RESUMEN
Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
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Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Eliminación de Gen , Transmisión Sináptica/genética , Proteínas de Pez Cebra/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/psicología , Trastorno Autístico/genética , Trastorno Autístico/psicología , Encéfalo/anatomía & histología , Encéfalo/citología , Encéfalo/patología , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Proteínas Portadoras/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/psicología , Cromosomas Humanos Par 16/genética , Proteínas Cullin/metabolismo , Femenino , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Masculino , Ratones , Herencia Multifactorial/genética , Neurogénesis/genética , Tamaño de los Órganos/genética , Reproducibilidad de los Resultados , Transmisión Sináptica/efectos de los fármacos , Complejos de Ubiquitina-Proteína Ligasa , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoARESUMEN
TGF-ß signal pathway activation is vital in the pathogenesis of DKD. We aim to investigate the role of Yishenhuoxue formula on TGF-ß/Smad signal transduction in DKD rats. 60 male adult Wistar rats were enrolled and randomly allocated into four groups: N group, M group (given STZ 60mg/kg, ip), H group (given Yishenhuoxue formula 1.0g/kg/day, ig) and L group (given Yishenhuoxue formula 0.5g/kg/day, ig). The levels of BW, 24h UV, SCr, UCr, mALB were measured after 8 weeks treatment, while the levels of KW/BW index, CCr and UAER were calculated by relevant formula. The rats' left kidneys were harvested to detect histological changes by PAS staining and right kidneys were harvested to detect the levels of TGF-ß, Smad2/3, phosphorylated Smad 2/3, Smad 7 and CTGF by western blot analysis. We found that Yishenhuoxue formula treatment can protect kidneys from DKD injury, which is illustrated with following criteria: 1) a significant decrement in KW/BW index, 24h UV, SCr, mALB and UAER, while a significant increment in BW, UCr, CCr (p<0.05 vs. M group); 2) minor and segmental changes as slight expansion of the glomerular basement membrane compared with M group; 3) an apparent decrease in levels of TGF-ß1, phosphorylated Smad 2/3 and CTGF, while an apparent increase in levels of Smad 2/3 and Smad7 compared with M group (p<0.05). The studies confirm that Yishenhuoxue formula has strong inhibitory effect on TGF-ß/Smad signal transduction in DKD rats' kidneys by decreasing expression of TGF-ß1, weakening of Smad 2/3 phosphorylation and increasing expression of Smad 7.
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Nefropatías Diabéticas/prevención & control , Medicamentos Herbarios Chinos/farmacología , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Albuminuria , Animales , Peso Corporal/efectos de los fármacos , Creatinina/sangre , Creatinina/orina , Riñón/metabolismo , Riñón/patología , Masculino , Fosforilación/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Even when treated with aggressive current therapies, patients with glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection of CpG into glioblastoma tumors showed promise as an immunotherapy in mouse models but proved disappointing in human trials. One aspect of glioma that is not addressed by CpG therapy alone is the highly invasive nature of glioma cells, which is associated with resistance to radiation and chemotherapy. Here, we demonstrate that single-walled carbon nanotubes noncovalently functionalized with CpG (SWNT/CpG), which retain the immunostimulatory property of the CpG, selectively inhibit the migration of glioma cells and not macrophages without affecting cell viability or proliferation. SWNT/CpG also selectively decreased NF-κB activation in glioma cells, while activating macrophages by induction of the TLR9/NF-κB pathway, as we have previously reported. The migration inhibition of glioma cells was correlated with selective reduction of intracellular levels of reactive oxygen species (ROS), suggesting that an antioxidant-based mechanism mediates the observed effects. To the best of our knowledge, SWNT/CpG is the first nanomaterial that inhibits the migration of cancer cells while stimulating the immune system.
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Adyuvantes Inmunológicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Glioma/tratamiento farmacológico , Nanotubos de Carbono/química , Oligodesoxirribonucleótidos/farmacología , Adyuvantes Inmunológicos/química , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioma/patología , Humanos , Ratones , Oligodesoxirribonucleótidos/químicaRESUMEN
BACKGROUND: A proper restoration of sagittal alignment is essential in AIS patients, but few studies provided a formula to predict an optimal surgical thoracic kyphosis (TK) gain in adolescent idiopathic scoliosis (AIS) patients. A formula was recently proposed (LL = (PI+TK)/2 + 10) to predict the optimal lumbar lordosis (LL) in adult spinal deformity patients, which has not been validated in adolescents. The aim of this study is to establish a formula with TK and pelvic parameters in normal adolescents and predict an optimal TK with this formula pre- and post-operatively in Lenke 1 AIS patients. METHODS: A total of 60 asymptomatic adolescents were used to validate the proposed formula. The subject was considered to match with the formula, if the difference between the virtual TK and the theoretical TK was less than 10°. Then regression analysis was performed to establish a new formula to predict TK in adolescents. The predictive efficiency of the new formula was also validated in 40 Lenke 1 AIS patients. RESULTS: Of the 60 asymptomatic adolescents, only 26 (43.33%) asymptomatic adolescents matched with the adjusted formula: TK = 2 × (LL-10)-PI. The paired t test revealed a significantly different theoretical TK (tTK) compared to the virtual TK (41.23 ± 18.29° vs. 24.80 ± 8.75°, P < 0.001). Multiple linear regression showed that TK had a relationship with LL, SS and age (R2 = 0.331): TK = - 0.785 × LL-0.843 × SS + 0.858 × age + 3.754. There were 27 (67.50%), 32 (80.00%) and 35 (87.50%) Lenke 1 AIS patients matched this formula preoperatively, postoperatively and at the last follow-up. CONCLUSION: Our results revealed that the predictive formula for sagittal alignment for adults was not applicable in adolescents. This study established a new predictive formula for TK based on asymptomatic adolescents. In Lenke 1 AIS patients, post-op TK in 87.5% of patients matched the predictive value, indicating that the new formula can be considered as a reference when making a surgery strategy.
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Cifosis/diagnóstico por imagen , Huesos Pélvicos/diagnóstico por imagen , Cuidados Posoperatorios/métodos , Escoliosis/diagnóstico por imagen , Vértebras Torácicas/diagnóstico por imagen , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Cifosis/cirugía , Masculino , Cuidados Posoperatorios/tendencias , Estudios Retrospectivos , Escoliosis/cirugía , Vértebras Torácicas/cirugíaRESUMEN
BACKGROUND: The factors associated with lateral curve flexibility in degenerative scoliosis have not been well documented. Disc degeneration could result in significant change in stiffness and range of motion in lateral bending films. The osteophytes could be commonly observed in degenerative spine but the relationship between osteophyte formation and curve flexibility remains controversial. The aim of the current study is to clarify if the disc degeneration and osteophyte formation were both associated with curve flexibility of degenerative scoliosis. METHODS: A total of 85 patients were retrospectively analyzed. The inclusion criteria were as follow: age greater than 45 years, diagnosed as degenerative scoliosis and coronal Cobb angle greater than 20°. Curve flexibility was calculated based on Cobb angle, and range of motion (ROM) was based on disc angle evaluation. Regional disc degeneration score (RDS) was obtained according to Pfirrmann classification and osteophyte formation score (OFS) was based on Nanthan classification. Spearman correlation was performed to analyze the relationship between curve flexibility and RDS as well as OFS. RESULTS: Moderate correlation was found between RDS and curve flexibility with a Spearman coefficient of -0.487 (P = 0.009). Similarly, moderate correlation was observed between curve flexibility and OFS with a Spearman coefficient of -0.429 (P = 0.012). Strong correlation was found between apical ROM and OFS compared to the relationship between curve flexibility and OFS with a Spearman coefficient of -0.627 (P < 0.001). CONCLUSIONS: Both disc degeneration and osteophytes formation correlated with curve rigidity. The pre-operative evaluation of both features may aid in the surgical decision-making in degenerative scoliosis patients.
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Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/epidemiología , Osteofito/diagnóstico por imagen , Osteofito/epidemiología , Escoliosis/diagnóstico por imagen , Escoliosis/epidemiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: DMP-1 supplement has a satisfactory effect on diabetic kidney disease in patients with whether T1DM or T2DM. Oxidative stress and TGF-ß signal pathway activation are essential in the pathogenesis of DKD. We aim to investigate the effect of DMP-1 on oxidative stress and TGF-ß activation in rats with DKD. MATERIALS AND METHODS: Male Wistar rats were enrolled and randomly allocated into five groups: Control group, STZ group (60 mg/kg, ip), DMP-1 low dose group (0.5 g/kg/day, ig), DMP-1 medium dose group (1.0 g/kg/day, ig) and DMP-1 high dose group (2.0 g/kg/day, ig). The levels of UREA, BUN, UCr, ß2-MG, mALB, NOS, CAT, MDA and T-AOC were measured after 8 weeks treatment. And rats' left kidneys were harvested to detect the expression of TGF-ß, Smad2/3 and Smad7 by immunohistochemical analysis. RESULTS: DMP-1 treatment has protective effects on kidney injury induced by STZ, which is demonstrated as following criteria: (1) a significant reduction in levels of UREA (p < 0.05), BUN (p < 0.05), UCr (p < 0.05), ß2-MG (p < 0.05) and mALB (p < 0.05) in rats treated by DMP-1 compared with the ones injected with STZ only; (2) an apparent increment levels of NOS (p < 0.05), CAT (p < 0.05) and T-AOC (p < 0.05), while reduction in level of MDA (p < 0.05) in DMP-1 groups compared with STZ group; (3) a significant inhibition of TGF-ß and Smad2/3 overexpression induced by STZ in kidney tissue. What's more, DMP-1 can increase Smad7 expression. CONCLUSION: DMP-1 could slow pathological process and protect kidney from DKD injury by decreasing oxidative stress and inhibiting TGF-ß signal pathway activation in rats.
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Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Glucemia , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/etiología , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Proteína smad7/metabolismo , EstreptozocinaRESUMEN
SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind.
Asunto(s)
Exones/genética , Trastornos Mentales/genética , Mutagénesis Insercional/métodos , Mutación/genética , Proteínas del Tejido Nervioso/genética , Transmisión Sináptica/genética , Animales , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/fisiología , Femenino , Aseo Animal/fisiología , Hipocampo/citología , Locomoción/genética , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos , N-Metilaspartato/farmacología , Comportamiento de Nidificación/fisiología , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacologíaRESUMEN
The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory.
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Síntomas Conductuales/genética , Síntomas Conductuales/patología , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transmisión Sináptica/fisiología , Adaptación Fisiológica/genética , Animales , Síntomas Conductuales/metabolismo , Conducta Exploratoria/fisiología , Hipocampo/patología , Locomoción/genética , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos , Actividad Motora/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Densidad Postsináptica/genética , Densidad Postsináptica/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Desempeño Psicomotor/fisiología , Receptor del Glutamato Metabotropico 5/metabolismo , Reflejo de Sobresalto/genética , Transmisión Sináptica/genética , Sinaptosomas/metabolismo , Sinaptosomas/ultraestructuraRESUMEN
Atopic dermatitis (AD) is a frequent skin disorder that is associated with immune dysfunction and skin inflammation. Histone deacetylase 3 (HDAC3) possesses strong immune and inflammatory modulatory properties in multiple diseases. However, the role and mechanism of HDAC3 in AD remain unknown. Here, we reported that HDAC3 expression was aberrantly upregulated in 2,4-dinitrochlorobenzene (DNCB)-induced lesional AD skin in mice. Inhibition of HDAC3 by RGFP966 protected against DNCB-induced AD, indicated by improved histological damages, relieved inflammatory and immune dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway activity in lesional AD skin was significantly decreased and RGFP966 attenuated the decrease. Inhibition of Nrf2/HO-1 signaling pathway via Nrf2 inhibitor ML385 blunted anti-AD effect of RGFP966 in DNCB-treated mice. Mechanistically, RGFP966 promoted Nrf2 expression and upregulated H3K27ac deposition on the promoter region of Nrf2. Collectively, HDAC3 inhibition protects against AD via epigenetically activating Nrf2 transcription to upregulate Nrf2/HO-1 signaling pathway activity. HDAC3 may act as a promising therapeutic target for the treatment of AD.
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Dermatitis Atópica , Animales , Ratones , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Dinitroclorobenceno , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Citocinas/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Transducción de Señal , Piel/patología , Ratones Endogámicos BALB CRESUMEN
AIM: Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that is closely linked to genetic factors. Previous studies have revealed numerous single nucleotide polymorphisms (SNPs) that been related to susceptibility to AD; however, the results are conflicting. Therefore, a meta-analysis was conducted to assess the associations of these polymorphisms and AD risk. MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were retrieved to identify eligible studies, with selected polymorphisms being reported in a minimum of three separate studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. Review Manager 5.3 and STATA 14.0 were used to perform the meta-analysis. RESULTS: After screening, 64 studies involving 13 genes (24 SNPs) were selected for inclusion in the meta-analysis. Nine SNPs were positively correlated with AD susceptibility [filaggrin (FLG) R501X, FLG 2282del4, chromosome 11q13.5 rs7927894, interleukin (IL)-17A rs2275913, IL-18 -137 G/C, Toll-like receptor 2 (TLR2) rs5743708, TLR2 A-16934 T, serine protease inhibitor Kazal type-5 (SPINK5) Asn368Ser, interferon-γ (IFN-γ) T874A] and one was negatively associated with AD susceptibility (IL-4 -1098 T/G). The 14 remaining SNPs were not significantly associated with AD susceptibility. CONCLUSIONS: Nine SNPs that may be risk factors and one SNP that may be a protective factor for AD were identified, providing a reference for AD prediction, prevention, and therapy.
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Dermatitis Atópica , Humanos , Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Receptor Toll-Like 2/genética , Polimorfismo de Nucleótido Simple , Piel , Proteínas de Filamentos Intermediarios/genéticaRESUMEN
Background: CeRNA axis is an important way to regulate the occurrence and development of Nasopharyngeal carcinoma (NPC). Although the research on inducing cuproptosis of tumor cells is in the early stage of clinical practice, its mechanism of action is still of great significance for tumor treatment, including NPC. However, the regulation mechanism of cuproptosis in NPC by ceRNA network remains unclear. Methods: The ceRNA network related to the survival of nasopharyngeal carcinoma related genes was constructed by bioinformatics. Dual-luciferase reporter assay and other experiments were used to prove the conclusion. Results: Our findings indicate that the AC008083.2/miR-142-3p axis drives STRN3 to promote the malignant progression of NPC. By performing enrichment analysis and phenotypic assays, we demonstrated that the changes in the expressions of AC008083.2/miR-142-3p/NPC can affect the proliferation of NPC. Mechanistically, luciferase reporter gene assays suggested that AC008083.2 acts as a ceRNA of miR-142-3p to regulate the content of STRN3. Furthermore, the regulations of STRN3 and the malignant progression of NPC by AC008083.2 depends on miR-142-3p to some extent. Conclusions: Our study reveals an innovative ceRNA regulatory network in NPC, which can be considered a new potential target for diagnosing and treating NPC.
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Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , MicroARNs , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Animales , ARN Endógeno CompetitivoRESUMEN
A topic dermatitis (AD) is a common chronic and recurrent skin disorder. The protective effects of sodium butyrate (NaB), a metabolite of short-chain fatty acid breakdown by the gut microbiota, have been widely reported in numerous inflammatory diseases. However, the effect of NaB treatment alone on AD has not been reported. In the current study, AD was induced in BALB/c mice with 2,4-dinitrochlorobenzene (DNCB) for 28 days with NaB (200 mg/kg) treatment by gavage. NaB attenuated AD-induced skin bleeding, scarring, dryness, abrasions and erosions. In addition, NaB inhibited inflammatory cells infiltration and attenuated the expression of inflammatory cytokines and chemokines. Mechanistically, NaB reduced histone deacetylase 3 (HDAC3) expression and NF-κB p65 nuclear translocation by increasing the lysine acetylation levels of STAT1 and NF-κB p65 in AD. Taken together, our study suggests that NaB inhibits inflammatory mediators and ameliorates AD by inhibiting HDAC3 expression, thereby upregulating STAT1 and NF-κB p65 lysine acetylation levels and reducing NF-κB p65 nuclear translocation. Therefore, this study provides a new theoretical basis for NaB in the treatment of AD.
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Ácido Butírico , Dermatitis Atópica , Histona Desacetilasas , Inflamación , Ratones Endogámicos BALB C , FN-kappa B , Factor de Transcripción STAT1 , Animales , Histona Desacetilasas/metabolismo , Factor de Transcripción STAT1/metabolismo , Ratones , Ácido Butírico/farmacología , Ácido Butírico/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dermatitis Atópica/metabolismo , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismoRESUMEN
Considerable endeavors have focused on tightly combining adsorption with photocatalysis in designing composite materials for environmental pollution treatment. Recent advances in coupling titanium dioxide/bismuth trioxide (TiO2/Bi2O3) with activated carbon (AC) show significantly enhanced photocatalytic performance but face critical limitations including low adsorption capacity and multi-step synthesis. In this work, we introduce a one-pot synthesis of activated carbon modified TiO2/Bi2O3 composite materials (TiO2/Bi2O3/AC). Thanks to the integrated adsorbent/photocatalyst system, TiO2/Bi2O3/AC shows a drastically enhanced removal efficiency for sulfamethazine (>81%), far beyond the corresponding value of the reported AC/TiO2/Bi2O3 adsorbent (<40%). Notably, the removal rates of other typical pollutants including tetracyclines, methyl orange, and rhodamine B are as high as >98%. Furthermore, TiO2/Bi2O3/AC obtains >80% of its adsorption rate for the fifth cycle after simple photo-regeneration without any other post-treatments. Kinetic analysis and photoelectric characterization are carried out to provide insight into adsorption mechanism. Therefore, this work demonstrates a considerable potential to design and construct other multifunctional adsorbents with advanced performance.
RESUMEN
To uncover the role of satellite cells (SCs) in paravertebral muscle development and aging, we constructed a single-nucleus transcriptomic atlas of mouse paravertebral muscle across seven timepoints spanning the embryo (day 16.5) to old (month 24) stages. Eight cell types, including SCs, fast muscle cells, and slow muscle cells, were identified. An energy metabolism-related gene set, TCA CYCLE IN SENESCENCE, was enriched in SCs. Forty-two skeletal muscle disease-related genes were highly expressed in SCs and exhibited similar expression patterns. Among them, Pdha1 was the core gene in the TCA CYCLE IN SENESCENCE; Pgam2, Sod1, and Suclg1 are transcription factors closely associated with skeletal muscle energy metabolism. Transcription factor enrichment analysis of the 42 genes revealed that Myod1 and Mef2a were also highly expressed in SCs, which regulated Pdha1 expression and were associated with skeletal muscle development. These findings hint that energy metabolism may be pivotal in SCs development and aging. Three ligand-receptor pairs of extracellular matrix (ECM)-receptor interactions, Lamc1-Dag1, Lama2-Dag1, and Hspg2-Dag1, may play a vital role in SCs interactions with slow/fast muscle cells and SCs self-renewal. Finally, we built the first database of a skeletal muscle single-cell transcriptome, the Musculoskeletal Cell Atlas (http://www.mskca.tech), which lists 630,040 skeletal muscle cells and provides interactive visualization, a useful resource for revealing skeletal muscle cellular heterogeneity during development and aging. Our study could provide new targets and ideas for developing drugs to inhibit skeletal muscle aging and treat skeletal muscle diseases.
RESUMEN
BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.
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Galectina 3 , Glioma , Ratones , Humanos , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Galectina 3/genética , Ligandos , Línea Celular Tumoral , Glioma/patología , Inmunidad , Microambiente Tumoral/genéticaRESUMEN
PURPOSE: Over the past 12 years, vertebral body tethering (VBT) has been gradually promoted for treating scoliosis, but there are few published studies, with only short-term follow-up. This study aimed to systematically review VBT efficacy and safety for treating scoliosis. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for studies on VBT treatment of scoliosis published up to November 2021. Two researchers independently screened the literature, extracted data, and assessed the risk of bias in included studies. Data on clinical efficacy, unplanned reoperations, and complications were extracted. The meta-analysis was performed with R 4.1.0. RESULTS: Twenty-six studies involving 1045 patients were included in the meta-analysis. The correction rate of major curve immediately post-operation was 46.6% ± 13.8% (16%-69%) and that at final follow-up was 53.2% ± 17.9% (16%-79%). The single-arm meta-analysis results of all included studies showed that VBT was effective in general. The overall clinical success rate was 73.02% (95% confidence interval [CI]: 68.31%-78.05%). The pooled overall unplanned reoperation rate was 8.66% (95% CI: 5.53%-13.31%). The overall incidence rate of complications was 36.8% (95% CI: 23.9%-49.7%). The subgroup analysis based on follow-up time indicated that patients with follow-up time >36 months had increased clinical success rate, unplanned reoperation rate, and incidence rate of complications compared with those with <36 months' follow-up time. The preliminary results showed that after 36 months of follow-up, only 7.17% (95% CI: 4.81%-10.55%) of patients required posterior spinal fusion (PSF) surgery and nearly 93% of patients avoided spinal fusion surgeries. CONCLUSIONS: The current evidence from at least 3-year follow-up in different countries indicates that VBT is an effective surgical approach for treating scoliosis, with 73.88% of patients achieving clinical success. Nevertheless, about one in seven patients (15.8%) required unplanned reoperations, but only 7.17% required PSF. About half (52.17%) of the patients experienced complications. Due to the limitation of the study number and quality, our conclusion may be biased and requires verification by further studies with longer follow-up times.
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Escoliosis , Fusión Vertebral , Humanos , Escoliosis/cirugía , Escoliosis/epidemiología , Cuerpo Vertebral , Fusión Vertebral/métodos , Resultado del Tratamiento , ReoperaciónRESUMEN
COVID-19, caused by SARS-CoV-2, is the most consequential pandemic of this century. Since the outbreak in late 2019, animal models have been playing crucial roles in aiding the rapid development of vaccines/drugs for prevention and therapy, as well as understanding the pathogenesis of SARS-CoV-2 infection and immune responses of hosts. However, the current animal models have some deficits and there is an urgent need for novel models to evaluate the virulence of variants of concerns (VOC), antibody-dependent enhancement (ADE), and various comorbidities of COVID-19. This review summarizes the clinical features of COVID-19 in different populations, and the characteristics of the major animal models of SARS-CoV-2, including those naturally susceptible animals, such as non-human primates, Syrian hamster, ferret, minks, poultry, livestock, and mouse models sensitized by genetically modified, AAV/adenoviral transduced, mouse-adapted strain of SARS-CoV-2, and by engraftment of human tissues or cells. Since understanding the host receptors and proteases is essential for designing advanced genetically modified animal models, successful studies on receptors and proteases are also reviewed. Several improved alternatives for future mouse models are proposed, including the reselection of alternative receptor genes or multiple gene combinations, the use of transgenic or knock-in method, and different strains for establishing the next generation of genetically modified mice.
Asunto(s)
COVID-19 , Animales , Cricetinae , Modelos Animales de Enfermedad , Hurones , Ratones , Péptido Hidrolasas , SARS-CoV-2RESUMEN
Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.
Asunto(s)
Antiinflamatorios , Edema Encefálico , Neoplasias Encefálicas , Receptor para Productos Finales de Glicación Avanzada , Animales , Antiinflamatorios/farmacología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Lesiones Encefálicas/complicaciones , Neoplasias Encefálicas/cirugía , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Ratones , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidoresRESUMEN
Enterovirus D68 (EV-D68) is a respiratory viral pathogen that causes severe respiratory diseases and neurologic manifestations. Since the 2014 outbreak, EV-D68 has been reported to cause severe complications worldwide. However, there are currently no approved antiviral agents or vaccines for EV-D68. In this study, we found that zinc ions exerted substantial antiviral activity against EV-D68 infection in vitro. Zinc salt treatment potently suppressed EV-D68 RNA replication, protein synthesis, and infectious virion production and inhibited cytopathic effects without producing significant cytotoxicity at virucidal concentrations (EC50=0.033mM). Zinc chloride (ZnCl2) treatment moderately inhibited EV-D68 attachment. Time-dose analysis of EV-D68 structural protein VP1 synthesis showed stronger suppression of VP1 in the culture medium than that in the cell lysates. Furthermore, a zinc ionophore, pyrrolidine dithiocarbamate, which can transport zinc ions into cells, also enhanced the anti-EV-D68 activity of ZnCl2 treatment. Taken together, our results demonstrated that the enhancement of zinc influx could serve as a powerful strategy for the therapeutic treatment of EV-D68 infections.
RESUMEN
Multispectral analysis combined with the Periodic Acid-Schiff method was used to investigate cytological features of insoluble polysaccharides and changes in total insoluble polysaccharide content (TPC) during pollen development in rice, including four cytoplasmic male sterility lines (MSLs) and their corresponding fertility-maintaining lines (FMLs). The multispectral curves of the relative transmittance value (RTV) and the images of developing pollen cells were obtained across a range of successive wavelengths (400-720 nm). A minimum RTV was found near 550 nm indicating an absorption peak of the TPC. Thus, the TPC was measured using the RTV of 550 nm. In the four FMLs, the minimum TPC of developing pollen cells occurred at the late microspore stage, while the maximum TPC occurred at the mature pollen grain stage. The TPC levels of pollen cells were significantly higher in the four FMLs than in their corresponding MSLs during and after pollen abortion. Notably, a steep decrease of multispectral curves at 420 nm appeared before the occurrence of abortion, implying a marker associated with pollen abortion in rice. Our results will be helpful for exploring the changes in TPC during pollen ontogenesis in rice and provide a novel method for the study of bio-macromolecules.