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Autism spectrum disorder (ASD) is a multifaced neurodevelopmental disorder with considerable heterogeneity, in which over-generated reactive oxygen species (ROS) induce a cascade of pathological changes, including cellular apoptosis and inflammatory responses. Given the complex etiology of ASD, no effective treatment is available for ASD. In this work, a specific catalytic nanoenzyme, calcium hexacyanoferrate (III) nanocatalysts (CaH NCs), is designed and engineered for efficient ASD treatment. CaH NCs can mimic the activities of natural enzymes including superoxide dismutase, peroxidase, catalase, and glutathione peroxidase, which mitigates intracellular excessive ROS and regulates redox equilibrium. These CaH NCs modulate mitochondrial membrane potential, elevate B-cell lymphoma-2 levels, and suppress pro-apoptotic proteins, including Caspase-3 and B-cell lymphoma-2-associated X, thus effectively reducing cellular apoptosis. Importantly, CaH NCs alleviate inflammation by upregulating anti-inflammatory cytokine interleukin-10 and downregulating pro-inflammatory factors, resulting in attenuated activation of microglial and astrocytic and subsequent reduction in neuroinflammation. Subsequently, CaH NCs enhance social abilities, decrease anxiety levels, ameliorate repetitive behaviors, and improve learning and memory in ASD animal models through inflammation regulation and apoptosis inhibition. The CaH NCs in managing and preventing ASD represents a paradigm shift in autism treatment, paving the alternative but efficient way for clinical interventions in neurological conditions.
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Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.
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Transtorno do Espectro Autista , Autofagia , Barreira Hematoencefálica , Nanopartículas , Estresse Oxidativo , Sirolimo , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Animais , Autofagia/efeitos dos fármacos , Nanopartículas/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos , Humanos , Sistemas de Liberação de Medicamentos/métodos , Modelos Animais de Doenças , Masculino , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Biomimética/métodos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Peptídeos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologiaRESUMO
The construction and modification of novel energetic frameworks to achieve an ideal balance between high energy density and good stability are a continuous pursuit for researchers. In this work, a fused [5,6,5]-tricyclic framework was utilized as the energetic host to encapsulate the oxidant molecules for the first time. A series of new pyridazine-based [5,6] and [5,6,5] fused polycyclic nitrogen-rich skeletons and their derivatives were designed and synthesized. Two strategies, amino oxidation and host-guest inclusion, were used to modify the skeleton in only one step. All compounds exhibit good comprehensive properties (Td (onset) > 200 °C, ρ > 1.85 g cm-3, Dv > 8400 m s-1, IS > 20 J, FS > 360 N). Benefiting from the pyridazine-based fused tricyclic structure with more hydrogen bonding units and larger conjugated systems, the first example of [5,6,5]-tricyclic host-guest energetic material triamino-9H-pyrazolo[3,4-d][1,2,4]triazolo[4,3-b]pyridazine-diperchloric acid (10), shows high decomposition temperature (Td (onset) = 336 °C), high density and heats of formation (ρ = 1.94 g cm-3, ΔHf = 733.4 kJ mol-1), high detonation performance (Dv = 8820 m s-1, P = 36.2 GPa), high specific impulse (Isp = 269 s), and low sensitivity (IS = 30 J, FS > 360 N). The comprehensive performance of 10 is superior to that of high-energy explosive RDX and heat-resistant explosives such as HNS and LLM-105. 10 has the potential to become a comprehensive advanced energetic material that simultaneously satisfies the requirements of high-energy and low-sensitivity explosives, heat-resistant explosives, and solid propellants. This work may give new insights into the construction and modification of a nitrogen-rich polycyclic framework and broaden the applications of fused polycyclic framework for the development of host-guest energetic materials.
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The evolution of nano-drug delivery systems addresses the limitations of conventional cancer treatments with stimulus-responsive nanomaterial-based delivery systems presenting temporal and spatial advantages. Among various nanomaterials, boron nitride nanoparticles (BNNs) demonstrate significant potential in drug delivery and cancer treatment, providing a high drug loading capacity, multifunctionality, and low toxicity. However, the challenge lies in augmenting nanomaterial accumulation exclusively within tumors while preserving healthy tissues. To address this, we introduce a novel approach involving cancer cell membrane-functionalized BNNs (CM-BIDdT) for the codelivery of doxorubicin (Dox) and indocyanine green to treat homologous tumor. The cancer cell membrane biomimetic CM-BIDdT nanoparticles possess highly efficient homologous targeting capabilities toward tumor cells. The surface modification with acylated TAT peptides (dTAT) further enhances the nanoparticle intracellular accumulation. Consequently, CM-BIDdT nanoparticles, responsive to the acidic tumor microenvironment, hydrolyze amide bonds, activate the transmembrane penetrating function, and achieve precise targeting with substantial accumulation at the tumor site. Additionally, the photothermal effect of CM-BIDdT under laser irradiation not only kills cells through thermal ablation but also destroys the membrane on the surface of the nanoparticles, facilitating Dox release. Therefore, the fabricated CM-BIDdT nanoparticles orchestrate chemo-photothermal combination therapy and effectively inhibit tumor growth with minimal adverse effects, holding promise as a new modality for synergistic cancer treatment.
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Compostos de Boro , Doxorrubicina , Verde de Indocianina , Nanopartículas , Doxorrubicina/química , Doxorrubicina/farmacologia , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Animais , Humanos , Camundongos , Nanopartículas/química , Linhagem Celular Tumoral , Terapia Fototérmica , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/terapia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Camundongos Endogâmicos BALB C , Portadores de Fármacos/química , Sistemas de Liberação de MedicamentosRESUMO
Recent clinical studies have highlighted mutations in the voltage-gated potassium channel Kv10.2 encoded by the KCNH5 gene among individuals with autism spectrum disorder (ASD). Our preliminary study found that Kv10.2 was decreased in the hippocampus of valproic acid (VPA) - induced ASD rats. Nevertheless, it is currently unclear how KCNH5 regulates autism-like features, or becomes a new target for autism treatment. We employed KCNH5 knockout (KCNH5-/-) rats and VPA - induced ASD rats in this study. Then, we used behavioral assessments, combined with electrophysiological recordings and hippocampal brain slice, to elucidate the impact of KCNH5 deletion and environmental factors on neural development and function in rats. We found that KCNH5-/- rats showed early developmental delay, neuronal overdevelopment, and abnormal electroencephalogram (EEG) signals, but did not exhibit autism-like behavior. KCNH5-/- rats exposed to VPA (KCNH5-/--VPA) exhibit even more severe autism-like behaviors and abnormal neuronal development. The absence of KCNH5 excessively enhances the activity of the Protein Kinase B (Akt)/Mechanistic Target of Rapamycin (mTOR) signaling pathway in the hippocampus of rats after exposure to VPA. Overall, our findings underscore the deficiency of KCNH5 increases the susceptibility to autism under environmental exposures, suggesting its potential utility as a target for screening and diagnosis in ASD.
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Transtorno do Espectro Autista , Hipocampo , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Animais , Masculino , Ratos , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/genética , Transtorno Autístico/metabolismo , Transtorno Autístico/genética , Modelos Animais de Doenças , Canal de Potássio ERG1/metabolismo , Canal de Potássio ERG1/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Canais de Potássio Éter-A-Go-Go/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Ácido Valproico/farmacologiaRESUMO
A Lewis acid-promoted electrophilic thiocyanation/cyclization of ortho-alkynylanilines for the synthesis of indole derivatives has been developed. The reaction utilizes Me3SiBr as the Lewis acid and N-thiocyanatosuccinimide as the thiocyanation reagent. A series of 2-aryl-3-thiocyanato indoles were prepared in moderate to high yields under mild conditions without metals and oxidants. It provides an efficient protocol for the construction of the indole skeleton and C-SCN and C-N bonds in one step as well.
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The remote C(sp3)-SCN bond formation via ring-opening functionalization of cycloalkanols with N-thiocyanatosaccharin as the precursor of SCN radicals and pyrylium salt as the organic photocatalyst under visible light has been developed. Thus, various terminal keto thiocyanates were prepared without transition metals and oxidants in moderate to good yields. The simplicity, wide substrate scope and mild conditions feature its synthetic application capability.
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Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.
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Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus to understand ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglial-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.
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BACKGROUND: Dysfunctional neurons and microglia in the rostral ventrolateral medulla (RVLM) have been implicated in the pathogenesis of stress-induced hypertension (SIH). Functional perturbation of microglial synaptic engulfment can induce aberrant brain circuit activity. IFN-γ is a pleiotropic cytokine that plays a role in regulating neuronal activity. However, existing research on the exploration of the effects of microglia on synapses in the RVLM is lacking, particularly on the function of IFN-γ in microglial synaptic engulfment involved in SIH. METHODS: A SIH rat model was established by electric foot shocks combined with noise stimulation. The underlying mechanism of IFN-γ on synaptic density and microglial synaptic engulfment was investigated through in-vivo and in-vitro experiments involving gain of function, immunofluorescence, quantitative real-time PCR, western blot, and morphometric analysis. Furthermore, the function of IFN-γ in neuronal activity, renal sympathetic nerve activity (RSNA), and blood pressure (BP) regulation was determined through in-vivo and in-vitro experiments involving Ca 2+ imaging, immunofluorescence, platinum-iridium electrode recording, ELISA, the femoral artery cannulation test, and the tail-cuff method. RESULTS: The BP, heart rate, RSNA, plasma norepinephrine, and the number of c-Fos-positive neurons in SIH rats increased compared with those in control rats. Pre and postsynaptic densities in the RVLM also increased in SIH rats. IFN-γ and CCL2 expression levels were significantly reduced in the RVLM of the SIH group, whose microglia also exhibited an impaired capacity for synapse engulfment. IFN-γ elevation increased CCL2 expression and microglial synaptic engulfment and decreased synaptic density in vivo and in vitro . However, CCL2 inhibition reversed these effects. Moreover, the reduction of neuronal excitability, RSNA, plasma norepinephrine, and BP by IFN-γ was abrogated through CCL2 expression. CONCLUSION: IFN-γ deficiency in the RVLM impaired the microglial engulfment of synapses by inhibiting CCL2 expression and increasing synaptic density and neuronal excitability, thereby contributing to SIH progression. Targeting IFN-γ may be considered a potential strategy to combat SIH.
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Hipertensão , Microglia , Animais , Ratos , Pressão Sanguínea , Rim/inervação , Bulbo , Microglia/metabolismo , Microglia/patologia , Sistema Nervoso Simpático , Interferon gama/metabolismoRESUMO
A Lewis acid-catalyzed electrophilic dearomatizative thiocyanation and cyclization of benzofurans with N-thiocyanatosuccinimide has been accomplished by Lewis acid catalysis with CuOTf under mild conditions. It was suggested that the electrophilic thiocyanating reagent was activated by CuOTf, and difunctionalization was achieved through a thiocyanation/spirocyclization pathway. Thus, a series of thiocyanato-containing spiroketals were obtained in moderate to high yields. It provides an alternative approach for the synthesis of functionalized [6,5]/[5,5]-spiroketals.
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Boron nitride nanomaterials are being increasingly recognized as vehicles for cancer drug delivery that increase drug loading and control drug release because of their excellent physicochemical properties and biocompatibility. However, these nanoparticles are often cleared rapidly by the immune system and have poor tumor targeting effects. As a result, biomimetic nanotechnology has emerged to address these challenges in recent times. Cell-derived biomimetic carriers have the characteristics of good biocompatibility, long circulation time, and strong targeting ability. Here, we report a biomimetic nanoplatform (CM@BN/DOX) prepared by encapsulating boron nitride nanoparticles (BN) and doxorubicin (DOX) together using cancer cell membrane (CCM) for targeted drug delivery and tumor therapy. The CM@BN/DOX nanoparticles (NPs) were able to target cancer cells of the same type on its own initiative through homologous targeting of cancer cell membranes. This led to a remarkable increase in cellular uptake. In vitro simulation of an acidic tumor microenvironment could effectively promote drug release from CM@BN/DOX. Furthermore, the CM@BN/DOX complex exhibited an excellent inhibitory effect against homotypic cancer cells. These findings suggest that CM@BN/DOX are promising in targeted drug delivery and potentially personalized therapy against their homologous tumor.
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A tandem electrophilic thiocyanation and cyclization of arene-alkynes has been developed under mild conditions, affording thiocyanato-substituted phenanthrenes, dihydronaphthalenes, 2H-chromenes and dihydroquinolines in moderate to excellent yields. This reaction provides an efficient protocol for the construction of C-SCN and C-C bonds in one step. In this transformation, N-thiocyanato reagent serves as a convenient precursor to transfer SCN+ in the presence of trimethylchlorosilane, and the cyclization exhibited exclusive 6-endo-dig selectivity. Finally, a gram scale reaction and further derivatizations highlight the utility of this synthetic strategy.
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Pyrola corbieri Levl has been used to strengthen bones and nourish the kidney (the kidney governs the bone and is beneficial to the brain) by the local Miao people in China. However, the functional components and neurotrophic activity have not been reported. A new acidic homogeneous heteropolysaccharide named LTC-1 was obtained and characterized by periodate oxidation, Smith degradation, partial acid hydrolysis, GC-MS spectrometry, methylation analysis, and Fourier transform infrared spectroscopy, and its molecular weight was 3239 Da. The content of mannuronic acid (Man A) in LTC-1 was 46%, and the neutral sugar was composed of L-rhamnose (L-Rha), L-arabinose (L-Ara), D-xylose (D-Xyl), D-mannose (D-Man), D-glucose (D-Glc) and D-galactose (D-Gal) with a molar ratio of 1.00:3.63:0.86:1.30:6.97:1.30. The main chain of LTC-1 was composed of Glc, Gal, Man, Man A and the branched chain Ara, Glc, Gal. The terminal residues were composed of Glc and Gal. The main chain and branched chains were linked by (1â5)-linked-Ara, (1â3)-linked-Glc, (1â4)-linked-Glc, (1â6)-linked-Glc, (1â3)-linked-Gal, (1â6)-linked-Gal, (1â3, 6)-linked-Man and ManA. Meanwhile, neurotrophic activity was evaluated through PC12 and primary hippocampal neuronal cell models. LTC-1 exhibited neurotrophic activity in a concentration-dependent manner, which significantly induced the differentiation of PC12 cells, promoted the neurite outgrowth of PC12 cells, enhanced the formation of the web architecture of dendrites, and increased the density of dendritic spines in hippocampal neurons and the expression of PSD-95. These results displayed significant neurotrophic factor-like activity of LTC-1, which suggests that LTC-1 is a potential treatment option for neurodegenerative diseases.
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Pyrola , Humanos , Polissacarídeos/química , Carboidratos , Galactose , GlucoseRESUMO
The cytoplasmic multifunctional adaptor protein ß-arrestin 2 (Arrb2) is involved in the occurrence of various nervous system diseases, such as Alzheimer's disease and Parkinson's disease. Previous laboratory studies have shown that the expression and function of the Arrb2 gene was increased in valproic acid-induced autistic mice models. However, few reports have examined the possible role of Arrb2 in the pathogenesis of autism spectrum disorder. Therefore, Arrb2-deficient (Arrb2-/-) mice were further studied to uncover the physiological function of Arrb2 in the nervous system. In this study, we found that Arrb2-/- mice had normal behavioral characteristics compared with wild-type mice. The autophagy marker protein LC3B was decreased in the hippocampus of Arrb2-/- mice compared to wild-type mice. Western blot analysis revealed that deletion of Arrb2 caused hyperactivation of Akt-mTOR signaling in the hippocampus. In addition, abnormal mitochondrial dysfunction was observed in Arrb2-/- hippocampal neurons, which was characterized by a reduction in mitochondrial membrane potential and adenosine triphosphate production and an increase in reactive oxygen species levels. Therefore, this study elucidates the interaction between Arrb2 and the Akt-mTOR signaling pathway and provides insights into the role of Arrb2 in hippocampal neuron autophagy.
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Transtorno do Espectro Autista , Proteínas Proto-Oncogênicas c-akt , Camundongos , Animais , beta-Arrestina 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transtorno do Espectro Autista/patologia , Serina-Treonina Quinases TOR/metabolismo , Autofagia/fisiologia , Hipocampo/metabolismo , beta-Arrestina 2/genéticaRESUMO
Background: Pancreatic adenocarcinoma (PAAD) is a type of malignant tumors in the digestive tract. It is extremely aggressive. However, the molecular mechanism of the occurrence and development of pancreatic cancer has not yet been elucidated. New evidence shows that the dysregulation of small nucleolar RNAs (SnoRNAs) plays an important role in tumorigenesis and has a certain connection with tumor stem cells. In this study, we screened differentially expressed SnoRNAs in pancreatic cancer, further explored whether the HGF/C-Met pathway is involved in the regulation of SNORD35A in pancreatic cancer stem cells. Materials and Methods: AffymetrixmiRNA 4.0 and QRT-PCR was used for differential screening of SnoRNA. CCK8, wound healing assay and TransWell chamber were used to detect cell proliferation, migration and invasion. QRT-PCR was used to detect the changes of epithelial - mesenchymal Transition (EMT) related genes of tumors. We detected the expression levels of HGF/C-Met pathway and its related proteins by Western blotting. Result: We found that SNORD35A is significantly overexpressed in pancreatic cancer. After disturbing the expression of SNORD35A, the epithelial markers increased and the mesenchymal markers decreased during the EMT process. At the same time, down-regulation of SNORD35A inhibited the proliferation, migration and invasion of pancreatic cancer stem cells in cellular level. In nude mouse transplanted tumor models, low expression of SNORD35A reduced tumor growth volume and attenuated its pathological features. Finally, we found that silencing SNORD35A reduced the expression levels of C-Met and its phosphorylated proteins. Conclusion: These results suggest that the regulation of SNORD35A on proliferation, migration, invasion and EMT of pancreatic cancer stem cells involves HGF/C-Met signaling pathway. SNORD35A has carcinogenic effects in pancreatic cancer and may become a prognostic biomarker and therapeutic target for pancreatic cancer patients.
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Transient receptor potential vanillic acid 2 (TRPV2) are well recognized for their contributions to neuronal development, cardiac function, immunity and cancer. However, the precise roles for this thermo TRPchannels in neurological disorder remain unknown. In this study, we employed the CRISPR/Cas9 system to generate genetic mutations of TRPV2. Genetic mutation of TRPV2 resulted in autistic-like phenotypes in mice accompanied with the disordered electrical signals recorded by multi-channels in vivo. To determine possible molecular mechanisms, western blotting was further used to assess the possible involvement of several autism-related proteins. The significantly decreased expression of the R2 subunit of the GABA-B receptor in the hippocampus was observed. Together, our findings suggest that genetic mutation of TRPV2 induces autism-like behavior, results in decreased expression of the R2 subunit of the GABA-B receptor.
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Ansiedade/genética , Receptores de GABA-B , Canais de Cátion TRPV , Animais , Canais de Cálcio/metabolismo , Hipocampo/metabolismo , Camundongos , Mutação , Receptores de GABA-B/metabolismo , Canais de Cátion TRPV/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Pulmonary tuberculosis (TB) is a chronic infectious disease that is caused by respiratory infections, principally Mycobacterium tuberculosis. Increasingly, studies have shown that circular (circ)RNAs play regulatory roles in different diseases through different mechanisms. However, their roles and potential regulatory mechanisms in pulmonary TB remain unclear. In this study, we analyzed circRNA sequencing data from adjacent normal and diseased tissues from pulmonary TB patients and analyzed the differentially expressed genes. We then constructed machine learning models and used single-factor analysis to identify hub circRNAs. We downloaded the pulmonary TB micro (mi)RNA (GSE29190) and mRNA (GSE83456) gene expression datasets from the Gene Expression Omnibus database and performed differential expression analysis to determine the differentially expressed miRNAs and mRNAs. We also constructed a circRNA-miRNA-mRNA interaction network using Cytoscape. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to predict the biological functions of the identified RNAs and determine hub genes. Then, the STRING database and cytoHubba were used to construct protein-protein interaction networks. The results showed 125 differentially expressed circRNAs in the adjacent normal and diseased tissues of pulmonary TB patients. Among them, we identified three hub genes associated with the development of pulmonary TB: hsa_circ_0007919 (upregulated), hsa_circ_0002419 (downregulated), and hsa_circ_0005521 (downregulated). Through further screening, we determined 16 mRNAs of potential downstream genes for hsa-miR-409-5p and hsa_circ_0005521 and established an interaction network. This network may have important roles in the occurrence and development of pulmonary TB. We constructed a model with 100% prediction accuracy by machine learning and single-factor analysis. We constructed a protein-protein interaction network among the top 50 hub mRNAs, with FBXW7 scoring the highest and SOCS3 the second highest. These results may provide a new reference for the identification of candidate markers for the early diagnosis and treatment of pulmonary TB.
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MicroRNAs , Tuberculose Pulmonar , Biologia Computacional , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tuberculose Pulmonar/genéticaRESUMO
Autism is a complex neurodevelopmental disease that may be caused by genetic and environmental factors, that are incompletely understood. Overactivation of dopaminergic receptors can lead to autistic-like behavior. ß-arrestin2 (Arrb2) is a scaffolding protein of the arrestin family, which function as cytosolic multifunctional adapter proteins that activate cell signal transduction and mediate the signal termination and endocytosis of G-protein-coupled receptors (GPCRs) complexes. In this study, we established an Arrb2 knockout (Arrb2-/-) mouse to explore the biological function of Arrb2 in autistic-like behavior caused by abnormality in the dopaminergic system. We found that Arrb2-/- mice did not exhibit the autistic-like behavior normally induced by SKF38393, an agonist of the dopamine receptor 1 (D1R). Compared with wild-type (WT) untreated mice, the SKF38393-treated WT mice and Arrb2-/- mice, with or without SKF38393 treatment, showed abnormalities on electroencephalography (EEG) and increased stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via the PKA/Rap1/B-Raf/MEK pathway. These results demonstrated that Arrb2 regulated the dopaminergic system through the ERK signaling pathway in the occurrence and development of autism, and that targeted deletion of Arrb2 impeded the development of autistic-like behavior.
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Transtorno Autístico , Sistema de Sinalização das MAP Quinases , beta-Arrestina 2/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Transtorno Autístico/genética , Dopamina , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia , beta-Arrestina 1/genética , beta-Arrestina 1/metabolismo , beta-Arrestina 2/genética , beta-Arrestinas/metabolismoRESUMO
BACKGROUND: Trace elements may affect neurodevelopment. There is a lack of data on breast-milk rubidium (Rb) in relation to neurodevelopment in infants. The associations of copper (Cu), zinc (Zn) and strontium (Sr) with neurodevelopment in infants remain uncertain. OBJECTIVES: We sought to evaluate the associations of breast-milk Rb (primary exposure), Cu, Zn, and Sr with neurodevelopment in infants at age 8 months. METHODS: The study cohort included 117 breastfed infants. Breast-milk samples were collected at 42 days and 8 months postpartum. Breast-milk Rb, Zn, Cu, and Sr were measured by inductively coupled plasma mass spectrometer. Neurodevelopment was assessed at age 8 months. The primary outcomes were attention and working memory scores, as evaluated by the A-not-B task. Other outcomes included the Mental Development Index (MDI) and Psychomotor Development Index (PDI) as evaluated by the Bayley Scale of Infant Development III. Generalized linear models and restricted cubic spline regression were used to assess the associations between trace elements and neurodevelopment indices. Bonferroni correction was conducted on all data presented. RESULTS: A nonlinear association was observed between breast-milk Rb at 42 days and infant's attention at age 8 months (nonlinearity P = 0.037). Positive associations were observed with infant MDI scores and breast-milk Rb at 42 days (ß = 4.46; P = 0.06) and 8 months (ß = 3.79; P = 0.009) postpartum. Breast-milk Zn at 42 days was positively associated with infant's attention (ß = 0.31; P = 0.039). Sr at 42 days was positively correlated with attention (ß = 0.18; P = 0.043) and MDI scores (ß = 2.18; P = 0.015) at 8 months. Inverted U-shape associations were observed for breast-milk Cu at 42 days with infant attention and PDI scores. All associations were not significant after correction for multiple tests. CONCLUSIONS: Our data suggest that Rb, Zn, Cu, and Sr in breast milk at certain concentrations are associated with neurodevelopment in breastfed infants. Further studies are warranted to validate the findings.