primary schools in Linxia Hui Autonomous Prefecture of Gansu in 2006 and 2010 respectively. Intelligence quotient (IQ) were measured by the revised Chinese Combined Raven Test-C2 (CRT-C2). RESULTS: In 2006, the average IQ of children aged 8-10 was 85.1, including 16.7% of them with IQ ≤ 69. The average IQ was between 80-90 in different counties and cities, with significant differences (P < 0.05). The average IQs were 92.0, 90.6 and 81.8 among 8, 9 and 10 years old children respectively with 10 year old's low than those 8 and 9 year olds (P < 0.05). The average IQs of boys and girls were 84.5 and 85.6, but with no significant difference (P > 0.05). The average IQ of children aged 8-10 in 2010 was 97.2 and 12 points higher than in 2006 (P < 0.05), but 8 IQ points (P < 0.05) less than the average level 105 from the overall of Gansu province. 4.7% of the children having an IQ ≤ 69. IQ of children from Linxia city and Yongjing county, were up to the theoretical level of 100, with an average IQ at around 95 in other counties. The average IQs between counties or cities showed significant differences. The IQ of 8, 9 year olds and 10 year olds did not present significant difference (P > 0.05), but in boys (98.8) and in girls (95.9) the difference was significant (P < 0.05). CONCLUSION: The average IQ was close to the theoretical level (100) with the gradual implementation of universal salt iodization program, showing that the iodized salt did play a key role on children's intelligence. However, the average IQ was still lower than the average level of the whole Gansu province in 2010.

Similar potency of catechin and its enantiomers in alleviating 1-methyl-4-phenylpyridinium ion cytotoxicity in SH-SY5Y cells.

OBJECTIVES: Previously, the flavonoid (±)-catechin was shown to exert potent neuroprotective action in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease model. The purpose of this study was to investigate whether the different enantiomers of catechin ((+)-catechin, (-)-catechin and (±)-catechin, a 50:50 mixture of (+)-catechin and (-)-catechin) could protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP(+) ) toxicity by decreasing the generation of oxygen free radicals. The inhibitive effect of (±)-catechin on JNK/c-Jun activation was investigated. METHODS: The effects of (+)-catechin, (-)-catechin or (±)-catechin in protecting against MPP(+) toxicity were evaluated and compared in SH-SY5Y cells by testing the release of lactate dehydrogenase. The generation of reactive oxygen species (ROS) was measured by immunochemistry and the phosphorylation level of JNK/c-Jun was determined by Western blotting. KEY FINDINGS: In SH-SY5Y cells, (+)-catechin, (-)-catechin or (±)-catechin reduced apoptosis induced by MPP(+) and decreased ROS generation caused by MPP(+) . Different enantiomers of catechin showed protective effects at similar potency. Moreover (±)-catechin decreased JNK/c-Jun phosphorylation which was increased by MPP(+). CONCLUSIONS: Catechin and its two enantiomers could protect SH-SY5Y cells against MPP(+) cytotoxicity at a similar potency. Antioxidative stress and inhibition of the JNK/c-Jun signalling pathway might have been involved in the neuroprotective mechanisms of catechin against MPP(+) cytotoxicity in SH-SY5Y cells.

Down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-κB pathway.

BACKGROUND: Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid (PA) on the apoptosis and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in ßTC3 cells as well as the possible role of nuclear factor-κB (NF-κB) in this process. METHODS: Hoechst 33258 was used to detect ßTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase ß (IKKß), IκBα, NF-κB-inducing kinase (NIK) and Rel-B expressions were analyzed by Western blotting. MG132 was employed to block the endogenous IκBα degradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α mRNA expression was analyzed. RESULTS: Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA (0.5 mmol/L) could extensively reduced the expression of PGC-1α mRNA. After exposing ßTC3 cells to 0.5 mmol/L PA for different time periods (0, 4, 6, 8, 10 and 12 hours), IKKß protein expression increased while IκBα, NIK and Rel-B protein expression declined in a time-dependent manner. Pretreatment with MG132 to inhibit the degradation of IκBα, partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. CONCLUSIONS: NF-κB canonical pathway was activated in PA-mediated ßTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in ßTC3 cells could involve the activation of canonical NF-κB pathway, so as to deteriorate the PA induced apoptosis.

[Isolation and identification of Suavissimoside R1 from roots of Rubus parvifollus used for protecting dopaminergic neurons against MPP+ toxicity].

OBJECTIVE: Suavissimoside R1 was isolated and identified as an active ingredient from Roots of Rubus parvifollus L, which exhibited protective effect on dopaminergic neurons against MPP+ toxicity. METHODS: The protective effects of crude extracts were investigated after mice were treated with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). According to the protective effects of crude extracts, suavissimoside R1, one kind of triterpenoid saponin, was separated. It was investigated that whether Suavissimoside R1 can protect DA neurons from toxicity induced by MPP+ in rat mesencephalic cultures. RESULTS: Suavissimoside R1 was isolated from Roots of Rubus parvifollus L. Moreover, Suavissimoside R1, in dose of 100 micromol/L, alleviated the death of DA neurons induced by MPP+ obviously. CONCLUSION: These results suggest that suavissimoside R1 possesses potent neuroprotective activity and can be developed to be a potential anti-Parkinson's disease drug worthy for further study.

Noradrenaline release by activation of κ-bungarotoxin-sensitive nicotinic acetylcholine receptors participates in long-term potentiation-like response induced by nicotine.

Nicotine enhances the function of learning and memory, but the underlying mechanism still remains unclear. Hippocampal long-term potentiation (LTP) is assumed to be a cellular mechanism of learning and memory. Our previous experiments showed that with the single pulses evoking 80% of the maximal population spike (PS) amplitude, nicotine (10 µmol/L) induced LTP-like response in the hippocampal CA1 region. In the present study, the nicotinic acetylcholine receptor (nAChR) subtypes and relevant neurotransmitter releases involved in LTP-like response induced by nicotine were investigated by extracellularly recording the PS in the pyramidal cell layer in the hippocampal CA1 region in vitro. LTP-like response induced by nicotine was blocked by mecamylamine (1 µmol/L) or κ-bungarotoxin (0.1 µmol/L), but not by dihydro-ß-erythtroidine (DHßE, 10 µmol/L). Moreover, it was inhibited by propranolol (10 µmol/L), but not by phentolamine (10 µmol/L) or atropine (10 µmol/L). The results suggest that noradrenaline release secondary to the activation of κ-bungarotoxin-sensitive nAChRs participates in LTP-like response induced by nicotine in the hippocampal CA1 region.