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Peptide drugs have disadvantages such as low stability, short half-life and side effects, which limit their widespread use in clinical practice. Therefore, peptide drugs can be modified to improve these disadvantages. Numerous studies have shown that alkyl-modified peptide drugs can self-assemble to prolong the duration of efficacy and/or reduce side effects. However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming. To overcome this, a simple reductive amination reaction was employed, which can directly graft the alkyl chain to the peptide sequence and effectively avoid stepwise synthesis from C- to N-terminal with amino acids. In this study, ω-conotoxin MVIIA was used as the peptide drug, while myristic aldehyde was used as the alkylating agent. To obtain the maximum productivity of modified peptides, the molar ratio of peptide MVIIA to myristic aldehyde in the reductive amination reaction was optimized. Furthermore, the peptide modification sites in this reaction were confirmed by secondary mass spectrometry analysis. Besides, alkyl-modified peptide MVIIA was able to form micelles by self-assembly and improved stability in serum, which was related to our previous work where myristoylated peptide MVIIA micelles can improve the drug stability. Finally, this study was intended to provide a methodological basis for modifying the alkyl chain of peptide drugs.
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Micelas , Péptidos , omega-Conotoxinas , Aminación , Péptidos/química , AldehídosRESUMEN
Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, severe neurological side effects and low stability associated with peptide MVIIA have restricted its widespread use. Fortunately, self-assembly endows the peptide with high stability and multiple functions, which can effectively control its release to prolong its duration of action. Inspired by this, MVIIA was modified with appropriate fatty acid chains to render it amphiphilic and easier to self-assemble. In this paper, an N-terminal myristoylated MVIIA (Myr-MVIIA, medium carbon chain length) was designed and prepared to undergo self-assembly. The present results indicated that Myr-MVIIA can self-assemble into micelles. Self-assembled micelles formed by Myr-MVIIA at higher concentrations than MVIIA can prolong the duration of the analgesic effect and significantly reduce or even eliminate the side effects of tremor and coordinated motor dysfunction in mice.
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Dolor Crónico , omega-Conotoxinas , Ratones , Animales , Dolor Crónico/tratamiento farmacológico , Micelas , omega-Conotoxinas/farmacología , Péptidos/farmacología , Bloqueadores de los Canales de Calcio/farmacologíaRESUMEN
Objective: To assess prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score could predict overall survival (OS) and disease-free survival (DFS) in patients with breast cancer. Methods: PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar were searched from 1st January 2000 to 10th October 2021 for studies assessing the association between PNI or CONUT and outcomes of breast cancer by following the PRISMA guidelines. Keywords used were "Prognostic nutritional index", "Controlling nutritional status", "CONUT", and "Breast cancer". Results: Nine studies were included. On pooled analysis, we noted a statistically significant improved OS in patients with high PNI as compared to low PNI. Meta-analysis revealed no significant difference in DFS between patients with high PNI and low PNI. However, on the exclusion of one study, we noted that high PNI was associated with significantly improved DFS as compared to low PNI. On pooled analysis, we also noted that a high CONUT score was associated with significantly reduced OS in breast cancer patients. Conclusion: Our results indicate that PNI is an important prognostic factor for patients with breast cancer. Pre-treatment low PNI is associated with worse OS and DFS. Scarce data also indicates that a high CONUT score is predictive of poor OS in breast cancer.
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BACKGROUND: Mounting evidence indicates that the cerebral cortex is an important physiological system of emotional activity, and its dysfunction may be the main cause of stress. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), which initiates rapid signal transmission in the synapse before its reuptake into the surrounding glia, specifically astrocytes (ASTs). The astrocytic excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2) are the major transporters that take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with depression. Therefore, we hypothesized that the underlying antidepressant-like mechanism of Xiaoyaosan (XYS), a Chinese herbal formula, may be related to the regulation of astrocytic EAATs. Therefore, we studied the antidepressant mechanism of XYS on the basis of EAAT dysfunction in ASTs. METHODS: Eighty adult C57BL/6 J mice were randomly divided into 4 groups: a control group, a chronic unpredictable mild stress (CUMS) group, a Xiaoyaosan (XYS) treatment group and a fluoxetine hydrochloride (Flu) treatment group. Except for the control group, mice in the other groups all received chronic unpredictable mild stress for 21 days. Mice in the control and CUMS groups received gavage administration with 0.5 mL of normal saline (NS) for 21 days, and mice in the XYS and Flu treatment groups were administered dosages of 0.25 g/kg/d and 2.6 mg/kg/d by gavage. The effects of XYS on the depressive-like behavioral tests, including the open field test (OFT), forced swimming test (FST) and sucrose preference test (SPT), were examined. The glutamate (Glu) concentrations of the prefrontal cortex (PFC) were detected with colorimetry. The morphology of neurons in the PFC was observed by Nissl staining. The expression of glial fibrillary acidic protein (GFAP), NeuN, EAAT1 and EAAT2 proteins in the PFC of mice was detected by using Western blotting and immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of the GFAP, NeuN, EAAT1 and EAAT2 genes in the PFC of mice. RESULTS: The results of behavioral tests showed that CUMS-induced mice exhibited depressive-like behavior, which could be improved in some tests with XYS and Flu treatment. Immunohistochemistry and Western blot analysis showed that the protein levels of GFAP, NeuN, EAAT1 and EAAT2 in the PFC of CUMS mice were significantly lower than those in the control group, and these changes could be reversed by XYS and Flu. The results of qPCR analysis showed that the expression of GFAP, NeuN, EAAT1 and EAAT2 mRNAs in the PFC of CUMS mice was not significantly changed, with the exception of EAAT2, compared with that of the control group, while the expression of the above mRNAs was significantly higher in the XYS and Flu groups than that in the CUMS group. CONCLUSION: XYS may exert antidepressant-like effects by improving the functions of AST and EAATs and attenuating glutamate-induced neuronal damage in the frontal cortex.
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Antidepresivos/administración & dosificación , Astrocitos/efectos de los fármacos , Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Corteza Prefrontal/citología , Animales , Conducta Animal , Depresión/genética , Depresión/metabolismo , Modelos Animales de Enfermedad , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Ácido Glutámico/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacosRESUMEN
Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases. Traditionally, the fibrillar aggregation of FUS was considered to be the cause of those diseases, especially via its prion-like domains (PrLDs), which are rich in glutamine and asparagine residues. Lately, a nonfibrillar self-assembling phenomenon, liquid-liquid phase separation (LLPS), was observed in FUS, and studies of its functions, mechanism, and mutual transformation with pathogenic amyloid have been emerging. This review summarizes recent studies on FUS self-assembling, including both aggregation and LLPS as well as their relationship with the pathology of ALS, FTLD, and other neurodegenerative diseases.
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Enfermedades Neurodegenerativas/genética , Agregación Patológica de Proteínas/genética , Proteína FUS de Unión a ARN/química , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Asparagina/química , Asparagina/genética , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/patología , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/genética , Humanos , Enfermedades Neurodegenerativas/patología , Péptidos/química , Péptidos/genética , Priones/química , Priones/genética , Agregación Patológica de Proteínas/patología , Dominios Proteicos/genética , Proteína FUS de Unión a ARN/genéticaRESUMEN
Background: The apelin-APJ system has been considered to play a crucial role in HPA axis function, and how the traditional Chinese compound prescription Xiaoyaosan regulates the apelin-APJ system as a supplement to treat depressive disorders. Objective: To investigate the depression-like behaviors and expression of apelin and APJ in hypothalamus of chronic unpredictable mild stress (CUMS) mice and study whether these changes related to the regulation of Xiaoyaosan. Methods: 60 adult C57BL/6J mice were randomly divided into four groups, including control group, CUMS group, Xiaoyaosan treatment group and fluoxetine treatment group. Mice in the control group and CUMS group received 0.5 mL physiological saline once a day by intragastric administration. Mice in two treatment groups received Xiaoyaosan (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. After 21 days of modeling with CUMS, the expression of apelin and APJ in hypothalamus were measured by real-time fluorescence quantitative PCR, western blot and immunohistochemical staining. The physical condition, body weight, food intake and behavior tests such as open field test, sucrose preference test and force swimming test were measured to evaluate depressive-like behaviors. Results: In this study, significant behavioral changes were found in CUMS-induced mice, meanwhile the expressions of apelin and APJ in the hypothalamus were changed after modeling. The body weight, food-intake and depressive-like behaviors in CUMS-induced mice could be improved by Xiaoyaosan treatment which is similar with the efficacy of fluoxetine, while the expressions of apelin and APJ in hypothalamus were modified by Xiaoyaosan. Conclusions: The data suggest that apelin-APJ system changes in the hypothalamus may be a target of depressive disorders, and the beneficial effects of Chinese compound prescription Xiaoyaosan on depressive-like behaviors may be mediated by the apelin-APJ system.
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Antidepresivos/farmacología , Receptores de Apelina/metabolismo , Apelina/metabolismo , Depresión/metabolismo , Medicamentos Herbarios Chinos/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/etiología , Depresión/psicología , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , RatonesRESUMEN
Further discovery and design of new anticancer peptides are important for the development of anticancer therapeutics, and study on the detailed acting mechanism and structure-function relationship of peptides is critical for anticancer peptide design and application. In this study, a novel anticancer peptide ZXR-1 (FKIGGFIKKLWRSKLA) derived from a known anticancer peptide mauriporin was developed, and a mutant ZXR-2 (FKIGGFIKKLWRSLLA) with only one residue difference at the 14th position (LysâLeu) was also engineered. Replacement of the lysine with leucine made ZXR-2 more potent than ZXR-1 in general. Even with only one residue mutation, the two peptides displayed distinct anticancer modes of action. ZXR-1 could translocate into cells, target on the mitochondria and induce cell apoptosis, while ZXR-2 directly targeted on the cell membranes and caused membrane lysis. The variance in their acting mechanisms might be due to the different amphipathicity and positive charge distribution. In addition, the two Ile-Leu pairs (3-10 and 7-14) in ZXR-2 might also play a role in improving its cytotoxicity. Further study on the structure-function relationship of the two peptides may be beneficial for the design of novel anticancer peptides and peptide based therapeutics.
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Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/farmacología , Apoptosis/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Citotoxinas/farmacología , Péptidos/farmacología , Sustitución de Aminoácidos , Antineoplásicos/síntesis química , Antineoplásicos/química , Proteínas Reguladoras de la Apoptosis/síntesis química , Proteínas Reguladoras de la Apoptosis/química , Línea Celular Tumoral , Citotoxinas/síntesis química , Citotoxinas/química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Mitocondrias/efectos de los fármacos , Péptidos/síntesis química , Péptidos/química , Venenos de Escorpión/química , Suero , Relación Estructura-ActividadRESUMEN
The lipid raft microenvironment is implicated in the generation of the pathological amyloid-ß (Aß) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment. The results showed that C99 was anchored at the boundary of the lipid raft relying on the conserved hydrophobic motif of V710xxA713xxxV717xxxV721. Moreover, the dimerization of C99 was greatly destabilized by the lipid raft, which led to a susceptible switching packing conformation. The molecular driving forces were derived from the combined regulation of the saturated lipids and cholesterols rather than from the simple binding competition of cholesterol in the C99 dimerization. The molecular details of the differential dimerization in the raft-forming and bulk fluid bilayer environments were compared, and the structural information was helpful for further understanding the enzymolysis responsiveness of APP.
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Precursor de Proteína beta-Amiloide/química , Microdominios de Membrana/metabolismo , Simulación de Dinámica Molecular , Multimerización de Proteína , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/metabolismo , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Microdominios de Membrana/química , Dominios Proteicos , Estabilidad ProteicaRESUMEN
BACKGROUND: Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960-1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine cycle and glutamate transporters. METHODS: Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1-2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. RESULTS: After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. CONCLUSION: The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine cycle and glutamate transporter GLT-1 in the hippocampus.
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Antidepresivos/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Animales , China , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/psicología , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Humanos , Masculino , RatonesRESUMEN
Background: Breast cancer is among the most prevalent malignancies in women worldwide, with substantial morbidity and mortality. Upper limb lymphedema (ULL) is a common complication after breast cancer surgery that affects patients' daily activities and quality of life. Decongestive lymphatic therapy (DLT) and intermittent pneumatic compression (IPC) therapy are 2 primary treatment methods for ULL. Objectives: This study aimed to compare the efficacy of DLT with IPC versus DLT alone in the management of ULL following breast cancer surgery. Method: PubMed Central, SCOPUS, EMBASE, MEDLINE, Cochrane Trial Registry, Google Scholar, and Clinicaltrials.gov databases were comprehensively searched for randomized controlled trials (RCTs) comparing DLT with IPC and DLT alone in patients with breast cancer-related ULL. The risk of bias was evaluated using the RoB 2 tool. Pooled effect sizes were calculated using random-effects models. Results: A total of 1,894 citations were identified by the systematic search. Of them, 9 RCTs were included in the analysis. The pooled standardized mean difference (SMD) for percentage volume reduction was 0.63 (95% confidence interval [CI]: -0.24 to 1.50; I 2 = 90.9%), showing no significant difference between the DLT alone and DLT combined with IPC (p = 0.15). Pain and heaviness scores were also comparable between the groups. However, there was a significant difference in external rotation joint mobility (SMD = 0.62; 95% CI: 0.08-1.16; I 2 = 23.8%), favoring DLT with IPC. Conclusions: Our findings suggest that DLT with IPC and DLT alone showed similar findings in managing ULL after breast cancer surgery, with DLT with IPC showing a greater impact on external rotation joint mobility. Healthcare providers should consider patient preferences and individual factors when selecting the most appropriate treatment modality for ULL management.
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Background: Studies have reported that exercise can effectively improve the quality of life of breast cancer (BC) patients. However, considering the differences in exercise form and intensity, it is difficult to quantify and unify the improved outcomes, and there are contradictions in the conclusions. This meta-analysis aimed to quantitatively evaluate the effects of exercise on the quality of life (QoL) of patients with BC based on the European Organization for Research and Treatment of Cancer QoL Questionnaire-C30 (QLQ-C30) scale, to provide optimization suggestions for the treatment plan of BC survivors. Methods: The literature were extracted from the databases of PubMed, Embase, Cochrane Library, Wanfang, and China National Knowledge Infrastructure. The main outcomes were extracted from the final included literature and chi square tests and I2 statistics were used to evaluate the heterogeneity among the included studies. Statistical analysis was performed by Stata/SE 16.0 software and Review Manager 5.4 software. The funnel plot was used to test for evaluation publication bias. Results: All 8 included articles were original studies. The risk bias evaluation showed that 2 articles had low risk of bias and 6 articles had uncertain risk of bias. The results of meta-analysis revealed the following: (I) exercise significantly improved the overall health status of BC patients [mean difference (Hedges's g) =0.81, 95% confidence interval (CI): 0.27, 1.34]; (II) exercise significantly improved the physiological function of patients (Hedges's g =0.78, 95% CI: 0.34, 1.22), daily life function (Hedges's g =0.45, 95% CI: 0.13, 0.77), emotional function (Hedges's g =0.52, 95% CI: 0.20, 0.84); (III) exercise significantly reduced the fatigue symptoms (Hedges's g =-0.51, 95% CI: -0.84, -0.19), nausea and vomiting symptoms (Hedges's g =-0.35, 95% CI: -0.60, -0.10), insomnia symptoms (Hedges's g =-0.59, 95% CI: -0.91, -0.26), and economic difficulties (Hedges's g =-0.48, 95% CI: -0.78, -0.18) of patients. Conclusions: Exercise can significantly improve the overall physical health and body functions of BC survivors. Exercise can also significantly reduce the symptoms of fatigue, nausea, vomiting, and insomnia in BC patients. Different levels of exercise have significant effects on improving the quality of life of BC survivors, which is worth being widely advocated.
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Self-assembly refers to the spontaneous process where basic units such as molecules and nanostructured materials form a stable and compact structure. Peptides can self-assemble by non-covalent driving forces to form various morphologies such as nanofibers, nano layered structures, and micelles. Peptide self-assembly technology has become a hot research topic in recent years due to the advantages of definite amino acid sequences, easy synthesis and design of peptides. It has been shown that the self-assembly design of certain peptide drugs or the use of self-assembled peptide materials as carriers for drug delivery can solve the problems such as short half-life, poor water solubility and poor penetration due to physiological barrier. This review summarizes the formation mechanism of self-assembled peptides, self-assembly morphology, influencing factors, self-assembly design methods and major applications in biomedical field, providing a reference for the efficient use of peptides.
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Nanoestructuras , Péptidos , Preparaciones Farmacéuticas , Péptidos/química , Secuencia de Aminoácidos , Nanoestructuras/química , Sistemas de Liberación de MedicamentosRESUMEN
In order to improve the quality of life of breast cancer patients, this paper will apply continuous early intervention to the nursing of breast cancer patients. The continuous early intervention nursing model can propose countermeasures for the health problems faced by patients with postoperative chemotherapy. In order to analyze the effect of continuous early intervention nursing on negative emotions and quality of life in breast cancer patients, the effect of continuous early intervention in improving the quality of life of breast cancer patients is analyzed by means of experimental research. The control group is given routine nursing, and the observation group is given continuous early intervention nursing intervention. Moreover, this paper obtains data statistics in combination with statistical analysis. Through the comparison of the test results, it can be seen that the implementation of continuous early intervention nursing intervention in breast cancer patients can improve the nursing effect, effectively relieve the negative emotions of patients, and improve the quality of life of patients.
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Neoplasias de la Mama , Calidad de Vida , Neoplasias de la Mama/terapia , Femenino , Humanos , Calidad de Vida/psicología , Proyectos de InvestigaciónRESUMEN
Background: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental conditions that affect people worldwide. Early diagnosis and clinical support help achieve good outcomes. However, medical system structure and restricted resource availability create challenges that increase the risk of poor outcomes. Understanding the research progress of childhood ASD in recent years, based on clinical literature reports, can give relevant researchers and rehabilitation therapists more resonable research guides. Objective: This bibliometric study aimed to summarize themes and trends in research on childhood ASD and to suggest directions for future enquiry. Methods: Citations were downloaded from the Web of Science Core Collection database on childhood ASD published from 1 January 2012, to 31 December 2021. The retrieved information was analyzed using CiteSpace.5.8. R3, and VOS viewer. Results: A total of 7,611 papers were published across 103 areas. The United States was the leading source of publications. The clusters that have continued into 2020 include coronavirus disease 2019, gut microbiota, and physical activity, which represent key research topics. Keywords with frequency spikes during 2018-2021 were "disabilities monitoring network," "United States," and "caregiver." Conclusions: The Autism and Developmental Disabilities Monitoring Network in the United States can be used as a reference for relevant workers worldwide. An intelligent medical assistant system is being developed. Further studies are required to elucidate challenges associated with caring for a child with ASD.
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Trastorno del Espectro Autista , COVID-19 , Microbioma Gastrointestinal , Bibliometría , COVID-19/epidemiología , Niño , Bases de Datos Factuales , Humanos , Estados UnidosRESUMEN
T-cell restriction intracellular antigen 1 (TIA1) is an RNA-binding protein that is a major component of stress granules (SGs). The low complexity domain (LCD) of TIA1 plays a central role in facilitating SGs assembly through liquid-liquid phase separation (LLPS). Disruption of the LLPS process has been associated with several diseases. It has recently been shown that the proline-rich domain affects the LLPS process of some proteins (such as UBQLN2 and Tau). Thus, proline may regulate LLPS. The LCD of TIA1 contains 11 proline residues, and several proline-related mutations have been shown to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we demonstrated that TIA1 can undergo phase separation in cells. Additionally, disease-associated proline-to-leucine (P-L) mutations, which altered droplet morphology, facilitated the liquid-to-solid phase transition of TIA1 into solid-like amyloid fibrils. The changes in the physical properties of the P-L mutation altered the behavior of TIA1 in vivo and led to abnormal SGs kinetics, resulting in the formation of the pathological inclusions of ALS. Prolines are the key residues for regulating the LLPS of TIA1.
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Gránulos Citoplasmáticos/metabolismo , Agregado de Proteínas/genética , Antígeno Intracelular 1 de las Células T/genética , Amiloide/genética , Gránulos Citoplasmáticos/fisiología , Cuerpos de Inclusión/patología , Extracción Líquido-Líquido , Mutación/genética , Prolina/metabolismo , Agregado de Proteínas/fisiología , Agregación Patológica de Proteínas , Dominios Proteicos/genética , Gránulos de Estrés/genética , Gránulos de Estrés/metabolismo , Antígeno Intracelular 1 de las Células T/metabolismoRESUMEN
The RNA-binding protein fused in sarcoma (FUS) forms physiological granules and pathological fibrils, which facilitate RNA functions and cause neurodegenerative diseases, respectively. Phosphorylation at Ser/Thr residues may regulate the functional assembly of FUS and prevent pathological aggregation in cells. However, the low-complexity nature of the FUS sequence makes it challenging to characterize how phosphorylation of specific sites within the core amyloid-forming segment affects aggregation. Taking advantage of the recently solved molecular structures of the fibrillar core of the FUS low-complexity (FUS-LC) domain, we systematically investigated the aggregation of repeated segments within the core. We identified a segment with a strong amyloid-forming tendency that induced the aggregation of FUS-LC domain in phase-separated liquid droplets and further seeded the aggregation of full-length FUS. The aggregation propensity and seeding ability of this amyloid-forming segment were modulated by site-specific phosphorylation. Solid-state nuclear magnetic resonance (NMR) spectroscopy and computational modeling implied that site-specific phosphorylation at Ser61 plays key roles in FUS assembly by disrupting both intra- and intermolecular interactions that maintain the amyloid core structure.
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Amiloide/genética , Amiloidosis/genética , Agregación Patológica de Proteínas/genética , Proteína FUS de Unión a ARN/genética , Proteínas de Unión al ARN/genética , Amiloide/ultraestructura , Proteínas Amiloidogénicas/genética , Proteínas Amiloidogénicas/ultraestructura , Amiloidosis/patología , Humanos , Estructura Molecular , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Resonancia Magnética Nuclear Biomolecular , Fosforilación/genética , Agregación Patológica de Proteínas/patología , Conformación Proteica , Dominios Proteicos/genética , Proteína FUS de Unión a ARN/ultraestructura , Proteínas de Unión al ARN/ultraestructuraRESUMEN
In addition to the standardized use of antidepressant medications and psychotherapy, the usage of traditional Chinese medicine has lead to an overall improvement of patients with major depressive disorder (MDD). Therefore, the purpose of this study was to establish the mouse depressive model, observe the behavior changes associated with chronic unpredictable mild stress (CUMS), and then evaluate the anti-depression effect of Xiaoyaosan. Mice were randomly divided into four groups: a control group, a model group, a treatment group with Xiaoyaosan, and a treatment group with fluoxetine. All mice were individually kept in cages, and depression was induced in the mice by exposing them to several designed manipulations of CUMS for 21 days, as described in the protocol. Mice in the control group and model group received 0.5 mL of distilled water, while mice in the treatment groups received either Xiaoyaosan (0.25 g/kg/day) or fluoxetine (2.6 mg/kg/day). The drugs used in the study were given intragastrically daily during the entire three weeks. To estimate the depressive-like behaviors, a series of parameters including the coat state, body weight, open field test score, and sucrose preference test score were recorded. Data analysis showed that behaviors of model mice were significantly changed compared to behaviors of mice in the control group, which were improved by the treatment of Xiaoyaosan and fluoxetine. The current findings demonstrated the anti-depression effects of Xiaoyaosan on the behaviors of CUMS-induced mice and revealed that compounds from the Xiaoyaosan prescription may be worthwhile for treating depression, considering their beneficial effects on depressive-like behaviors.
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Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Animales , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Masculino , RatonesRESUMEN
Cervical spondylosis (CS), which is resulted from degeneration of cervical intervertebral disc, is a common disease seriously threatening human health and quality of life. However, there is still no effective clinic strategies for the treatment of this disease. The acupoint stimulation with needle-scalpel is a widely used approach to treat orthopedic diseases. In the present study, we evaluated the therapeutic effects of acupoint stimulation around neck with needle-scalpel on delaying the degeneration of cervical intervertebral discs and hopefully provided an approach for the precaution and early intervention of CS. We firstly established a rat model of CS by cervical static-dynamic imbalance to mimics disc degeneration and then stimulated the acupoints around neck with needle-scalpel. The cervical intervertebral disc samples were collected to measure type I and II collagen by quantitative PCR (qPCR), immunohistochemistry, and western blot. The changes in micro-structure and ultra-structure of nucleus pulposus were analyzed under the optical microscope and electron microscope respectively. Acupoint stimulation with needle-scapelon increased type I collagen production and decreased type II collagen production, and improved the micro-structure and ultra-structure of nucleus pulposus. Our results suggest that acupoint stimulation around neck with needle-scapelon could inhibit intervertebral disc degeneration through modulating the extracellular matrix collagen system and improving the changed structure of nucleus pulposus.
Asunto(s)
Puntos de Acupuntura , Vértebras Cervicales , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/terapia , Agujas , Núcleo Pulposo/metabolismo , Animales , Colágeno Tipo I/metabolismo , Colágeno Tipo II/metabolismo , Femenino , Degeneración del Disco Intervertebral/patología , Núcleo Pulposo/patología , Núcleo Pulposo/ultraestructura , Ratas , Ratas Sprague-DawleyRESUMEN
Excitotoxicity and neuronal death following epilepsy involve α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). It forms a protein complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and co-internalizes upon activation of AMPA receptors after epilepsy. Disruption of the GluA2/GAPDH complex with an interfering peptide, TAT-GluA2NT1-3-2, protects cells against AMPAR-mediated excitotoxicity, which have been identified in in-vitro and in-vivo models of brain ischemia. We postulated that disruption of the GluA2/GAPDH interaction with the TAT-GluA2NT1-3-2 peptide would also protect against AMPAR-induced neuronal injury in an in-vivo model of status epilepticus (SE). In the present study, we divided pilocarpine-induced SE Wistar rats into three main groups: the TAT-GluA2NT1-3-2 peptide group, the TAT-GluA2NT-scram peptide group, and the normal saline group, and injected different doses of peptides stereotaxically into the hippocampus of SE rats to investigate whether the GluA2/GAPDH interaction could be disrupted by our TAT-GluA2NT1-3-2 peptide and determine its most appropriate dose. Then, the dose was administered stereotaxically at different time points after SE to determine the best administration time of neuronal protection. We found that the TAT-GluA2NT1-3-2 peptide can disrupt the GluA2/GAPDH interaction and protects against epilepsy-induced neuronal damage. The GluA2/GAPDH interaction may be a novel therapeutic target for epilepsy.