The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease...The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease.RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD.Specifically,RACK1 is involved in regulation of the amyloid-β precursor protein processing through α-or β-secretase by binding to different protein kinase C isoforms.Additionally,RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors,thereby preventing neuronal excitotoxicity.RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways,such as nuclear factor-kappa B,tumor necrosis factor-alpha,and NOD-like receptor family pyrin domain-containing 3 pathways.The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy,in which RACK1 is a potential target.In this review,we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.展开更多
BACKGROUND Acute kidney injury(AKI)is a common clinical syndrome with high morbidity and mortality rates.The use of pluripotent stem cells holds great promise for the treatment of AKI.Urine-derived stem cells(USCs)are...BACKGROUND Acute kidney injury(AKI)is a common clinical syndrome with high morbidity and mortality rates.The use of pluripotent stem cells holds great promise for the treatment of AKI.Urine-derived stem cells(USCs)are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive,simple,and low-cost approach and are induced with high multidifferentiation potential.Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined.METHODS Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid.AKI severe combined immune deficiency(SCID)mice models were induced by means of an intramuscular injection with glycerol.USCs isolated from human-voided urine were administered via tail veins.The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine.The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining.Meanwhile,we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells(MSCs).RESULTS Treatment with USCs significantly alleviated histological destruction and functional decline.The renal function was rapidly restored after intravenous injection of 5×105 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline.Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors.This suggests that a mixture of various mediators closely interacts with their biochemical functions.Two types of stem cells showed enhanced tubular cell prolif-eration and decreased tubular cell apoptosis,although USC treatment was not more effective than MSC treatment.We found that USC therapy significantly improved renal function and histological damage,inhibited inflammation and apoptosis processes in the kidney,and promoted tubular epithelial proliferation.CONCLUSION Our study demonstrated the potential of USCs for the treatment of AKI,representing a new clinical therapeutic strategy.展开更多
Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively investigated.However,mo...Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively investigated.However,most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models,and whether various medications and natural products prevent the development of DCM,associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis.The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies,with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors.We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link,given that several studies have provided both direct and indirect evidence under specific conditions.This editorial emphasizes that the current investigation should be circumspect in its conclusion,i.e.,not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models.Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM,targeting these biomarkers.展开更多
This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor ag...This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
In this editorial,we comment on the article by He et al,specifically in relation to the efficacy of bariatric surgery vs glucagon-like peptide-1 receptor agonist(GLP-1RA)therapy in the management of type 2 diabetes(T2...In this editorial,we comment on the article by He et al,specifically in relation to the efficacy of bariatric surgery vs glucagon-like peptide-1 receptor agonist(GLP-1RA)therapy in the management of type 2 diabetes(T2D)associated with obesity.Bariatric surgery has now also been shown to be safe and effective in pre-teens and teenagers with obesity and T2D,but information on newer GLP-1RAs in these groups is predictably limited.In older individuals(age>65 years),both bariatric surgery and GLP-1RA therapy improve cardiovascular outcomes.Baria-tric surgery is not infrequently associated with post-operative postprandial hypoglycemia,which is not the case with GLP-1RAs and,paradoxically,there is evidence that GLP-1RAs may reduce both the frequency and severity of postprandial hypoglycemia.Comparative trials of the long-term efficacy of bariatric surgery and GLP-1RAs are indicated.展开更多
Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveil...Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.展开更多
Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the devel...Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the developed world,the majority are still prevalent,with an increasing trend in the developing world.Currently used therapies are mainly‘glucocentric’,focusing on the optimization of glycemic control to prevent,delay or manage diabetes-associated complications-other common comorbidities,such as dyslipidemia and hypertension are often underestimated.Although a number of novel therapeutic approaches have been reported recently,some of them have not received comparable attention in relation to either further studies or potential clinical implementation.This editorial briefly discusses some recent therapeutic approaches to the prevention and management of diabetes and its associated complications,as well as potential directions for future research and development in this area.展开更多
Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia.However,given its inherent complexity,few animal models of delir...Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia.However,given its inherent complexity,few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive.Here,we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors,including anesthesia with surgery(AS),systemic inflammation,and neurotransmission modulation.We found that both bacterial lipopolysaccharide(LPS)and cholinergic receptor antagonist scopolamine(Scop)induction reduced neuronal activities in the delirium-related brain network,with the latter presenting a similar pattern of reduction as found in delirium patients.Consistently,Scop injection resulted in reversible cognitive impairment with hyperactive behavior.No loss of cholinergic neurons was found with treatment,but hippocampal synaptic functions were affected.These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.展开更多
Uncontrolled hyperglycemia or poorly managed disease increases the propensityfor a number of diabetes-related complications targeting major organs includingthe heart, eyes, and kidney. Although the mechanisms by which...Uncontrolled hyperglycemia or poorly managed disease increases the propensityfor a number of diabetes-related complications targeting major organs includingthe heart, eyes, and kidney. Although the mechanisms by which diabetes inducescardiovascular diseases include oxidative stress and inflammation, when insulinresistance remains the key to the pathogenesis, as implicated in the two reviews inthis issue. This editorial mainly comments on the potential preventive applicationof glycyrrhetinic acid (or 18β-GA) in relation to diabetic nephropathy. The therapeuticor preventive effects of 18β-GA, as a hydrolytic product of glycy-rrhizicacid that is a component of licorice, have been appreciated in other disorders, buthave received much less attention in relation to diabetic complications. A study inthis issue has identified 18β-GA as a therapeutic for preventing diabeticnephropathy and provides evidence to support efficacy in cultured human renaltubule cells in vitro. Although it represents a pilot study, the observations supporta new therapeutic approach that warrants further ex-ploration.展开更多
Neuroblastoma(NB)is a common pediatric extracranial solid tumor that exhibits varied characteristics,clinical features,and prognosis.1 Totally 1%-2%of cases show familial history with genetic links like ALK,PHOX2B mut...Neuroblastoma(NB)is a common pediatric extracranial solid tumor that exhibits varied characteristics,clinical features,and prognosis.1 Totally 1%-2%of cases show familial history with genetic links like ALK,PHOX2B mutations,and1p36or11q14-23locusdeletions.Gastrointestinal stromal tumors(GISTs)are rare mesenchymal neoplasms of the gastrointestinal tract.展开更多
Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing ...Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.展开更多
Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain da...Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017.展开更多
AIM: To investigate the effect of a new infant formula supplemented with a low level (0.24 g/100 mL) of galacto-oligosaccharide (GOS) on intestinal micro-flora (Bif idobacteria, Lactobacilli and E. coli) and fermentat...AIM: To investigate the effect of a new infant formula supplemented with a low level (0.24 g/100 mL) of galacto-oligosaccharide (GOS) on intestinal micro-flora (Bif idobacteria, Lactobacilli and E. coli) and fermentation characteristics in term infants, compared with human milk and a standard infant formula without GOS. METHODS: Term infants (n = 371) were approached in this study in three hospitals of China. All infants started breast-feeding. Those who changed to formula-feeding within 4 wk after birth were randomly assigned to one of the two formula groups. Growth and stool characteristics, and side effects that occurred in recruited infants were recorded in a 3-mo follow-up period. Fecal samples were collected from a subpopulation of recruited infants for analysis of intestinal bacteria (culture technique), acetic acid (gas chromatography) and pH (indicator strip). RESULTS: After 3 mo, the intestinal Bifidobacteria, Lactobacilli , acetic acid and stool frequency were significantly increased, and fecal pH was decreased in infants fed with the GOS-formula or human milk, compared with those fed with the formula withoutGOS. No significant differences were observed between the GOS formula and human milk groups. Supplementation with GOS did not influence the incidence of crying, regurgitation and vomiting. CONCLUSION: A low level of GOS (0.24 g/100 mL) in infant formula can improve stool frequency, decrease fecal pH, and stimulate intestinal Bifidobacteria and Lactobacilli as in those fed with human milk.展开更多
AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical c...AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11(STK11) gene analysis was also performed using a DNA sample from this infant.RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the STK11 gene further revealed a novel frameshift mutation(c.64_65het_del AT) in exon 1 in this PJS infant.CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the STK11 gene mutation is the primary cause of PJS.展开更多
AIM： To study the evolution of the refractive status and examine the affected factors in infants during the first year of life in a large sample size in China. METHODS： A total of 1258 babies （2516 eyes） aged 32w...AIM： To study the evolution of the refractive status and examine the affected factors in infants during the first year of life in a large sample size in China. METHODS： A total of 1258 babies （2516 eyes） aged 32wk gestational age to ty participated in the study, including 766 premature and 492 full-term infants. First, each baby received an orthoptic examination, slit-lamp checking and fundus imaging. Patients with diseases which might affect refractive status were excluded from the cohort. The cycloplegia retinoscopy was performed. Their neonatal histories were reviewed. Each measurement contained the refractive status and calculation of the spherical equivalent （SE）. RESULTS： Refractive state showed an average hyperopia of ＋0.94_＋1.63 D at early ages, followed by a trend toward more hyperopia. The refractive state reached the top （＋2.431.46 D） at the age of one to two months. Then gliding till one year old when the refractive state reached ＋0.59：1.41 D. The prevalence of astigmatism was 42.17% in the study, being 2.82% myopic astigmatism and 39.35% hyperopic astigmatism. The 94.1% of hyperopic astigmatism was with-the-rule astigmatism and 71.83% of myopic astigmatism was with-the-rule astigmatism. Refractive state between boys and girls was different. The mean SE of boys was ＋1.97＋1.57 D, while that of girls was ＋1.79＋1.46 D, and the difference was significant. CONCLUSION： Before one year old, the change of refractive status is associated with checking age and sex. At the age of one to two months, the degree of hyperopia reaches the top. Boys have more hyperopic degree than girls, and with- the-rule astigmatism is predominant. Excluding premature infants with advanced retinopathy of prematurity, premature and full-term children have same refraction status.展开更多
Background:The chronic unpredictable mild stress(CUMS)model has long been considered the best model for exploring the pathophysiological mechanisms underlying depression.However,there are no widely recognised standard...Background:The chronic unpredictable mild stress(CUMS)model has long been considered the best model for exploring the pathophysiological mechanisms underlying depression.However,there are no widely recognised standards for strategies for modeling and for behavioral testing.The present study aimed to optimize the protocols for food deprivation and the sucrose preference test(SPT)for the CUMS model.Methods:We first evaluated the effects of different long periods of food deprivation on the body weight of Sprague Dawley(SD)rats by testing food deprivation for 24 hours(8:00-8:00^+),food deprivation for 12 hours during the daytime(8:00-20:00)and food deprivation for 12 hours at night(20:00-8:00^+).Next,we established a SD rat CUMS model with 15 different stimulations,and used body weight measurement,SPT,forced swim test(FST),open field test(OFT)and Morris water maze(MWM)test to verify the success of the modeling.In the SPT,consumption of sucrose and pure water within 1 and 12 hours was measured.Results:Twelve hours of food deprivation during the daytime(8:00-20:00)had no effect on body weight,while 12 hours of food deprivation at night(20:00-8:00^+)and 24 hours of food deprivation(8:00-8:00^+)significantly reduced the mean body weight of the SD rats.When SPT was used to verify the successful establishment of the CUMS rat model,sucrose consumption measured within 12 hours was less variable than that measured within 1 hour.Conclusions:Twelve hours of food deprivation in the daytime(8:00-20:00)may be considered a mild stimulus for the establishment of a CUMS rat model.Measuring sucrose consumption over 12 hours is recommended for SPT.展开更多
Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts th...Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts the gut microbiota,leading to neuroinflammation and psychological disturbances.However,it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns.In the present study,MSD was performed on pregnant SpragueDawley rats in the third trimester of pregnancy(gestational days 15-21),after which intestinal contents and brain tissues were collected from offspring at different postnatal days(P1,P7,P14,and P56).Based on microbial profiling,microbial diversity and richness increased in pregnant rats subjected to MSD,as reflected by the significant increase in the phylum Firmicutes.In addition,microbial dysbiosis marked by abundant Firmicutes bacteria was observed in the MSD offspring.Furthermore,quantitative real-time polymerase chain reaction(q RT-PCR)and enzyme-linked immunosorbent assay(ELISA)showed that the expression levels of proinflammatory cytokines interleukin 1β(IL-1β)and tumor necrosis factorα(TNF-α)were significantly higher in the MSD offspring at adulthood(P56)than in the control group.Through Spearman correlation analysis,IL-1βand TNF-αwere also shown to be positively correlated with Ruminococcus_1 and Ruminococcaceae_UCG-005 at P56,which may determine the microbiota-host interactions in MSDrelated neuroinflammation.Collectively,these results indicate that MSD changes maternal gut microbiota and affects the establishment of neonatal gut microbiota,leading to neuroinflammation in MSD offspring.Therefore,understanding the role of gut microbiota during physiological development may provide potential interventions for cognitive dysfunction in MSD-impacted offspring.展开更多
Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a r...Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.82071395)the Natural Science Foundation of Chongqing(Grant Nos.cstc2021ycjh-bgzxm0186,cstc2020jcyj-zdxmX0004,and cstc2021jcyj-bsh0023)the CQMU Program for Youth Innovation in Future Medicine(Grant No.W0044).
文摘The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease.RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD.Specifically,RACK1 is involved in regulation of the amyloid-β precursor protein processing through α-or β-secretase by binding to different protein kinase C isoforms.Additionally,RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors,thereby preventing neuronal excitotoxicity.RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways,such as nuclear factor-kappa B,tumor necrosis factor-alpha,and NOD-like receptor family pyrin domain-containing 3 pathways.The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy,in which RACK1 is a potential target.In this review,we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.
文摘BACKGROUND Acute kidney injury(AKI)is a common clinical syndrome with high morbidity and mortality rates.The use of pluripotent stem cells holds great promise for the treatment of AKI.Urine-derived stem cells(USCs)are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive,simple,and low-cost approach and are induced with high multidifferentiation potential.Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined.METHODS Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid.AKI severe combined immune deficiency(SCID)mice models were induced by means of an intramuscular injection with glycerol.USCs isolated from human-voided urine were administered via tail veins.The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine.The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining.Meanwhile,we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells(MSCs).RESULTS Treatment with USCs significantly alleviated histological destruction and functional decline.The renal function was rapidly restored after intravenous injection of 5×105 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline.Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors.This suggests that a mixture of various mediators closely interacts with their biochemical functions.Two types of stem cells showed enhanced tubular cell prolif-eration and decreased tubular cell apoptosis,although USC treatment was not more effective than MSC treatment.We found that USC therapy significantly improved renal function and histological damage,inhibited inflammation and apoptosis processes in the kidney,and promoted tubular epithelial proliferation.CONCLUSION Our study demonstrated the potential of USCs for the treatment of AKI,representing a new clinical therapeutic strategy.
文摘Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively investigated.However,most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models,and whether various medications and natural products prevent the development of DCM,associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis.The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies,with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors.We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link,given that several studies have provided both direct and indirect evidence under specific conditions.This editorial emphasizes that the current investigation should be circumspect in its conclusion,i.e.,not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models.Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM,targeting these biomarkers.
文摘This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
文摘In this editorial,we comment on the article by He et al,specifically in relation to the efficacy of bariatric surgery vs glucagon-like peptide-1 receptor agonist(GLP-1RA)therapy in the management of type 2 diabetes(T2D)associated with obesity.Bariatric surgery has now also been shown to be safe and effective in pre-teens and teenagers with obesity and T2D,but information on newer GLP-1RAs in these groups is predictably limited.In older individuals(age>65 years),both bariatric surgery and GLP-1RA therapy improve cardiovascular outcomes.Baria-tric surgery is not infrequently associated with post-operative postprandial hypoglycemia,which is not the case with GLP-1RAs and,paradoxically,there is evidence that GLP-1RAs may reduce both the frequency and severity of postprandial hypoglycemia.Comparative trials of the long-term efficacy of bariatric surgery and GLP-1RAs are indicated.
基金supported by Scientific Research Project of Beijing Children's Hospital(2012MS08)Beijing Municipal Science and Technology Project(D131100005313014)
文摘Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.
文摘Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the developed world,the majority are still prevalent,with an increasing trend in the developing world.Currently used therapies are mainly‘glucocentric’,focusing on the optimization of glycemic control to prevent,delay or manage diabetes-associated complications-other common comorbidities,such as dyslipidemia and hypertension are often underestimated.Although a number of novel therapeutic approaches have been reported recently,some of them have not received comparable attention in relation to either further studies or potential clinical implementation.This editorial briefly discusses some recent therapeutic approaches to the prevention and management of diabetes and its associated complications,as well as potential directions for future research and development in this area.
基金supported by the National Natural Science Foundation of China(82071191,82001129)Natural Science Foundation of Sichuan Province(2022NSFSC1509)+1 种基金National Clinical Research Center for Geriatrics of West China Hospital(Z2021LC001)West China Hospital 1.3.5 Project for Disciplines of Excellence(ZYYC20009)。
文摘Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia.However,given its inherent complexity,few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive.Here,we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors,including anesthesia with surgery(AS),systemic inflammation,and neurotransmission modulation.We found that both bacterial lipopolysaccharide(LPS)and cholinergic receptor antagonist scopolamine(Scop)induction reduced neuronal activities in the delirium-related brain network,with the latter presenting a similar pattern of reduction as found in delirium patients.Consistently,Scop injection resulted in reversible cognitive impairment with hyperactive behavior.No loss of cholinergic neurons was found with treatment,but hippocampal synaptic functions were affected.These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.
文摘Uncontrolled hyperglycemia or poorly managed disease increases the propensityfor a number of diabetes-related complications targeting major organs includingthe heart, eyes, and kidney. Although the mechanisms by which diabetes inducescardiovascular diseases include oxidative stress and inflammation, when insulinresistance remains the key to the pathogenesis, as implicated in the two reviews inthis issue. This editorial mainly comments on the potential preventive applicationof glycyrrhetinic acid (or 18β-GA) in relation to diabetic nephropathy. The therapeuticor preventive effects of 18β-GA, as a hydrolytic product of glycy-rrhizicacid that is a component of licorice, have been appreciated in other disorders, buthave received much less attention in relation to diabetic complications. A study inthis issue has identified 18β-GA as a therapeutic for preventing diabeticnephropathy and provides evidence to support efficacy in cultured human renaltubule cells in vitro. Although it represents a pilot study, the observations supporta new therapeutic approach that warrants further ex-ploration.
基金supported by the National Natural Science Foundation of China (No.82293660,82293665)the Consulting and Research Project of the Chinese Academy of Engineering (No.2019-XY-34).
文摘Neuroblastoma(NB)is a common pediatric extracranial solid tumor that exhibits varied characteristics,clinical features,and prognosis.1 Totally 1%-2%of cases show familial history with genetic links like ALK,PHOX2B mutations,and1p36or11q14-23locusdeletions.Gastrointestinal stromal tumors(GISTs)are rare mesenchymal neoplasms of the gastrointestinal tract.
基金supported by grants from the National Natural Science Foundation of China(81730057,82130062)the Key Project of Military Medical Innovation Program of Chinese PLA(18CXZ026)+1 种基金the Guangdong Clinical Research Center for Critical Care Medicine(2020B1111170005)the Sun Yat?sen University Clinical Research Program 5010(2019002)。
文摘Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.
基金supported by the National Natural Science Foundation of China,Nos.81872845(to ML),81771625(to XF)the Natural Science Foundation of Jiangsu Province of China,No.BK20180207(to ML)+4 种基金Jiangsu Provincial Medical Youth Talent of China,No.QNRC2016762(to ML)the Pediatric Clinical Center of Suzhou City of China,No.Szzx201504(to XF)Postgraduate Research&Practice Innovation Program of Jiangsu Province of China,No.KYCX19_1998(to LLT)Jiangsu Government Scholarship for Overseas Studies of China,No.JS-2017-127(to ML)the Fifth Batch of Gusu Health Talent Plan of China(to ML).
文摘Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017.
文摘AIM: To investigate the effect of a new infant formula supplemented with a low level (0.24 g/100 mL) of galacto-oligosaccharide (GOS) on intestinal micro-flora (Bif idobacteria, Lactobacilli and E. coli) and fermentation characteristics in term infants, compared with human milk and a standard infant formula without GOS. METHODS: Term infants (n = 371) were approached in this study in three hospitals of China. All infants started breast-feeding. Those who changed to formula-feeding within 4 wk after birth were randomly assigned to one of the two formula groups. Growth and stool characteristics, and side effects that occurred in recruited infants were recorded in a 3-mo follow-up period. Fecal samples were collected from a subpopulation of recruited infants for analysis of intestinal bacteria (culture technique), acetic acid (gas chromatography) and pH (indicator strip). RESULTS: After 3 mo, the intestinal Bifidobacteria, Lactobacilli , acetic acid and stool frequency were significantly increased, and fecal pH was decreased in infants fed with the GOS-formula or human milk, compared with those fed with the formula withoutGOS. No significant differences were observed between the GOS formula and human milk groups. Supplementation with GOS did not influence the incidence of crying, regurgitation and vomiting. CONCLUSION: A low level of GOS (0.24 g/100 mL) in infant formula can improve stool frequency, decrease fecal pH, and stimulate intestinal Bifidobacteria and Lactobacilli as in those fed with human milk.
文摘AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11(STK11) gene analysis was also performed using a DNA sample from this infant.RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the STK11 gene further revealed a novel frameshift mutation(c.64_65het_del AT) in exon 1 in this PJS infant.CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the STK11 gene mutation is the primary cause of PJS.
基金Supported by Shandong Nature Scienc Foundation(No.ZR2015HM026)
文摘AIM： To study the evolution of the refractive status and examine the affected factors in infants during the first year of life in a large sample size in China. METHODS： A total of 1258 babies （2516 eyes） aged 32wk gestational age to ty participated in the study, including 766 premature and 492 full-term infants. First, each baby received an orthoptic examination, slit-lamp checking and fundus imaging. Patients with diseases which might affect refractive status were excluded from the cohort. The cycloplegia retinoscopy was performed. Their neonatal histories were reviewed. Each measurement contained the refractive status and calculation of the spherical equivalent （SE）. RESULTS： Refractive state showed an average hyperopia of ＋0.94_＋1.63 D at early ages, followed by a trend toward more hyperopia. The refractive state reached the top （＋2.431.46 D） at the age of one to two months. Then gliding till one year old when the refractive state reached ＋0.59：1.41 D. The prevalence of astigmatism was 42.17% in the study, being 2.82% myopic astigmatism and 39.35% hyperopic astigmatism. The 94.1% of hyperopic astigmatism was with-the-rule astigmatism and 71.83% of myopic astigmatism was with-the-rule astigmatism. Refractive state between boys and girls was different. The mean SE of boys was ＋1.97＋1.57 D, while that of girls was ＋1.79＋1.46 D, and the difference was significant. CONCLUSION： Before one year old, the change of refractive status is associated with checking age and sex. At the age of one to two months, the degree of hyperopia reaches the top. Boys have more hyperopic degree than girls, and with- the-rule astigmatism is predominant. Excluding premature infants with advanced retinopathy of prematurity, premature and full-term children have same refraction status.
基金This work was supported by Social livelihood projects of Chongqing Science and Technology Bureau(cstc2017shms-zdyfX0048,csts2017shmsA00007).
文摘Background:The chronic unpredictable mild stress(CUMS)model has long been considered the best model for exploring the pathophysiological mechanisms underlying depression.However,there are no widely recognised standards for strategies for modeling and for behavioral testing.The present study aimed to optimize the protocols for food deprivation and the sucrose preference test(SPT)for the CUMS model.Methods:We first evaluated the effects of different long periods of food deprivation on the body weight of Sprague Dawley(SD)rats by testing food deprivation for 24 hours(8:00-8:00^+),food deprivation for 12 hours during the daytime(8:00-20:00)and food deprivation for 12 hours at night(20:00-8:00^+).Next,we established a SD rat CUMS model with 15 different stimulations,and used body weight measurement,SPT,forced swim test(FST),open field test(OFT)and Morris water maze(MWM)test to verify the success of the modeling.In the SPT,consumption of sucrose and pure water within 1 and 12 hours was measured.Results:Twelve hours of food deprivation during the daytime(8:00-20:00)had no effect on body weight,while 12 hours of food deprivation at night(20:00-8:00^+)and 24 hours of food deprivation(8:00-8:00^+)significantly reduced the mean body weight of the SD rats.When SPT was used to verify the successful establishment of the CUMS rat model,sucrose consumption measured within 12 hours was less variable than that measured within 1 hour.Conclusions:Twelve hours of food deprivation in the daytime(8:00-20:00)may be considered a mild stimulus for the establishment of a CUMS rat model.Measuring sucrose consumption over 12 hours is recommended for SPT.
基金supported by the National Natural Science Foundation of China(82071395,91749116)Natural Science Foundation of Chongqing(cstc2021ycjh-bgzxm0186,cstc2020jcyjzdxm X0004)+1 种基金Science and Technology Research Program of Chongqing Municipal Education Commission(KJZD-K201900403)Innovation Research Group at Institutions of Higher Education in Chongqing(CXQTP19034)。
文摘Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts the gut microbiota,leading to neuroinflammation and psychological disturbances.However,it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns.In the present study,MSD was performed on pregnant SpragueDawley rats in the third trimester of pregnancy(gestational days 15-21),after which intestinal contents and brain tissues were collected from offspring at different postnatal days(P1,P7,P14,and P56).Based on microbial profiling,microbial diversity and richness increased in pregnant rats subjected to MSD,as reflected by the significant increase in the phylum Firmicutes.In addition,microbial dysbiosis marked by abundant Firmicutes bacteria was observed in the MSD offspring.Furthermore,quantitative real-time polymerase chain reaction(q RT-PCR)and enzyme-linked immunosorbent assay(ELISA)showed that the expression levels of proinflammatory cytokines interleukin 1β(IL-1β)and tumor necrosis factorα(TNF-α)were significantly higher in the MSD offspring at adulthood(P56)than in the control group.Through Spearman correlation analysis,IL-1βand TNF-αwere also shown to be positively correlated with Ruminococcus_1 and Ruminococcaceae_UCG-005 at P56,which may determine the microbiota-host interactions in MSDrelated neuroinflammation.Collectively,these results indicate that MSD changes maternal gut microbiota and affects the establishment of neonatal gut microbiota,leading to neuroinflammation in MSD offspring.Therefore,understanding the role of gut microbiota during physiological development may provide potential interventions for cognitive dysfunction in MSD-impacted offspring.
基金This study was supported by the National Natural Science Foundation of China,Nos.81871193(to XD),81671532(to BS),81771625&81701490(to XF),81801505(to MG)Jiangsu Provincial Medical Youth Talent of China,Nos.QNRC2016763(to XD),QNRC2016758(to LXX),QNRC2016762(to ML)+7 种基金the Science and Technology Project of Suzhou City of China,No.SS201709(to XD)the Natural Science Foundation of Jiangsu Province of China,No.BK20180205(to XD)the Training Program Foundation for Health Talents of Gusu of China,No.GSWS2019049(to XD)the Jiangsu Provincial Key Medical Discipline of China,No.ZDXKA2016013(to XF)the Jiangsu Province Women and Children Health Research Project of China,No.F201750(to LXX)the Pediatric Clinical Center of Suzhou City of China,No.Szzx201504(to XF)Suzhou Industrial Technology Innovation Project of China,No.SYS201765(to LZ)the Project of Suzhou Science,Education and Health and Technology,China,No.KJXW2018018(to ML).
文摘Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.
