This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.I...This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.It has been revealed that Rheb1 promotesβ-cell regeneration through a dual pathway,activating mammalian target of rapamycin complex 1 and simultaneously inhibiting AMP-activated protein kinase(AMPK).Blocking mammalian target of rapamycin complex 1 while stimulating AMPK was necessary to haltβ-cell expansion,challenging traditional single-target approaches.Rheb1 also supportedβ-cell identity by triggering neurogenic locus notch homolog protein 1 signaling and interacting with hepatocyte nuclear factor 4 alpha,linked to maturity-onset diabetes of the young 1.An age-related decline of Rheb1 in human islets suggests its role in diminished regenerative capacity in adulthood.These findings make Rheb1 a promising therapeutic target for rejuvenatingβ-cells by linking nutrient sensing and energy regulation.Focusing on Rheb1 could alter diabetes treatment,merging proliferation with identity preservation for next-generation therapies.The gaps and translational opportunities,from Rheb1 modulators to biomarkers,were emphasized,advocating for interdisciplinary collaboration to maximize this pathway for positive clinical outcomes.Additional studies are needed to thoroughly investigate AMPK’s involvement in the Rheb1 metabolic biomarker associated with brain health and its possible therapeutic benefits.展开更多
This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulato...This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.展开更多
BACKGROUND Each year,more than a million people are diagnosed with gastric cancer(GC)worldwide,and the incidence of this disease is projected to increase.Helicobacter pylori(H.pylori)is the major cause of GC.Managing ...BACKGROUND Each year,more than a million people are diagnosed with gastric cancer(GC)worldwide,and the incidence of this disease is projected to increase.Helicobacter pylori(H.pylori)is the major cause of GC.Managing infections caused by H.pylori and investigating their contribution to GC carcinogenesis are crucial for advancing diagnosis and treatment.Deleted in malignant brain tumors 1(DMBT1)is associated with the development of H.pylori and GC.However,the precise underlying mechanism is unclear.AIM To explore the role of DMBT1,as modulated by H.pylori,in the development,proliferation,and metastasis of GC.METHODS Utilizing human GC cells,DMBT1 gene silencing,and H.pylori treatment,four cell groups(control,H.pylori,si-DMBT1,and H.pylori+si-DMBT1)were subjected to cell counting kit-8,scratch,and Transwell assays.The DMBT1 expression was assessed by quantitative real-time polymerase chain reaction and Western blot.RESULTS In cellular tests,H.pylori+si-DMBT1 showed the greatest ability to proliferate,migration,and invasion capabilities,followed by the si-DMBT1,H.pylori,and control groups.DMBT1 mRNA was found to be the highest in control group,next in si-DMBT1,H.pylori and H.pylori+si-DMBT1,while H.pylori+si-DMBT1 showed the least expression.The results the Western blot assay showed a consistent trend of decreasing DMBT1 protein and mRNA levels.CONCLUSION Through inhibition of DMBT1,H.pylori could enhance GC’s proliferation,metastasis and invasion.Our findings revealed a novel connection between H.pylori infection,inflammation,and GC.展开更多
Gastric cancer(GC)remains a major health challenge worldwide,with Helicobacter pylori(H.pylori)infection playing a key role in its development.H.pylori creates a mutagenic environment in the stomach by causing chronic...Gastric cancer(GC)remains a major health challenge worldwide,with Helicobacter pylori(H.pylori)infection playing a key role in its development.H.pylori creates a mutagenic environment in the stomach by causing chronic inflammation,oxidative DNA damage,inducing DNA double-strand breaks,and disrupting DNA repair mechanisms and cell cycle checkpoints.Cytotoxin-associated gene A is the main carcinogenic component of H.pylori and interacts with signaling pathways to promote carcinogenesis.Deleted in malignant brain tumors 1(DMBT1),a potential tumor suppressor gene,shows variable expression patterns in GC.DMBT1 is frequently downregulated in well-differentiated gastric adenocarcinomas but upregulated in other GC types.The correlation between DMBT1 expression and H.pylori infection is important,as maintained DMBT1 expression in precancerous states may protect against gastric carcinogenesis,while its downregulation may facilitate tumor progression.DMBT1 functions as a pattern recognition receptor that binds to H.pylori and other pathogens and modulates inflammatory and immune responses.H.pylori colonization of gastric mucosa can induce an inflammatory microenvironment,which influences tumor suppressor gene expression,including DMBT1.Understanding the interactions between DMBT1 and H.pylori may reveal new therapeutic targets and preventive strategies for H.pylori-associated gastric disease.展开更多
The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimenta...The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies.Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues,primarily manifested as a dysfunction of core clock components(particularly circadian locomotor output cycles kaput(CLOCK)and brain and muscle ARNT-like 1(BMAL1))and the widespread dysregulation of their downstream target genes.Notably,CLOCK demonstrates non-canonical oncogenic functions,including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways.This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1,encompassing multidimensional effects such as cell cycle control,DNA damage response,metabolic reprogramming,and tumor microenvironment(TME)remodeling.Regarding the therapeutic strategies,we focus on cutting-edge approaches such as chrononutritional interventions,chronopharmacological modulation,and treatment regimen optimization,along with a discussion of future perspectives.The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology,particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.展开更多
The hypobaric hypoxic environment in highaltitude areas often aggravates the severity of inflammation and induces brain injury as a consequence. However, the critical genes regulating this process remain largely unkno...The hypobaric hypoxic environment in highaltitude areas often aggravates the severity of inflammation and induces brain injury as a consequence. However, the critical genes regulating this process remain largely unknown. The phosphatase wild-type p53-induced phosphatase 1（WIP1） plays important roles in various physiological and pathological processes, including the regulation of inflammation in normoxia, but its functions in hypoxic inflammation-induced brain injury remain unclear.Here, we established a mouse model of this type of injury and found that WIP1 deficiency augmented the release of inflammatory cytokines in the peripheral circulation and brain tissue, increased the numbers of activated microglia/macrophages in the brain, aggravated cerebral histological lesions, and exacerbated the impairment of motor and cognitive abilities. Collectively, these results provide the first in vivo evidence that WIP1 is a critical neuroprotector against hypoxic inflammation-induced brain injury.展开更多
BACKGROUND The expression of brain cytoplasmic RNA1(BCYRN1)is linked to the clinicopathology and prognosis of several types of cancers,among which hepatocellular carcinoma(HCC)is one of the most frequent types of canc...BACKGROUND The expression of brain cytoplasmic RNA1(BCYRN1)is linked to the clinicopathology and prognosis of several types of cancers,among which hepatocellular carcinoma(HCC)is one of the most frequent types of cancer worldwide.AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.METHODS Information was obtained from the Cancer Genome Atlas database.First,the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored.Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis.Secondly,potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes.The relationships between BCYRN1 expression and tumor microenvironment,immune cell infiltration,immune checkpoint,drug sensitivity and immunotherapy effect were also investigated.Finally,three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics.Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules,participates in the metabolism of nutrients,such as proteins,and participates in tumor-related pathways.BCYRN1 expression was linked to the tumor microenvironment,immune cell infiltration,drug sensitivity and the efficacy of immunotherapy.Furthermore,the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.展开更多
As a leading cause for morbidity and mortality in young adults,traumatic brain injury（TBI）,along with the poorly understood TBI-related seizures inducing their predispositions,pose a major health and socioeconomic p...As a leading cause for morbidity and mortality in young adults,traumatic brain injury（TBI）,along with the poorly understood TBI-related seizures inducing their predispositions,pose a major health and socioeconomic problem in the world（Huang,2013）.展开更多
AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein...AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.展开更多
BACKGROUND： Elk-1 mRNA distributes extensively in the neurons of mice, rat and human brains, and the Elk-1 expression may be correlated with the synaptic plasticity, learning and memory. OBJECTIVE： To observe the di...BACKGROUND： Elk-1 mRNA distributes extensively in the neurons of mice, rat and human brains, and the Elk-1 expression may be correlated with the synaptic plasticity, learning and memory. OBJECTIVE： To observe the distribution of phosphorylated Elk-1 （pEIk-1） in whole brain of rats received Y-maze active avoidance training and the changes of pEIk-1 expression at different time points after training. DESIGN ： A randomized controlled study SETTING ： Research Room of Neurobiology, the Second Affiliated Hospital of Southern Medical University MATERIALS ： Fifty-five male clean-degree SD rats of 3-4 months old, weighing 200-250 g, were provided by the Experimental Animal Center of Southem Medical University. The rabbit anti-monoclonal pEIk-1 antibody was purchased from Cell Signal Transduction Company, and ABC kit from Vector Company. METHODS ： The experiments were carried out in the Research Room of Neurobiology, Second Affiliated Hospital of Southern Medical University from September 2004 to February 2005. ① Grouping： The rats were randomly divided into training group （n = 25）, sham-training group （n = 25） and normal control group （n = 5）, and the training and sham-training groups were observed at 0, 1, 3, 6 and 24 hours after training, which represented the five phases in the process of leaming and memory. ② Y-maze training： The rats were preconditioned in the electrical Y-maze apparatus, 20 minutes a day for 3 days continuously, and training began from the 4^th day. In the training group, the rats were trained with the combination of light and electddty. Each rat repeated for 60 times in each training, and the correct times were recorded, those correct for less than 25 times were taken as unqualified, and excluded from the training group, and supplemented by other rats in time. In the sham-training group, there was no fixed correlation between the application of light and electricity. The rats in the normal contrel group were given not any training. ③Detection of pEIk-1 expression： The rats were anesthetized after Y-maze training, brain tissue was removed to prepare coronal freezing sections, and the pEIk-1 expression was detected with routine ABC method. MATN OUTCOME MEASURES： ① Distribution of pEIk-1 immuno-positive neurons in whole brain of rats in the normal control group. ②Comparison of the expression of pEIk-1 immuno-positive neurons in whole brain at different time points after training between the training group and sham-training group. RESULTS ： All the 55 rats were involved in result analysis. ③ Distribution of pEIk-1 immuno-positive neurons in the whole brain of rats in the normal control group： Strong expressions of pEIk-1 immuno-positive neurons were observed in prefrontal lobe, granular layer of olfactory bulbs, Purkinje cell layer and granular layer of cerebellum, whole stdate cortex, temporal cortex, pre-pyriform cortex, hypothalamic supraoptic nucleus, hypothalamic paraventricular nucleus and periventricular nucleus, thalamic paraventricular nucleus, pronucleus and postnucleus of amygdala cortex, central nucleus of amygdala, medial amygdaloid nucleus, entorhinal cortex, hippocampal dentate gyros, CA1-4 regions, caudate-putamen, material division, brain stem spinal nucleus of trigeminal nerve, and superior olivary nucleus, and those in hippocampal dentate gyrus and CA1 region were the strongest.② Distribution of pEIk-1 immuno-positive neurons in the whole brain of rats at different time points after training in the training group and sham-training group： In the training group, the expressions were obviously enhanced in caudate-putamen of striatum, material division, most cortexes, hippocampal dentate gyrus, hippocampal CA regions, nucleus amygdalae, thalamic paraventricular nucleus, Purkinje cell layer of cerebellum, entorhinal cortex, hypothalamic supraoptic nucleus, hypothalamic paraventricular nucleus, and periventricular nucleus at 0 hour after training, and the enhancement lasted for 6 hours at least, and those at 24 hours were decreased to normal. In the sham-training group, obvious enhanced expressions of pEIk-1 immuno-positive neurons could be observed in most cortexes, nucleus amygdalae, entorhinal cortex, hypothalamic supraoptic nucleus, hypothalamic paraventdoular nucleus and periventricular nucleus, brain stem spinal nucleus of trigeminal nerve, Purkinje cell layer and granular layer of cerebellum at O, 1, 3 and 6 hours, and decreased to normal after 24 hours. The expressions in material division, caudate-putamen of striatum, hippocampus were not obviously enhanced as compared with those in the normal control group, but significantly different from those in the training group （0, 1, 3, 6 hours after training, material division： F= 0.576, 0.023, 0.116, 8.873, P〈 0.01; caudate-putamen： F= 0.157, 0.427, 0.030, 0.001, P〈 0.01; hippocampus： F= 6.716, 2.405, 14.137, 1.416, P 〈 0.05-0.01 ）. CONCLUSION： The expression of activated pEIk-1 can be detected in the learning related brain areas under normal status, and the perk-1 expression in the brain areas dynamically changed in a time-dependent manner after Y-maze training, and it is indicated that pEIk-1 is involved in the learning and memory process in Y-maze related brain areas.展开更多
Amentoflavone is a natural biflavone compound with many biological properties, including anti-inflammatory, antioxidative, and neuroprotective effects. We presumed that amentoflavone exerts a neuroprotective effect in...Amentoflavone is a natural biflavone compound with many biological properties, including anti-inflammatory, antioxidative, and neuroprotective effects. We presumed that amentoflavone exerts a neuroprotective effect in epilepsy models. Prior to model establishment, mice were intragastrically administered 25 mg/kg amentoflavone for 3 consecutive days. Amentoflavone effectively prevented pilocarpine-induced epilepsy in a mouse kindling model, suppressed nuclear factor-κB activation and expression, inhibited excessive discharge of hippocampal neurons resulting in a reduction in epileptic seizures, shortened attack time, and diminished loss and apoptosis of hippocampal neurons. Results suggested that amentoflavone protected hippocampal neurons in epilepsy mice via anti-inflammation, antioxidation, and antiapoptosis, and then effectively prevented the occurrence of seizures.展开更多
BACKGROUND： Hypoxia inducible factor-1 alpha （HIF-1 （x） and erythropoietin（EPO）, possessing neuroprotective effect in the cerebral ischemia, might play an important role in the formation of cerebral ischemic tol...BACKGROUND： Hypoxia inducible factor-1 alpha （HIF-1 （x） and erythropoietin（EPO）, possessing neuroprotective effect in the cerebral ischemia, might play an important role in the formation of cerebral ischemic tolerance （IT）. OBJECTIVE：To observe the neuroprotective effect of cerebral ischemic preconditioning（IPC） of rats, and the expression and mechanism of HIF-1α and target gene erythropoietin in the brain tissue following the formation of cerebral IT. DESIGN ： A randomized and controlled observation SETTING： Department of Neurology, the Affiliated Hospital of Medical College, Qingdao University MATERIALS： Totally 84 enrolled adult healthy male Wistar rats of clean grade, weighing 250 to 300 g, were provided by the Animal Experimental Department, Tongji Medical College of Huazhong University of Science and Technology. Ready-to-use SABC reagent kit and rabbit anti-rat HIF-1α monoclonal antibody were purchased from Boshide Bioengineering Co.Ltd （Wuhan）; Rabbit anti-rat EPO monoclonal antibody was purchased from Santa Cruz Company （USA）. METHODS： This experiment was carried out in the Department of Anatomy, Medical College, Qingdao University during March 2005 to March 2006. ① The 84 rats were divided into 3 groups by a lot： IPC group （n=40）, sham-operation group （n=40） and control group （n=4）. In the IPC group, middle cerebral artery was occluded for 2 hours respectively on the 1^st, 3^rd, 7^th, 14^th and 21^st days of the reperfusion following 10-minute preischemia was made using a modified middle cerebral artery second suture method from Zea-Longa. The rats were sacrificed 22 hours after reperfusion in the end of middle cerebral artery occlusion （MCAO）. That was to say, after 10-minute preischemia, suture was exited to the extemal carotid artery and embedded subcutaneously. Middle cerebral artery was occluded again to form the second reperfusion at the set time point after reperfusion. Twenty-two hours later, rats were sacrificed; In the sham-operation group,the preischemia was substituted by sham-operation（only common carotid artery and crotch were exposed, and MCAO by suture was omitted）, and the other procedures were the same as those in the IPC group. In the control group, rats were given sham-operation twice at an interval of one day, and they were sacrificed 24 hours after the second sham-operation. ② Brain tissue was taken from the rats in each group. Cerebral infarction area of each layer was measured with TTC staining, and total cerebral infarction volume （The total cerebral infarction area of each layerxinterspace ） was calculated. After brain tissue was stained by haematoxylin-esoin （HE）, the form of nerve cells was observed under an optical microscope, and the expressions of HIF-1α（and EPO protein in the brain tissue were detected with immunohistochemical method. MAIN OUTCOME MEASURES： ①Cerebral infarction volume;②form of nerve cell; ③ the expression of HIF-1α and EPO protein in the brain tissue. RESULTS：Totally 84 rats were enrolled in the experiment. The dead rats were randomly supplied during the experiment, and finally 84 rats entered the stage of result analysis. ① Detection of cerebral infarction volume of rats in each group： Cerebral infarction volume in the IPC group was significantly smaller than that in the sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively [（161.2±6.9） mm^3 vs （219.9±11.2） mm^3, （134.9±9.0） mm^3 vs （218.6±13.0） mm^3, （142.9±13.7） mm^3 vs （221.3±14.2） mm^3, t=-8.924, 10.587,7.947, P〈 0.01]. ② Observation of nerve cell form of brain tissue： HE staining showed that the ischemic degree, range and cerebral edema degree of IPC group were significantly milder than those of sham-operation group. ③ The expressions of HIF-1α and EPO protein in cerebral cortex and hippocampus ： The expression of HIF-1αof IPC group was significantly higher than that of sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively （125.93±3.79 vs 117.65±5.60, 140.63±4.64 vs 119.33±4.26, 131.15±2.74 vs 107.60±3.89, t=2.449, 6.763,9.899,P 〈 0.05-0.01）. The expression of EPO of IPC group was significantly higher than that of sham-operation group on the 3^rd and 7^th days after perfusion respectively （141.68±3.29 vs 126.33±4.51, 138.88±2.59 vs 125.58±6.18,t=5.499,3.970, P〈 0.05）. CONCLUSION ： ①IPC can protect the never cells in rat brain and the best time to onset of cerebral IT induced by IPC is 1 to 7 days after reperfusion. ② Neuroprotective effect of cerebral IT might be related to the expression of HIF-1α and its target gene EPO.展开更多
Ischemic edema can alter the structure and permeability of the blood-brain barrier. Recent studies have reported that progesterone reduces cerebral edema after cerebral ischemia. However, the underlying mechanism of t...Ischemic edema can alter the structure and permeability of the blood-brain barrier. Recent studies have reported that progesterone reduces cerebral edema after cerebral ischemia. However, the underlying mechanism of this effect has not yet been elucidated. In the present study, progesterone effectively reduced Evans blue extravasation in the ischemic penumbra, but not in the ischemic core, 48 hours after cerebral ischemia in rats. Progesterone also inhibited the down-regulation of gene and protein levels of occludin and zonula occludens-1 in the penumbra. These results indicate that progesterone may effectively inhibit the down-regulation of tight junctions, thereby maintaining the integrity of the blood-brain barrier and reducing cerebral edema.展开更多
BACKGROUND: The mechanism of intracerebral hemorrhage (ICH)-induced hemorrhagic brain injury is very complicated, involving the position-occupying effect of cephalophyma, ischemic factors, the toxic effect of hematoma...BACKGROUND: The mechanism of intracerebral hemorrhage (ICH)-induced hemorrhagic brain injury is very complicated, involving the position-occupying effect of cephalophyma, ischemic factors, the toxic effect of hematoma components, the destruction of blood-brain barrier, etc. The expression and effect of hemeoxygenase-1 (HO-1) in the cerebrovascular disease has been paid close attention. OBJECTIVE: To observe the expression of HO-1 and change of superoxide dismutase (SOD) in the peri-hematomal brain tissue of rats following ICH. DESIGN: Randomized controlled animal experiment. SETTING: Department of Neurology, Yijishan Hospital Affiliated to Wannan Medical College. MATERIALS: Forty healthy male SD rats, of clean grade, weighing from 250 to 300 g, were provided by Qinglongshan Animal Farm of Nanjing. The involved 40 rats were randomized into sham-operation group (n =5) and ICH group (n =35), and ICH group was divided into 7 subgroups with 5 rats in each: ICH 6, 12, 24, 48, 72, 100 and 168 hours groups. Rabbit anti-rat HO-1 immunohistochemial kit ( Boster Co., Ltd., Wuhan) and SOD kit (Jiancheng Bioengineering Institute, Nanjing)were used in this experiment. METHODS: This experiment was carried out in the Department of Neurology, Yijishan Hospital Affiliated to Wannan Medical College Between April and July 2005. In the ICH group: Autologous blood of rats was injected into the head of caudate nucleus to create ICH animal models. In the sham-operation group, the same amount of normal saline was injected into the head of caudate nucleus of rats. The brains of rats in each group were harvested at different time points. The hematoma-side brain tissue was cut open in the coronal plane taking hematomal region as center, and the posterior part was fixed with 100 g/L neutral formaldehyde. 100 mg brain tissue was taken from anterior part. The number of positive cells in HO-1 and SOD activity in peri-hematomal brain tissue at different time after ICH were detected by immunohistochemical method and xanthine oxidation method respectively. MAIN OUTCOME MEASURES: ① The expression of HO-1 in the peri-hematomal brain tissue of rats in two groups following ICH.② The expression of SOD activity in the peri-hematomal brain tissue of rats in two groups following ICH. RESULTS: ①The number of HO-1 positive cells in the peri-hematomal brain tissue of rats in two groups following ICH 6, 12, 24, 48, 72, 120 and 168 hours was (11.03±2.01),(16.47±2.98),(25.50±5.65),(51.57±7.05),(47.33±4.73),(26.57±5.12),(7.63±2.17) cells/high-fold visual field , respectively; The number of HO-1 positive cells in the ICH 12-120 hours groups was significantly higher than that of sham-operation group [(6.07±1.85)cells/high-fold visual field, P < 0.01]; The HO-1 positive cells were the most in the ICH 48 hours group and were still expressed a little in the ICH 168 hours group. ② The SOD in the brain tissue of rats at ICH 6, 12, 24, 48, 72, 120 and 168 hours was (404.46±8.14),(396.84±10.97),(387.74±5.32),(356.21±9.27),(307.95±10.15),(357.48±11.28) and (402.98±7.23) kNU/g, respectively; The SOD activity of ICH 12 to 120 hours groups was significantly lower than that of sham-operation group [(415.47±11.44) kNU/g,P < 0.01], and that of ICH 72 hours group was the lowest. There was no significant difference of SOD activity between ICH 168 hours group and sham-operation group (P > 0.05). CONCLUSION: Following ICH, the expression of HO-1 in peri-hematomal brain tissue of rats in two groups is obviously increased, but the antioxidant ability of brain tissue is decreased. The changes of both maybe play an important role in the formation of ICH-induced hemorrhagic brain injury.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a hepatic metabolic syndrome arisingfrom lipid metabolic imbalance,with its prevalence increasing globally.In this study,weobserved a significant up-regulation of interferon ...Non-alcoholic fatty liver disease(NAFLD)is a hepatic metabolic syndrome arisingfrom lipid metabolic imbalance,with its prevalence increasing globally.In this study,weobserved a significant up-regulation of interferon regulatory factor 8(IRF8)in the liver ofNAFLD model mice and patients.Overexpression of IRF8 induced lipid accumulation in themouse primary hepatocytes.Mice with adeno-associated virus-mediated IRF8 overexpressionexhibited hepatic steatosis due to up-regulated peroxisome proliferator-activated receptorγ(PPARγ)expression and increased fatty acid uptake and lipogenesis.In vitro,small interfering RNA-mediated IRF8 knockdown attenuated triglyceride accumulation by dampening PPARγexpression through transcriptional inhibition of brain and muscle ARNT-like 1.ThePPARγ-specific antagonist GW9662 abolished the effect of IRF8 overexpression.Furthermore,adeno-associated virus-mediated IRF8 knockdown in the mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome.These findings indicate that IRF8 playsa vital role in modulating hepatic lipid metabolism in a PPARγ-dependent manner and providea previously unknown insight into NAFLD therapeutic strategies.展开更多
Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the ...Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. Methods： BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed, pcDNA-BASP 1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines （BHT- I 01 and KMH-2）. The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenografl tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. Results： BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues （P = 0.000）. pcDNA-BASP1 restored the expression of BASPI and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice （P = 0.000）. pcDNA-BASPI induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. Conclusions： Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASPI expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASPI gene might act as a potential therapeutic agent for the treatment of thyroid cancer.展开更多
Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overpr...Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.展开更多
基金Supported by Zhejiang University Global Partnership Fund,No.BIO-0322023.
文摘This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.It has been revealed that Rheb1 promotesβ-cell regeneration through a dual pathway,activating mammalian target of rapamycin complex 1 and simultaneously inhibiting AMP-activated protein kinase(AMPK).Blocking mammalian target of rapamycin complex 1 while stimulating AMPK was necessary to haltβ-cell expansion,challenging traditional single-target approaches.Rheb1 also supportedβ-cell identity by triggering neurogenic locus notch homolog protein 1 signaling and interacting with hepatocyte nuclear factor 4 alpha,linked to maturity-onset diabetes of the young 1.An age-related decline of Rheb1 in human islets suggests its role in diminished regenerative capacity in adulthood.These findings make Rheb1 a promising therapeutic target for rejuvenatingβ-cells by linking nutrient sensing and energy regulation.Focusing on Rheb1 could alter diabetes treatment,merging proliferation with identity preservation for next-generation therapies.The gaps and translational opportunities,from Rheb1 modulators to biomarkers,were emphasized,advocating for interdisciplinary collaboration to maximize this pathway for positive clinical outcomes.Additional studies are needed to thoroughly investigate AMPK’s involvement in the Rheb1 metabolic biomarker associated with brain health and its possible therapeutic benefits.
基金Supported by Hubei Provincial Natural Science Foundation,No.2025AFB845Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology,No.JCX2024044.
文摘This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.
文摘BACKGROUND Each year,more than a million people are diagnosed with gastric cancer(GC)worldwide,and the incidence of this disease is projected to increase.Helicobacter pylori(H.pylori)is the major cause of GC.Managing infections caused by H.pylori and investigating their contribution to GC carcinogenesis are crucial for advancing diagnosis and treatment.Deleted in malignant brain tumors 1(DMBT1)is associated with the development of H.pylori and GC.However,the precise underlying mechanism is unclear.AIM To explore the role of DMBT1,as modulated by H.pylori,in the development,proliferation,and metastasis of GC.METHODS Utilizing human GC cells,DMBT1 gene silencing,and H.pylori treatment,four cell groups(control,H.pylori,si-DMBT1,and H.pylori+si-DMBT1)were subjected to cell counting kit-8,scratch,and Transwell assays.The DMBT1 expression was assessed by quantitative real-time polymerase chain reaction and Western blot.RESULTS In cellular tests,H.pylori+si-DMBT1 showed the greatest ability to proliferate,migration,and invasion capabilities,followed by the si-DMBT1,H.pylori,and control groups.DMBT1 mRNA was found to be the highest in control group,next in si-DMBT1,H.pylori and H.pylori+si-DMBT1,while H.pylori+si-DMBT1 showed the least expression.The results the Western blot assay showed a consistent trend of decreasing DMBT1 protein and mRNA levels.CONCLUSION Through inhibition of DMBT1,H.pylori could enhance GC’s proliferation,metastasis and invasion.Our findings revealed a novel connection between H.pylori infection,inflammation,and GC.
文摘Gastric cancer(GC)remains a major health challenge worldwide,with Helicobacter pylori(H.pylori)infection playing a key role in its development.H.pylori creates a mutagenic environment in the stomach by causing chronic inflammation,oxidative DNA damage,inducing DNA double-strand breaks,and disrupting DNA repair mechanisms and cell cycle checkpoints.Cytotoxin-associated gene A is the main carcinogenic component of H.pylori and interacts with signaling pathways to promote carcinogenesis.Deleted in malignant brain tumors 1(DMBT1),a potential tumor suppressor gene,shows variable expression patterns in GC.DMBT1 is frequently downregulated in well-differentiated gastric adenocarcinomas but upregulated in other GC types.The correlation between DMBT1 expression and H.pylori infection is important,as maintained DMBT1 expression in precancerous states may protect against gastric carcinogenesis,while its downregulation may facilitate tumor progression.DMBT1 functions as a pattern recognition receptor that binds to H.pylori and other pathogens and modulates inflammatory and immune responses.H.pylori colonization of gastric mucosa can induce an inflammatory microenvironment,which influences tumor suppressor gene expression,including DMBT1.Understanding the interactions between DMBT1 and H.pylori may reveal new therapeutic targets and preventive strategies for H.pylori-associated gastric disease.
基金supported by the Ministry of Science and Technology of the People’s Republic of China(Nos.2020YFA0803300 and 2021YFA0805600)the National Natural Science Foundation of China(Nos.92157113,82072630,82173114,82072903,82272872,82002811,82188102,and 82030074)+2 种基金the Zhejiang Natural Science Foundation Key Project(Nos.LD22H160002 and LD21H160003)the Zhejiang Natural Science Foundation Discovery Project(No.LQ22H160023)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(No.2019R01001),China.
文摘The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies.Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues,primarily manifested as a dysfunction of core clock components(particularly circadian locomotor output cycles kaput(CLOCK)and brain and muscle ARNT-like 1(BMAL1))and the widespread dysregulation of their downstream target genes.Notably,CLOCK demonstrates non-canonical oncogenic functions,including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways.This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1,encompassing multidimensional effects such as cell cycle control,DNA damage response,metabolic reprogramming,and tumor microenvironment(TME)remodeling.Regarding the therapeutic strategies,we focus on cutting-edge approaches such as chrononutritional interventions,chronopharmacological modulation,and treatment regimen optimization,along with a discussion of future perspectives.The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology,particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.
基金supported by the National Natural Science Foundation of China(31401000 and 81430044)the Youth Medicine Program of the People’s Liberation Army of China(13QNP148)+1 种基金the National Basic Research Development Program(973 Program)of China(2012CB518200)the Integrated Drug Discovery Technology Platform of National Science and Technology Major Projects for‘‘Major New Drugs Innovation and Development’’,China(2012ZX09J12201-005)
文摘The hypobaric hypoxic environment in highaltitude areas often aggravates the severity of inflammation and induces brain injury as a consequence. However, the critical genes regulating this process remain largely unknown. The phosphatase wild-type p53-induced phosphatase 1（WIP1） plays important roles in various physiological and pathological processes, including the regulation of inflammation in normoxia, but its functions in hypoxic inflammation-induced brain injury remain unclear.Here, we established a mouse model of this type of injury and found that WIP1 deficiency augmented the release of inflammatory cytokines in the peripheral circulation and brain tissue, increased the numbers of activated microglia/macrophages in the brain, aggravated cerebral histological lesions, and exacerbated the impairment of motor and cognitive abilities. Collectively, these results provide the first in vivo evidence that WIP1 is a critical neuroprotector against hypoxic inflammation-induced brain injury.
基金Supported by the 2021 Central-Guided Local Science and Technology Development Fund,No.ZYYDDFFZZJ-1Gansu Key Laboratory of Molecular Diagnosis and Precision Treatment of Surgical Tumors,No.18JR2RA033+2 种基金Key Laboratory of Gastrointestinal Cancer Diagnosis and Treatment of National Health Commission,No.2019PT320005Key Talent Project of Gansu Province of the Organization Department of Gansu Provincial Party Committee,No.2020RCXM076Guiding Plan for Scientific and Technological Development of Lanzhou,No.2019-ZD-102.
文摘BACKGROUND The expression of brain cytoplasmic RNA1(BCYRN1)is linked to the clinicopathology and prognosis of several types of cancers,among which hepatocellular carcinoma(HCC)is one of the most frequent types of cancer worldwide.AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.METHODS Information was obtained from the Cancer Genome Atlas database.First,the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored.Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis.Secondly,potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes.The relationships between BCYRN1 expression and tumor microenvironment,immune cell infiltration,immune checkpoint,drug sensitivity and immunotherapy effect were also investigated.Finally,three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics.Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules,participates in the metabolism of nutrients,such as proteins,and participates in tumor-related pathways.BCYRN1 expression was linked to the tumor microenvironment,immune cell infiltration,drug sensitivity and the efficacy of immunotherapy.Furthermore,the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.
文摘As a leading cause for morbidity and mortality in young adults,traumatic brain injury（TBI）,along with the poorly understood TBI-related seizures inducing their predispositions,pose a major health and socioeconomic problem in the world（Huang,2013）.
基金Supported by A grant from the Instituto de Salud CarlosTM,PI051371,PI080809
文摘AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.
文摘BACKGROUND： Elk-1 mRNA distributes extensively in the neurons of mice, rat and human brains, and the Elk-1 expression may be correlated with the synaptic plasticity, learning and memory. OBJECTIVE： To observe the distribution of phosphorylated Elk-1 （pEIk-1） in whole brain of rats received Y-maze active avoidance training and the changes of pEIk-1 expression at different time points after training. DESIGN ： A randomized controlled study SETTING ： Research Room of Neurobiology, the Second Affiliated Hospital of Southern Medical University MATERIALS ： Fifty-five male clean-degree SD rats of 3-4 months old, weighing 200-250 g, were provided by the Experimental Animal Center of Southem Medical University. The rabbit anti-monoclonal pEIk-1 antibody was purchased from Cell Signal Transduction Company, and ABC kit from Vector Company. METHODS ： The experiments were carried out in the Research Room of Neurobiology, Second Affiliated Hospital of Southern Medical University from September 2004 to February 2005. ① Grouping： The rats were randomly divided into training group （n = 25）, sham-training group （n = 25） and normal control group （n = 5）, and the training and sham-training groups were observed at 0, 1, 3, 6 and 24 hours after training, which represented the five phases in the process of leaming and memory. ② Y-maze training： The rats were preconditioned in the electrical Y-maze apparatus, 20 minutes a day for 3 days continuously, and training began from the 4^th day. In the training group, the rats were trained with the combination of light and electddty. Each rat repeated for 60 times in each training, and the correct times were recorded, those correct for less than 25 times were taken as unqualified, and excluded from the training group, and supplemented by other rats in time. In the sham-training group, there was no fixed correlation between the application of light and electricity. The rats in the normal contrel group were given not any training. ③Detection of pEIk-1 expression： The rats were anesthetized after Y-maze training, brain tissue was removed to prepare coronal freezing sections, and the pEIk-1 expression was detected with routine ABC method. MATN OUTCOME MEASURES： ① Distribution of pEIk-1 immuno-positive neurons in whole brain of rats in the normal control group. ②Comparison of the expression of pEIk-1 immuno-positive neurons in whole brain at different time points after training between the training group and sham-training group. RESULTS ： All the 55 rats were involved in result analysis. ③ Distribution of pEIk-1 immuno-positive neurons in the whole brain of rats in the normal control group： Strong expressions of pEIk-1 immuno-positive neurons were observed in prefrontal lobe, granular layer of olfactory bulbs, Purkinje cell layer and granular layer of cerebellum, whole stdate cortex, temporal cortex, pre-pyriform cortex, hypothalamic supraoptic nucleus, hypothalamic paraventricular nucleus and periventricular nucleus, thalamic paraventricular nucleus, pronucleus and postnucleus of amygdala cortex, central nucleus of amygdala, medial amygdaloid nucleus, entorhinal cortex, hippocampal dentate gyros, CA1-4 regions, caudate-putamen, material division, brain stem spinal nucleus of trigeminal nerve, and superior olivary nucleus, and those in hippocampal dentate gyrus and CA1 region were the strongest.② Distribution of pEIk-1 immuno-positive neurons in the whole brain of rats at different time points after training in the training group and sham-training group： In the training group, the expressions were obviously enhanced in caudate-putamen of striatum, material division, most cortexes, hippocampal dentate gyrus, hippocampal CA regions, nucleus amygdalae, thalamic paraventricular nucleus, Purkinje cell layer of cerebellum, entorhinal cortex, hypothalamic supraoptic nucleus, hypothalamic paraventricular nucleus, and periventricular nucleus at 0 hour after training, and the enhancement lasted for 6 hours at least, and those at 24 hours were decreased to normal. In the sham-training group, obvious enhanced expressions of pEIk-1 immuno-positive neurons could be observed in most cortexes, nucleus amygdalae, entorhinal cortex, hypothalamic supraoptic nucleus, hypothalamic paraventdoular nucleus and periventricular nucleus, brain stem spinal nucleus of trigeminal nerve, Purkinje cell layer and granular layer of cerebellum at O, 1, 3 and 6 hours, and decreased to normal after 24 hours. The expressions in material division, caudate-putamen of striatum, hippocampus were not obviously enhanced as compared with those in the normal control group, but significantly different from those in the training group （0, 1, 3, 6 hours after training, material division： F= 0.576, 0.023, 0.116, 8.873, P〈 0.01; caudate-putamen： F= 0.157, 0.427, 0.030, 0.001, P〈 0.01; hippocampus： F= 6.716, 2.405, 14.137, 1.416, P 〈 0.05-0.01 ）. CONCLUSION： The expression of activated pEIk-1 can be detected in the learning related brain areas under normal status, and the perk-1 expression in the brain areas dynamically changed in a time-dependent manner after Y-maze training, and it is indicated that pEIk-1 is involved in the learning and memory process in Y-maze related brain areas.
基金supported by the National Natural Science Foundation of China,No.81460208the Ningxia Natural Science Foundation of China,No.NZ13163
文摘Amentoflavone is a natural biflavone compound with many biological properties, including anti-inflammatory, antioxidative, and neuroprotective effects. We presumed that amentoflavone exerts a neuroprotective effect in epilepsy models. Prior to model establishment, mice were intragastrically administered 25 mg/kg amentoflavone for 3 consecutive days. Amentoflavone effectively prevented pilocarpine-induced epilepsy in a mouse kindling model, suppressed nuclear factor-κB activation and expression, inhibited excessive discharge of hippocampal neurons resulting in a reduction in epileptic seizures, shortened attack time, and diminished loss and apoptosis of hippocampal neurons. Results suggested that amentoflavone protected hippocampal neurons in epilepsy mice via anti-inflammation, antioxidation, and antiapoptosis, and then effectively prevented the occurrence of seizures.
基金the Scientific andTechnological DevelopmentProgram of Qingdao City, No.No.05-1-NS-73
文摘BACKGROUND： Hypoxia inducible factor-1 alpha （HIF-1 （x） and erythropoietin（EPO）, possessing neuroprotective effect in the cerebral ischemia, might play an important role in the formation of cerebral ischemic tolerance （IT）. OBJECTIVE：To observe the neuroprotective effect of cerebral ischemic preconditioning（IPC） of rats, and the expression and mechanism of HIF-1α and target gene erythropoietin in the brain tissue following the formation of cerebral IT. DESIGN ： A randomized and controlled observation SETTING： Department of Neurology, the Affiliated Hospital of Medical College, Qingdao University MATERIALS： Totally 84 enrolled adult healthy male Wistar rats of clean grade, weighing 250 to 300 g, were provided by the Animal Experimental Department, Tongji Medical College of Huazhong University of Science and Technology. Ready-to-use SABC reagent kit and rabbit anti-rat HIF-1α monoclonal antibody were purchased from Boshide Bioengineering Co.Ltd （Wuhan）; Rabbit anti-rat EPO monoclonal antibody was purchased from Santa Cruz Company （USA）. METHODS： This experiment was carried out in the Department of Anatomy, Medical College, Qingdao University during March 2005 to March 2006. ① The 84 rats were divided into 3 groups by a lot： IPC group （n=40）, sham-operation group （n=40） and control group （n=4）. In the IPC group, middle cerebral artery was occluded for 2 hours respectively on the 1^st, 3^rd, 7^th, 14^th and 21^st days of the reperfusion following 10-minute preischemia was made using a modified middle cerebral artery second suture method from Zea-Longa. The rats were sacrificed 22 hours after reperfusion in the end of middle cerebral artery occlusion （MCAO）. That was to say, after 10-minute preischemia, suture was exited to the extemal carotid artery and embedded subcutaneously. Middle cerebral artery was occluded again to form the second reperfusion at the set time point after reperfusion. Twenty-two hours later, rats were sacrificed; In the sham-operation group,the preischemia was substituted by sham-operation（only common carotid artery and crotch were exposed, and MCAO by suture was omitted）, and the other procedures were the same as those in the IPC group. In the control group, rats were given sham-operation twice at an interval of one day, and they were sacrificed 24 hours after the second sham-operation. ② Brain tissue was taken from the rats in each group. Cerebral infarction area of each layer was measured with TTC staining, and total cerebral infarction volume （The total cerebral infarction area of each layerxinterspace ） was calculated. After brain tissue was stained by haematoxylin-esoin （HE）, the form of nerve cells was observed under an optical microscope, and the expressions of HIF-1α（and EPO protein in the brain tissue were detected with immunohistochemical method. MAIN OUTCOME MEASURES： ①Cerebral infarction volume;②form of nerve cell; ③ the expression of HIF-1α and EPO protein in the brain tissue. RESULTS：Totally 84 rats were enrolled in the experiment. The dead rats were randomly supplied during the experiment, and finally 84 rats entered the stage of result analysis. ① Detection of cerebral infarction volume of rats in each group： Cerebral infarction volume in the IPC group was significantly smaller than that in the sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively [（161.2±6.9） mm^3 vs （219.9±11.2） mm^3, （134.9±9.0） mm^3 vs （218.6±13.0） mm^3, （142.9±13.7） mm^3 vs （221.3±14.2） mm^3, t=-8.924, 10.587,7.947, P〈 0.01]. ② Observation of nerve cell form of brain tissue： HE staining showed that the ischemic degree, range and cerebral edema degree of IPC group were significantly milder than those of sham-operation group. ③ The expressions of HIF-1α and EPO protein in cerebral cortex and hippocampus ： The expression of HIF-1αof IPC group was significantly higher than that of sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively （125.93±3.79 vs 117.65±5.60, 140.63±4.64 vs 119.33±4.26, 131.15±2.74 vs 107.60±3.89, t=2.449, 6.763,9.899,P 〈 0.05-0.01）. The expression of EPO of IPC group was significantly higher than that of sham-operation group on the 3^rd and 7^th days after perfusion respectively （141.68±3.29 vs 126.33±4.51, 138.88±2.59 vs 125.58±6.18,t=5.499,3.970, P〈 0.05）. CONCLUSION ： ①IPC can protect the never cells in rat brain and the best time to onset of cerebral IT induced by IPC is 1 to 7 days after reperfusion. ② Neuroprotective effect of cerebral IT might be related to the expression of HIF-1α and its target gene EPO.
基金financially supported by the National Natural Science Foundation of China,No.81301006a grant from Henan Provincial Scientific and Technological Research Projects of China,No.132102310092
文摘Ischemic edema can alter the structure and permeability of the blood-brain barrier. Recent studies have reported that progesterone reduces cerebral edema after cerebral ischemia. However, the underlying mechanism of this effect has not yet been elucidated. In the present study, progesterone effectively reduced Evans blue extravasation in the ischemic penumbra, but not in the ischemic core, 48 hours after cerebral ischemia in rats. Progesterone also inhibited the down-regulation of gene and protein levels of occludin and zonula occludens-1 in the penumbra. These results indicate that progesterone may effectively inhibit the down-regulation of tight junctions, thereby maintaining the integrity of the blood-brain barrier and reducing cerebral edema.
文摘BACKGROUND: The mechanism of intracerebral hemorrhage (ICH)-induced hemorrhagic brain injury is very complicated, involving the position-occupying effect of cephalophyma, ischemic factors, the toxic effect of hematoma components, the destruction of blood-brain barrier, etc. The expression and effect of hemeoxygenase-1 (HO-1) in the cerebrovascular disease has been paid close attention. OBJECTIVE: To observe the expression of HO-1 and change of superoxide dismutase (SOD) in the peri-hematomal brain tissue of rats following ICH. DESIGN: Randomized controlled animal experiment. SETTING: Department of Neurology, Yijishan Hospital Affiliated to Wannan Medical College. MATERIALS: Forty healthy male SD rats, of clean grade, weighing from 250 to 300 g, were provided by Qinglongshan Animal Farm of Nanjing. The involved 40 rats were randomized into sham-operation group (n =5) and ICH group (n =35), and ICH group was divided into 7 subgroups with 5 rats in each: ICH 6, 12, 24, 48, 72, 100 and 168 hours groups. Rabbit anti-rat HO-1 immunohistochemial kit ( Boster Co., Ltd., Wuhan) and SOD kit (Jiancheng Bioengineering Institute, Nanjing)were used in this experiment. METHODS: This experiment was carried out in the Department of Neurology, Yijishan Hospital Affiliated to Wannan Medical College Between April and July 2005. In the ICH group: Autologous blood of rats was injected into the head of caudate nucleus to create ICH animal models. In the sham-operation group, the same amount of normal saline was injected into the head of caudate nucleus of rats. The brains of rats in each group were harvested at different time points. The hematoma-side brain tissue was cut open in the coronal plane taking hematomal region as center, and the posterior part was fixed with 100 g/L neutral formaldehyde. 100 mg brain tissue was taken from anterior part. The number of positive cells in HO-1 and SOD activity in peri-hematomal brain tissue at different time after ICH were detected by immunohistochemical method and xanthine oxidation method respectively. MAIN OUTCOME MEASURES: ① The expression of HO-1 in the peri-hematomal brain tissue of rats in two groups following ICH.② The expression of SOD activity in the peri-hematomal brain tissue of rats in two groups following ICH. RESULTS: ①The number of HO-1 positive cells in the peri-hematomal brain tissue of rats in two groups following ICH 6, 12, 24, 48, 72, 120 and 168 hours was (11.03±2.01),(16.47±2.98),(25.50±5.65),(51.57±7.05),(47.33±4.73),(26.57±5.12),(7.63±2.17) cells/high-fold visual field , respectively; The number of HO-1 positive cells in the ICH 12-120 hours groups was significantly higher than that of sham-operation group [(6.07±1.85)cells/high-fold visual field, P < 0.01]; The HO-1 positive cells were the most in the ICH 48 hours group and were still expressed a little in the ICH 168 hours group. ② The SOD in the brain tissue of rats at ICH 6, 12, 24, 48, 72, 120 and 168 hours was (404.46±8.14),(396.84±10.97),(387.74±5.32),(356.21±9.27),(307.95±10.15),(357.48±11.28) and (402.98±7.23) kNU/g, respectively; The SOD activity of ICH 12 to 120 hours groups was significantly lower than that of sham-operation group [(415.47±11.44) kNU/g,P < 0.01], and that of ICH 72 hours group was the lowest. There was no significant difference of SOD activity between ICH 168 hours group and sham-operation group (P > 0.05). CONCLUSION: Following ICH, the expression of HO-1 in peri-hematomal brain tissue of rats in two groups is obviously increased, but the antioxidant ability of brain tissue is decreased. The changes of both maybe play an important role in the formation of ICH-induced hemorrhagic brain injury.
基金supported by grants from the National Science Foundation of China(No.81974118,82325010)The Shanghai Outstanding Academic Leaders(China)(No.20XD1433300)+4 种基金the Shuguang Project of China(21SG11)the Innovative Research Team of High-level Local Universities in Shanghai,China(No.SHSMU-ZDCX20212700)the Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education(China)(No.2023ZKZD17)the Shanghai Research Center for Endocrine and Metabolic Diseases(China)(No.2022ZZ01002)the Shanghai Sixth People’s Hospital Foundation(China)(No.ynqn202105).
文摘Non-alcoholic fatty liver disease(NAFLD)is a hepatic metabolic syndrome arisingfrom lipid metabolic imbalance,with its prevalence increasing globally.In this study,weobserved a significant up-regulation of interferon regulatory factor 8(IRF8)in the liver ofNAFLD model mice and patients.Overexpression of IRF8 induced lipid accumulation in themouse primary hepatocytes.Mice with adeno-associated virus-mediated IRF8 overexpressionexhibited hepatic steatosis due to up-regulated peroxisome proliferator-activated receptorγ(PPARγ)expression and increased fatty acid uptake and lipogenesis.In vitro,small interfering RNA-mediated IRF8 knockdown attenuated triglyceride accumulation by dampening PPARγexpression through transcriptional inhibition of brain and muscle ARNT-like 1.ThePPARγ-specific antagonist GW9662 abolished the effect of IRF8 overexpression.Furthermore,adeno-associated virus-mediated IRF8 knockdown in the mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome.These findings indicate that IRF8 playsa vital role in modulating hepatic lipid metabolism in a PPARγ-dependent manner and providea previously unknown insight into NAFLD therapeutic strategies.
文摘Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. Methods： BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed, pcDNA-BASP 1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines （BHT- I 01 and KMH-2）. The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenografl tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. Results： BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues （P = 0.000）. pcDNA-BASP1 restored the expression of BASPI and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice （P = 0.000）. pcDNA-BASPI induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. Conclusions： Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASPI expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASPI gene might act as a potential therapeutic agent for the treatment of thyroid cancer.
基金supported by National Science Foundation of China(Grant No.32271409,82002370,31800806)National Basic Research Program of China(2021YFA1201404)+5 种基金China Postdoctoral Science Foundation(Grant No.2019M661806)Major Project of NSFC(81991514)Natural Science Foundation of Jiangsu Province(Grant No.BK20200117)Jiangsu postdoctoral research support project(Grant No.2021K059A)Program of Innovation and Entrepreneurship of Jiangsu Province,Jiangsu Provincial Key Medical Center Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Medical Youth Talent Foundation and Jiangsu Provincial Key Medical Talent Foundation,the Fundamental Research Funds for the Central Universities(14380493,14380494)Changzhou Sci&Tech Program(Grant No.CJ20220103).
文摘Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.
