RESUMO
Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.
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Adipócitos Bege , Adipócitos Marrons , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica , Camundongos , Termogênese/genéticaRESUMO
BACKGROUND: To investigate the feasibility of a deformable self-assembled magnetic anastomosis ring (DSAMAR), designed and developed by us, for endoscopic gastrointestinal bypass anastomosis. METHODS: Ten experimental pigs were used as model animals. The DSAMAR comprises 10 trapezoidal magnetic units, arranged in a straight line under the constraint of a guide wire. When the desired anastomosis site is reached under the guidance of an endoscope, the catheter pushes the magnetic unit along the guide wire. The linear DSAMAR can be assembled into a circular DSAMAR. Two DSAMARs were inserted, one at the end of the duodenum and the other into the stomach successively. They attracted each other and compressed the wall of the stomach and duodenum to establish gastrointestinal bypass anastomosis. The experimental pigs were euthanized 4 weeks after the operation, and the gastrointestinal bypass anastomosis specimens were obtained. The anastomosis formation was evaluated by the naked eye and histology. RESULTS: Gastrointestinal bypass anastomosis with DSAMARs was successfully performed. The average operation time under an endoscope was 70.30 ± 19.05 min (range: 43-95 min). The DSAMARs were discharged through the anus 10-17 days after surgery. There were no complications such as gastrointestinal bleeding, perforation, anastomotic fistula, and gastrointestinal obstruction during and after the operation. Gastroscopy and gross specimen of the anastomosis showed a well-formed magnetic anastomosis. Histological observation showed good continuity of the serous membrane and the mucosa of magnetic anastomosis. CONCLUSION: The DSAMAR is a safe and feasible device for fashioning gastrointestinal bypass anastomosis in this animal model.
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Gastroscopia , Estômago , Suínos , Animais , Anastomose Cirúrgica , Estômago/cirurgia , Duodeno , Fenômenos MagnéticosRESUMO
Dysregulation of oxidative stress serves as a pivotal predisposing or exacerbating factor in the intricate development of numerous pathological processes and diseases. In recent years, substantial evidence has illuminated the crucial role of reactive oxygen species (ROS) in many fundamental cellular functions, including proliferation, inflammation, apoptosis, and gene expression. Notably, producing free radicals within ROS profoundly impacts a wide range of biomolecules, such as proteins and DNA, instigating cellular damage and impairing vital cellular functions. Consequently, oxidative stress emerges as a closely intertwined factor across diverse disease spectra. Remarkably, the pathogenesis of several eye diseases, including age-related macular degeneration, glaucoma, and diabetic retinopathy, manifests an intrinsic association with oxidative stress. In this comprehensive review, we briefly summarize the recent progress in elucidating the intricate role of oxidative stress in the development of ophthalmic diseases, shedding light on potential therapeutic avenues and future research directions.
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Antioxidantes , Glaucoma , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Olho/metabolismo , Estresse Oxidativo , Glaucoma/tratamento farmacológicoRESUMO
INTRODUCTION: The magnetic compression technique (MCT) is used for the anastomosis of hollow organs by the means of suction between magnets. The MCT is useful for establishing digestive tract anastomoses in rats, for example, end-to-side small intestinal anastomosis and colonic anastomosis. We aim to determine the feasibility of MCT-based esophageal anastomosis in rats. METHODS: Twenty-four Sprague-Dawley albino rats (230-250 g) were randomly divided into an MCT group and a control group (hand-sewn esophageal anastomosis). The time required to construct the anastomosis, postoperative complications, and survival rate was compared between the two groups. At 2 wk postoperatively, the animals were sacrificed to assess the burst pressure and histological features of the anastomoses. RESULTS: The mean anastomosis time was significantly lower for MCT (11.17 ± 1.64 min) than for the hand-sewn technique (27.42 ± 2.23 min; P < 0.001). The survival rate was slightly higher in the MCT group (91.67%) than in the control group (66.67%, P = 0.317). The magnets were discharged from the body after 8.33 ± 0.89 d (range, 7-10 d). No anastomotic leakage or stenosis occurred in the MCT group. Three rats developed anastomotic stenosis and two rats developed anastomotic leakage in the control group. The burst pressures were similar in the two groups. An histological examination showed that compared with the control group, the MCT group had better alignment of the tissue layers and less inflammation. CONCLUSIONS: The MCT is a simple and feasible technique for esophageal anastomosis in rats and has the potential for clinical application.
Assuntos
Anastomose Cirúrgica , Procedimentos Cirúrgicos do Sistema Digestório , Esôfago , Imãs , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/instrumentação , Anastomose Cirúrgica/métodos , Fístula Anastomótica/etiologia , Fístula Anastomótica/prevenção & controle , Animais , Constrição Patológica/etiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/instrumentação , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Esôfago/cirurgia , Fenômenos Magnéticos , Ratos , Ratos Sprague-Dawley , Técnicas de SuturaRESUMO
BACKGROUND: Being one of the core techniques of magnetic surgery, magnetic compression technique (MCT) has been used for digestive tract anastomosis reconstruction in experimental studies. This study verified the feasibility of gastroenteric anastomosis through natural orifice using MCT in rats. METHODS: The parent and daughter magnets were designed and manufactured for oral and anal insertion in 20 Sprague-Dawley rats. After anesthesia, the parent magnet was inserted into the colon spleen area through the anus, and the daughter magnet was inserted into the stomach through the mouth. Then the two magnets were positioned to attract each other and bind together. The position of the two magnets was monitored using X-ray. The time required for the formation of the anastomosis and expulsion of the magnets were recorded. 2 weeks later, the animal was sacrificed and the anastomotic specimen was obtained which was observed under naked eye and microscope. RESULTS: The gastroenteric anastomosis was successfully performed via natural orifices in 18 out of 20 rats. The mean time to construct the anastomosis was 3.78 ± 0.88 min. X-ray examination showed that the magnets were in the appropriate position in 17 rats. The magnets were excreted in 9.47 ± 1.62 days after surgery. The gross and microscopic examination of the specimen showed that the anastomoses were patent and the mucosa at the anastomotic was smooth. The mean bursting pressure of the anastomosis was 136.94 ± 6.79 mmHg. CONCLUSION: It is feasible to perform gastroenteric anastomosis through natural orifices by MCT.
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Magnetismo , Imãs , Ratos , Animais , Ratos Sprague-Dawley , Anastomose Cirúrgica/métodos , Fenômenos MagnéticosRESUMO
Lung surfactant protein A (SP-A) is critical for immunomodulation. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) drive T follicular helper (Tfh) cells differentiation in allergic asthma. We employed wild-type (WT) and SP-A-/- mice injected with TSLP and ovalbumin (OVA)-activated DCs and challenged with OVA. Compared with WT mice, we showed that allergic inflammation was dramatically increased in SP-A-/- mice. In parallel, both IL-4-producing CD45RA-CXCR5+PD-1+CD4+ cells (Tfh2) and IgE were markedly increased in SP-A-/- mice. Further study showed that SP-A prohibited TSLP activated-DCs from expressing OX40L. When we blocked OX40L-OX40 and IL-4R signaling, the differentiation of Tfh2 and IgE responses in SP-A-/- mice was significantly inhibited. In severe asthma patients, SP-A is dysfunctional in modulating the TSLP-DCs-mediated differentiation of Tfh cells. This study suggests that SP-A acts as a modulator of Tfh differentiation and IgE generation in asthma.
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Asma/imunologia , Citocinas/imunologia , Imunoglobulina E/biossíntese , Proteína A Associada a Surfactante Pulmonar/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Idoso , Animais , Asma/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Feminino , Humanos , Imunoglobulina E/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína A Associada a Surfactante Pulmonar/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: Craniosynostosis, defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000-2500 live births. Sagittal craniosynostosis (CS), the most prevalent form of isolated craniosynostosis, is caused by interplay between genetic and perinatal environmental insults. However, the underlying details remain largely unknown. METHODS: The proband (a female monochorionic twin diagnosed with CS), her healthy co-twin sister and parents were enrolled. Obstetric history was extracted from medical records. Genetic screening was performed by whole exome sequencing (WES) and confirmed by Sanger sequencing. Functional annotation, conservation and structural analysis were predicted in public database. Phenotype data of Axin2 knockout mice was downloaded from The International Mouse Phenotyping Consortium (IMPC, http://www.mousephenotype.org ). RESULTS: Obstetric medical records showed that, except for the shared perinatal risk factors by the twins, the proband suffered additional persistent breech presentation and intrauterine growth restriction. We identified a heterozygous mutation of Axin2 (c.1181G > A, p.R394H, rs200899695) in monochorionic twins and their father, but not in the mother. This mutation is not reported in Asian population and results in replacement of Arg at residue 394 by His (p.R394H). Arg 394 is located at the GSK3ß binding domain of Axin2 protein, which is highly conserved across species. The mutation was predicted to be potentially deleterious by in silico analysis. Incomplete penetrance of Axin2 haploinsufficiency was found in female mice. CONCLUSIONS: Axin2 (c.1181G > A, p.R394H, rs200899695) mutation confers susceptibility and perinatal risk factors trigger the occurrence of sagittal craniosynostosis. Our findings provide a new evidence for the gene-environment interplay in understanding pathogenesis of craniosynostosis in Chinese population.
Assuntos
Proteína Axina/genética , Craniossinostoses/genética , Animais , Povo Asiático/genética , China , Feminino , Humanos , Camundongos , Camundongos Knockout , Mutação , Fatores de Risco , Gêmeos Monozigóticos , Sequenciamento do ExomaRESUMO
Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.
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Remodelação Óssea/genética , Fatores de Transcrição Forkhead , Locomoção/genética , Mutação , Proteínas Repressoras , Crânio/metabolismo , Vocalização Animal , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Membro Posterior/metabolismo , Humanos , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
BPF, a substitute of BPA, has been widely detected in environment and human bodies. Although the genotoxicity, endocrine disrupting effects, reproductive toxicity of BPF has been well documented, its neurodevelopmental toxicity still remains nebulous. In our study, zebrafish embryos were exposed to BPF treatment (0, 7, 70 and 700⯵g/L) for 3 or 6 days. Our results showed that BPF exposure markedly decreased zebrafish locomotor behavior, increased oxidative stress, promoted apoptosis and altered brain structure in zebrafish. In addition, the expressions of neurodevelopment related genes were also downregulated upon BPF treatment. In conclusion, our results systematically demonstrated the developmental neurotoxicity of BPF in zebrafish.
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Compostos Benzidrílicos/toxicidade , Encéfalo/efeitos dos fármacos , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Exposição Ambiental , Feminino , Locomoção/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis. At the same time, some suggestions for future mRNA vaccine development about storage methods, safety concerns, and personalized vaccine synthesis can be found in the context.
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Vacinas Sintéticas , Sistemas de Liberação de Medicamentos , Imunogenicidade da Vacina , RNA Mensageiro/síntese química , RNA Mensageiro/imunologia , Vacinas de mRNARESUMO
Thermostability plays an important role in the application of L-asparaginase in the pharmaceutical and food industries. Understanding the key residues and structures that influence thermostability in L-asparaginase is necessary to obtain suitable L-asparaginase candidates. In this study, special residues and structures that altered thermostability in thermophilic L-asparaginase and non-thermophilic L-asparaginase II were identified. Interchanging these special residues and structures of L-asparaginases from the four strains, that is, Pyrococcus yayanosii CH1 (PYA), Thermococcus gammatolerans (TGA), Bacillus subtilis (BSA II), and Escherichia coli (ECA II), revealed the 51st and 298th residues of PYA (corresponding to 57th, 305th residues of ECA II) as the key residues responsible for thermal stability of thermophilic L-asparaginase and non-thermophilic L-asparaginase II. Moreover, the C terminal tightness, loop rigidity, and low surface charge around activity sites were of great significance to the thermostability of L-asparaginase. This study therefore revealed the crucial amino acid residues and structures responsible for the difference in thermostability of the thermophilic and non-thermophilic L-asparaginase and provides a reference for engineering thermostability in L-asparaginase II.
Assuntos
Asparaginase/química , Asparaginase/fisiologia , Sequência de Aminoácidos , Proteínas Arqueais/química , Proteínas Arqueais/fisiologia , Proteínas de Bactérias/química , Proteínas de Bactérias/fisiologia , Domínio Catalítico , Biologia Computacional , Estabilidade Enzimática , Temperatura Alta , Modelos Moleculares , Mutação , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Previous animal studies have linked white matter damage to certain schizophrenia-like behaviors in cuprizone (CPZ)-exposed mouse. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and oligodendrocyte loss coexist in the brain of such mice. The aim of this study was to examine effects of the antioxidant N-acetylcysteine (NAC) on CPZ-induced behavioral changes and concurrent oligodendrocyte loss, oxidative stress, and neuroinflammation in these animals. Male C57BL/6 mice were given intraperitoneal saline or NAC at doses of 100, 200, and 400 mg/kg/day for 2 weeks; animals were fed a CPZ-containing diet (0.2%, w/w) during days 5-14. During days 15-17, the mice were examined in open-field, social recognition, and Y-maze tests (1 test per day). Six mice in each group were then used for biochemical and enzyme-linked immunosorbent assay analyses, while the remaining animals were used for immunohistochemical and immunofluorescence staining. The mice exposed to CPZ for 10 days showed significantly lower spontaneous alternation in the Y-maze, lower activity of total superoxide dismutase, and glutathione peroxidase, but higher levels of malondialdehyde in the cerebral cortex and hippocampus, elevated concentrations of interleukin-1ß and tumor necrosis factor-α in the brain regions mentioned above and caudate putamen, and a decreased number of mature oligodendrocytes, but increased number of microglia in all the brain regions examined. These changes, however, were not seen or effectively alleviated in NAC-treated mice at all three doses. These results demonstrate that NAC protected mature oligodendrocytes against the toxic effects of CPZ, likely via its antioxidant and anti-inflammatory actions.
Assuntos
Acetilcisteína/farmacologia , Comportamento Animal/efeitos dos fármacos , Cuprizona/farmacologia , Oligodendroglia/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Quelantes/farmacologia , Interações Medicamentosas , Glutationa Peroxidase/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Distribuição Aleatória , Reconhecimento Psicológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Microbial production of chondroitin and chondroitin-like polysaccharides from renewable feedstock is a promising and sustainable alternative to extraction from animal tissues. In this study, we attempted to improve production of fructosylated chondroitin in Escherichia coli K4 by balancing intracellular levels of the precursors UDP-GalNAc and UDP-GlcA. To this end, we deleted pfkA to favor the production of Fru-6-P. Then, we identified rate-limiting enzymes in the synthesis of UDP-precursors. Third, UDP-GalNAc synthesis, UDP-GlcA synthesis, and chondroitin polymerization were combinatorially optimized by altering the expression of relevant enzymes. The ratio of intracellular UDP-GalNAc to UDP-GlcA increased from 0.17 in the wild-type strain to 1.05 in a 30-L fed-batch culture of the engineered strain. Titer and productivity of fructosylated chondroitin also increased to 8.43â¯g/L and 227.84â¯mg/L/h; the latter represented the highest productivity level achieved to date.
Assuntos
Condroitina/biossíntese , Escherichia coli , Frutosefosfatos , Açúcares de Uridina Difosfato , Condroitina/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Frutosefosfatos/genética , Frutosefosfatos/metabolismo , Deleção de Genes , Glicosilação , Humanos , Açúcares de Uridina Difosfato/genética , Açúcares de Uridina Difosfato/metabolismoRESUMO
BACKGROUND: For many years, ND has been one of the most important infectious pigeon diseases in China. In recent years, a high mortality has been observed in ND-infected pigeons in China. Mortality is from 40% to 80% or 100% in some cases. METHODS: The full-length genomes of four pigeon paramyxovirus type 1 (PPMV-1) strains, which were isolated from infected pigeons in China in 2012 and 2013, were sequenced and analyzed to determine the phylogenetic characteristics of PPMV-1 circulating in pigeons of China in recent years. Furthermore, cross hemagglutination inhibition and cross virus neutralization assays, as well as animal experiments were conducted to determine the antigenicity and pathogenicity of those viruses. Proteolytic cleavage sites (residues 112-117) of the F proteins were identified as the typical virulence motif, 112RRQKR↓F117 for all four PPMV-1 strains investigated. RESULTS: Phylogenetic analysis based on sequences of complete genomes and F gene revealed that the four PPMV-1 isolates and most of recent isolates in China were highly homologous to European isolates from 1998 to 2011. All those isolates were clustered in one clade of genotype VI NDV, termed as subgroup 4bii f. The R value was calculated based on cross hemagglutination inhibition and cross virus neutralization results, and confirmed antigenic difference of the PPMV-1 strains isolated in 2013 from the LaSota vaccine strain. Several mutations were identified in the surface glycoproteins F and HN, which probably gave rise to those antigenic differences. CONCLUSION: Our result suggested that the PPMV-1 strain prevailing in China in the last decade diverged from a common ancestor and was presumably transmitted from Europe. PPMV-1 isolates displayed obvious antigenic differences from vaccine strain LaSota. Even though PPMV-1 did not cause high mortality in experimental pigeons, the infected pigeons were exhibiting viral shedding for 3 weeks after infection, suggesting PPMV-1 is a potential threat to NDV control worldwide.
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Columbidae/virologia , Doença de Newcastle/imunologia , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/classificação , Vírus da Doença de Newcastle/fisiologia , Filogenia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , China/epidemiologia , Reações Cruzadas/imunologia , Genoma Viral , Testes de Inibição da Hemaglutinação , Testes de Neutralização , Doença de Newcastle/epidemiologia , RNA Viral , Sequenciamento Completo do GenomaRESUMO
Naringin is a natural flavonoid with therapeutic properties found in citrus fruits and an active natural product from herbal plants. Naringin has become a focus of attention in recent years because of its ability to actively participate in the body's immune response and maintain the integrity of the immune barrier. This review aims to elucidate the mechanism of action and therapeutic efficacy of naringin in various inflammatory diseases and to provide a valuable reference for further research in this field. The review provided the chemical structure, bioavailability, pharmacological properties, and pharmacokinetics of naringin and found that naringin has good therapeutic potential for inflammatory diseases, exerting anti-inflammatory, anti-apoptotic, anti-oxidative stress, anti-ulcerative and detoxifying effects in the disease. Moreover, we found that the great advantage of naringin treatment is that it is safe and can even alleviate the toxic side effects associated with some of the other drugs, which may become a highlight of naringin research. Naringin, an active natural product, plays a significant role in systemic diseases' anti-inflammatory and antioxidant regulation through various signaling pathways and molecular mechanisms.
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Uveitis is an autoimmune eye disease that can be involved in the entire body and is one of the leading causes of blindness. Therefore, comprehending the mechanisms underlying the development and regulation of ocular immune responses in uveitis is crucial for designing effective therapeutic interventions. In this study, we investigated how RBPJ regulates macrophage polarization in uveitis. We demonstrated that targeted RBPJ knockdown (RBPJKD) promotes M2 macrophage polarization and ameliorates uveitis through the mtROS-mediated Notch1-Jagged1-Hes1 signaling pathway. Real-time quantitative (Q-PCR) analysis revealed that the Notch1-Jagged1-Hes1 signaling pathway was active in the eye tissues of experimental autoimmune uveitis (EAU) rats. Immunofluorescence double staining confirmed enhanced signaling primarily occurring in macrophages, establishing a correlation between the Notch1 signaling pathway and macrophages. Transmission electron microscopy evaluated the morphological and functional changes of mitochondria in each group's eye tissues. It demonstrated significant swelling and disorganization in the EAU group, which were effectively restored upon RBPJ knockdown intervention. Finally, by employing an antioxidant N-acetyl-L-cysteine (NAC) to eliminate mtROS in vivo, we observed a decrease in the M2 macrophage polarization level, which prevented the cytoprotective effect conferred by RBPJKD. These findings underscore the relevance of the Notch signaling pathway to the immune system while highlighting the potential role of mtROS as a therapeutic target for inflammation and other related diseases.
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Objective: Studies on the baseline vitamin D levels in osteogenesis imperfecta (OI) patients before medication are scarce. This study assessed the vitamin D status of a population with OI at both the overall level and within different age groups. It correlated baseline 25-hydroxyvitamin D (25(OH)D) levels with other bone-related factors, biochemical markers, and bone density. Patients and methods: We collected 25(OH)D levels from 95 OI patients in East China (59 under 18 years old and 36 over 18 years old). Postmenopausal women and men over 50 years old are excluded. Measurements included body indicators, biochemical markers, and bone mineral density (BMD) assessed by Dual-energy X-ray absorptiometry (DXA). Data analysis was performed using SPSS 26.0. Results: In the overall population, among those under 18 years old, and among those over 18 years old, 87.4, 83.1, and 94.4%, respectively, were vitamin D deficient (<30 ng/mL), while 47.4, 40.7, and 58.3% had vitamin D deficiency (<20 ng/mL), respectively. In the overall population and among those under 18 years old, serum 25(OH)D levels were negatively correlated with age and parathyroid hormone (PTH) levels, and 25(OH)D levels (<10 ng/mL, 10-20 ng/mL, 20-30 ng/mL, >30 ng/mL) showed a negative correlation with BMI. In OI patients under 18 years old, serum 25(OH)D was negatively correlated with serum ß-CTX levels. In adult male OI population, 25(OH)D levels were negatively correlated with OI severity (Type I, IV, III). No statistically significant correlation was found between 25(OH)D levels and BMD Z-scores. Conclusion: This study on OI in East China reveals significant vitamin D insufficiency and deficiency in baseline levels among pediatric, adolescent and adult OI patients. It assesses the correlation of 25(OH)D levels with various influencing factors, providing crucial insights into understanding the impact of OI on vitamin D status across different age groups and aiding in better clinical management of OI patients.
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Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2fl/fl;Prx1Cre) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2fl/fl;Prx1Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.
Assuntos
Fator de Crescimento do Tecido Conjuntivo , Osteocondrodisplasias , Peixe-Zebra , Humanos , Animais , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Osteocondrodisplasias/metabolismo , Peixe-Zebra/genética , Masculino , Feminino , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Camundongos , Alelos , Linhagem , Osteogênese/genética , Adolescente , Densidade Óssea/genética , Criança , Camundongos KnockoutRESUMO
Introduction: Multiple targets are considered as the causes of ambient fine particulate matter [aerodynamic diameters of < 2.5 µm (PM2.5)] induced lung function injury. Qiju granules are derived from the traditional Chinese medicine (TCM) formula known as Qi-Ju-Di-Huang-Wan (Lycium, Chrysanthemum, and Rehmannia Formula, QJDHW), which has been traditionally used to treat symptoms such as cough with phlegm, dry mouth and throat, and liver heat. This treatment approach involves attenuating inflammation, oxidative stress, and fibrosis response. This study investigated the effects of Qiju granules on protecting lung function against PM2.5 exposure in a clinical trial. Methods: A randomized, double-blinded, and placebo-controlled trial was performed among 47 healthy college students in Hangzhou, Zhejiang Province in China. The participants were randomly assigned to the Qiju granules group or the control group based on gender. Clinical follow-ups were conducted once every 2 weeks during a total of 4 weeks of intervention. Real-time monitoring of PM2.5 concentrations in the individually exposed participants was carried out. Data on individual characteristics, heart rate (HR), blood pressure (BP), and lung function at baseline and during the follow-ups were collected. The effects of PM2.5 exposure on lung function were assessed within each group using linear mixed-effect models. Results: In total, 40 eligible participants completed the scheduled follow-ups. The average PM2.5 level was found to be 64.72 µg/m3 during the study period. A significant negative correlation of lung function with PM2.5 exposure concentrations was observed, and a 1-week lag effect was observed. Forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FVC) (FEF75), forced expiratory flow at 50% of FVC (FEF50), and forced expiratory flow at 25% of FVC (FEF25) were significantly decreased due to PM2.5 exposure in the control group. Small airway function was impaired more seriously than large airway function when PM2.5 exposure concentrations were increased. In the Qiju granules group, the associations between lung function and PM2.5 exposure were much weaker, and no statistical significance was observed. Conclusion: The results of the study showed that PM2.5 exposure was associated with reduced lung function. Qiju granules could potentially be effective in protecting lung functions from the adverse effects of PM2.5 exposure. Clinical Trial Registration: identifier: ChiCTR1900021235.