IGFBP5 Promotes Neuronal Apoptosis in a 6-OHDA-Toxicant Model of Parkinson's Disease by Inhibiting the Sonic Hedgehog Signaling Pathway.

INTRODUCTION: Parkinson's disease (PD) is the most common neurodegenerative disease worldwide. Studies have shown that insulin-like growth factor-binding protein 5 (IGFBP5) may contribute to methamphetamine-induced neurotoxicity and neuronal apoptosis in PC-12 cells and rat striatum. Here, we studied the expression and role of IGFBP5 in the 6-OHDA-toxicant model of PD. METHODS: PC-12 and SH-SY5Y cells were exposed to 50 µm 6-OHDA for 24 h. qRT-PCR, western blotting, CCK-8 assay, EdU staining, annexin V staining, and immunofluorescence were performed to study the effects of IGFBP5-specific siRNAs. The effects of IGFBP5 on a rat 6-OHDA model of PD were confirmed by performing behavioral tests, tyrosine hydroxylase (TH) immunofluorescence staining, and western blotting. RESULTS: In the GSE7621 dataset, IGFBP5 was highly expressed in the substantia nigra tissues of PD patients compared to healthy controls. In PC-12 and SH-SY5Y cells, IGFBP5 was upregulated following 6-OHDA exposure in a dose-dependent manner. Silencing of IGFBP5 promoted PC-12 and SH-SY5Y proliferation and inhibited apoptosis under 6-OHDA stimulation. Silencing of IGFBP5 relieved 6-OHDA-induced TH-positive neuron loss. Hedgehog signaling pathway was predicted as a downstream signaling pathway of IGFBP5. Negative regulation between IGFBP5 and sonic hedgehog (SHH) signaling pathway was confirmed in vitro. The effects of IGFBP5 silencing on SH-SY5Y cells were partially reversed using cyclopamine, a direct inhibitor of the SHH signaling pathway. In addition, silencing of IGFBP5 attenuated motor deficits and neuronal damage in 6-OHDA-induced PD rats. CONCLUSION: Elevated IGFBP5 expression may be involved in 6-OHDA-induced neurotoxicity through regulation of the SHH signaling pathway.

Sinigrin improves cerebral ischaemia-reperfusion injury by inhibiting the TLR4 pathway-mediated oxidative stress.

Cerebral ischaemia-reperfusion (CIR) injury occurs in stroke patients after the restoration of cerebral perfusion. Sinigrin, a phytochemical found in cruciferous vegetables, exhibits strong antioxidant activity. This study investigated the role of sinigrin in oxidative stress using a CIR injury model. The effects of sinigrin were studied in middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-injured SH-SY5Y cells. Sinigrin treatment improved brain injury and neurological deficits induced by MCAO surgery in rats. Sinigrin inhibited apoptosis in brain tissues and SH-SY5Y cells following OGD/R induction. Additionally, sinigrin elevated the levels of superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) levels. Furthermore, sinigrin inhibited the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signalling pathway. The anti-apoptotic and antioxidant activities of sinigrin in OGD/R-injured SH-SY5Y cells were reversed by TLR4 overexpression. In conclusion, sinigrin inhibits oxidative stress in CIR injury by suppressing the TLR4/MyD88 signalling pathway.

Edaravone Attenuates Aß 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells.

Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer's disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aß 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aß1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1ß and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aß 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.

Che-1 inhibits oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis associated with inhibition of the p53-mediated proapoptotic signaling pathway.

Accumulating evidence suggests that Che-1 is a strong antiapoptotic protein and can protect cells against various insults. However, whether Che-1 is involved in the protection of neurons against cerebral ischemia/reperfusion injury remains unclear. In this study, we aimed to investigate the potential role of Che-1 in regulating cerebral ischemia/reperfusion injury-induced neuronal injury using the oxygen-glucose deprivation and reoxygenation (OGD/R) model in vitro. We found that Che-1 expression was induced in neurons following OGD/R treatment. Functional experiments showed that Che-1 knockdown aggravated OGD/R-induced neuronal apoptosis. In contrast, Che-1 overexpression exerted a protective effect against OGD/R-induced neuronal apoptosis. Moreover, our results showed that the protective effect of Che-1 was associated with the inhibition of p53-mediated proapoptotic genes, including Puma, Noxa, and Bax. In addition, we showed that Che-1 impeded the transcript activity of p53 toward apoptosis. Taken together, our results indicate that Che-1 alleviates OGD/R-induced neuronal apoptosis in-vitro through inhibition of p53-mediated proapoptotic signaling. Our study suggests that Che-1 may serve as a potential therapeutic target for the treatment of cerebral ischemic/reperfusion injury in vivo.

Mfn2-Mediated Preservation of Mitochondrial Function Contributes to the Protective Effects of BHAPI in Response to Ischemia.

Disturbances in intracellular iron homeostasis are associated with neuronal injury after stroke. However, exposure of cells to classical chelators may interfere with physiological iron functions. BHAPI is an iron prochelator that exerts strong iron binding capacity only under oxidative stress conditions. This study investigated the protective effects of N'-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene (BHAPI) on an in vitro ischemia model mimicked by oxygen and glucose deprivation (OGD) in neuronal HT22 cells. The results showed that BHAPI significantly increased cell viability and decreased lactate dehydrogenase (LDH) release after OGD. BHAPI treatment also reduced apoptosis, as measured by flow cytometry, and suppressed caspase-3 activation. These protective effects were accompanied by preserved mitochondrial membrane potential (MMP), reduced mitochondrial swelling, promoted mitochondrial calcium buffering capacity, and increased mitochondrial respiration. The results of MitoTracker staining showed that BHAPI partially prevented the OGD-induced changes in mitochondrial morphology. Furthermore, BHAPI selectively increased the expression of mitochondrial dynamic protein Mfn2, with no effect on Mfn1 expression. Knockdown of Mfn2 with specific siRNA partially reversed the protective effects of BHAPI. In summary, the iron prochelator BHAPI protects HT22 cells against ischemic injury through preservation of mitochondrial function and Mfn2 signaling.

Laparoscopic colectomy for serosa-positive colon cancer (pT4a) in patients with preoperative diagnosis of cancer without serosal invasion.

PURPOSE: Although general surgeons normally perform laparoscopic colectomies in patients with colon cancer, the procedure is also indicated for serosa-negative tumors (≤ cT3). Serosal invasion (T4a) is regarded as a potential risk factor for peritoneal dissemination due to pneumoperitoneum effects and tumor manipulation during laparoscopic colectomy. We compared short- and long-term outcomes of patients who underwent laparoscopic and open colectomies for serosa-involving colon cancer (pT4a) and had a preoperative diagnosis of cancer without serosal invasion (≤cT3). METHODS: A total of 179 patients (102 patients treated with laparoscopic colectomies and 77 with open colectomies) who were treated between 2009 and 2015 were included. These patients were first diagnosed preoperatively with ≤ cT3 disease based on computed tomography, endoscopy, or endoscopic ultrasound, but they were diagnosed with pT4a disease based on final pathology results. Recurrence and survival rates between the two groups were compared. RESULTS: Baseline characteristics, clinical stage, type of colectomy, and short-term outcome did not differ between the groups. Five-year overall survival (OS) (p=0.248) and disease- free survival (DFS) rates (p=0.113) were comparable between the laparoscopic and open groups. Recurrence patterns did not differ between groups. Moreover, laparoscopic colectomy did not increase peritoneal recurrence compared to open colectomy. By multivariate analysis, surgical approach was not an independent prognostic factor for OS or DFS. CONCLUSION: Similar survival and recurrence patterns were observed in patients with serosa-involving colon cancer (pT4a) who were preoperatively diagnosed with serosa negative disease (≤cT3) and underwent either laparoscopic or open colectomies. Laparoscopic colectomy may be safely performed in patients with serosa-positive tumors.

Ape1 protects against MPP+-induced neurotoxicity through ERK1/2 signaling in PC12 cells.

Oxidative stress, induced by reactive oxygen species (ROS), is an apoptosis activator. Oxidative stress causes dopaminergic neuron loss and plays a pivotal role in the pathogenesis of Parkinson's disease (PD). A recent study showed that apurinic/apyrimidinic endonuclease 1 (Ape1) decreases cytotoxicity and promotes neuron survival under oxidative stress. Furthermore, it has been proven that Ape1 is involved in the pathogenesis of PD. However, little is known about the contribution of Ape1 toward the development of PD. Thus, the present study was designed to define a critical pathway by which Ape1 mediates neurotoxicity in a model of PD. The results show that Ape1 was upregulated in MPP-treated PC12 cells. Ape1 overexpression significantly increased cell viability and inhibited apoptosis compared with MPP treatment, whereas Ape1 knockdown showed the opposite effect. Ape1 overexpression markedly suppressed ROS levels, whereas Ape1 knockdown significantly elevated ROS levels. Furthermore, Ape1 overexpression markedly upregulated the p-ERK1/2 protein expression level and inhibited ERK1/2 signaling. The ERK1/2 inhibitor PD98059 significantly decreased cell viability and increased apoptosis and the ROS level compared with the Ape1 overexpression group. Taken together, these results suggest that Ape1 protects against neuron death by activating the ERK1/2 signaling pathway.