铅暴露大鼠脑不同区域NMDA受体亚基(NR1、NR2A、NR2B)表达的研究

目的:观察铅暴露大鼠中不同脑区NMDAR1(NR1)、NMDAR2A(NR2A)和NMDAR2B(NR2B)亚基蛋白和mRNA水平的表达情况。方法:采用Western Blot及RT-PCR技术,测定NR1、NR2A和NR2B亚基蛋白和mRNA在铅暴露大鼠脑中额叶皮质、新小脑、海马及纹状体中的表达情况。结果:铅暴露大鼠中NR1、NR2A和NR2B亚基的蛋白水平和mRNA表达在各个脑区均有不同程度的下调。结论:在铅暴露大鼠的额叶皮质、海马、新小脑和纹状体中,NMDA受体亚基NR1,NR2A和NR2B的表达在mRNA水平就已经发生了改变。

Knowledge domain and emerging trends in Alzheimer’s disease: a scientometric review based on CiteSpace analysis

Alzheimer’s disease is the most common cause of dementia.It is an increasingly serious global health problem and has a significant impact on individuals and society.However,the precise cause of Alzheimer’s disease is still unknown.In this study,11,748 Web-of-Science-indexed manuscripts regarding Alzheimer’s disease,all published from 2015 to 2019,and their 693,938 references were analyzed.A document co-citation network map was drawn using CiteSpace software.Research frontiers and development trends were determined by retrieving subject headings with apparent changing word frequency trends,which can be used to forecast future research developments in Alzheimer’s disease.

Nutritional status and nutritional therapy in inflammatory bowel diseases

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease(IBD).In addition,a significant number of children with IBD,especially Crohn's disease(CD) have impaired linear growth.Nutrition has an important role in the management of IBD.In adults with CD,enteral nutrition(EN) is effective in inducing clinical remission of IBD,although it is less efficient than corticosteroids.Exclusive EN is an established primary therapy for pediatric CD.Limited data suggests that EN is as efficient as corticosteroids for induction of remission.Additional advantages of nutritional therapy are control of inflammation,mucosal healing,positive benefits to growth and overall nutritional status with minimal adverse effects.The available evidence suggests that supplementary EN may be effective also for maintenance of remission in CD.More studies are needed to confirm these findings.However,EN supplementation could be considered as an alternative or as an adjunct to maintenance drug therapy in CD.EN does not have a primary therapeutic role in ulcerative colitis.Specific compositions of enteral dietselemental diets or diets containing specific components-were not shown to have any advantage over standard polymeric diets and their place in the treatment of CD or UC need further evaluation.Recent theories suggest that diet may be implicated in the etiology of IBD,however there are no proven dietary approaches to reduce the risk of developing IBD.

Hepatic portal venous gas: Physiopathology, etiology, prognosis and treatment

Hepatic portal venous gas (HPVG), an ominous radiologic sign, is associated in some cases with a severe underlying abdominal disease requiring urgent operative intervention. HPVG has been reported with increasing frequency in medical literature and usually accompanies severe or lethal conditions. The diagnosis of HPVG is usually made by plain abdominal radiography, sonography, color Doppler flow imaging or computed tomography (CT) scan. Currently, the increased use of CT scan and ultrasound in the inpatient setting allows early and highly sensitive detection of such severe illnesses and also the recognition of an increasing number of benign and non-life threatening causes of HPVG. HPVG is not by itself a surgical indication and the treatment depends mainly on the underlying disease. The prognosis is related to the pathology itself and is not influenced by the presence of HPVG. Based on a review of the literature, we discuss in this paper the pathophysiology, risk factors, radiographic findings, management, and prognosis of pathologies associated with HPVG.

Haemostatic system in inflammatory bowel diseases:New players in gut inflammation

Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important in chronic inflammatory settings,such as inflammatory bowel disease(IBD).Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events,and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels,where most severe inflammatory abnormalities occur.The aims of this review are to update and classify the type of coagulation system abnormalities in IBD,and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level.Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.

Sonography of the small intestine

In the last two decades, there has been substantial development in the diagnostic possibilities for examining the small intestine. Compared with computerized tomography, magnetic resonance imaging, capsule endoscopy and double-balloon endoscopy, ultrasonography has the advantage of being cheap, portable, flexible and user-and patient-friendly, while at the same time providing the clinician with image data of high temporal and spatial resolution. The method has limitations with penetration in obesity and with intestinal air impairing image quality. The flexibility ultrasonography offers the examiner also implies that a systematic approach during scanning is needed. This paper reviews the basic scanning techniques and new modalities such as contrast-enhanced ultrasound, elastography, strain rate imaging, hydrosonography, allergosonography, endoscopic sonography and nutritional imaging, and the literature on disease-specific findings in the small intestine. Some of these methods have shown clinical benefit, while others are under research and development to establish their role in the diagnostic repertoire. However, along with improved overall image quality of new ultrasound scanners, these methodshave enabled more anatomical and physiological changes in the small intestine to be observed. Accordingly, ultrasound of the small intestine is an attractive clinical tool to study patients with a range of diseases.

Eosinophilic gastroenteritis with cytomegalovirus infection in an immunocompetent child

A 3-year-old boy developed transient protein-losing gastroenteropathy associated with cytomegalovirus (CMV) infection. Both IgG and IgM antibodies to CMV were positive in a serologic blood test. Upper gastrointestinal endoscopy showed multiple erosions throughout the body of the stomach, without enlarged gastric folds. Histological examination of the biopsy specimens indicated eosinophilic gastroenteritis and CMV infection. The patient had complete resolution without specific therapy for CMV in four weeks. An allergic reaction as well as CMV infection played important roles in the pathogenesis of this case.

Neuroprotective mechanism of Kai Xin San: upregulation of hippocampal insulin-degrading enzyme protein expression and acceleration of amyloid-beta degradation

Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β （Aβ） induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme （IDE）, which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42 （200 μM, 5 μL） into the hippocampus and subsequently administered Kai Xin San （0.54 or 1.08 g/kg/d） intragastrically for 21 consecutive days. Hematoxylin eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.

Optogenetics and its application in neural degeneration and regeneration

Neural degeneration and regeneration are important topics in neurological diseases. There are limited options for therapeutic interventions in neurological diseases that provide simultaneous spatial and temporal control of neurons. This drawback increases side effects due to non-specific targeting. Optogenetics is a technology that allows precise spatial and temporal control of cells. Therefore, this technique has high potential as a therapeutic strategy for neurological diseases. Even though the application of optogenetics in understanding brain functional organization and complex behaviour states have been elaborated, reviews of its therapeutic potential especially in neurodegeneration and regeneration are still limited. This short review presents representative work in optogenetics in disease models such as spinal cord injury, multiple sclerosis, epilepsy, Alzheimer＇s disease and Parkinson＇s disease. It is aimed to provide a broader perspective on optogenetic therapeutic potential in neurodegeneration and neural regeneration.

Micro RNA-124 slows down the progression of Huntington's disease by promoting neurogenesis in the striatum

MicroRNA-124 contributes to neurogenesis through regulating its targets, but its expression both in the brain of Huntington＇s disease mouse models and patients is decreased. However, the effects of microRNA-124 on the progression of Huntington＇s disease have not been reported. Results from this study showed that microRNA-124 increased the latency to fall for each R6/2 Hunting- ton＇s disease transgenic mouse in the rotarod test. 5-Bromo-2＇-deoxyuridine （BrdU） staining of the striatum shows an increase in neurogenesis. In addition, brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein levels in the striatum were increased and SRY-related HMG box transcription factor 9 protein level was de- creased. These findings suggest that microRNA-124 slows down the progression of Huntington＇s disease possibly through its important role in neuronal differentiation and survival.

Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease

The principal pathology of Alzheimer＇s disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice （aged 4-4.5 months） for 45 days. Unbiased stereology analysis found that triptolide dose-dependent- ly reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide （5 μg/kg/d） also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS 1 double transgenic mice with Alzheimer＇s disease.

Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson＇s like symptoms in rodents.Quercetin（QC）is a natural polyphenolic bioflavonoid with potent antioxidant and anti-inflammatory properties but lacks of clinical attraction due to low oral bioavailability.Piperine is a well established bioavailability enhancer used pre-clinically to improve the bioavailability of antioxidants（e.g.,Quercetin）.Therefore,the present study was designed to evaluate the neuroprotective potential of QC together with piperine against MPTP-induced neurotoxicity in rats.MPTP（100μg/μL/rat,bilaterally）was injected intranigrally on days 1,4 and 7 using a digital stereotaxic apparatus.QC（25 and 50 mg/kg,intragastrically）and QC（25 mg/kg,intragastrically）in combination with piperine（2.5 mg/kg,intragastrically）were administered daily for 14 days starting from day 8 after the 3^（rd） injection of MPTP.On day 22,animals were sacrificed and the striatum was isolated for oxidative stress parameter（thiobarbituric acid reactive substances,nitrite and glutathione）,neuroinflammatory cytokine（interleukin-1β,interleukin-6,and tumor necrosis factor-α）and neurotransmitter（dopamine,norepinephrine,serotonin,gamma-aminobutyric acid,glutamate,3,4-dihydroxyphenylacetic acid,homovanillic acid,and 5-hydroxyindoleacetic acid）evaluations.Bilateral infusion of MPTP into substantia nigra pars compacta led to significant motor deficits as evidenced by impairments in locomotor activity and rotarod performance in open field test and grip strength and narrow beam walk performance.Both QC（25 and 50 mg/kg）and QC（25 mg/kg）in combination with piperine（2.5 mg/kg）,in particular the combination therapy,significantly improved MPTP-induced behavioral abnormalities in rats,reversed the abnormal alterations of neurotransmitters in the striatum,and alleviated oxidative stress and inflammatory response in the striatum.These findings indicate that piperine can enhance the antioxidant and anti-inflammatory properties of QC,and QC in combination with piperine exhibits strong neuroprotective effects against MPTP-induced neurotoxicity.

Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children

Inflammatory bowel disease is a chronic,debilitating disorder of the gastrointestinal tract.The etiology of inflammatory bowel disease has not been elucidated,but is thought to be multifactorial with both environmental and genetic influences.A large body of research has been conducted to elucidate the etiology of inflammatory bowel disease.This article reviews this literature,emphasizing the studies of breastfeeding and the studies of genetic factors,particularly NOD2 polymorphisms.

Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy

There are several major pathological changes in Alzheimer＇s disease, including apoptosis of cho- linergic neurons, overactivity or overexpression of 13-site amyloid precursor protein cleaving enzyme 1 （BACE1） and inflammation. In this study, we synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein （AI3） production, and introduced it into the pSilenCircle vector to construct a short hairpin （shRNA） expression plasmid against the BACE1 gene. We transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing AI3 protein production. We anticipate that this technique combining cell transplantation and gene ther- apy will open up novel therapeutic avenues for Alzheimer＇s disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.

Neuroprotective effects of berry fruits on neurodegenerative diseases

Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents.

Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult-and pediatric-onset inflammatory bowel disease in Italy

AIM: To investigate gene variants in a large Italian inflammatory bowel disease (IBD) cohort, and to analyze the correlation of sub-phenotypes (including age at diagnosis) and epistatic interaction with other IBD genes. METHODS: Total of 763 patients with Crohn's disease (CD, 189 diagnosed at age < 19 years), 843 with ulcerative colitis (UC, 179 diagnosed <19 years), 749 healthy controls, and 546 healthy parents (273 trios) were included in the study. The rs2241880 [autophagy-related 16-like 1 (ATG16L1)], rs11209026 and rs7517847 [interleukin 23 receptor (IL23R)], rs2066844, rs2066845, rs2066847 (CARD15), rs1050152 (OCTN1), and rs2631367 (OCTN2) gene variants were genotyped. RESULTS: The frequency of G allele of ATG16L1 SNP (Ala197Thr) was increased in patients with CD compared with controls (59% vs 54% respectively) (OR = 1.25, CI = 1.08-1.45, P = 0.003), but not in UC (55%). The frequency of A and G (minor) alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD (4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P < 0.01), compared with controls (6% and 38%, respectively). The A allele (but not G) was also reduced signifi cantly in UC (4%, OR = 0.69, CI = 0.5-0.94, P = 0.019). No association was demonstrated with sub-phenotypes and interaction with CARD15 , and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION: The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.

Treating Alzheimer's disease with Yizhijiannao granules by regulating expression of multiple proteins in temporal lobe

Yizhijiannao granules have been shown to improve cognitive function in Alzheimer＇s disease patients. The present study sought to explore the mechanisms involved in the cognitive enhancing effects of Yizhijiannao granule. Senescence-accelerated mouse prone 8 mice with learning and memory disorders were intragastrically treated with Yizhijiannao granule for 8 weeks. Mice intragastrically treated with double distilled water for 8 weeks were considered as the control group. 2D gel electrophoresis was used to isolate total protein from the temporal lobe of senescence-accelerated mouse prone 8 mice, and differential protein spots were obtained by mass spectrometry. Thirty-seven differential protein spots were found in the temporal lobe area of both groups. Ten protein spots were identified： high mobility group box 1, dimethylarginine dimethylaminohydrolase-1, nenroglobin, hemoglobin beta adult major chain, peroxiredoxin-6, cofilin-1, flotiUin 1, peptidylprolyl isomerase A, voltage-dependent anion channel-2 and chaperonin containing TCP1, and subunit 2. Among other functions, these proteins are separately involved in the regulation of amyloid beta production, oxidative stress, neuroinflammation, regulation of tau phosphorylation, and regulation of neuronal apoptosis. Our results revealed that Yizhijiannao granule can regulate the expression of various proteins in the temporal lobe of senescence-accelerated mouse prone 8 mice, and may be therapeutically beneficial for the treatment of Alzheimer＇s disease.

Influence of RNA interference on the mitochondrial subcellular localization of alpha-synuclein and on the formation of Lewy body-like inclusions in the cytoplasm of human embryonic kidney 293 cells induced by the overexpression of alphasynuclein

The specific and effective a-synuclein RNA interference （RNAi） plasmids, and the a-synuclein-pEGFP recombinant plasmids were co-transfected into human embryonic kidney 293 （HEK293） cells using the lipofectamine method. Using an inverted fluorescence microscope, a-synuclein proteins were observed to aggregate in the cytoplasm and nucleus. Wild-type a-synuclein proteins co-localized with mitochondria. Hematoxylin-eosin staining revealed round eosinophilic bodies （Lewy body-like inclusions） in the cytoplasm of some cells transfected with a-synuclein-pEGFP plasmid. However, the formation of Lewy body-like inclusions was not observed following transfection with the RNAi pSYN-1 plasmid. RNAi blocked Lewy body-like inclusions in the cytoplasm of HEK293 cells induced by wild-type a-synuclein overexpression, but RNAi did not affect the subcellular localization of wild-type a-synuclein in mitochondria.

Crypt abscess-associated microbiota in inflammatory bowel disease and acute self-limited colitis

AIM:To evaluate whether crypt abscesses frominflammatory bowel disease(IBD)patients containbacteria and to establish their nature.METHODS:We studied 17 ulcerative colitis patients,11 Crohn's disease patients,7 patients with acute selflimited colitis(ASLC)and normal colonic biopsies from5 subjects who underwent colonoscopy for colon cancer screening.A fluorescent in situ hybridization techniquewas applied to colonic biopsies to assess the microbiotacomposition of the crypts and crypt abscesses.RESULTS:Crypts colonized by bacteria were observedin 42.9%and 3.6%of ASLC and IBD patients,respectively(P=0.019).Crypt abscesses colonized bybacteria were observed in 28.6%and 0.0%of ASLCand IBD patients,respectively(P=0.035).CONCLUSION:These results do not support thehypothesis that crypt abscesses in IBD are the resultof localized dysbiosis arising from persistence of livingbacteria colonizing the crypts.

Stevens-Johnson syndrome complicating adalimumab therapy in Crohn's disease

The anti-tumor necrosis factor(TNF)αmedications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions.With the increasing number of patients receiving anti-TNFαagents,however,less common adverse reactions will occur.Cutaneous eruptions complicating treatment with an anti-TNFαagent are not uncommon,occurring in around 20%of patients. Adalimumab,a fully humanized antibody against TNFα, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody,infliximab.We,however,report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn’ s disease(CD).In this case report,a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis,peripheral rash and desquamation,fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy.Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded.The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome.Desquamating skin reactions have now been described in three of the TNFαantagonists(infliximab,etanercept and adalimumab).These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents,especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.