Effects of auricular thumbtack needle on lactation function and TDP-43/Btn1A1/XDH pathway in primiparous women with cesarean section / 中国针灸

OBJECTIVE@#To observe the effects of auricular thumbtack needle on breast feeding and lactation function in primiparous women with cesarean section, and to explore its mechanism of action from the perspective of lactation-related gene expression.@*METHODS@#One hundred cases of primiparous women with cesarean section were randomly divided into an observation group (50 cases, 3 cases dropped off) and a control group (50 cases, 2 cases were eliminated). The patients in the control group were treated with routine obstetric care. Based on the treatment of the control group, the patients in the observation group were treated with auricular thumbtack needle at Neifenmi (CO18), Xiong (AH10), Xiongzhui (AH11), Shenmen (TF4), and Jiaogan (AH6a), etc., with one side of auricular point selected, only once for a total of 3 d. The lactation initiation time, lactation adequacy rate at postpartum 72 h, exclusive breastfeeding rate at postpartum 42 d, and breastfeeding score after treatment were compared between the two groups. Real-time quantitative PCR and Western blot method were used to detect the mRNA and protein expression levels of TDP-43, Btn1A1 and XDH.@*RESULTS@#After treatment, the lactation initiation time in the observation group was earlier than that in the control group (P<0.01), and breastfeeding score in the observation group was higher than that in the control group (P<0.01). The lactation adequacy rate at postpartum 72 h was 63.8% (30/47) in the observation group, which was higher than 41.7% (20/48) in the control group (P<0.05). The exclusive breastfeeding rate at postpartum 42 d was 72.3% (34/47) in the observation group, which was higher than 47.9% (23/48) in the control group (P<0.05). The mRNA and protein expression levels of TDP-43 and Btn1A1 in breast milk in the observation group were higher than those in the control group (P<0.01), while there was no statistically significant difference in mRNA and protein expression of XDH in breast milk between the two groups (P>0.05).@*CONCLUSION@#The auricular thumbtack needle in addition to routine care could promote lactation initiation, improve lactation adequacy rate and exclusive breastfeeding rate in primiparous women with cesarean section, and the action mechanism may be related to up-regulation of TDP-43 and Btn1A1 expression.

TBN improves motor function and prolongs survival in SOD1G93A and TDP-43M337V mouse model of ALS / 中国药理学与毒理学杂志

OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fetal neurodegenerative disease characterized by the progressive loss of upper and lower motor neu-rons,leading to skeletal muscle atrophy,weakness,and paralysis.Oxidative stress plays a crucial role in ALS pathogenesis,including the familial forms of the disease arising from mutations in the gene coding for superox-ide dismutase(SOD1).Additionally,the abnormal accu-mulation of TAR DNA-binding protein of 43 ku(TDP-43)is a pathological feature present in almost all patients,even though the pathogenesis of ALS is unclear.Current-ly,there is no drug that can cure ALS/FTLD.Tetramethyl-pyrazine nitrone(TBN)is a derivative of tetramethylapyr-azine,derived from traditional Chinese medicine Ligusti-cum chuanxiong,which has been extensively proven to have therapeutic effects on various models of neurode-generative diseases.METHODS We investigated the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse models.In the SOD1G93A trans-genic mouse model,TBN was administered to mice via intraperitoneal or intragastric injection after the onset of motor deficits.We injected the TDP-43M337V virus into the striatum of mice unilaterally and bilaterally,and then administered TBN 30 mg·kg-1 intragastrically to observe changes in behavior and survival rate of mice.RESULTS TBN slowed the progression of motor neuron disease,as evidenced by improved motor performance,reduced spi-nal motor neuron loss and associated glial response,and decreased skeletal muscle fiber denervation and fibrosis.TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1.In the mice with unilateral injection of TDP-43M337V into the striatum,TBN improved motor deficits and cognitive impairment in the early stages of disease progression.In mice with bilateral injection of TDP-43M337V into the striatum,TBN not only improved motor function but also prolonged survival.Moreover,we demonstrate that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways.CONCLUSION TBN shows promise as an agent for the treatment of ALS/FTLD.TBN is currently undergoing clinical investigation for several indications,including a Phase Ⅱ trial for ALS.

MiR-218-5p Promotes Rotenone-induced Apoptosis of Gastric Cancer Cells by Inhibiting TDP1 Expression / 肿瘤防治研究

Objective To investigate the effect of overexpression of miR-218-5p and inhibition of TDP1 expression on rotenone-induced apoptosis of gastric cancer cells, and to elucidate its possible mechanism. Methods The expression levels of miR-218-5p and TDP1 in human normal gastric epithelial cells and four gastric cancer cells were detected by RT-PCR, and their correlation was analyzed. The targeting regulation of miR-218-5p on TDP1 was verified by dual luciferase reporter gene assay. Gastric cancer cell injury model was induced by 1.0 μmol/L rotenone. Cell cycle and apoptotic rate were detected by flow cytometry. TDP1 level in mitochondria and the expression of Bax and Cyt-c protein were detected by Western blot. Results The expression of miR-218-5p was low in gastric cancer cells (P < 0.05), and TDP1 was high (P < 0.01). There was a negative correlation between the expression of miR-218-5p and TDP1 (R2=0.9580, P=0.0212). Compared with the control group, SGC-7901 cells in the injured group developed G1 phase arrest and the apoptotic rate increased (P < 0.01). After transfection of miR-218-5p-mimic, the cell arrest and apoptotic rate further increased (P < 0.01), the expression of Bax and Cyt-c increased (P < 0.01), while the level of TDP1 in mitochondria decreased (P < 0.01). The G1 phase arrest of cells in TDP1 overexpression group was relieved, the apoptotic rate was decreased (P < 0.01), the level of TDP1 in mitochondria was increased (P < 0.01), and Bax and Cyt-c expression were decreased (P < 0.01). Conclusion MiR-218-5p can target TDP1 expression and induce apoptosis of gastric cancer cells. Its mechanism may be related to inhibiting mitochondrial DNA damage repair and function maintenance and activating mitochondrial endogenous apoptosis pathway.

Proliferation and apoptosis of chondrocytes co-cultured with TDP43 lentivirus transfected-humanumbilical cord mesenchymal stem cells / 中国组织工程研究

BACKGROUND: TDP43 may be a negative regulator of MAPK signaling pathway under hypoxic-ischemic conditions. However, its effect on JNK and p38 MAPK signaling pathways in osteoarthritis remains unclear.OBJECTIVE: To investigate the expression of chondrocyte lesion-related gene RACK1 in wild type TDP43 involved in osteoarthritis, and to analyze its stress effect. METHODS: Human umbilical cord mesenchymal stem cells were transfected by TDP43 lentivirus, and the ability to differentiate into chondrocytes in vitro was analyzed. Umbilical cord mesenchymal stem cells transfected by TDP43 lentivirus, empty vector and without transfection were co-cultured with chondrocytes for 12 days. The chondrocyte proliferation was detected at 0, 3, 6, 9 and 12 days of co-culture. The chondrocyte apoptosis rate was detected by flow cytometry at 3 days of co-culture. The expression levels of TDP43, RACK1, p38, JNK, AP-1 and cl-xl in chondrocytes were detected by qRT-PCR at 3 days of co-culture. RESULTS AND CONCLUSION: (1) After TDP43 lentivirus transfection, human umbilical cord mesenchymal stem cells could differentiate into chondrocytes. (2) The morphology of chondrocytes co-cultured with TDP43 lentivirus transfected-umbilical cord mesenchymal stem cells showed significant change, and the cells became large with abundant branches. Chondrocytes co-cultured with empty vector transfected- or non-transfected umbilical cord mesenchymal stem cells were spindle-shaped in appearance and showed adherent growth with no morphological changes. (3) After co-cultured with TDP43 lentivirus transfected-umbilical cord mesenchymal stem cells, the apoptosis of chondrocytes was promoted, and the cell proliferation was inhibited (P < 0.05). (4) The expression levels of TDP43, RACK1, p38, JNK, AP-1 and Bcl-xl in the chondrocytes co-cultured with TDP43 lentivirus transfected-umbilical cord mesenchymal stem cells were significantly higher than those in the chondrocytes co-cultured with non-transfected- and empty vector-transfected-umbilical cord mesenchymal stem cells. (5) To conclude, high expression of TDP43 in chondrocytes can activate the expression of RACK1, and further regulate chondrocyte proliferation and apoptosis.

Over-expression of Hsp83 in grossly depleted hsrω lncRNA background causes synthetic lethality and l(2)gl phenocopy in Drosophila

We examined interactions between the 83 kDa heat-shock protein (Hsp83) and hsrω long noncoding RNAs (lncRNAs) inhsrω66 Hsp90GFP homozygotes, which almost completely lack hsrω lncRNAs but over-express Hsp83. All +/+; hsrω66Hsp90GFP progeny died before the third instar. Rare Sp/CyO; hsrω66 Hsp90GFP reached the third instar stage butphenocopied l(2)gl mutants, becoming progressively bulbous and transparent with enlarged brain and died after prolongedlarval life. Additionally, ventral ganglia too were elongated. However, hsrω66 Hsp90GFP/TM6B heterozygotes, carrying +/+ or Sp/CyO second chromosomes, developed normally. Total RNA sequencing (+/+, +/+; hsrω66/hsrω66, Sp/CyO; hsrω66/hsrω66, +/+; Hsp90GFP/Hsp90GFP and Sp/CyO; hsrω66 Hsp90GFP/hsrω66 Hsp90GFP late third instar larvae) revealedsimilar effects on many genes in hsrω66 and Hsp90GFP homozygotes. Besides additive effect on many of them, numerousadditional genes were affected in Sp/CyO; hsrω66 Hsp90GFP larvae, with l(2)gl and several genes regulating the centralnervous system being highly down-regulated in surviving Sp/CyO; hsrω66 Hsp90GFP larvae, but not in hsrω66 orHsp90GFP single mutants. Hsp83 and several omega speckle-associated hnRNPs were bioinformatically found topotentially bind with these gene promoters and transcripts. Since Hsp83 and hnRNPs are also known to interact, elevatedHsp83 in an altered background of hnRNP distribution and dynamics, due to near absence of hsrω lncRNAs and omegaspeckles, can severely perturb regulatory circuits with unexpected consequences, including down-regulation of tumoursuppressor genes such as l(2)gl.

Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy / 神经科学通报·英文版

Primary age-related tauopathy (PART) is characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. In the present study, we analyzed the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART, Alzheimer's disease (AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages > 0 and ≤ IV, and a Thal phase of 0 (no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus, stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.

Research Progress of the Relationship of the Expression of TAR DNA/RNA-binding Domain Protein 43 in Neurodegenerative Disease and Brain Injury / 昆明医科大学学报

TAR DNA/RNA -binding domain protein 43 (TDP-43) is a highly conserved and widely expressed nuclear protein. TDP-43 is recognized as a pathological marker protein of amyotrophic lateral sclerosis (ALS),frontotemporal lobar degeneration (FTLD) and alzheimer disease (AD).This article discusses the structure and the function ofTDP-43 and the relationship of its expression in neurodegenerative disease.Meanwhile, this article emphatically probes into the specific expression andfunction of TDP-43 in acute and chronic brain injury based on the knowledge of its biological characteristics,aiming to explore the feasibility for determining the cause of death and the injury and disability situations by TDP-43 in forensic pathology.

An Autopsy Confirmed Case of Semantic Variant Primary Progressive Aphasia with Frontotemporal Lobar Degeneration-TDP type C

A 62-year-old man presented with a one-year history of word finding difficulty, impaired single word comprehension and personality changes including aggression, apathy and eating change. Brain MRIs showed severe atrophy in the left anterior temporal lobe. The clinical syndromic diagnosis was semantic variant primary progressive aphasia. He died at age 70 of pneumonia. At autopsy, transactive response DNA-binding protein (TDP) immunoreactive long dystrophic neurites were predominantly found in the cerebral cortices, which were compatible with frontotemporal lobar degeneration-TDP type C pathology.

TDP-43 regulates cancer-associated microRNAs

Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.

Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS / Distribuição cerebral distinta de fosfo-tdp-43 em dois casos de dft, um associado com ela

ABSTRACT. INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aß, AT8, anti-α-synuclein and anti-phospho-TDP-43. RESULTS: Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aß and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II). DISCUSSION: The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

RESUMO. INTRODUÇÃO: TDP-43 é uma proteína intranuclear envolvida em vários processos celulares. Essa molécula, quando alterada, mostra padrões de distribuição modificados, assim como de funcionamento, ao longo das estruturas do Sistema Nervoso Central. A Degeneração Lobar Frontotemporal (DLFT) e a Esclerose Lateral Amiotrófica (ELA) são dois exemplos de proteinopatia de TDP-43. Esses transtornos formam um espectro clínico, com alguns pacientes apresentando um transtorno cognitivo puro enquanto outros também apresentam disfunções motoras. MÉTODOS: Nós estudamos dois cérebros doados de pacientes com diagnóstico de Demência Frontotemporal (DFT), um dos quais se associava com ELA (ELA-DFT). Após fixação e exame macroscópico, foram realizadas análises de amostras. Regiões específicas foram escolhidas para aplicação de imunohistoquímica (IHQ) com anti-Aß, AT8, anti-α-sinucleina e anti-fosfo-TDP-43. RESULTADOS: Ambos os cérebros foram positivos para anti-fosfo-TDP-43, mas de forma não igualmente distribuida pelas regiões encefálicas. No caso DFT, o cérebro estudado apresentou TDP-43-fosforilada no córtex frontal, hipocampo, córtex entorrinal e mesencéfalo; no caso ELA-DFT, a proteína anormal também foi vista na ponte e no bulbo. O cérebro do caso ELA-DFT foi positivo para Aß e AT8 no hipocampo e no córtex entorrinal (Braak I e II). DISCUSSÃO: O presente estudo corrobora a hipótese atualmente sustentada pela literatura científica de que essas duas doenças neurodegenerativas possuem a mesma etiologia, mas acometem regiões encefálicas distintas.

Application of He-Ne laser combined with TDP irradiation in the treatment of herpes zoster ophthalmicus / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the effect of He-Ne laser combined with TDP irradiation in the treatment of herpes zoster ophthalmicus.METHODS: Totally 22 patients (22 eyes) with herpes zoster ophthalmicus were treated by He-Ne laser irradiation combined with TDP (Group A).Another 22 patients (22 eyes) with herpes zoster ophthalmicus (Group B) were treated by medication.The duration of the disease, the incidence of complications, and the time of pain relief were compared between the two groups.RESULTS: The cure rate of Group A was 91%, that of Group B was 73%, there was no significant difference between the two groups (x2=1.375, P>0.05).The average cure time of Group A was 8±2.22d, Group B was 12±1.88d, the difference between the two groups was statistically significant (t=5.22, P<0.05).The complication rate of Group A was 18%, Group B was 59%, the difference between the two groups was statistically significant (x2=6.86, P<0.05).The average pain relief time of Group A was 5±1.23d, Group B was 10±1.34d, the difference between the two groups was statistically significant (t=11.17, P<0.05).CONCLUSION: He-Ne laser combined with TDP irradiation can shorten the treatment time of herpes zoster ophthalmicus, shorten the course of disease, reduce the incidence of complications, relieve pain, with no significant effect on the cure rate of herpes zoster ophthalmicus.

Observations on the Efficacy of Acupuncture plus TDP in Treating StageⅡ-Ⅲ Pressure sore / 上海针灸杂志

Objective To investigate the clinical efficacy of acupuncture plus TDP in treating stageⅡ-Ⅲ pressure sore.Methods Thirty-three patients with pressure sore meeting the inclusion criteria were randomly allocated to treatment and control groups, 17 cases each. Both groups were first given routine clean care. The control group received routine surgical asepsis dressing change and the treatment group, fire needling, surrounding electroacupuncture and TDP irradiation to the affected part. The pressure sore area was observed and the PUSH score was recorded in the two groups before and after treatment. The clinical therapeutic effects were compared between the two groups of patients. Results The total efficacy rate was 88.0% in the treatment group and 71.0% in the control group; there was no statistically significant difference between the two groups (P>0.05). The total efficacy rate was 88.0% in the treatment group and 71.0% in the control group; there was no statistically significant difference between the two groups (P>0.05). The cure and marked efficacy rate was 58.8% in the treatment group and 23.5% in the control group; there was a statistically significant difference between the two groups (P<0.05). There was a statistically significant pre-/post- treatment difference in the pressure sore area in the two groups at one, two and three weeks after treatment (allP<0.05). There was a statistically significant difference in the pressure sore area between the two groups at two and three weeksafter treatment (bothP<0.05). There was a statistically significant pre-/post-treatment difference in the PUSH score in the two groups at two and three weeks after treatment (bothP<0.05). There was a statistically significant difference in the PUSH score between the two groups at three weeks after treatment (P<0.01).Conclusions Acupuncture plus TDP can markedly relieve the clinical symptoms and accelerate the sore healing in treating stageⅡ-Ⅲ pressure sore.

La agregación de TDP-43 como posible blanco terapéutico contra la Esclerosis Lateral Amiotrófica / TDP-43 aggregation as a possible therapeutic target for Amyotrophic Lateral Sclerosis / Agregação de TDP-43 como um possível alvo terapêutico para a Esclerose Lateral Amiotrófica

Los agregados de TDP-43 representan una de las característica histopatológicas más importantes de varias enfermedades neurodegenerativas, entre las que se incluye la Esclerosis Lateral Amiotrófica (ELA). TDP-43 está localizada principalmente en el núcleo. Sin embargo, los pacientes afectados por ELA presentan agregados de TDP-43 en el citoplasma de las neuronas comprometidas, con lo que se despoja al núcleo de TDP-43 funcional. Aún se desconoce si la degeneración causada por la agregación de TDP-43 es debida a una toxicidad intrínseca de los agregados o a la pérdida de función de TDP-43 como consecuencia del vaciamiento del núcleo. Varias investigaciones, incluidas las de estos autores, indican que la pérdida de función es el factor fundamental responsable de la neurodegeneración observada en presencia de inclusiones de TDP-43. Por otro lado, aún no existen tratamientos efectivos para la ELA. Por lo tanto, es de crucial importancia conocer las bases moleculares que conllevan al desarrollo de la enfermedad, con el objetivo de encontrar posibles estrategias terapéuticas. Para ello, estos autores han desarrollado un modelo celular capaz de imitar la agregación de TDP-43 y sus consecuencias. Finalmente, se ha utilizado este modelo para analizar el efecto de diferentes compuestos capaces de degradar los agregados de TDP-43 y se ha demostrado que esta podría ser una estrategia terapéutica válida para la ELA.

TDP-43 inclusions are important histopathological features of various neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). TDP-43 is mainly a nuclear protein, but it shuffles from the nucleus to the cytoplasm. In patients’ brains, TDP-43 is retained in the cytoplasm of the affected motorneurons to form insoluble aggregates, which results in TDP-43 nuclear clearance. There is still no consensus whether TDP-43-mediated neurodegeneration results from a gain or loss of function of the protein or a combination of both. The work from several laboratories, including this, points towards a strong loss of function component. On the other hand, there is no effective treatment or cure for ALS. Thus, there is obviously a need to find new therapeutic strategies for ALS. In order to gain new insights into the molecular mechanism of the disease, and with the aim of looking for new methodologies that can revert it, a cellular model of TDP-43 aggregation that can mimic the phenotypic consequences found in ALS patients has been developed. Finally, this model was used to search for compounds that can dissolve these aggregates, and it was shown that the clearance of TDP-43 aggregates could be a therapeutic strategy for ALS.

Os agregados proteicos TDP-43 são características histopatológicas importantes de muitas doenças neurodegenerativas, incluindo a Esclerose Lateral Amiotrófica (ALS). A proteína TDP-43 se localiza principalmente no núcleo, porém nos cérebros de indivíduos afetados, a proteína TDP-43 fica retida no citoplasma dos neurônios motores, o que leva a formação de agregados insolúveis, resultando em deposição nuclear. Ainda não existe um consenso se a neurodegeneração mediada por TDP43 é causada por ganho ou perda da função da proteína ou uma combinação de ambos. O trabalho de muitos laboratórios, bem como este trabalho, apontam para uma forte perda da função da proteína. Por outro lado, não existe um tratamento efetivo ou cura para a ALS. Portanto, existe uma grande necessidade de identificar novos tratamentos para a ALS. Para entender o mecanismo molecular da doença, e com o objetivo de identificar novas metodologias para reverter a doença, desenvolvemos o modelo celular de agregados de TDP-43, o qual mimetiza as consequências fenotípicas encontradas em pacientes com ALS. Por fim, utilizamos esse modelo para identificar compostos que podem dissolver os agregados, e demonstramos que a liberação de inclusões de TDP-43 poderiam ser usados como tratamentos para a ALS.

Caracterização das alterações da proteína TDP-43 durante o envelhecimento normal: uma análise em cérebros humanos postmortem / Characterization of TDP-43 changes during normal aging: a human brain post-mortem study

INTRODUÇÃO: A proteína TDP-43 (Transactive DNA-binding protein 43) é o principal agregado proteico anormal verificado em casos de Degeneração Lobar Frontotemporal (DLFT) e Esclerose Lateral Amiotrófica (ELA). Apesar dos avanços na área, o papel da TDP-43 no envelhecimento normal ainda é pouco compreendido. A falta de indivíduos controles em estudos de associação clinicopatológica com tecido cerebral humano é resultado do alto custo da prática de autópsia mundialmente. O que é um diferencial do Brasil, onde essa prática é obrigatória em casos de morte natural sem causa definida. O Banco de Encéfalos Humanos do Grupo de Estudos em Envelhecimento Cerebral (BEHGEEC) possui grande número de encéfalos de sujeitos sem déficit cognitivo com alta miscigenação étnica e variação de graus de escolaridade. O que possibilita estudos mais aprofundados sobre envelhecimento cerebral humano não-patológico. OBJETIVOS: (1) investigar de maneira sistemática a distribuição dos achados neuropatológicos da TDP-43 no envelhecimento humano normal; (2) caracterizar a distribuição dessa proteína em diferentes áreas encefálicas; (3) explorar associação de características, clínicas, sociodemográficas ou neuropatológicas com o aparecimento das inclusões de TDP-43. MÉTODOS: Foram incluídos participantes com idade acima de 50 anos e classificados clinicamente e anatomopatologicamente como normais. Reação imunoistoquímica contra a conformação anormal da TDP-43 foi realizada em três regiões cerebrais de interesse córtex temporal, amígdala e hipocampo. RESULTADOS: Os agregados de TDP-43 estavam presentes em 10,5% dos indivíduos estudados (n=323). A região mais frequentemente acometida foi a amígdala (85,3% dos casos). O acúmulo de TDP-43 foi associado à idade e raça (p=0,002). Análise de regressão logística demonstrou que indivíduos da raça asiática possuem maior chance de apresentar os agregados de TDP-43 do que caucasianos, independente dos fatores gênero, idade, estágio de Braak para...

BACKGROUND: Transactive DNA-binding protein 43 (TDP-43) is the major abnormal aggregate present in Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Slcerosis (ALS). Although all the efforts in research in this field, the role played by TDP-43 in normal aging is still unknown. The lack of normal controls in studies focusing on clinicopathological associations is a result of the high cost of autopsy practice worldwide. In Brazil, autopsy is mandatory by law in cases without a certificate. The Brain Bank of the Brazilian Aging Study Group (BBBASG) comprises a large number of cognitively normal elderly subjects highly ethnically admixtured and with broad education attainment. This allow us to further study the non-pathological process of the human aging brain. GOALS: (1) sistematically investigate the distrubution of neuropathological findings of TDP-43 in the normal human brain; (2) characterize the distribution of theses findings in different brain regions; (3) explore clinical, sociodemographics or neuropathological variables that could be associated with TDP-43 inclusion outcome. METHODS: We included participants over 50 years old previously classified cognitively and neuropathologically as normals. Imunnohistochemistry against abnormal form of TDP-43 was performed in three brain regions: temporal cortex, hippocampal formation and amygdala. RESULTS: TDP-43 aggregates were present in 10,5% of the study subjects (n=323). Amygdala was the most frequently affected brain region (85.3% of the cases). TDP-43 accumulation was associated with age at death and race (p=0.002). Logistic regression analysis showed that asians older adults have higher odds of presenting TDP-43 inclusions than caucasians, regardless of gender, age, Braak stage for neurofibrilarly tangles and education attainment (OD=3.5, CI: 1.41-8.69, p=0.007). CONCLUSIONS: Our results suggest that TDP-43 abnormal accumulation increases along aging process and the amygdala is the brain...

Recent advances of tyrosyl-DNA phosdiesterase Ⅰ (TdpⅠ) inhibitors / 药学实践杂志

Tyrosyl-DNA phosphodiesterase Ⅰ (TdpⅠ ) is a recently discovered proteinthat catalyzes the hydrolysis of 3′-phosphotyrosyl bonds .Such linkages form in vivo during the interaction of DNA and topoisomerase Ⅰ (TopⅠ) .TdpⅠ has been regarded as a potential therapeutic co-target of TopⅠ because it has the functions of repairing Top Ⅰ compound and coun-teracting the effects of Top Ⅰ inhibitors .TdpⅠ inhibitors can not only synergizing with Top Ⅰ-targeting drugs (camptoth-ecins) ,but also strength the function of bleomycin ,topoisomerase Ⅱ (TopⅡ ) inhibitors (etoposide ,doxorubicin) and DNA alkylating agents .We summarized the researching advance of TdpⅠ inhibitors and focused on the introduction of the mecha-nism ,bioactivity and structure-activity relationship .

Therapeutic Observation of Acupoint Application in Canicular Days plus TDP for Primary Dysmenorrhea Due to Cold-dampness / 上海针灸杂志

Objective To observe the clinical efficacy of acupoint application in canicular days plus TDP radiation in treating primary dysmenorrhea due to cold-dampness.Method Eighty-three patients were randomized into group A of 32 cases, group B of 20 cases, and group C of 31 cases. Group A was intervened by acupoint application plus TDP, group B was by acupoint application alone, while group C was by oral administration ofTong Jing Bao granules. The Visual Analogue Scale (VAS) scores of the three groups were observed before and after treatment, and the clinical efficacies were compared.Result The total effective rate was 93.1% in group A, versus 85.0% in group B and 77.4% in group C. The total effective rate of group A was significantly different from that of group B and group C (P<0.05). The total effective rate of group B was significantly different from that of group C (P<0.05). The VAS scores were changed significantly after treatment in the three groups (P<0.05). After treatment, the VAS scores of group A and B were both significantly different from that of group C (P<0.05).Conclusion Acupoint application plus TDP is an effective method in treating primary dysmenorrhea due to cold-dampness.

The pathological TDP-43 protein expression in the central nervous system of motor neuron disease / 中华内科杂志

Objective To understand pathological TDP-43 features in the central nervous systems of patients with clinically and autopsy confirmed motor neuron disease (MND).Methods The clinical and histopathological features of 4 cases with MND confirmed by autopsy were summarized; anti-ubiquitin (Ub) and anti-TDP-43 immunohistochemical staining were carried out on tissue of brains and spinal cords from 4 cases with MND and 3 control cases without history of neurological disorders.Results These 4 cases presented with typical clinical and histologic features of MND.Ub-positive inclusions were observed in brain and spinal cord from 3 cases with the Ub-positive inclusions of skein-round-and lewy body-like structures.Strong TDP-43 pathological staining in brain and spinal cord was identified in 2 cases with MND presented as neuronal and glial cytoplasmic inclusions with various shapes.The TDP-43 positive inclusions were widely distributed in the motor cortex of brain and the anterior horn of spinal cord.TDP-43 weak staining in the spinal cord tissue was observed in 1 case with MND.No Ub-and TDP-43 positive inclusions were found in 3 control cases.Conclusion There is widespread pathological TDP-43 expression in the central nervous system of MND.TDP-43 positive inclusions in MND have relatively high specificity.It is worth further study on their formation mechanism.

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.

TDP therapy nursing research to promote wound healing caesarean / 中国医学装备

Objective:To use TDP therapy combined with special care and treatment of cesarean section wound, clinical observation. Methods:The therapy combined with psychological, pain, health education and other special nursing treatment with TDP for 38 cases of the observation group of patients, the patients in control group took traditional postoperative nursing. Results:in the observation group were the wound infection rate was 7.9%, the incidence of complications was 18.4%, the control group were 28.9%, 42.1%, And the observation group at the end of the third week wound shrinking rate was 38.62±26.31, control group was 27.14±12.42, the observation group at the end of the 1 week, 2 week, 3 week pain levels were 4.68±1.24, 4.14±1.21, 3.96±1.02, comparing the two groups of patients, the wound infection rate reduced rate and pain level, (x2=4.2903, x2=4.2113;P<0.05),the difference has statistical significance. Conclusion:combined with special care, the postoperative parturient with TDP therapy effect is good, is worth the clinical promotion.

Therapeutic Observation of Acupuncture plus TDP and Auricular Point Sticking for Chronic Pelvic Infection / 上海针灸杂志

ObjectiveTo observe the clinical efficacy of acupuncture plus TDP (specific electromagnetic treatment apparatus) and auricular point sticking in treating chronic pelvic infection.MethodSixty patients diagnosed with chronic pelvic infection were randomized into two groups. Thirty cases in the treatment group were intervened by acupuncture plus TDP and auricular point sticking, while the other 30 in the control group were by acupuncture plus TDP, 10 d as a treatment course in both groups, and the therapeutic efficacies were compared after 3 courses.ResultThe total effective rate was 96.7% in the treatment group versus 83.3% in the control group, and the difference was statistically significant (P<0.05).ConclusionAcupuncture plus TDP and auricular point sticking can produce a marked therapeutic efficacy in treating chronic pelvic infection, and its total effective rate is higher than that of acupuncture plus TDP.