Antibacterial-Antioxidative Thiolated Gelatin/Methacrylated Silk Fibroin Hydrogels with Nitric Oxide Release Catalyzed by Metal-Polyphenol Nanoparticles for MRSA-Infected Wound Healing.

Chronic wound infection often leads to irregular tissue closure and accompanies delayed healing and economy issues. Developing an ideal wound dressing that can control the occurrence of antibacterial infections and biological responses is highly desirable. In this study, a multifunctional hybrid hydrogel (GS@EG-Cu-CA NPs) containing synthesized thiolated gelatin, methacrylated silk fibroin, and (-)-epigallocatechin gallate-copper ionic-carrageenan nanoparticles (EG-Cu-CA NPs) was engineered by a thio-ene click reaction. The metal-polyphenol EG-Cu-CA NPs were encapsulated with kappa-carrageenan to enhance its aqueous-soluble, mechanical, and bioactive properties and endowed the hydrogel dressing with fascinating antibacterial, antioxidation, and nitric oxide (NO) generation by catalyzing. The hybrid hydrogels also illustrated a favorable cytocompatibility. Benefiting from the thio-ene click reaction, the hybrid hydrogels were injected and photocured rapidly in situ to cover an irregular wound. In an SD rat full-thickness skin-wound-infected model, the methicillin-resistant Staphylococcus aureus-infected wound covered with GS@EG-Cu-CA NPs was almost completely healed after 10 days. This study presents a facile design of hydrogel dressing incorporating metal-polyphenol nanoparticles, which demonstrates a promising potential way for dealing with effective wound infection management and other complicated wound healings.

Case report of non-tracheal intubation-an alternative for postpneumonectomy patients undergoing contralateral pulmonary resection.

BACKGROUND: Surgery on the contralateral or other lungs after pneumonectomy on one side is highly challenging and complex. It is critical to creating conditions for fluent surgical maneuvers while ensuring adequate ventilation for a patient during such an operation in the same chest cavity that appears incompatible. CASE PRESENTATION: We have reported herein the case of a patient who, following a left pneumonectomy, underwent a right upper pulmonary nodule wedge resection via video-assisted thoracoscopic surgery without requiring endotracheal intubation. We managed ventilation with a laryngeal mask airway under general anesthesia combined with a thoracic epidural block. The diseased lobe collapsed well for the surgical procedure during VATS without hypoxia, after which the resection was safely performed. CONCLUSIONS: Non-tracheal intubation anesthesia can be a potentially attractive alternative for patients undergoing contralateral pulmonary resection after pneumonectomy.

Association between hypertension and Epstein-Barr virus reactivation among the population in a high-risk area for nasopharyngeal carcinoma.

BACKGROUND: Hypertension may increase the infection risk of multiple viruses. The evidence for the association between hypertension and Epstein-Barr virus (EBV) reactivation is still largely lacking. METHODS: The study was based on the baseline information of a population-based prospective cohort from high-risk areas of nasopharyngeal carcinoma (NPC). Using two EBV reactivation classification criteria, we explored the relationship between hypertension and EBV reactivation through logistic regression models. RESULTS: We included a total of 12,159 subjects. Among them, 3,945 (32.45%) were EBV arbitrary seropositive, and 1,547 (12.72%) were EBV comprehensive seropositive. Hypertension was associated with an increased risk of EBV reactivation, with odds ratios (ORs) of 1.17 (95% CI = 1.08-1.27) for EBV arbitrary seropositive subjects and 1.16 (95% CI = 1.03-1.30) for EBV comprehensive seropositive subjects. Two types of antihypertensive drugs were associated with decreased risk of EBV reactivation: ß-adrenergic receptor-blocking agents (ß-blockers) (OR = 0.51, 95% CI = 0.42-0.61 for EBV arbitrary seropositive subjects; OR = 0.62, 95% CI = 0.47-0.81 for EBV comprehensive seropositive subjects) and angiotensin converting enzyme inhibitors (ACEIs) (OR = 0.61, 95% CI = 0.41-0.88 for EBV arbitrary seropositive subjects; OR = 0.58, 95% CI = 0.32-0.98 for EBV comprehensive seropositive subjects). CONCLUSIONS: Hypertension was associated with an increased risk of EBV reactivation in high-incidence areas of NPC. ß-blockers and ACEIs reduce this risk, and thus might be used for NPC prevention in endemic areas.

Cyanoacrylate glue foreign body after CT-guided localization of a pulmonary nodule during video-assisted thoracoscopic surgery: a case report.

BACKGROUND: A tracheal foreign body is a common airway aspiration that creates an emergency, which often causes unobserved respiratory problems and requires management. Iatrogenic tracheal foreign bodies are rarely observed, which results in tracheal obstruction. If the foreign body were removed from the tracheobronchial system, it would save lives. A similar case of a tracheal foreign body was focused on, which was caused by medical glue used during preoperative computed tomography localization of pulmonary nodules. CASE PRESENTATION: The foreign body was deposited in the right upper bronchi, accidentally discovered after anesthesia when a double-lumen tube was located by fiber bronchoscopy. Following a video-assisted thoracoscopic surgery, the foreign body was removed using a respiratory endoscopy without subsequent adverse consequences for the patient. CONCLUSIONS: There is a risk of complications from iatrogenic airway foreign bodies for preoperative localization of pulmonary nodules by injecting cyanoacrylate glue.

Development and Internal Validation of a Prediction Model for Difficult Laryngoscopy Using Ultrasound-Derived Factor in Comatose Patients.

OBJECTIVES: The distance from skin to the hyoid bone (DSHB) and skin to the anterior commissure of vocal cords (DSAC) are reliable parameters for pre-operative airway ultrasound assessment in awake patients and can be assessed in comatose patients. This study aimed to inspect its feasibility and accuracy in predicting difficult laryngoscopy for comatose patients. METHODS: A prospective cohort study included patients with a Glasgow Coma Scale (GCS) of ≤8 who underwent emergency tracheal intubation between November 2019 and August 2020. The outcome was difficult laryngoscopy and classified according to the Cormack-Lehane grading. RESULTS: A total of 151 patients were included in the study. Fifty-two (34.4%) patients were categorized as having difficult laryngoscopy. The DSHB add DSAC (hereinafter referred to as the "DSBAC") was superior to either parameter alone in the predictive performance, and the optimal cut-off value was 1.90. To optimize the predictive value, DSBAC (adjusted odds ratio [OR]: 7.76; 95% confidence interval [CI]: 2.88-20.94; P < .001), GCS (adjusted OR: 1.39; 95% CI: 3.93-26.28; P = .039), mandibular retraction (adjusted OR: 8.20; 95% CI: 1.92-35.09; P = .005) and edentulous (adjusted OR: 4.23; 95% CI: 1.40-12.80; P = .011) were included in a multivariable model and constructed a nomogram. Discrimination and calibration statistics were satisfactory, with C-index above 0.80 from both model development and internal validation. CONCLUSIONS: Ultrasound-derived factor, DSBAC, can be easily assessed and help predict difficult laryngoscopy among comatose patients. A simple nomogram including only four clinical items exhibited excellent discrimination performance and was useful when comatose patients underwent emergency tracheal intubation.

Transcatheter closure for the treatment of pseudoventricular aneurysm after acute myocardial infarction: a case report.

Left ventricular free wall rupture (LVFWR) is a rare but lethal complication of acute myocardial infarction (AMI). Urgent surgery is essential but associated with high postoperative mortality. Even worse, LVFWR patients may experience sudden death without a chance for surgery. In this article, we report our successful transcatheter closure of a patient with the most extensive pseudoventricular aneurysm after AMI reported thus far. Cardiac magnetic resonance imaging (MRI) revealed a giant pseudoventricular aneurysm located in the inferior and lateral walls of the left ventricle; the rupture diameter was 28 mm, and the maximum tumor diameter was 90.2 mm. We used transcarotid approach (TCA) and atrial septal defect closure umbrella to complete the operation, which solved the lack of special interventional instruments to treat pseudoventricular aneurysm after AMI. In addition, we still needed to treat liver and kidney failure caused by hemolysis after operation, and undergone strict follow-up. In conclusion, transcatheter closure is practical and feasible for the treatment of pseudoventricular aneurysm after AMI, although hemolysis and decline of cardiac pumping function after the successful interventional treatment deserve special attention. Future multicenter studies are required to identify patients best suited for interventional treatment timing. And further developments in devices and delivery techniques are required in order to optimize interventional outcomes.

Inhibition of histone deacetylase 11 promotes human liver cancer cell apoptosis.

The apoptosis machinery is compromised in liver cancer (LC). The underlying mechanism needs to be further investigated. Histone deacetylases (HDAC) have multiple and strong biochemical activities. This study tests a hypothesis that HDAC11 prevents LC cell (LCC) apoptosis via modulating the p53 gene transcription. In this study, the LC tissues were collected from patients with LC. The LCCs were purified by magnetic cell sorting. The gene transcription activities of the LCCs were analyzed by immunoprecipitation (IP) and chromatin IP. We observed that the LCCs expressed high levels of HDAC11, which was negatively correlated with the expression of p53 in LCCs. Further findings indicated that HDAC11 formed a complex with Egr1, the transcription factor of p53. HDAC11 induced Egr1 deacetylation and thus prevented the p53 gene transcription. Over expression of HDAC11 in liver cells inhibited the cell apoptosis. Inhibition of the expression of HDAC11 in LCCs promoted the LCC apoptosis. In conclusion, HDAC11 plays a critical role in the compromising the expression p53 in LCC, which can be reversed by the inhibition of HDAC11. To regulate HDAC11 may have therapeutic potential for LC treatment.

Synthesis and characterization of incorporating mussel mimetic moieties into photoactive hydrogel adhesive.

Surgical adhesive is the optimal candidate for the replacement of traditional mechanical wound closure. In our paper, mussel adhesive proteins inspired hydrogel adhesive was prepared with 3, 4-dihydroxyphyenylanine acrylamide (DOPA-AA), poly (ethylene glycol) diacrylate (PEGDAA) and thiolated chitosan (CSS) by UV irradiation. DOPA-AA, containing catechol group and vinyl group, was successful synthesized and characterized by FTIR and 1HNMR. The gelation time, equilibrium water content, degradation, materials properties and adhesive strength of the hydrogels were studied. We found that the gelation time was retarded and the materials mechanical strength was decreased because of the inhibitory effect of catechol group. Equilibrium water content was slightly affect by the increasing concentration of DOPA-AA (1-5%). Nevertheless, catechol group can remarkably improve the adhesive properties because of the complex and durable interactions of the hydrogel, especially, the interaction between the thiol group of CSS and catechol group of DOPA-AA, which also greatly slowed down the degradation of the adhesive hydrogels. CSS and DOPA-AA was introduced to ensure the adhesive properties, DOPA-AA lend the adhesive nature to hydrogel and CSS can protect the catechol group from oxidation and enhance durable adhesion. Moreover, cytotoxicity of the resulting hydrogels showed that the L929 cell viability was weaken, it mostly probably induced by the catechol oxidation.

Transplantation of bone marrow stromal stem cells overexpressing tropomyosin receptor kinase A for peripheral nerve repair.

BACKGROUND AIMS: Previously we reported that overexpression of tropomyosin receptor kinase A (TrkA) could improve the survival and Schwann-like cell differentiation of bone marrow stromal stem cells (BMSCs) in nerve grafts for bridging rat sciatic nerve defects. The aim of this study was to investigate how TrkA affects the efficacy of BMSCs transplantation on peripheral nerve regeneration and functional recovery. METHODS: Rat BMSCs were infected with recombinant lentiviruses to construct TrkA-overexpressing BMSCs and TrkA-shRNA-expressing BMSCs, which were then seeded in acellular nerve allografts for bridging 10-mm rat sciatic nerve defects. RESULTS: At 8 weeks post-transplantation, compared with Vector and Control BMSCs-laden groups, TrkA-overexpressing BMSCs-laden group demonstrated obviously improved axon growth, such as significantly higher expression of myelin basic protein and superior results of myelinated fiber density, axon diameter and myelin sheaths thickness. In accordance with this increased nerve regeneration, the animals of TrkA-overexpressing BMSCs-laden group showed significantly better restoration of sciatic nerve function, manifested as greater sciatic function index value and superior electrophysiological parameters including shorter onset latency and higher peak amplitude of compound motor action potentials and faster nerve conduction velocity. However, these beneficial effects could be reversed in TrkA-shRNA-expressing BMSCs-laden group, which showed much fewer and smaller axons with thinner myelin sheaths and correspondingly poor functional recovery. CONCLUSIONS: These results demonstrated that TrkA may regulate the regenerative potential of BMSCs in nerve grafts, and TrkA overexpression can enhance the efficacy of BMSCs on peripheral nerve regeneration and functional recovery, which may help establish novel strategies for repairing peripheral nerve injuries.

Artemisinin protects PC12 cells against ß-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway.

Accumulating evidence displays that an abnormal deposition of amyloid beta-peptide (Aß) is the primary cause of the pathogenesis of Alzheimer's disease (AD). And therefore the elimination of Aß is regarded as an important strategy for AD treatment. The discovery of drug candidates using culture neuronal cells against Aß peptide toxicity is believed to be an effective approach to develop drug for the treatment of AD patients. We have previously showed that artemisinin, a FDA-approved anti-malaria drug, has neuroprotective effects recently. In the present study, we aimed to investigate the effects and potential mechanism of artemisinin in protecting neuronal PC12 cells from toxicity of ß amyloid peptide. Our studies revealed that artemisinin, in clinical relevant concentration, protected and rescued PC12 cells from Aß25-35-induced cell death. Further study showed that artemisinin significantly ameliorated cell death due to Aß25-35 insult by restoring abnormal changes in nuclear morphology, lactate dehydrogenase, intracellular ROS, mitochondrial membrane potential and activity of apoptotic caspase. Western blotting analysis demonstrated that artemisinin activated extracellular regulated kinase ERK1/2 but not Akt survival signaling. Consistent with the role of ERK1/2, preincubation of cells with ERK1/2 pathway inhibitor PD98059 blocked the effect of artemisinin while PI3K inhibitor LY294002 has no effect. Moreover, Aß1-42 also caused cells death of PC12 cells while artemisinin suppressed Aß1-42 cytotoxicity in PC12 cells. Taken together, these results, at the first time, suggest that artemisinin is a potential protectant against ß amyloid insult through activation of the ERK1/2 pathway. Our finding provides a potential application of artemisinin in prevention and treatment of AD.

The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway.

Schizophrenia is one of the most severe psychiatric disorders. Increasing evidence implicates that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics are neuroprotective and successful in slowing the progressive morphological brain changes. As an antipsychotic agent, clozapine has superior and unique effects, but the intracellular signaling pathways that mediate clozapine action remain to be elucidated. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is crucial for neuronal survival. However, little information is available regarding this pathway with clozapine. In the present study, we investigated the protective effect of clozapine on the PC12 cells against corticosterone toxicity. Our results showed that corticosterone decreases the phosphorylation of Akt and FoxO3a, leading to the nuclear localization of FoxO3a and the apoptosis of PC12 cells, while clozapine concentration dependently protected PC12 cells against corticosterone insult. Pathway inhibitors studies displayed that the protective effect of clozapine was reversed by LY294002 and wortmannin, two PI3K inhibitors, or Akt inhibitor VIII although several other inhibitors had no effect. The shRNA knockdown results displayed that downregulated Akt1 or FoxO3a attenuated the protective effect of clozapine. Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone. Together, our data indicates that clozapine protects PC12 cells against corticosterone-induced cell death by modulating activity of the PI3K/Akt/FoxO3a pathway.

Palmitic acid triggers cell apoptosis in RGC-5 retinal ganglion cells through the Akt/FoxO1 signaling pathway.

Hallmarks of the pathophysiology of glaucoma are oxidative stress and apoptotic death of retinal ganglion cells (RGCs). Lipotoxicity, involving a series of pathological cellular responses after exposure to elevated levels of fatty acids, leads to oxidative stress and cell death in various cell types. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O1 (PI3K/Akt/FoxO1) pathway is crucial for cell survival and apoptosis. More importantly, FoxO1 gene has been reported to confer relatively higher risks for eye diseases including glaucoma. However, little information is available regarding the interaction between FoxO1 and RGC apoptosis, much less a precise mechanism. In the present study, immortalized rat retinal ganglion cell line 5 (RGC-5) was used as a model to study the toxicity of palmitic acid (PA), as well as underlying mechanisms. We found that PA exposure significantly decreased cell viability by enhancing apoptosis in RGC-5 cells, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. PA also induced a remarkable increase in reactive oxygen species and malondialdehyde. Moreover, PA significantly decreased the level of phospho-Akt and phospho-FoxO1 in cells. Finally, shRNA knockdown and plasmid overexpression studies displayed that downregulation of Akt protein or upregulation of FoxO1 protein augmented cell death, while knockdown of FoxO1 or overexpression of Akt1 abolished PA-induced cell death. Collectively, our results indicated that PA-induced cell death is mediated through modulation of Akt/FoxO1 pathway activity.

ß-arrestin1 promotes epithelial-mesenchymal transition via modulating GSK-3ß/ß-catenin pathway in prostate cancer cells.

Recently, ß-arrestin1 was indicated as a tumor promoter in prostate cancer, but its exact role in cancer metastasis still have not been well clarified. Here, our data revealed that ß-arrestin1 could promote the migration and invasion of prostate cancer cells via initiating epithelial-mesenchymal transition (EMT). Mechanically, ß-arrestin1 could increase the transcriptional activity and expression of ß-catenin, together with Akt activity, whereas decrease the activities of GSK-3ß and PP2A. In addition, ß-arrestin1 could function as a scaffold protein in modulating the interactions between PP2A, Akt, GSK-3ß and ß-catenin. These results reveal a novel mechanism of ß-arrestin1 in modulating EMT and GSK-3ß/ß-catenin signaling in prostate cancer, thereby suggest that assessment of ß-arrestin1 may provide a potential therapeutic target for prostate cancer.

Overexpression of tropomyosin receptor kinase A improves the survival and Schwann-like cell differentiation of bone marrow stromal cells in nerve grafts for bridging rat sciatic nerve defects.

BACKGROUND AIMS: Bone marrow stromal cells (BMSCs) can differentiate into Schwann-like cells in vivo and effectively promote nerve regeneration and functional recovery as the seed cells for peripheral nerve repair. However, the survival rate and neural differentiation rate of the transplanted BMSCs are very low, which would limit their efficacy. METHODS: In this work, rat BMSCs were infected by recombinant lentiviruses to construct tropomyosin receptor kinase A (TrkA)-overexpressing BMSCs and TrkA-shRNA-expressing BMSCs, which were then used in transplantation for rat sciatic nerve defects. RESULTS: We showed that lentivirus-mediated overexpression of TrkA in BMSCs can promote cell survival and protect against serum-starve-induced apoptosis in vitro. At 8 weeks after transplantation, the Schwann-like differentiated ratio of the existing implanted cells had reached 74.8 ± 1.6% in TrkA-overexpressing BMSCs-laden nerve grafts, while 40.7 ± 2.3% and 42.3 ± 1.5% in vector and control BMSCs-laden nerve grafts, but only 8.2 ± 1.8% in TrkA-shRNA-expressing BMSCs-laden nerve grafts. The cell apoptosis ratio of the existing implanted cells in TrkA-overexpressing BMSCs-laden nerve grafts was 16.5 ± 1.2%, while 33.9 ± 1.9% and 42.6 ± 2.9% in vector and control BMSCs-laden nerve grafts, but 87.2 ± 2.5% in TrkA-shRNA-expressing BMSCs-laden nerve grafts. CONCLUSIONS: These results demonstrate that TrkA overexpression can improve the survival and Schwann-like cell differentiation of BMSCs and prevent cell death in nerve grafts, which may have potential implication in advancing cell transplantation for peripheral nerve repair.

Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways.

RATIONALE: Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms. OBJECTIVES: PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms. METHODS: Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot. RESULTS: Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion. CONCLUSIONS: The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.

An in situ forming tissue adhesive based on poly(ethylene glycol)-dimethacrylate and thiolated chitosan through the Michael reaction.

In this paper, a novel biocompatible and biodegradable tissue adhesive composed of poly(ethylene glycol)-methacrylate (PEGDMA) and thiolated chitosan (CSS) was prepared. PEGDMA and CSS cross-linked rapidly under physiological conditions through the Michael addition reaction via UV lamp irradiation. The chemical structures of PEGDMA and CSS were confirmed via FTIR and 1H NMR. The equilibrium swelling ratio and biodegradation of the hydrogels were tunable by varying the component ratios of the hydrogels. The compression strength and adhesive strength of the resulting hydrogels were measured with a tensile tester, and the adhesion strength of the hydrogel was higher than the fibrin glues. Moreover, the cytotoxicity of the PEGDMA/CSS hydrogels for L929 cells was evaluated by the MTT assay, and the results indicate that the photocured hydrogels are biocompatible and less cytotoxic towards the growth of L929 cells. These findings imply that the obtained hydrogel adhesives are a potential bioadhesive for clinical application in the future.

ß-Arrestin2 Contributes to Cell Viability and Proliferation via the Down-Regulation of FOXO1 in Castration-Resistant Prostate Cancer.

ß-Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen-dependent prostate cancer cells; however, little is known regarding its role in castration-resistant prostate cancer (CRPC) progression. Here, our data demonstrated that ß-arrestin2 contributes to the cell viability and proliferation of CRPC via the downregulation of FOXO1 activity and expression. Mechanistically, in addition to its requirement for FOXO1 phosphorylation induced by IGF-1, ß-arrestin2 could inhibit FOXO1 activity in an Akt-independent manner and delay FOXO1 dephosphorylation through the inhibition of PP2A phosphatase activity and the attenuation of the interaction between FOXO1 and PP2A. Furthermore, ß-arrestin2 could downregulate FOXO1 expression via ubiquitylation and proteasomal degradation. Together, our results identified a novel role for ß-arrestin2 in the modulation of the CRPC progress through FOXO1. Thus, the characterization of ß-arrestin2 may represent an alternative therapeutic target for CRPC treatment.

[Protective effect and mechanisms of dihydromyricetin on PC12 cells induced by oxidative injury].

OBJECTIVE: To study the protective effect and possible mechanisms of Dihydromyricetin(DMY)on PC12 cells injury in- duced by sodium nitroprusside( SNP). METHODS: SNP toxicity cellular model was established using PC12 cells treated with SNP. Cell via- bility was determined by MTT assay. The apoptosis of treated cells was detected by Hoechst Staining. Effect of DMY on accumulation of ROS in PC12 cells induced by SNP was detected by fluorometric analysis. The pathways involved were studied by kinase specific inhibi- tors; The level of phosphorylated Akt and ERK1/2 was detected by Western blot with specific phosphor-antibodies. RESULTS: SNP in- duced the apoptosis of PC12 cells in a dose-dependent manner. DMY dose-dependently protected PC12 cells from injury induced by SNP. Hoechst staining indicated that SNP decreased the number of viable cells and induced shrinkage and aggregation of the nucleus, whereas DMY attenuiated the toxic effects of SNP. The level of ROS induced by SNP in PC12 cells was decreased gradually by DMY. PI3K specific inhibitor LY294002 and the MAPK pathway specific inhibitor PD98059 attenuated the protective effect of DMY on SNP-induced injury of PC12 cells. However, the effect of DMY could be blocked by LY294002 and PD98059 respectively. CONCLUSION: DMY possesses protective effect against apoptosis induced by SNP in PC12 cells,and its mechanisms may be partially related with Akt and ERK1/2 signaling.

Lithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in rats.

Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague-Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p-FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt-FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders.