Plasma TNF-α and phosphorylated α-syn are associated with fatigue in patients with Parkinson's disease.

BACKGROUD: Fatigue is one of the most common non-motor symptoms among patients with Parkinson's disease (PD).However, the pathogenesis keeps largely unknown. Moreover, it is lack of objective biomarker. OBJECTIVE: To investigate the relationship between plasma inflammatory cytokines and α-syn levels and fatigue in patients with PD. METHODS: A total of 63 PD patients were enrolled, including 35 patients with fatigue and 28 patients without fatigue. We compared the difference between plasma cytokines and alpha-synuclein (α-syn) in the two groups. Meanwhile, we analyzed the relationship between plasma cytokines and p-α-syn levels and fatigue. RESULTS: PD patients with fatigue had older age, longer disease duration, more severe motor scores. There were significant differences in the plasma levels of IL-1ß, IL-18, TNF-α, and phosphorylated α-syn (p-α-syn) between the two groups. The plasm inflammatory cytokine levels (IL-1ß, IL-18 and TNF-α) were positively associated with FSS scores. Moreover, the plasma p-α-syn level was significantly positively correlated with FSS scores. Furthermore, the higher PDQ-39 scores and higher plasma levels of TNF-α and p-α-syn were strongly associated with fatigue in PD. The ROC curve analysis showed the AUC of TNF-α for fatigue in PD was 0.663 with a sensitivity of 65.71% and specificity of 67.86%, while the AUC of p-α-syn was 0.786 with a sensitivity of 74.29% and specificity of 64.29%. The combination of TNF-α and p-α-syn improves the AUC to 0.803 with a sensitivity of 88.57% and specificity of 64.29%. CONCLUSION: The high plasma levels of TNF-α and p-α-syn were strongly associated with fatigue in PD.

NLRP3 Inflammasome Inhibition Prevents α-Synuclein Pathology by Relieving Autophagy Dysfunction in Chronic MPTP-Treated NLRP3 Knockout Mice.

Recent researches showed that nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome inhibition exerted dopaminergic neuroprotection in cellular or animal models of Parkinson's disease (PD). NLRP3 inflammasome has been proposed as a drug target for treatment of PD. However, the interplay between chronic NLRP3 inflammasome and progressive α-synuclein pathology keeps poorly understood. Moreover, the potential mechanism keeps unknown. In the present study, we investigate whether NLRP3 inflammasome inhibition prevents α-synuclein pathology by relieving autophagy dysfunction in the chronic 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD. NLRP3 knockout mice and their wild-type counterparts were treated with continuous MPTP administration via osmotic mini-pumps. Dopaminergic neuronal degeneration was assessed by western blotting and immunohistochemistry (IHC). The levels of dopamine and its metabolites were determined using high-performance liquid chromatography. NLRP3 inflammasome activation and autophagy biomarkers were assessed by western blot. The expressions of pro-inflammatory cytokines were measured by ELISA. The glial reaction and α-synuclein pathology were assessed by IHC and immunofluorescence. Our results show that NLRP3 inflammasome inhibition via NLRP3 knockout not only protects against nigral dopaminergic degeneration and striatal dopamine deletion but also prevents nigral pathological α-synuclein formation in PD mice. Furthermore, it significantly suppresses MPTP-induced glial reaction accompanied by the secretion of pro-inflammatory cytokines in the midbrain of mice. Most importantly, it relieves autophagy dysfunction in the midbrain of PD mice. Collectively, we demonstrate for the first time that improving autophagy function is involved in the preventive effect of NLRP3 inflammasome inhibition on α-synuclein pathology in PD.

MFN2 ameliorates cell apoptosis in a cellular model of Parkinson's disease induced by rotenone.

A number of studies indicated that apoptosis, a specific type of programmed cell death, contributed to the loss of dopaminergic neurons during progression of Parkinson's disease (PD). Previously, the authors of the present study demonstrated that apoptosis of dopaminergic neurons was mainly achieved via the mitochondria-mediated apoptosis pathway, however, the precise molecular mechanisms remain to be elucidated. The present study aimed to determine whether mitofusin-2 (MFN2), a mitochondrial protein, participated in the apoptosis of dopaminergic neurons in a cellular model of PD induced by rotenone. The present study demonstrated that the expression of MFN2 was relatively stable following treatment with rotenone. Lentiviral knockdown and overexpression experiments for the first time, to the best of the authors knowledge, revealed that MFN2 prevented rotenone-induced cell death by amelioration of apoptosis. These results revealed a protective role of MFN2 against apoptosis in an in vitro model of PD and may be used to establish MFN2 as a potential therapeutic target for the treatment of this disease.

Correction to: Identification of the functional role of peroxiredoxin 6 in the progression of breast cancer.

After the publication of this work [1] an error in Fig. 1c was brought to our attention: the Western blots for PRDX6 and ß-actin were similar to those shown in lanes 5-6 of Fig. 4g. To verify these findings, we have repeated this experiment and the results are shown in a new Fig. 1c below. The repeated experimental results are consistent with the previously reported findings in the original study [1] and the functional role for PRDX6 in malignant progression of human cancer including breast cancer has been widely documented and recognized in numerous other studies [2]. We apologize for the error. However, this correction does not affect the conclusions of the article.

PM2.5 exposure aggravates oligomeric amyloid beta-induced neuronal injury and promotes NLRP3 inflammasome activation in an in vitro model of Alzheimer's disease.

BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.

Anti-Cervical Cancer Role of Matrine, Oxymatrine and Sophora Flavescens Alkaloid Gels and its Mechanism.

Background: Cervical cancer is one of the leading severe malignancies throughout the world. Sophra flavescens alkaloid (SFA) gels, a compound Traditional Chinese Medicine, has been clinically used in China for many years. Its individual active ingredients are matrine and oxymatrine, which has been showed that they can restrain primary tumorigenesis, while the underlying molecular mechanisms of SFA gels in cervical cancer cells remain unclear. Methods: To detect the effect of SFA gels and its active ingredients, CCK-8 assay and colony assay were used on cervical cancer cells proliferation. Transwell assay was used to detect cancer cell migration. Apoptosis and cell cycle arrest were used to detect whether SFA gels effect the cervical cancer cells proliferation. Western blot was used to detect whether SFA gels regulate the cervical cancer cells via the suppression of AKT/mTOR signaling pathway. Results: SFA gels can restrain cervical cancer cell proliferation, inhibit metastasis, induce cell cycle arrest in G2/M phase, induce cellular apoptosis through stimulation of Bax and E-cadherin, and suppression of Bcl-2, cyclin A, MMP2. Further study shows that SFA gels may regulate the cervical cancer cells via the suppression of AKT/mTOR signaling pathway. Conclusions: SFA gels, like its active ingredients, can restrain cervical cancer cells proliferation, suppress cervical cancer cell migration, induce the apoptosis and cell cycle arrest in cervical cancer cells. SFA gels may be a potential anti-tumor therapeutic agent for treating cervical cancer.

AVE0991, a nonpeptide analogue of Ang-(1-7), attenuates aging-related neuroinflammation.

During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.

TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response.

As a recently identified susceptibility gene for Alzheimer's disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) encodes an immune receptor that is uniquely expressed on microglia, functioning as a modulator of microglial functions including phagocytosis and inflammatory response. Several lines of evidence suggest that TREM2 is upregulated and positively correlates with tau pathology in the brains of AD patients. Meanwhile, our recent study showed that knockdown of TREM2 markedly exacerbated neuronal tau hyperphosphorylation in the brains of P301S-tau transgenic mice, implying that TREM2 might exert a protective role against tau pathology under AD context. However, the precise mechanisms underlying this observation remain largely unclear. In this study, by employing a microglial-neuronal co-culture model, we showed that microglial inflammatory response induced by lipopolysaccharide led to tau hyperphosphorylation in neurons via activation of a major tau kinase glycogen synthase kinase 3ß, confirming the pathogenic effects of activated microglia on the progression of tau pathology. More importantly, by manipulating TREM2 levels in microglia with a lentiviral-mediated strategy, we demonstrated that TREM2 ameliorated the pathological effects of activated microglia on neuronal tau hyperphosphorylation via suppression of microglial inflammatory response. Taken together, these findings uncover the underlying mechanisms by which TREM2 protects against tau pathology and highlight TREM2 as a potential therapeutic target for AD.

Up-regulation of angiotensin-converting enzyme in response to acute ischemic stroke via ERK/NF-κB pathway in spontaneously hypertensive rats.

Cerebral ischemic stroke is usually caused by a temporary or permanent decrease in blood supply to the brain. Despite general progress in diagnosis and treatment, the prognosis of stroke is still unsatisfactory, and more detailed potential mechanisms are needed to investigate underlying the pathological process. Here, we showed that serum angiotensin-converting enzyme (ACE) concentration was positively correlated with infarct volume after acute ischemic stroke (AIS). Moreover, using a permanent middle cerebral artery occlusion rat model, we indicated for the first time that increased ACE expression in response to AIS was regulated by the ERK/NF-κB pathway in peri-infarct regions. More importantly, we disclosed that angiotensin II type 1 receptors were implicated in up-regulation of ACE expression in peri-infarct regions. These findings offer insight into ACE expression and activity in response to stroke, and further our understanding of ACE mechanisms.

The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer.

BACKGROUND: Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family. However, its function in various cancer types is unknown. The G protein-coupled receptor 35 (GPR35) was identified as the receptor of CXCL17 and named recently as CXCR8. The function of the CXCL17-CXCR8 (GPR35) biological axis in cancer has not been reported. METHODS: The expression of CXCL17 and CXCR8 (GPR35) in breast cancer cell lines and a tissue microarray (TMA) was detected through western blot and immunohistochemistry (IHC). Expression data in IHC were analyzed using clinicopatholigical and survival information. RESULTS: CXCL17 and CXCR8 (GPR35) were found to be variably expressed in breast cancer cell lines. Both expressed higher in breast cancer tissue than normal adjacent tissue. Although CXCL17 can interact with CXCR8 (GPR35) in breast cancer cells in vitro, the expression correlation between these two markers in breast cancer tissue was not found to be significant. As to clinical significance, CXCR8 (GPR35) expression was found to be significantly associated with advanced histological grade and higher proliferation rate indicated by Ki-67 expression. Although CXCL17 was not found to statistically correlate with any clinicopathological characteristics, it was found to be associated with shorter overall survival and is an independent marker of poor prognosis in breast cancer. In addition, CXCL17 was found to promote proliferation and migration of breast cancer cells in vitro and in vivo. CONCLUSIONS: We investigated the role of the CXCL17-CXCR8 (GPR35) axis in breast cancer for the first time. CXCL17 is a potential oncogene and promising therapeutic target, is an independent biomarker of poor prognosis in patients with breast cancer, and can promote proliferation and migration of breast cancer cells in vitro and in vivo.

CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis.

Breast cancer is one of the most commonly diagnosed cancers worldwide and the second leading cause of cancer-related deaths among females. CCL28 (mucosa-associated epithelial chemokine, MEC), a CC subfamily chemokine, has been well studied in the process of inflammation, and recently increasing evidence indicates that CCL28 is related to tumor progression. However, little is known concerning its function in breast cancer. In the present study, we generated a CCL28-overexpressing breast cancer cell line MDA-MB-231HM/CCL28 from parental MDA-MB­231HM cells. We found that overexpression of CCL28 promoted cell proliferation and tumor formation, and also enhanced migration, invasion and metastasis both in vitro and in vivo. Mechanistic studies revealed that CCL28 mediated intracellular activation of the mitogen-activated protein kinase (MAPK) signaling pathway to promote breast cancer cell proliferation and metastasis by upregulating anti-apoptotic protein Bcl-2 and suppressing cell adhesion protein ß-catenin. However, overexpression of CCL28 did not influence the expression of metastasis­related protein matrix metalloproteinase MMP2 and MMP9 and VEGF. Tissue sample analysis from animal models also indicated that overexpression of CCL28 was associated with enhanced pERK expression and reduced ß-catenin expression in breast carcinomas. Thus, our results show for the first time that CCL28 contributes to breast cancer progression through the ERK/MAPK­mediated anti-apoptotic and metastatic signaling pathway. Antagonists of CCL28 and the MAPK signaling pathway may be used synergistically to treat breast cancer patients.

Azilsartan ameliorates apoptosis of dopaminergic neurons and rescues characteristic parkinsonian behaviors in a rat model of Parkinson's disease.

Loss of dopaminergic neurons within the substantia nigra (SN) is a pathological hallmark of Parkinson's disease (PD), which leads to the onset of motor symptoms. Previously, our in vitro studies revealed that Angiotensin II (Ang II) induced apoptosis of dopaminergic neurons through its type 1 receptor (AT1R), but these findings needed to be confirmed via animal experiments. Here, using a rotenone-induced rat model of PD, we observed an overactivation of Ang II/AT1R axis in the SN, since Ang II level and AT1R expression were markedly increased. Furthermore, we provided in vivo evidence that Ang II directly elicited apoptosis of dopaminergic neurons via activation of AT1R in the SN of rats. More importantly, we showed for the first time that oral administration of azilsartan, a newly developed AT1R blocker approved by the U.S. Food and Drug Administration for hypertension treatment, rescued the apoptosis of dopaminergic neurons and relieved the characteristic parkinsonian symptoms in PD rats. These results support the application of AT1R blockers in PD therapy, and strengthen the notion that many therapeutic agents may possess pleiotropic action in addition to their main applications.

The role of the chemokine receptor XCR1 in breast cancer cells.

Considerable attention has recently been paid to the application of chemokines to cancer immunotherapy due to their complex role in cell proliferation, invasion, metastasis, and tumorigenesis, which extends beyond the regulation of lymphocyte migration during immune responses. The expression and the function of the chemokine receptor XCR1 on breast cancer have remained elusive to date. In this study, the expressions of XCR1 mRNA were tested by quantitative real-time polymerase chain reaction in one breast epithelial cell line (MCF-10A) and nine breast cancer cell lines (MDA-MB-231, 231HM, 231BO, MDA-MB-468, MCF-7, T47D, Bcap-37, ZR-75-30, and SK-BR-3). We established XCR1-overexpressing breast cancer cell line MDA-MB-231 (231/XCR1) in XCR1 low expression cell line MDA-MB-231 (231). The ability of proliferation, invasion, and metastasis was measured by CCK8, plate cloning formation, and transwell analysis, respectively, in XCR1-overexpressing breast cancer cell lines (231/XCR1) and their parental cell line MDA-MB-231/Vector (simplified as "231/Vector"); 5×106/100 µL cells were inoculated in mammary fat pad of BALB/c nude mice. There were six BALB/c nude mice in the experimental group and control group. Protein expression was analyzed by cell immunofluorescence and Western blot. The growth of XCR1-overexpressing human breast cancer cell line MDA-MB-231 in vitro was restrained and tumorigenesis in vivo was also extenuated, its mechanism may involve in the inhibition of MAPK and PI3K/AKT/mTOR signaling pathway, but increase in LC3 expression. However, the overexpression of XCR1 in human breast cancer cell line MDA-MB-231 in vitro can promote the migration and invasion partially due to decreasing the protein level of ß-catenin. Therefore, XCR1 can affect the biological characteristics of some special breast cancer cells through complex signal transduction pathway.

Validation of the Chinese version of Addenbrooke's Cognitive Examination III for diagnosing dementia.

OBJECTIVE: The aim of this study was to validate the reliability of the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) for detecting dementia. Furthermore, the present study compares the diagnostic accuracy of ACE-III with that of mini-mental state examination (MMSE). METHODS: One hundred seventy-seven patients with dementia and 180 healthy controls were included in the study. RESULTS: The reliability of ACE-III was very good (α-coefficient = 0.888). There was a significant negative correlation between Clinical Dementia Rating Scale score and total ACE-III score. Further, there was a positive correlation between MMSE score and total ACE-III score. Age exerted a significant effect on total ACE-III score, memory score, and language score. In the present study, the cutoff score of 83 showed a sensitivity of 91.1% and a specificity of 83.1%. CONCLUSIONS: The present findings support that the Chinese version of ACE-III is a reliable assessment tool for dementia. Copyright © 2017 John Wiley & Sons, Ltd.

Mitochondrial-dependent mechanisms are involved in angiotensin II-induced apoptosis in dopaminergic neurons.

INTRODUCTION: We recently demonstrated that angiotensin II (Ang II) was involved in the etiology of Parkinson's disease (PD) via induction of apoptosis of dopaminergic neurons, but the mechanisms are not completely elucidated. Here, we asked whether mitochondrial-dependent mechanisms contributed to the Ang II-induced dopaminergic neuronal apoptosis. MATERIALS AND METHODS: CATH.a cells were incubated with Ang II in combination with mitochondrial permeability transition pore (mPTP) inhibitors or angiotensin receptor antagonists, and apoptosis rate, caspase-3 activity, cytochrome c levels, and mPTP opening were assessed. RESULTS: We showed that Ang II triggered apoptosis via a mitochondrial-dependent pathway, as elevated cytochrome c levels were observed in the cytosol. By employing cyclosporin A and sanglifehrin A, two specific mPTP inhibitors, we revealed that cytochrome c release from mitochondria into cytoplasm was ascribed to mPTP opening. Meanwhile, the aforementioned effects could be abrogated by an AT1 receptor antagonist losartan rather than an AT2 receptor antagonist PD123319. CONCLUSION: This study demonstrates that Ang II triggers mitochondrial-dependent apoptosis via facilitating mPTP opening through an AT1 receptor-mediated fashion in dopaminergic neurons. These findings give insight into the effect of Ang II in the etiology of PD, and reinforce the application of AT1 receptor antagonists for PD treatment.

Independent Correlation of Serum Homocysteine with Cerebral Microbleeds in Patients with Acute Ischemic Stroke due to Large-Artery Atherosclerosis.

BACKGROUND AND AIM: The severity of cerebral microbleeds (CMBs) affected the prognosis of patients with acute cerebrovascular disease. Considering the impact of CMBs on clinical decision, it is necessary to assess the risk factors of CMBs. We aimed to evaluate the independent risk factors of CMBs in patients with acute ischemic stroke of large-artery atherosclerosis. MATERIALS AND METHODS: 112 patients were enrolled in the study. The baseline information, the results of laboratory examination and cranial MRI were collected. The independent risk factors of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis were evaluated. RESULTS: CMBs were found in 56 (50%) patients. Older age and higher homocysteine (Hcy) level were associated with an elevated chance of occurrence of CMBs. Further, there was a positive correlation between CMBs grade and serum Hcy level. CONCLUSIONS: Serum Hcy level is strongly associated with the presence of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis. Serum Hcy level may be a potential therapeutic target for alleviating adverse clinical outcomes of CMBs.

Inhibition of endoplasmic reticulum stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson's disease.

Telmisartan, one unique angiotensin II type 1 receptor blocker, has been attracting attention due to its putative peroxisome proliferator-activated receptor (PPAR)-γ or ß/δ actions. Recently, telmisartan has been reported to exert neuroprotective effects in animal models of Parkinson's disease (PD). However, the underlying mechanisms have not been fully clarified. Recently, accumulating evidence has shown that endoplasmic reticulum (ER) stress plays a crucial role in rotenone-induced neuronal apoptosis. Additionally, studies have revealed that inositol-requiring enzyme/endonuclease 1α (IRE1α) is necessary and sufficient to trigger ER stress. In the present study, we aimed to determine whether ER stress-activated IRE1α-mediated apoptotic pathway is involved in the neuroprotection of telmisartan in the rotenone rats of PD and explore the possible involvement of PPAR-ß/δ activation. The catalepsy tests were performed to test the catalepsy symptom. The dopamine content and α-synuclein expression were ascertained through high-performance liquid chromatography and immunohistochemistry, respectively. The expression of IRE1α, TNF receptor associated factor 2 (TRAF2), caspase-12 and PPAR-ß/δ was detected by western blot. Neuronal apoptosis was assessed by TUNEL and immunohistochemistry. Our results show that telmisartan ameliorated the catalepsy symptom and attenuated dopamine depletion as well as α-synuclein accumulation. Moreover, telmisartan decreased ER stress-mediated neuronal apoptosis. Furthermore, telmisartan inhibited IRE1α-TRAF2-caspase-12 apoptotic signaling pathway. Additionally, telmisartan activated PPAR ß/δ, implying that PPAR-ß/δ activation properties of telmisartan are possibly or partially involved in the neuroprotective effects. In conclusion, our findings suggest that suppressing ER stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rats of PD.

PPARß/δ Agonist Provides Neuroprotection by Suppression of IRE1α-Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson's Disease.

Two recent studies demonstrated that peroxisome proliferator-activated receptor ß/δ (PPARß/δ) agonists exerted neuroprotective effects in mouse model of Parkinson's disease (PD). However, the underlying mechanisms remain unknown. Endoplasmic reticulum (ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. In the present study, we explored whether GW501516, a selective and high-affinity PPARß/δ agonist, could protect the dopaminergic neurons against degeneration and improve PD behavior via suppressing the ER stress in the rotenone rat model of PD. GW501516 was administered intracerebroventricular infusion. Catalepsy and open field tests were used to test catalepsy and locomotor activities. The levels of dopamine and its metabolites were determined using high-performance liquid chromatography. Western blot and immunohistochemistry analysis were performed to assess dopaminergic neuronal degeneration. Quantitative real-time RT-PCR and Western blot analysis were executed to detect ER stress. TUNEL and immunohistochemistry assays were used to detect ER stress-mediated apoptosis. Our results showed that GW501516 ameliorated the catalepsy symptom and increased locomotor activity. Meanwhile, GW501516 partially reversed the loss of dopaminergic neurons. Moreover, GW501516 suppressed the activation of ER stress markers including inositol-requiring enzyme 1α (IRE1α) and caspase-12. Furthermore, GW501516 inhibited caspase-12-mediated neuronal apoptosis. These findings suggest that GW501516 conferred neuroprotection of not only biochemical and pathological attenuation but also behavioral improvement in the rotenone rat model of PD. More importantly, we demonstrated for the first time that suppressing IRE1α-caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPARß/δ agonist in the rotenone rat model of PD.

Activation of Autophagy Contributes to the Angiotensin II-Triggered Apoptosis in a Dopaminergic Neuronal Cell Line.

Our recent study indicated that angiotensin II (Ang II), the main component of renin-angiotensin system, participated in the pathogenesis of Parkinson's disease (PD) by triggering the apoptosis of dopaminergic neuronal cells. However, the underlying mechanisms are still not fully understood. In this study, by using CATH.a cells, a dopaminergic neuronal cell line stably expressing angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R), we tested the hypothesis that activation of autophagy contributed to the apoptosis triggered by Ang II. We showed that Ang II activated autophagy and triggered apoptosis in CATH.a cells in a dose-dependent manner. More importantly, inhibition of autophagy by 3-methyladenine markedly attenuated the apoptosis caused by Ang II in CATH.a cells. In addition, the Ang II-induced autophagy and subsequent cell apoptosis could be fully abolished by an AT1R antagonist losartan rather than PD1223319, an antagonist for AT2R. Taken together, our study provides the first evidence that Ang II triggers apoptosis via activation of autophagy in a dopaminergic neuronal cell line through an AT1R-mediated manner. These findings have deepened our understanding on the role of Ang II in the pathogenesis of PD and support the use of AT1R antagonists for the treatment of this devastating neurodegenerative disease.