BACKGROUND Cardiac syndrome X(CSX)is characterized by persistent angina with normal coronary arteries.Several pathophysiologic mechanisms have been introduced,particularly Helicobacter pylori(H.pylori)infection.AIM To...BACKGROUND Cardiac syndrome X(CSX)is characterized by persistent angina with normal coronary arteries.Several pathophysiologic mechanisms have been introduced,particularly Helicobacter pylori(H.pylori)infection.AIM To investigate the association between H.pylori infection and CSX.METHODS All studies related to H.pylori infection and CSX were evaluated by comprehensive searches of global databases such as ISI Web of Knowledge,PubMed,Scopus,EMBASE,and Google scholar.Statistical analyses of selected articles were evaluated based on the summary odds ratio(OR).Finally,heterogeneity and publication bias were estimated using the I2 statistic and Cochrane Q-test as well as Begg’s and Egger’s tests.RESULTS A total of 11 studies met our inclusion criteria and 1435 patients(63%female,and 37%male)were reviewed.A significant association was observed between female patients and this syndrome(P=0.02).Our results showed a positive association between infection with this pathogen and presence of CSX(OR:5.65;95%confidence interval[CI]:4.17-7.64;I2:82.20).However,no significant association was observed with cagA-positive H. pylori strains and this syndrome (OR: 0.97;0.56-1.70 with 95%CI). Given the heterogeneity and publication bias, the resultsneed to confirmed by further prospective investigation.CONCLUSIONBased on our results, H. pylori infection is associated with an increased risk ofCSX. This bacterium appears to play a major role in the pathogenesis of CXS byinducing persistent inflammation.展开更多
Objective: To evaluate the efficacy and safety of Tongxinluo Capsule(通心络胶囊, TXL) for patients with cardiac syndrome X(CSX). Methods: Randomized controlled trials(RCTs) regarding TXL in the treatment of CS...Objective: To evaluate the efficacy and safety of Tongxinluo Capsule(通心络胶囊, TXL) for patients with cardiac syndrome X(CSX). Methods: Randomized controlled trials(RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, Pub Med, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction(AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph(ECG) improvement, and serum endothelin-1(ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses. Results: Twelve RCTs(696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio(RR): 1.46, 95% confidence interval(CI)(1.25, 1.71), P〈0.01], and improving ECG [RR: 1.45, 95% CI(1.21, 1.74), P〈0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI(0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number: –1.63, 95% CI(–2.29, –0.96), P〈0.01]. No serious adverse events were reported. Conclusions: TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety.展开更多
Objective: To evaluate the clinical effect of Liqi Kuanxiong Huoxue method (宽胸活血,LKH, traditional Chinese medicine, TCM therapeutic method for regulating qi, relieving chest stuffiness and promoting blood circul...Objective: To evaluate the clinical effect of Liqi Kuanxiong Huoxue method (宽胸活血,LKH, traditional Chinese medicine, TCM therapeutic method for regulating qi, relieving chest stuffiness and promoting blood circulation) in treating patients with cardiac syndrome X (CSX). Methods: The prospective, non-randomized controlled study was conducted on 51 selected patients with CSX, who were non-randomly assigned to 2 groups, the treated group treated with LKH in addition to the conventional treatment (32 patients), and the control group treated with conventional treatment (19 patients) like nitrate, diltiazem hydrochloride, etc. The treatment course was 14 days. The changes of such symptoms as angina pectoris, TCM syndrome and indexes of treadmill exercise test before and after treatment were observed. Results: After treatment, such symptoms as chest pain and stuffy feeling and palpitation in the treated group were improved more than those in the control group (P〈0.05); the total effective rate on angina pectoris and TCM syndrome in the treated group was better than that in the control group (P〈0.05). The treadmill exercise test showed that the maximal metabolic equivalent (Max MET), the time of angina onset and ST segment depression by 0.1 mV were obviously improved after treatment in both groups, but the improvement in the treated group was better than that in the control group respectively (P〈0.05). Conclusion: The LKH method could reduce the frequency of angina attacks and improve the clinical condition of patients with CSX.展开更多
Background The purpose of this study was to assess the morphological changes and physiological function of coronary arteries in patients presenting with chest pain but having normal coronary angiograms, using intrava...Background The purpose of this study was to assess the morphological changes and physiological function of coronary arteries in patients presenting with chest pain but having normal coronary angiograms, using intravascular ultrasound imaging (IVUS) and intracoronary Doppler (ICD) flow measurements, in order to elucidate the mechanism of syndrome X. Methods A total of 126 patients [67 males, 59 females, mean age (53.1±13.0) years] who experienced chest pain but had normal coronary angiograms were included in this study. ICD flow measurements of the left anterior descending coronary artery (LAD) were performed using a Cardiometrics FloMap Ⅱ system. Coronary flow velocity reserve (CFVR) was defined as the ratio of the average peak velocity during hyperemia to that at baseline, induced by an intracoronary bolus injection of 18 μg adenosine. A 3.2F or 2.9F 30 MHz mechanical rotating ultrasound catheter (CVIS, Boston Scientific) or a 3.0F 20MHz electronic ultrasound catheter (Endosonics) was used for IVUS. Results The mean CFVR value of the LAD was 2.71±0.74. Reduction of CFVR (<3.0) was found in 82 of 126 (65.1%) patients. IVUS images of the LAD were available for 109 patients. Plaque formation was detected in 76/109 (69.7%) patients. Based on the presence or absence of plaque formation as well as the reduction or non-reduction of CFVR, patients were divided into four groups: Group Ⅰ (n=10), normal IVUS findings and normal CFVR; Group Ⅱ (n=23), normal IVUS findings with reduction in CFVR; Group Ⅲ (n=29), IVUS evidence of plaque formation but normal CFVR; and Group Ⅳ (n=47), IVUS evidence of plaque formation with reduction in CFVR. Conclusion This study shows the important clinical value of a combination of IVUS and ICD in diagnosing patients with angiographically normal coronary arteries. Only 10% of patients studied (Group Ⅰ) were found to be truly free of coronary disease, while 20% of patients (Group Ⅱ) would be diagnosed as suffering from syndrome X.展开更多
Clinical reports on cardiac syndrome X(CSX) have been increasing in recent years.In general, CSX does not increase the cardiovascular mortality,but it can affect the patient's quality of life(QOL) and increase th...Clinical reports on cardiac syndrome X(CSX) have been increasing in recent years.In general, CSX does not increase the cardiovascular mortality,but it can affect the patient's quality of life(QOL) and increase the incidence rates of cardiovascular and cerebrovascular events.Although a variety of drugs and therapies have been utilized in the clinical treatment,the management of CSX still represents a major challenge due to its unclear pathogenesis.It is necessary to explore more effective treatment programs.Many attempts have been made on trials of the Chinese medicine(CM) treatment for CSX and proved that CM has a certain advantage in efficacy to improve clinical symptoms and QOL.CM may provide a new approach for the effective treatment of CSX.展开更多
In the present study,Fmr1 knockout mice (KO mice) were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error cou...In the present study,Fmr1 knockout mice (KO mice) were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts,indicating a learning and memory disorder.After treatment with 30,60,90,120,or 200 mg/kg lithium chloride,the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated,in particular,the 200 mg/kg lithium chloride treatment had the most significant effect.Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta,an inactive form of glycogen synthase kinase 3 beta,in the cerebral cortex and hippocampus of the Fmr1 KO mice.These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice,possibly by inhibiting glycogen synthase kinase 3 beta activity.展开更多
Polymerase chain reaction (PCR) technique combined with direct detection by silver staining on denaturing DNA sequencing gel was used to analyze the (CGG)n repeats within the FMR1 gene on 169 suspected patients wit...Polymerase chain reaction (PCR) technique combined with direct detection by silver staining on denaturing DNA sequencing gel was used to analyze the (CGG)n repeats within the FMR1 gene on 169 suspected patients with mental retardation and 33 kindreds of 6 fragile X families. The results showed that : (1) No PCR products were detected in 3 males in the suspected group. (2) In the fragile X family studies, the 5 male probands failed to show any PCR products. (3) Diplex PCR with the primers flanking the FRAXE locus was used to serve as an internal control for the 8 above mentioned males and only normal products of the FRAXE locus were detected, indicating that the possibility of false negative results of the FRAXA locus could be eliminated. These findings suggested that analysis of (CGG)n repeat within the FMR1 gene by PCR technique could efficiently detect premutation carriers and that negative PCR products in mentally retarded males might highly imply the diagnosis of fragile X syndrome after the false negative results have been excluded by diplex PCR. This PCR assay is suitable for the screening and diagnosis of fragile X syndrome in a large number of populations due to its rapidity, simplicity, stability and reliability.展开更多
Fragile X syndrome(FXS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile X mental retardation protein(FMRP).Patients with FXS suffer lifelong cognitive disabilities,but the funct...Fragile X syndrome(FXS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile X mental retardation protein(FMRP).Patients with FXS suffer lifelong cognitive disabilities,but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood.Here,we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs).Consequently,FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion,leading to cognitive impairment in mature adult mice.Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice.Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel ther⁃apeutic strategy for treating adult FXS patients.展开更多
BACKGROUND: Microalbuminuria (MAU) is a key component of metabolic syndrome (MetS) and is an early sign of diabetic nephropathy as well. Although routine Western medicine treatments are given to MetS patients to ...BACKGROUND: Microalbuminuria (MAU) is a key component of metabolic syndrome (MetS) and is an early sign of diabetic nephropathy as well. Although routine Western medicine treatments are given to MetS patients to control high blood pressure, hyperglycemia and dyslipidemia, some patients still experience progressive renal lesions and it is necessary to modify and improve the treatment strategy for MetS patients. OBJECTIVE: To investigate the efficacy of Yiqi Huaju Qingli Herb Formula, a compound traditional Chinese herbal medicine, in MetS patients with MAU when it is combined with routine Western medicine treatment. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty patients with MetS were randomized into the Chinese herbal formula group (CHF, Yiqi Huaju Qingli formula treatment in combination with Western medicine) and control group (placebo in combination with Western medicine). All treatments were administered for 12 weeks. MAIN OUTCOME MEASURES: Urinary microalbumin (MA), urinary albumin-to-creatinine ratio (UACR), 24-hour total urine protein (24-hTP), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2-hPPG), glycosylated hemoglobin (HbAlc), homeostasis model assessment for insulin resistance (HOMA-IR), blood lipid profile and blood pressure were observed. RESULTS: Compared with the control group, CHF treatment significantly decreased BMI (P〈0.05), WC (P〈0.01) and WHR (P〈0.01). Both groups had significant decreases in FPG, 2-hPPG, HbAlc, HOMA-IR, MA, and UACR, with CHF treatment showing better effects on these parameters compared with the control treatment (P〈0.05). Both treatments significantly reduced the levels of total cholesterol, low-density lipoprotein cholesterol and triacylglycerol (TAG), and a greater reduction in TAG was observed with CHF treatment (P〈0.05). The level of high-density lipoprotein cholesterol did not change in the control group after treatment (P〉0.05), whereas it significantly increased with CHF treatment (P〈0.01). Compared with before the treatment, significant decreases in systolic blood pressure, diastolic blood pressure and mean arterial blood pressure were observed in both groups (P〈0.01). However, there was no significant difference between the two groups (P〉0.05). CONCLUSION: Combined treatment ofYiqi Huaju Qingli Formula and Western medicine significantly alleviated MAU, which may correlate with the improvement of insulin sensitivity and glucose and lipid metabolism. TRIAL REGISTRATION IDENTIFIER: This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-11001633.展开更多
Metabolic syndrome, with the main clinical manifestations of obesity, dyslipidemia, elevated blood pressure, and elevated blood glucose levels, has become an increasingly prevalant global public health concern. Metab...Metabolic syndrome, with the main clinical manifestations of obesity, dyslipidemia, elevated blood pressure, and elevated blood glucose levels, has become an increasingly prevalant global public health concern. Metabolic syndrome is a convergence of multiple risk factors related to cardiovascular disease. When the concept of metabolic syndrome was initially proposed, some researchers thought the concept was unnecessary, since there were already measures in place to describe the separate cardiovascular risk factors such as dyslipidemia, hypertension and diabetes. However, a large number of epidemiological investigations confirmed that even if blood glucose or blood pressure did not reach the cutoff point of the diseases,展开更多
Objective To understand the associations of physical activity domains with metabolic syndrome among a middle-aged Chinese population. Methods In all, 3326 professional adults aged 35-64 years from Beijing and Zhejiang...Objective To understand the associations of physical activity domains with metabolic syndrome among a middle-aged Chinese population. Methods In all, 3326 professional adults aged 35-64 years from Beijing and Zhejiang province were recruited with a cluster random sampling method. The Global Physical Activity Questionnaire was modified, and the recommended Asia-Pacific cut-offs of waist circumstance were introduced into the criteria for metabolic syndrome from the Adult Treatment Panel III. A binary logistic regression model was applied to examine the association of all physical activity domains with the risk of the syndrome. Results Participants who engaged in domestic activity for 〉1176 MET-min/week had a 41.6% less chance of having metabolic syndrome [odds ratio (OR), 0.584; 95% confidence interval (CI), 0.480-0.710] than those without this activity. In adjusted models, adults who actively commuted for 〉33 MET-rain/week but 〈52g MET-min/week had a 25% less chance of having the syndrome (OR, 0.750; 95% CI, 0.582-0.966) than those who did not. No interaction was detected between the two domains of activity and the syndrome. Conclusion This study highlighted the independently negative association of traffic and house activity with the prevalence of the syndrome in this sample with a generally low level of moderate activity.展开更多
Metabolic syndrome is an epidemic that affects more and more people, increasing the probability of suffering metabolic and cardiovascular diseases in the short, medium or long term depending on the severity. The purpo...Metabolic syndrome is an epidemic that affects more and more people, increasing the probability of suffering metabolic and cardiovascular diseases in the short, medium or long term depending on the severity. The purpose of this article is to review the metabolic syndrome, assessing consensus, controversy and prevalence. The methodology was the preparation of a literature review on various health care databases, which were from 43 articles published from 2010 to 2015, in the general population. SM rate ranges from 0% to 90% depending on genders, ages and regions. There is still lack of consensus on cutoffs of diagnostic criteria. Thus, it is concluded that the prevalence of metabolic syndrome is being increased, urging the need for early diagnosis and treatment to promote the health of the global population.展开更多
The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral scl...The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,have been characterized by pathological changes in neuronal axons,including abnormal mRNA translation,the loss of protein expression,or abnormal axon transport.Moreover,the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks.In this review,we briefly examine fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,with a focus on disease pathogenesis with regard to local mRNA translation and axon transport,suggesting possible treatment directions.展开更多
BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver ...BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.展开更多
Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the resul...Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.展开更多
Fragile X syndrome(FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1(FMR1), leading to decreased or absent expression of its encoded fragile X mental retardati...Fragile X syndrome(FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1(FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein(FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here,we performed in-vitro neuronal differentiation of human induced pluripotent stem(iPS) cells that were derived from fibroblasts of a FXS patient(FXS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FXS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation(WNT1, BMP4,POU3F4, TFAP2 C, and PAX3), down-regulation of potassium channels(KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9,and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FXS symptoms.展开更多
Fragile X syndrome(FXS)is the leading inherited cause of intellectual disability,resulting from the lack of functional fragile X mental retardation protein(FMRP),an mRNA binding protein mainly serving as a translation...Fragile X syndrome(FXS)is the leading inherited cause of intellectual disability,resulting from the lack of functional fragile X mental retardation protein(FMRP),an mRNA binding protein mainly serving as a translational regulator.Loss of FMRP leads to dysregulation of target mRNAs.The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network.Yet the FMRP targets involved in circadian regulation have not been identified.Here,we identified collapsing response mediator protein(CRMP)mRNA as a target of FMRP.Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons(ventral lateral neurons)in dfmr1 mutant flies.Furthermore,specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors.Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation.Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.展开更多
Background:Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome(FXS).In light of thes...Background:Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome(FXS).In light of these findings,several clinical trials are now underway for therapeutic translation to humans.Data sources:Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov.The search terms included"fragile X syndrome","FXS and medication","FXS and therapeutics"and"FXS and treatment".Based on the publications identified in this search,we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research,from basic studies to clinical trials.Results:The pathological mechanisms of FXS were categorized on the basis of neuroanatomy,synaptic structure,synaptic transmission and fragile X mental retardation protein(FMRP)loss of function.The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations.Mechanism-directed molecular medicines were classified according to their target pathological mechanisms,and the most recent progress in clinical trials was discussed.Conclusions:Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics.Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the effi cacy of treatments.展开更多
Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents ...Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.展开更多
Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syn- drome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product F...Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syn- drome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product FMRP. Impairment in the nor- mal functioning of FMRP leads to learning and memory deficits and heightened sensitivity to sensory stimuli, including sound (hyperacusis). The molecular basis of fragile X syndrome is thoroughly understood; however, the neural mechanisms underly- ing hyperacusis have not yet been determined. As the inferior colliculus (IC) is the principal midbrain nucleus of the auditory pathway, the current study addresses the questions underlying the neural mechanism of hyperacusis within the IC of fragile X mice. Acute experiments were performed in which electrophysiological recordings of the IC in FMR1-KO and WT mice were measured. Results showed that Q-values for WT were significantly larger than that of FMR-1 KO mice, indicating that WT mice exhibit sharper tuning curves than FMR1-KO mice. We also found the ratio of the monotonic neurons in the KO mice was much higher than the WT mice. These results suggest that lack of FMRP in the auditory system affects the developmental maturation and function of structures within the auditory pathway, and in this case specifically the IC. The dysfunction ob- served within the auditory neural pathway and in particular the IC may be related to the increased susceptibility to sound as seen in individuals with fragile X syndrome. Our study may help on understanding the mechanisms of the fragile X syndrome and hyperacusis.展开更多
文摘BACKGROUND Cardiac syndrome X(CSX)is characterized by persistent angina with normal coronary arteries.Several pathophysiologic mechanisms have been introduced,particularly Helicobacter pylori(H.pylori)infection.AIM To investigate the association between H.pylori infection and CSX.METHODS All studies related to H.pylori infection and CSX were evaluated by comprehensive searches of global databases such as ISI Web of Knowledge,PubMed,Scopus,EMBASE,and Google scholar.Statistical analyses of selected articles were evaluated based on the summary odds ratio(OR).Finally,heterogeneity and publication bias were estimated using the I2 statistic and Cochrane Q-test as well as Begg’s and Egger’s tests.RESULTS A total of 11 studies met our inclusion criteria and 1435 patients(63%female,and 37%male)were reviewed.A significant association was observed between female patients and this syndrome(P=0.02).Our results showed a positive association between infection with this pathogen and presence of CSX(OR:5.65;95%confidence interval[CI]:4.17-7.64;I2:82.20).However,no significant association was observed with cagA-positive H. pylori strains and this syndrome (OR: 0.97;0.56-1.70 with 95%CI). Given the heterogeneity and publication bias, the resultsneed to confirmed by further prospective investigation.CONCLUSIONBased on our results, H. pylori infection is associated with an increased risk ofCSX. This bacterium appears to play a major role in the pathogenesis of CXS byinducing persistent inflammation.
基金Supported by the National Science and Technology Support Plan of China(No.2013BAI02B01)
文摘Objective: To evaluate the efficacy and safety of Tongxinluo Capsule(通心络胶囊, TXL) for patients with cardiac syndrome X(CSX). Methods: Randomized controlled trials(RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, Pub Med, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction(AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph(ECG) improvement, and serum endothelin-1(ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses. Results: Twelve RCTs(696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio(RR): 1.46, 95% confidence interval(CI)(1.25, 1.71), P〈0.01], and improving ECG [RR: 1.45, 95% CI(1.21, 1.74), P〈0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI(0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number: –1.63, 95% CI(–2.29, –0.96), P〈0.01]. No serious adverse events were reported. Conclusions: TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety.
基金Priority Project of Tianjin Science Technical Commission (No. 05YFGDSF02200)Yan De-xin Foundation Project (No. 05-012)
文摘Objective: To evaluate the clinical effect of Liqi Kuanxiong Huoxue method (宽胸活血,LKH, traditional Chinese medicine, TCM therapeutic method for regulating qi, relieving chest stuffiness and promoting blood circulation) in treating patients with cardiac syndrome X (CSX). Methods: The prospective, non-randomized controlled study was conducted on 51 selected patients with CSX, who were non-randomly assigned to 2 groups, the treated group treated with LKH in addition to the conventional treatment (32 patients), and the control group treated with conventional treatment (19 patients) like nitrate, diltiazem hydrochloride, etc. The treatment course was 14 days. The changes of such symptoms as angina pectoris, TCM syndrome and indexes of treadmill exercise test before and after treatment were observed. Results: After treatment, such symptoms as chest pain and stuffy feeling and palpitation in the treated group were improved more than those in the control group (P〈0.05); the total effective rate on angina pectoris and TCM syndrome in the treated group was better than that in the control group (P〈0.05). The treadmill exercise test showed that the maximal metabolic equivalent (Max MET), the time of angina onset and ST segment depression by 0.1 mV were obviously improved after treatment in both groups, but the improvement in the treated group was better than that in the control group respectively (P〈0.05). Conclusion: The LKH method could reduce the frequency of angina attacks and improve the clinical condition of patients with CSX.
文摘Background The purpose of this study was to assess the morphological changes and physiological function of coronary arteries in patients presenting with chest pain but having normal coronary angiograms, using intravascular ultrasound imaging (IVUS) and intracoronary Doppler (ICD) flow measurements, in order to elucidate the mechanism of syndrome X. Methods A total of 126 patients [67 males, 59 females, mean age (53.1±13.0) years] who experienced chest pain but had normal coronary angiograms were included in this study. ICD flow measurements of the left anterior descending coronary artery (LAD) were performed using a Cardiometrics FloMap Ⅱ system. Coronary flow velocity reserve (CFVR) was defined as the ratio of the average peak velocity during hyperemia to that at baseline, induced by an intracoronary bolus injection of 18 μg adenosine. A 3.2F or 2.9F 30 MHz mechanical rotating ultrasound catheter (CVIS, Boston Scientific) or a 3.0F 20MHz electronic ultrasound catheter (Endosonics) was used for IVUS. Results The mean CFVR value of the LAD was 2.71±0.74. Reduction of CFVR (<3.0) was found in 82 of 126 (65.1%) patients. IVUS images of the LAD were available for 109 patients. Plaque formation was detected in 76/109 (69.7%) patients. Based on the presence or absence of plaque formation as well as the reduction or non-reduction of CFVR, patients were divided into four groups: Group Ⅰ (n=10), normal IVUS findings and normal CFVR; Group Ⅱ (n=23), normal IVUS findings with reduction in CFVR; Group Ⅲ (n=29), IVUS evidence of plaque formation but normal CFVR; and Group Ⅳ (n=47), IVUS evidence of plaque formation with reduction in CFVR. Conclusion This study shows the important clinical value of a combination of IVUS and ICD in diagnosing patients with angiographically normal coronary arteries. Only 10% of patients studied (Group Ⅰ) were found to be truly free of coronary disease, while 20% of patients (Group Ⅱ) would be diagnosed as suffering from syndrome X.
文摘Clinical reports on cardiac syndrome X(CSX) have been increasing in recent years.In general, CSX does not increase the cardiovascular mortality,but it can affect the patient's quality of life(QOL) and increase the incidence rates of cardiovascular and cerebrovascular events.Although a variety of drugs and therapies have been utilized in the clinical treatment,the management of CSX still represents a major challenge due to its unclear pathogenesis.It is necessary to explore more effective treatment programs.Many attempts have been made on trials of the Chinese medicine(CM) treatment for CSX and proved that CM has a certain advantage in efficacy to improve clinical symptoms and QOL.CM may provide a new approach for the effective treatment of CSX.
基金the National Natural Science Foundation of China,No.30870876the Natural Science Foundation of Guangdong Province,No.815101700100005+2 种基金the Science and Technology Program of Guangdong Province,No.2005B60302004,2008B030301371,2009B030801368the Traditional Chinese Medicineand Combination of Traditional Chinese and Western Medicine Program of Guangzhou,No.2008A52the Medical and Health Scientific Research Program of Guangzhou,No.2009-YB-167
文摘In the present study,Fmr1 knockout mice (KO mice) were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts,indicating a learning and memory disorder.After treatment with 30,60,90,120,or 200 mg/kg lithium chloride,the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated,in particular,the 200 mg/kg lithium chloride treatment had the most significant effect.Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta,an inactive form of glycogen synthase kinase 3 beta,in the cerebral cortex and hippocampus of the Fmr1 KO mice.These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice,possibly by inhibiting glycogen synthase kinase 3 beta activity.
文摘Polymerase chain reaction (PCR) technique combined with direct detection by silver staining on denaturing DNA sequencing gel was used to analyze the (CGG)n repeats within the FMR1 gene on 169 suspected patients with mental retardation and 33 kindreds of 6 fragile X families. The results showed that : (1) No PCR products were detected in 3 males in the suspected group. (2) In the fragile X family studies, the 5 male probands failed to show any PCR products. (3) Diplex PCR with the primers flanking the FRAXE locus was used to serve as an internal control for the 8 above mentioned males and only normal products of the FRAXE locus were detected, indicating that the possibility of false negative results of the FRAXA locus could be eliminated. These findings suggested that analysis of (CGG)n repeat within the FMR1 gene by PCR technique could efficiently detect premutation carriers and that negative PCR products in mentally retarded males might highly imply the diagnosis of fragile X syndrome after the false negative results have been excluded by diplex PCR. This PCR assay is suitable for the screening and diagnosis of fragile X syndrome in a large number of populations due to its rapidity, simplicity, stability and reliability.
文摘Fragile X syndrome(FXS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile X mental retardation protein(FMRP).Patients with FXS suffer lifelong cognitive disabilities,but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood.Here,we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs).Consequently,FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion,leading to cognitive impairment in mature adult mice.Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice.Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel ther⁃apeutic strategy for treating adult FXS patients.
基金supported by Ministry of Education 211 Project,Fudan UniversityProject of Innovation of Shanghai Municipal Committee of Science and Technology (No.08dj1400600)+6 种基金National Natural Science Foundation of China(No.81001574)Leading Medical Projects at Science and Technology Commission of Shanghai Municipality (No.12401905100)Three-year Projects to Promote Traditional Chinese Medicine,Shanghai(No.ZYSNXD-CC-ZDYJ050)Project of Shanghai Cerebrated TCM Doctor Workshop (No.ZYSNXD-CC-MZY034)Shanghai Association of Chinese Integrative Medicine(No.zxyQ-1245)The Fok Ying-Tong Education Foundation for Young Teacher of University(No.114036)the Foundation of Leading Academic Discipline Project of Shanghai Municipal Education Commission(No.J50307)
文摘BACKGROUND: Microalbuminuria (MAU) is a key component of metabolic syndrome (MetS) and is an early sign of diabetic nephropathy as well. Although routine Western medicine treatments are given to MetS patients to control high blood pressure, hyperglycemia and dyslipidemia, some patients still experience progressive renal lesions and it is necessary to modify and improve the treatment strategy for MetS patients. OBJECTIVE: To investigate the efficacy of Yiqi Huaju Qingli Herb Formula, a compound traditional Chinese herbal medicine, in MetS patients with MAU when it is combined with routine Western medicine treatment. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty patients with MetS were randomized into the Chinese herbal formula group (CHF, Yiqi Huaju Qingli formula treatment in combination with Western medicine) and control group (placebo in combination with Western medicine). All treatments were administered for 12 weeks. MAIN OUTCOME MEASURES: Urinary microalbumin (MA), urinary albumin-to-creatinine ratio (UACR), 24-hour total urine protein (24-hTP), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2-hPPG), glycosylated hemoglobin (HbAlc), homeostasis model assessment for insulin resistance (HOMA-IR), blood lipid profile and blood pressure were observed. RESULTS: Compared with the control group, CHF treatment significantly decreased BMI (P〈0.05), WC (P〈0.01) and WHR (P〈0.01). Both groups had significant decreases in FPG, 2-hPPG, HbAlc, HOMA-IR, MA, and UACR, with CHF treatment showing better effects on these parameters compared with the control treatment (P〈0.05). Both treatments significantly reduced the levels of total cholesterol, low-density lipoprotein cholesterol and triacylglycerol (TAG), and a greater reduction in TAG was observed with CHF treatment (P〈0.05). The level of high-density lipoprotein cholesterol did not change in the control group after treatment (P〉0.05), whereas it significantly increased with CHF treatment (P〈0.01). Compared with before the treatment, significant decreases in systolic blood pressure, diastolic blood pressure and mean arterial blood pressure were observed in both groups (P〈0.01). However, there was no significant difference between the two groups (P〉0.05). CONCLUSION: Combined treatment ofYiqi Huaju Qingli Formula and Western medicine significantly alleviated MAU, which may correlate with the improvement of insulin sensitivity and glucose and lipid metabolism. TRIAL REGISTRATION IDENTIFIER: This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-11001633.
文摘Metabolic syndrome, with the main clinical manifestations of obesity, dyslipidemia, elevated blood pressure, and elevated blood glucose levels, has become an increasingly prevalant global public health concern. Metabolic syndrome is a convergence of multiple risk factors related to cardiovascular disease. When the concept of metabolic syndrome was initially proposed, some researchers thought the concept was unnecessary, since there were already measures in place to describe the separate cardiovascular risk factors such as dyslipidemia, hypertension and diabetes. However, a large number of epidemiological investigations confirmed that even if blood glucose or blood pressure did not reach the cutoff point of the diseases,
基金supported by China's Ministry of Science&Technology(No.2008BAI56B04)
文摘Objective To understand the associations of physical activity domains with metabolic syndrome among a middle-aged Chinese population. Methods In all, 3326 professional adults aged 35-64 years from Beijing and Zhejiang province were recruited with a cluster random sampling method. The Global Physical Activity Questionnaire was modified, and the recommended Asia-Pacific cut-offs of waist circumstance were introduced into the criteria for metabolic syndrome from the Adult Treatment Panel III. A binary logistic regression model was applied to examine the association of all physical activity domains with the risk of the syndrome. Results Participants who engaged in domestic activity for 〉1176 MET-min/week had a 41.6% less chance of having metabolic syndrome [odds ratio (OR), 0.584; 95% confidence interval (CI), 0.480-0.710] than those without this activity. In adjusted models, adults who actively commuted for 〉33 MET-rain/week but 〈52g MET-min/week had a 25% less chance of having the syndrome (OR, 0.750; 95% CI, 0.582-0.966) than those who did not. No interaction was detected between the two domains of activity and the syndrome. Conclusion This study highlighted the independently negative association of traffic and house activity with the prevalence of the syndrome in this sample with a generally low level of moderate activity.
文摘Metabolic syndrome is an epidemic that affects more and more people, increasing the probability of suffering metabolic and cardiovascular diseases in the short, medium or long term depending on the severity. The purpose of this article is to review the metabolic syndrome, assessing consensus, controversy and prevalence. The methodology was the preparation of a literature review on various health care databases, which were from 43 articles published from 2010 to 2015, in the general population. SM rate ranges from 0% to 90% depending on genders, ages and regions. There is still lack of consensus on cutoffs of diagnostic criteria. Thus, it is concluded that the prevalence of metabolic syndrome is being increased, urging the need for early diagnosis and treatment to promote the health of the global population.
基金This work was supported by the National Natural Science Foundation of China,Nos.81830036(to GC),81771255(to GC),81771254(to HYL),81971106(to ZQY)Project of Jiangsu Provincial Medical Innovation Team,No.CXTDA2017003(to GC)+2 种基金Jiangsu Provincial Medical Youth Talent,No.QNRC2016728(to HYL)the Natural Science Foundation of Jiangsu Province,No.BK20170363(to HYL)Gusu Health Personnel Training Project,No.GSWS2019030(to HYL)。
文摘The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,have been characterized by pathological changes in neuronal axons,including abnormal mRNA translation,the loss of protein expression,or abnormal axon transport.Moreover,the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks.In this review,we briefly examine fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,with a focus on disease pathogenesis with regard to local mRNA translation and axon transport,suggesting possible treatment directions.
基金supported by agrant from Medical University of Gdansk(W-175)
文摘BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.
基金supported by the National Natural Science Foundation of China(82071662,to Q.G.)。
文摘Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.
基金supported by National Program on Key Basic Research Project(2015CB964601,2015CB964702)Joint Research Fund for Overseas Chinese,Hong Kong and Macao Young Scholars(31428016)+3 种基金National Natural Science Foundation of China(Key Program 81430026)Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry(Xianmin Zhu)Shanghai Municipal Commission of Health and Family Planning(XBR2013094)Jiangsu Science and Technology Planning Project(BM2014052)
文摘Fragile X syndrome(FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1(FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein(FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here,we performed in-vitro neuronal differentiation of human induced pluripotent stem(iPS) cells that were derived from fibroblasts of a FXS patient(FXS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FXS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation(WNT1, BMP4,POU3F4, TFAP2 C, and PAX3), down-regulation of potassium channels(KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9,and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FXS symptoms.
基金the Hunan Science and Technology major project of Birth Defect Cooperative Control(2019SK1010)the National Natural Science Foundation of China(81571253 and 81771385)+1 种基金the Hunan Provincial Natural Science Foundation(2016JJ3135)the Changsha Municipal Natural Science Foundation(kq2007073).
文摘Fragile X syndrome(FXS)is the leading inherited cause of intellectual disability,resulting from the lack of functional fragile X mental retardation protein(FMRP),an mRNA binding protein mainly serving as a translational regulator.Loss of FMRP leads to dysregulation of target mRNAs.The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network.Yet the FMRP targets involved in circadian regulation have not been identified.Here,we identified collapsing response mediator protein(CRMP)mRNA as a target of FMRP.Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons(ventral lateral neurons)in dfmr1 mutant flies.Furthermore,specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors.Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation.Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.
基金supported in part by grants from the National Key Basic Research Program of China(No.2012CB944600)National Natural Science Foundation of China(No.81071028,81172513)Program for New Century Excellent Talents in University(No.NCET-10-0832).
文摘Background:Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome(FXS).In light of these findings,several clinical trials are now underway for therapeutic translation to humans.Data sources:Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov.The search terms included"fragile X syndrome","FXS and medication","FXS and therapeutics"and"FXS and treatment".Based on the publications identified in this search,we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research,from basic studies to clinical trials.Results:The pathological mechanisms of FXS were categorized on the basis of neuroanatomy,synaptic structure,synaptic transmission and fragile X mental retardation protein(FMRP)loss of function.The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations.Mechanism-directed molecular medicines were classified according to their target pathological mechanisms,and the most recent progress in clinical trials was discussed.Conclusions:Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics.Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the effi cacy of treatments.
文摘Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.
文摘Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syn- drome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product FMRP. Impairment in the nor- mal functioning of FMRP leads to learning and memory deficits and heightened sensitivity to sensory stimuli, including sound (hyperacusis). The molecular basis of fragile X syndrome is thoroughly understood; however, the neural mechanisms underly- ing hyperacusis have not yet been determined. As the inferior colliculus (IC) is the principal midbrain nucleus of the auditory pathway, the current study addresses the questions underlying the neural mechanism of hyperacusis within the IC of fragile X mice. Acute experiments were performed in which electrophysiological recordings of the IC in FMR1-KO and WT mice were measured. Results showed that Q-values for WT were significantly larger than that of FMR-1 KO mice, indicating that WT mice exhibit sharper tuning curves than FMR1-KO mice. We also found the ratio of the monotonic neurons in the KO mice was much higher than the WT mice. These results suggest that lack of FMRP in the auditory system affects the developmental maturation and function of structures within the auditory pathway, and in this case specifically the IC. The dysfunction ob- served within the auditory neural pathway and in particular the IC may be related to the increased susceptibility to sound as seen in individuals with fragile X syndrome. Our study may help on understanding the mechanisms of the fragile X syndrome and hyperacusis.