Stanniocalcin 2 promotes neuronal differentiation in neural stem/progenitor cells of the mouse subventricular zone through activation of AKT pathway.

Neural stem/progenitor cells (NSPCs) persist in the mammalian subventricular zone throughout life, responding to various pathophysiological stimuli and playing a crucial role in central nervous system repair. Although numerous studies have elucidated the role of stanniocalcin 2 (STC2) in regulating cell differentiation processes, its specific function in NSPCs differentiation remains poorly understood. Clarifying the role of STC2 in NSPCs is essential for devising novel strategies to enhance the intrinsic potential for brain regeneration post-injury. Our study revealed the expression of STC2 in NSPCs derived from the subventricular zone (SVZ) of C57BL/6N mouse. In cultured SVZ-derived NSPCs, STC2 treatment significantly increased the number of Tuj1 and DCX-positive cells. Furthermore, STC2 injection into the lateral ventricle promoted the neuronal differentiation of NSPCs and migration to the olfactory bulb. Conversely, STC2 knockdown produced the opposite effect. Further investigation showed that STC2 treatment enhanced AKT phosphorylation in cultured NSPCs, while STC2 inhibition hindered AKT activation. Notably, the neuronal differentiation induced by STC2 was blocked by AKT inhibitor GSK690693, while the AKT activator SC79 reversed the impact of STC2 knockdown on neuronal differentiation. Our findings indicate that enhancing STC2 expression in SVZ-derived NSPCs facilitates neuronal differentiation, with AKT regulation potentially serving as a key intracellular target of STC2 signaling.

CCN3/NOV inhibition attenuates oxidative stress-induced apoptosis of mouse neural stem/progenitor cells by blocking the activation of p38 MAPK: An in vitro study.

Neural stem/progenitor cells (NSPCs) hold immense promise in clinical applications, yet the harsh conditions resulting from central nervous system (CNS) injuries, particularly oxidative stress, lead to the demise of both native and transplanted NSPCs. Cellular communication network factor 3 (CCN3) exhibits a protective effect against oxidative stress in various cell types. This study investigates the impact of CCN3 on NSPCs apoptosis induced by oxidative stress. To establish models of primary cultured mouse NSPCs under oxidative stress, we exposed them to 50 µM H2O2 for 4 h. Remarkably, pre-exposing CCN3 exacerbated the H2O2-induced decline in cell viability in a concentration-dependent manner. However, employing gene-targeted siRNA to inhibit CCN3 protected NSPCs against H2O2-induced cell death. Conversely, CCN3 replenishment reversed this protective effect, as evidenced by TUNEL staining, the ratio of Cleaved-caspase-3 to Pro-caspase-3, and Bcl-2/Bax. Further investigations revealed that CCN3 pretreatment increased the phosphorylation level of p38 MAPK, while silencing CCN3 diminished p38 MAPK activation. Ultimately, the impact of changes in CCN3 protein expression on H2O2-induced apoptosis was nullified using anisomycin (a p38 activator) and SB 203580 (a p38 inhibitor). Our findings suggest that CCN3 inhibition prevents H2O2-induced cell death in cultured mouse NSPCs via the p38 pathway. These discoveries may contribute to the development of strategies aimed at enhancing the survival of both endogenous and transplanted NSPCs following CNS oxidative stress insults.

Inhibition of the mTORC1 pathway alleviates adipose tissue fibrosis.

Background: Adipose fibrosis is a major factor of adipose dysfunction, which causes metabolic dysfunction during obesity, but its molecular mechanisms are poorly understood. This study investigated the role and potential mechanisms of mTORC1 in obesity-induced adipose fibrosis. Methods: ob/ob mice were injected with rapamycin or the same volume of normal saline. The level of fibrosis in epididymal adipose tissue (EAT) was detected by observing aberrant deposition of extracellular matrix. Expression of fibrotic related genes was analysed using RNA-seq. 3T3-L1 preadipocytes were treated with cobalt chloride (CoCl2) and TGF-ß1 to induce preadipocyte fibrosis. The fibrosis-related gene expression and protein levels were determined by RT-PCR, WB, and immunofluorescence in two types of fibrotic preadipocytes with or without rapamycin. Results: Compared with vehicle treatment, EAT fibrosis-related aberrant deposition of extracellular matrix proteins and fibrotic gene expression were reduced in ob/ob mice treated with rapamycin. Both CoCl2-induced hypoxia and TGF-ß1 successfully promoted adipocyte fibrosis, and the upregulated fibrosis-related genes expression was inhibited after the mTORC1 pathway was inhibited by rapamycin. Conclusion: Inhibition of the mTORC1 pathway ameliorates adipose fibrosis by suppressing fibrosis-related genes in hypoxia- and TGF-ß-induced fibrotic preadipocytes.

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway.

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

Parasellar epidermoid cyst with unique radiological features: A case report and review of the literature.

Intracranial epidermoid cysts (ECs) are encapsulated lesions lined by squamous cell epithelium and the most location is the cerebellopontine angle and appears with cerebrospinal fluid-like irregular mass. Occasionally, ECs present as high-density masses on computed tomography and atypical features in magnetic resonance images in the unusual area, which makes the diagnosis difficult. Here, we report a case of a female subject who complained of episodic left facial convulsions for more than 3 months. Computed tomography plain scan revealed a large hyperdense parasellar mass with atypical magnetic resonance findings. In this report, we analyzed retrospectively the radiological characteristics and histopathology of the parasellar EC, thus increasing awareness about this unusual image features.

Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation.

Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.

Periostin attenuates oxygen and glucose deprivation-induced death of mouse neural stem cells via inhibition of p38 MAPK activation.

Promoting neural stem cells (NSCs) survival in the harsh niche is essential to cell replacement therapy for various central nervous system diseases. As an integral component of the extracellular matrix, Periostin (POSTN) has been shown to protect various cell types from hypoxia-ischemia damage. This study aimed to investigate the neuroprotective effects of POSTN on NSCs injury induced by oxygen and glucose deprivation (OGD). Under challenge with OGD, cell viability significantly decreased in cultured mouse NSCs, and supplement POSTN rescued cell viability in a concentration-dependent manner, as shown by CCK-8. TUNEL and propidium iodide/Hoechst staining showed that POSTN pretreatment protected NSCs against OGD-induced apoptosis. Western blot assay demonstrated that POSTN pretreatment inhibited cleavage of caspase-3 and restored the balance of Bcl-2/Bax. And pretreatment with cilengitide (an inhibitor of POSTN receptors) abolished the protective effect of POSTN. Further investigation demonstrated that supplement POSTN inhibited phosphorylation of p38 in a concentration-dependent manner. Moreover, the neuroprotective effect of POSTN was hampered by anisomycin, an activator of p38. We conclude that POSTN pretreatment in cultured mouse NSCs mitigated OGD-induced cell death, and inhibition of the p38 MAPK pathway might be one of the underlying mechanisms. Our findings may provide a novel strategy for enhancing both endogenous and exogenous NSCs survival after ischemia and hypoxia injury.

Maternal High-Fat Diet Leads to Non-alcoholic Fatty Liver Disease Through Upregulating Hepatic SCD1 Expression in Neonate Rats.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children, with evidence that the maternal diet and the early life nutritional environment are potential risk for such disease. This study was aimed to investigate the effects of maternal high-fat diet (HFD) on the occurrence of NAFLD in offspring rats and the underlying mechanisms. In this study, the incidence of NAFLD was compared in F1 offspring rats between the maternal HFD group and standard chow (SC) group. In addition, the expression levels of inflammatory cytokines in the placenta, in the umbilical cord blood, and in the livers of neonate offsprings were compared between two groups. HepG2 cells were treated with recombinant IL6 (rIL6) to assess stearoyl-CoA desaturase 1 (SCD1) expression and lipid synthesis in an inflammatory condition. Lipid accumulation was assayed in both SCD1 overexpression and interference HepG2 cells as well as in neonatal rats. Our results showed that HFD exposure before and throughout the pregnancy induced the elevated hepatic TG content of F1 neonates. The levels of inflammatory cytokines in the placenta, umbilical cord blood, and the livers of HFD F1 neonates were significantly higher than those of the SC group. In addition, rIL6 treatment led to TG accumulation accompanied by the upregulation of SCD1 in HepG2 cell lines. Overexpression of SCD1 led to the accumulation of TG contents in HepG2 cells, whereas Scd1 knockdown attenuated the effects of rIL6 treatment. Overexpression of SCD1 in F1 neonatal rats led to hepatic lipid accumulation. Our study indicated that maternal HFD led to intrauterine inflammation, which subsequently caused transgenerationally abnormal hepatic lipid metabolism of F1 neonates. This modulation might be mediated by upregulating SCD1 expression in hepatic cells.

Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells.

PURPOSE: To investigate the role of thioredoxin 2 (Trx2) inhibition induced by intracellular methylglyoxal (MGO) in pancreatic beta-cell mitochondrial dysfunction and apoptosis. METHODS: Rat pancreatic beta-cell line INS-1 cells were treated with Glo1 siRNAs or exogenous MGO to increase intracellular MGO. AGEs formation was detected by ELISA and mitochondrial ROS was detected by probe MitoSOX. Transmission electron microscopy (TEM) analysis and ATP content were measured to evaluate mitochondrial function. Trx2 expression was manipulated by overexpression with recombinant Trx2 lentivirus or knockdown with Trx2 siRNAs, and effects on apoptosis and insulin secretion were measured by flow cytometry and ELISA, respectively. RESULTS: The increase of intracellular MGO by Glo1 blockage or MGO treatment led to advanced glycation end products (AGEs) overproduction, mitochondrial ROS increase, and insulin secretion paralysis. These were probably due to MGO-induced inhibition of mitochondrial Trx2. Trx2 inhibition by blockage of either Glo1 or Trx2 impaired mitochondrial integrity, inhibited cytochrome C oxidases subunit 1 and 4 (Cox1 and Cox4) expression and further reduced ATP generation, and all of these might lead to insulin paralysis; whereas Trx2 overexpression partially reversed MGO-induced oxidative stress, attenuated insulin secretion by preventing mitochondrial damage. Trx2 overexpression also retarded MGO-induced apoptosis of INS-1 cell through inhibiting ASK1 activation and downregulation of the ASK1-p38 MAPK pathway. CONCLUSIONS: Our results reveal a possible mechanism for beta-cell oxidative damage upon intracellular MGO-induced Trx2 inactivation and mitochondrial dysfunction and apoptosis.

LncRNA LEGLTBC Functions as a ceRNA to Antagonize the Effects of miR-34a on the Downregulation of SIRT1 in Glucolipotoxicity-Induced INS-1 Beta Cell Oxidative Stress and Apoptosis.

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

All-trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line.

The poor therapeutic effect of the current treatments for malignant glioma may be attributed to glioma stem cells (GSCs), which have been demonstrated to divide symmetrically. All-trans retinoic acid (ATRA)-induced differentiation is considered to target GSCs and has been reported to have the capability of eradicating cancer stem cells in specific malignancies. The aim of the present study was to investigate the effects of ATRA on the division mode of GSCs isolated from the U87MG glioblastoma cell line of unknown origin. The expressions of the GSC markers CD133 and nestin were detected using immunocytochemistry to identify GSCs. In addition, the differentiation potency of these GSCs was observed by detecting the expression of glial fibrillary acidic protein, ß-tubulin III and galactosylceramidase using immunofluorescent staining. The Numb protein distribution was analyzed in two daughter cells following a GSC division. The results of the present study demonstrated that Numb protein is symmetrically segregated into two daughter cells during GSC division. Furthermore, the present study demonstrated that treatment with ATRA increased the asymmetric cell division of GSCs. In conclusion, these results suggest a therapeutic effect from ATRA-induced asymmetric division of GSCs from the U87MG cell line.

Activity of Metabotropic Glutamate Receptor 4 Suppresses Proliferation and Promotes Apoptosis With Inhibition of Gli-1 in Human Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most lethal glioma variant in the adult brain and among the deadliest of human cancers. Increasing evidence has shown that metabotropic glutamate receptor subtype 4 (mGluR4) expression may play roles in regulating the growth of neural stem cells as well as several cancer cell lines. Here, we investigated the effects of mGluR4 on the growth and apoptosis of the LN229 GBM cell line. Involvement of Gli-1, one of the key transcription factors in the sonic Hedgehog (SHH) signaling pathway, was further explored. In this study, mGluR4 was activated using selective agonist VU0155041; and gene-targeted siRNAs were used to generate loss of function of mGluR4 and Gli-1 in LN229 cells. The results demonstrated that LN229 cells expressed mGluR4 and the agonist VU0155041 decreased cell viability in a dose- and time-dependent manner. Activation of mGluR4 inhibited cyclin D1 expression, activated pro-caspase-8/9/3, and disrupted the balance of Bcl-2/Bax expression, which indicated cell cycle arrest and apoptosis of LN229 cells, respectively. Furthermore, Gli-1 expression was reduced by mGluR4 activation in LN229 cells, and downregulation of Gli-1 expression by gene-targeted siRNA resulted in both inhibition of cell proliferation and promotion of apoptosis. Moreover, VU0155041 treatment substantially blocked SHH-induced cyclin D1 expression and cell proliferation, while increasing TUNEL-positive cells and the activation of apoptosis-related proteins. We concluded that activation of mGluR4 expressed in LN229 cells could inhibit GBM cell growth by decreasing cell proliferation and promoting apoptosis. Further suppression of intracellular Gli-1 expression might be involved in the action of mGluR4 on cancer cells. Our study suggested a novel role of mGluR4, which might serve as a potential drug target for control of GBM cell growth.

Maternal high-fat diet impairs glucose metabolism, ß-cell function and proliferation in the second generation of offspring rats.

BACKGROUND: This study aimed to assess the impact of perinatal high-fat (HF) diet in female Sprague-Dawley rats (F0) on glucose metabolism and islet function in their early life of second-generation of offspring (F2). METHODS: F0 rats were fed with a standard chow (SC) or HF diet for 8 weeks before mating, up to termination of lactation for their first-generation of offspring (F1-SC and F1-HF). F1 females were mated with normal males at the age of week 11, and producing F2 offspring (F2-SC, F2-HF). All the offspring were fed SC diet after weaning for 3 weeks. The glucose level and islet function of F2 offspring were assessed at the age of week 3 and 12. RESULTS: The F2-HF offspring had a high birth weight and maintained a higher body mass at the age of week 3 and 12, along with an impaired glucose tolerance and lower serum insulin levels compared with the F2-SC. ß-cell proliferation was also impaired in the islets of F2-HF rats at the age of week 3 and 12. The pancreatic and duodenal homeobox factor-1 (Pdx1) and Neurogenic differentiation 1 (NeuroD1) expressions were decreased in the islet of F2-HF rats at the age of week 12. CONCLUSIONS: Maternal HF diet during pre-gestation, gestation, and lactation in rats could result in the increased body weight and glucose intolerance in their early life of F2 offspring due to impaired ß-cell function and proliferation.

Maternal high-fat diet during pregnancy and lactation affects hepatic lipid metabolism in early life of offspring rat.

We investigated whether maternal over-nutrition during pregnancy and lactation affects the offspring's lipid metabolism at weaning by assessing liver lipid metabolic gene expressions and analysing its mechanisms on the development of metabolic abnormalities. Female Sprague-Dawley rats were fed with standard chow diet (CON) or high-fat diet (HFD) for 8 weeks, and then continued feeding during gestation and lactation. The offspring whose dams were fed with HFD had a lower birth weight but an increased body weight with impaired glucose tolerance, higher serum cholesterol, and hepatic steatosis at weaning. Microarray analyses showed that there were 120 genes differently expressed between the two groups. We further verified the results by qRT-PCR. Significant increase of the lipogenesis (Me1, Scd1) gene expression was found in HFD (P less than 0.05), and up-regulated expression of genes (PPAR-alpha, Cpt1 alpha, Ehhadh) involved in beta-oxidation was also observed (P less than 0.05), but the Acsl3 gene was down-regulated (P less than 0.05). Maternal over-nutrition could not only primarily induce lipogenesis, but also promote lipolysis through an oxidation pathway as compensation, eventually leading to an increased body weight, impaired glucose tolerance, elevated serum cholesterol and hepatic steatosis at weaning. This finding may provide some evidence for a healthy maternal diet in order to reduce the risk of metabolic diseases in the early life of the offspring.

Intracellular methylglyoxal induces oxidative damage to pancreatic beta cell line INS-1 cell through Ire1α-JNK and mitochondrial apoptotic pathway.

An increased intracellular methylglyoxal (MGO) under hyperglycemia led to pancreatic beta cell death. However, its mechanism in which way with MGO induced beta cell death remains unknown. We investigated both high glucose and MGO treatment significantly inclined intracellular MGO concentration and inhibited cell viability in vitro. MGO treatment also triggered intracellular advanced glycation end products (AGEs) formation, declined mitochondrial membrane potential (MMP), increased oxidative stress and the expression of ER stress mediators Grp78/Bip and p-PERK; activated mitochondrial apoptotic pathway, which could mimic by Glo1 knockdown. Aminoguanidine (AG), a MGO scavenger, however, prevented AGEs formation and MGO-induced cell death by inhibiting oxidative stress and ER stress. Furthermore, both antioxidant N-acetylcysteine (NAC) and ER stress inhibitor 4-phenylbutyrate (4-PBA) could attenuate MGO-induced cell death through ameliorating ER stress. MGO treatment down-regulated Ire1α, a key ER stress mediator, increased JNK phosphorylation and activated mitochondrial apoptosis; down-regulated Bcl-2 expression which could be attenuated by the JNK inhibitor SP600125 and further inhibited cytochrome c leakage from mitochondria and blocked the conversion of pro caspase 3 into cleaved caspase 3, all these might contribute to the inhibition of INS-1 cell apoptosis. Ire1α down-regulation by Ire1α siRNAs mimicked MGO-induced cytotoxicity by activating the JNK phosphorylation and mitochondrial apoptotic pathway. In summary, we demonstrated that increased intracellular MGO induced cytotoxicity in INS-1 cells primarily by activating oxidative stress and further triggering mitochondrial apoptotic pathway, and ER stress-mediated Ire1α-JNK pathway. These findings may have implication on new mechanism of glucotoxicity-mediated pancreatic beta-cell dysfunction.

Down-regulation of Homer1 attenuates t-BHP-induced oxidative stress through regulating calcium homeostasis and ER stress in brain endothelial cells.

Endothelial dysfunction in brain endothelial cells contributes to vasogenic cerebral edema and increased mortality after various neurological diseases. The postsynaptic density protein Homer1 plays an important role in neuronal synaptic activity and is extensively involved in neurological disorders. The present study investigated the role of Homer1 in modulating cell survival using an in vitro endothelial dysfunction model in murine brain endothelial cells (mBECs). Treatment with tert-butyl hydroperoxide (t-BHP) induced a dose-dependent toxicity in mBECs, with no effects on Homer1 expression and distribution. Knockdown of Homer1 using specific siRNA significantly alleviated lactate dehydrogenase (LDH) release, increased cell viability, and ultimately decreased apoptosis after t-BHP treatment. Moreover, Homer1 knockdown attenuated t-BHP-induced ROS generation, lipid peroxidation and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential (MMP), ATP synthesis collapse and mitochondrial swelling. The results of Ca(2+) imaging showed that Homer1 was involved in inositol trisphosphate receptors (IP3R)- and ryanodine receptor (RyR)-mediated intracellular Ca(2+) release, and also mediated t-BHP-induced Ca(2+) release from the endoplasmic reticulum (ER). In addition, knockdown of Homer1 significantly prevented activation of ER stress markers induced by t-BHP exposure. All these results showed that Homer1 is involved in t-BHP-induced endothelial dysfunction in mBECs, and may be an ideal candidate for searching gene intervention strategy for preventing endothelial oxidative stress in vitro.

A case report of successful conservative treatment for huge acute traumatic intracerebral hematoma.

Acute traumatic intracerebral hematoma (ICH) is a common intracranial injury after trauma. Surgery is preferred if the volume of supratentorial hematoma is >30 mL and complicated with disturbance of consciousness or other neurofunction impairment. When supratentorial hematoma is >50 mL, patients can rarely survive if only treated with medicine. Here we present a successful case of conservative treatment for an elderly female patient with acute traumatic ICH of about 80 mL. The patient was admitted to the emergency department, with a complaint of conscious disturbance for half a month after occipital injury. A diagnosis of left prefrontal lobe cerebral contusion complicated with ICH was made after computed tomography (CT) scan. She was then treated with mannitol and dexamethasone, which were reduced stepwise for 65 and 15 days in total, respectively. The hematoma and the surrounding edema have been gradually absorbed. Eventually, she was transferred to the local hospital for rehabilitation. This report may provide additional experience on the conservative treatment for elderly patients with large ICH, which, however, needs to be evaluated carefully in different clinical settings. In addition, the younger patients in better clinical condition are still suggested to receive operation.

Matrix metalloproteinase 2 contributes to pancreatic Beta cell injury induced by oxidative stress.

OBJECTIVE: To investigate the role of matrix metalloproteinase 2 (MMP2) in pancreatic beta cell injury induced by oxidative stress. METHODS: Rat pancreatic beta cell line INS-1 cells were treated with advanced glycation end-products (AGE) to induce intracellular oxidative stress. Intracellular MMP2 expression and activity were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and zymography, respectively. MMP2 expression and activity were manipulated by over-expression with recombinant MMP2 plasmids or knockdown with either MMP2 specific siRNA or inhibitors, and effects on apoptosis and insulin-secretion were measured by flow cytometry and ELISA. RESULTS: AGE treatment induced intracellular oxidative stress in INS-1 cells, as indicated by elevated ROS levels, apoptotic cell death, and suppressed insulin secretion. This was accompanied by increased MMP2 expression and activity. However, Antioxidant N-acetylcysteine (NAC) treatment inhibited MMP2 expression and activity, and partially reversed cell apoptosis and insulin secretion dysfunction induced by AGE. Forced expression of MMP2 mimicked the effects of AGE treatment while inhibition of MMP2 either by a specific MMP2 inhibitor or MMP2 siRNA protected oxidative stress induced by AGE. CONCLUSION: MMP2 expression and intracellular activity are increased by oxidative stress, contributing to cellular dysfunction and apoptosis in INS-1 cells after AGE challenge.

Changes of blood-brain barrier permeability following intracerebral hemorrhage and the therapeutic effect of minocycline in rats.

OBJECTIVE: to investigate the changes of blood-brain barrier (BBB) permeability and expressions of VEGF, NGF and HPS70 in brain at different time points following intracerebral hemorrhage (ICH) in rats, and observe therapeutic effect of minocycline (MC). METHODS: rat ICH model was induced with Type IV collagenase. Early MC treatment was administrated via intraperitoneal injection. BBB permeability was evaluated by Evans blue (EB) amount exuded out of cerebral vessels. VEGF, NGF, and HPS70 expressions were determined with immunohistochemical staining. RESULTS: EB exudation amount in MC treatment group was less than the ICH group (P < 0.05). The former showed a transient EB exudation peak only 1 h after modeling and then gradually decreased, while the latter showed two EB exudation peaks 1 and 4 days after modeling, respectively. The number of VEGF-positive cells in MC treatment group was less than the ICH group (P < 0.05), whereas the number of NGF- and HSP70-positive cells were more than the ICH group (P < 0.05). All three were mainly expressed in neurons and gitter cells, but there were only few expressions in the control group. CONCLUSION: after ICH, the BBB permeability was destroyed, with neuron function affected. In the early stage, VEGF increased BBB permeability, while NGF and HSP70 showed protective effects on nerve cells. Early intraperitoneal injection with MC could reduce the damage of BBB and increase the protective effect on nerve cells, the mechanism of which may be achieved by reducing VEGF expression and enhancing NGF and HSP70 expressions.

Effects of minocycline on the expression of NGF and HSP70 and its neuroprotection role following intracerebral hemorrhage in rats.

The present study was aimed to investigate the effects of minocycline (MC) on the expression of nerve growth factor (NGF) and heat shock protein 70 (HSP70) following intracerebral hemorrhage (ICH) in rats, and explore the neuroprotective function of MC. Seventy-eight male SD rats were randomly assigned to three groups: the ICH control group (n = 36), ICH intervention group (n = 36) and sham operation group (n = 6). The ICH control group and ICH intervention group were subdivided into 6 subgroups at 1, 2, 4, 5, 7 and 14 d after ICH with 6 rats in each subgroup. Type IV collagenase was injected into the basal nuclei to establish the ICH model. All rats showed symptoms of the nervous system after the model was established, and the sympotsm in the ICH control group were more serious than the ICH intervention group. The number of NGF-positive cells and HSP70-positive cells in the ICH intervention group was higher than that of the ICH control group. MC administration by intraperitoneal injection can increase the expression of NGF and HSP70. MC may inhibit the activation of microglia, the inflammatory reaction and factors, matrix metalloproteinases and apoptosis, thus protecting neurons. The change of the expression of NGF and HSP70 may be involved in the pathway of neuroprotection by MC.