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OBJECTIVE: To compare the efficacy of blood letting under pain point touch and ultrasound-guided puncture decompression in the treatment of acute supraspinatus muscle calcifying tendinitis. METHODS: From January 2020 to January 2023, 45 patients with acute supraspinatus muscle calcifying tendinitis were selected and divided into treatment group and control group. In the treatment group, a total of 22 patients were treated with ultrasound-guided puncture decompression, including 16 females and 6 males, aged from 20 to 64 years old(39.31±5.80) years old, 11 on the left shoulder and 11 on the right shoulder. In the control group, there were 23 cases, including 15 females and 8 males, aged from 19 to 66 years old (40.67±6.13) years old, 12 on the left shoulder and 13 on the right shoulder. The treatment was treated with pain point touch bloodletting therapy. The visual analog scale (VAS) pain score, University of California, Los Angeles(UCLA) shoulder system score and shoulder Constant-Murley score were used to evaluate the therapeutic effect before treatment, 1 weeks, 1 month and 3 months after treatment, respectively. RESULTS: One patient in the control group gave up follow-up for personal reasons after 1 week of treatment, and the other 44 patients completed all follow-up. Six months after treatment, there were no recurrence cases in both groups. After statistical analysis, VAS pain score, UCLA score and Constant-Murley score of the treatment group and the control group were significantly different from those before treatment (P<0.05), and the improvement was more obvious in the treatment group. There was no statistical significance between the two groups (P>0.05). CONCLUSION: Bloodletting under pain point touch and ultrasound-guided puncture decompression are effective in the treatment of acute calcific supraspinatus tendinitis, with simple operation and low cost, which can effectively reduce local pain and effectively improve shoulder joint function. Primary hospitals can selectively operate treatment according to their own conditions.
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Descompressão Cirúrgica , Flebotomia , Tendinopatia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Tendinopatia/cirurgia , Tendinopatia/terapia , Flebotomia/métodos , Descompressão Cirúrgica/métodos , Calcinose/cirurgia , Calcinose/terapia , Idoso , Adulto Jovem , Resultado do Tratamento , Ultrassonografia , Punções/métodos , Manguito Rotador/cirurgiaRESUMO
The oxidation of the complementarity-determining region (CDR) in monoclonal antibodies (mAbs) is a critical quality attribute that can affect the clinical efficacy and safety of recombinant mAb therapeutics. In this study, a robust hydrophobic interaction chromatography (HIC) method was developed to quantify and characterize CDR oxidation variants in mAb-A by using a Proteomix Butyl-NP5 column. The HIC analysis revealed oxidation variants that eluted earlier than the main species with weaker hydrophobicity. It was found that Met105 in the CDR was more susceptible to oxidation. Additionally, it was noted that the oxidation of Met105 on a single heavy chain resulted in elution at a distinct position compared to the oxidation on two heavy chains. This observation led to the fractionation and enrichment of the oxidized variants for further evaluation of their biofunction. The study also demonstrated that the oxidation of Met105 did not impact the antigen-binding capacity but significantly reduced the PD-1/PD-L1 blockade activity of mAb-A. The HIC method, which was employed to quantify CDR oxidation, underwent validation and was subsequently utilized for stability studies as well as for assessing the similarity between mAb-A and its reference product.
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The Shexiang Zhuifeng Zhitong Ointment with the effects of dispelling wind, removing dampness, dissipating cold, and relieving pain is used for treating arthralgia, muscular pain, and sprain pain caused by cold-dampness obstruction. To evaluate the efficacy and safety of Shexiang Zhuifeng Zhitong Ointment in relieving the pain due to knee osteoarthritis(syndrome of cold-dampness obstruction), a randomized, double-blind, parallel controlled, multicenter clinical trial was conducted. The stratified randomization method was used to randomize the 240 subjects into a treatment group and a control group in a ratio of 1â¶1. In each group, 60 patients received external application for 12 h and the other 60 patients received external application for 6 h. The treatment group received external application of Shexiang Zhuifeng Zhitong Ointment, while the control group received external application of Shexiang Zhuifeng Ointment. The treatment lasted for 21 days in both groups. Follow-up was conducted on days 7, 14, and 21 of treatment. The results based on the full analysis set were as follows.(1)In visual analog scale(VAS) score, the mean difference in the VAS score between baseline and 12 h post-treatment was 3.02 in the treatment group and 2.31 in the control group, with a significant difference(P<0.05). The mean difference in the VAS score between baseline and 6 h post-treatment was 3.19 in the treatment group and 2.48 in the control group, with a significant difference(P<0.05).(2)Response rate in terms of VAS score, after treatment for 12 h, the response rate was 93.22% in the treatment group and 73.33% in the control group, with a significant difference(P<0.05). After treatment for 6 h, theresponse rate in the treatment group was 88.33%, which was higher than that(63.33%) in the control group(P<0.05).The results showed that Shexiang Zhuifeng Zhitong Ointment applied for 12 and 6 h effectively relieved the knee joint pain of patients with knee osteoarthritis due to cold-dampness obstruction, as demonstrated by the reduced VAS score, Western Ontario and McMaster Universities Arthritis Index(WOMAC), stiffness, and joint function score. Moreover, Shexiang Zhuifeng Zhitong Ointment outperformed the positive control Shexiang Zhuifeng Ointment in terms of reducing the VAS score, demonstrating a definitetherapeutic effect on the pain due to knee osteoarthritis(syndrome of cold-dampness obstruction).In addition, Shexiang Zhuifeng Zhitong Ointment did not cause other adverse reactions except for mild allergic reactions, which were common in the external application of traditional Chinese medicine plasters on the skin, inseveral patients.Neither other adverse reactions nor abnormalities of liver and kidney functions and electrocardiogram were observed. This ointment had high safety and could be popularized in clinical application.
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Medicamentos de Ervas Chinesas , Pomadas , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Feminino , Método Duplo-Cego , Idoso , Resultado do Tratamento , Adulto , Dor/tratamento farmacológico , Dor/etiologiaRESUMO
Glioma, particularly glioblastomas (GBM), is incurable brain tumor. The most targeted receptor tyrosine kinase (RTKs) drugs did not bring benefit to GBM patients. The mechanism of glioma growth continues to be explored to find more effective treatment. Here, we reported that Ser/Thr protein kinase YANK2 (yet another kinase 2) is upregulated in glioma tissues and promotes the growth and proliferation of glioma in vitro and in vivo. Further, we confirmed that oncogene Fyn directly activated YANK2 through phosphorylation its Y110, and Fyn-mediated YANK2 phosphorylation at Y110 site promotes glioma growth by increasing its stability. Finally, YANK2 was proved to be a novel upstream kinase of p70S6K and promotes glioma growth by directly phosphorylating p70S6K at T389. Taken together, we found a new mTOR-independent p70S6K activation pathway, Fyn-YANK2-p70S6K, which promotes glioma growth, and YANK2 is a potential oncogene and serves as a novel therapeutic target for glioma.
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Proliferação de Células , Glioma , Proteínas Proto-Oncogênicas c-fyn , Proteínas Quinases S6 Ribossômicas 70-kDa , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Humanos , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Proteínas Proto-Oncogênicas c-fyn/genética , Serina-Treonina Quinases TOR/metabolismo , Glioma/metabolismo , Glioma/patologia , Glioma/genética , Animais , Linhagem Celular Tumoral , Fosforilação , Carcinogênese/genética , Carcinogênese/metabolismo , Camundongos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Camundongos Nus , Regulação Neoplásica da Expressão GênicaRESUMO
Bladder cancer is one of the most frequent malignant tumors of the urinary system. The prevalence of bladder cancer among men and women is roughly 5:2, and both its incidence and death have been rising steadily over the past few years. At the moment, metastasis and recurrence of advanced bladder cancer-which are believed to be connected to the malfunction of multigene and multilevel cell signaling network-remain the leading causes of bladder cancer-related death. The therapeutic treatment of bladder cancer will be greatly aided by the elucidation of these mechanisms. New concepts for the treatment of bladder cancer have been made possible by the advancement of research technologies and a number of new treatment options, including immunotherapy and targeted therapy. In this paper, we will extensively review the development of the tumor microenvironment and the possible molecular mechanisms of bladder cancer.
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Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.
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Proliferação de Células , Glioblastoma , Transaminases , Ubiquitinação , Animais , Humanos , Camundongos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Progressão da Doença , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/genética , Células HEK293 , Camundongos Nus , Fosforilação , Proteólise , Temozolomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Transaminases/metabolismoRESUMO
Driving in urban areas can be challenging and encounter acute stress. To detect driver stress, collecting data on real roads without interfering the driver is preferred. A smartphone-based data collection protocol was developed to support a naturalistic driving study. Sixty-one participants drove on predetermined real road routes, and driving information as well as physiological, psychological, and facial data were collected. The algorithm identified potentially stressful events based on the collected data. Participants classified these events as low, medium, or highly stressful events by watching recorded videos after the experiment. These events were then used to train prediction models. The best model achieved an accuracy of 92.5% in classifying low/medium/highly stressful events. The contribution of physiological, psychological, and facial expression indices and individual profile information was evaluated. The method can be applied to visualise the geographical distribution of stressors, monitor driver behaviour, and help drivers regulate their driving habits.
The data collection protocol for driving on real roads and the stressful event identification method could potentially be applied for in-vehicle driver status monitoring and stress intervention.
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Atopic dermatitis (AD), a chronic, highly pruritic, and inflammatory skin disorder, often coexists with psychiatric comorbidities including anxiety and depression, posing considerable challenges for treatment. The current research aims at evaluating the efficacy and potential therapeutic mechanism of galacto-oligosaccharides (GOS) on AD-like skin lesions and comorbid anxiety/depressive disorders. Macroscopical and histopathological examination showed that GOS could markedly relieve skin inflammation by decreasing the production of IgE, IL-4, IL-13, IFN-γ, and TNF-α and regulating the PPAR-γ/NF-κB signaling in DNFB-induced AD mice. Moreover, GOS significantly improved the anxiety- and depressive-like symptoms as mirrored by the behavior tests including FST, TST, OFT, and EZM through normalizing the neurotransmitter levels of 5-HT, DA, NE, and CORT in the brain. Mechanistically, by virtue of the high-throughput 16S rRNA gene sequencing and GC-MS techniques, GOS restructured the gut microbiota and specifically induced the proliferation of Lactobacillus and Alloprevotella, leading to an increase in the total content of fecal SCFAs, in particular acetate and butyrate. Pearson correlation analysis found a marked correlation among the altered gut microbiota/SCFAs, AD-associated skin manifestations, and comorbid behavioral phenotypes. Collectively, this work highlights that GOS is a promising strategy against both AD and associated depressive symptoms by modulating the gut microbiota-brain-skin axis.
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Dermatite Atópica , Microbioma Gastrointestinal , Camundongos , Animais , Dermatite Atópica/tratamento farmacológico , RNA Ribossômico 16S , Pele , Encéfalo , Inflamação/tratamento farmacológico , OligossacarídeosRESUMO
To reduce the risk of resistance development, a novel fungicide with dual specificity is demanded. Trehalose is absent in animals, and its synthases, trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP), are safe fungicide targets. Here, we report the discovery of a dual-specificity inhibitor of MoTps1 (Magnaporthe oryzae Tps1, TPS) and MoTps2 (M. oryzae Tps2, TPP). The inhibitor, named A1-4, was obtained from a virtual screening and subsequent surface plasmon resonance screening. In in vitro assays, A1-4 interacts with MoTps1 and MoTps2-TPP (MoTps2 TPP domain) and inhibits their enzyme activities. In biological activity assays, A1-4 not only inhibits the virulence of M. oryzae on host but also causes aggregation of conidia cytosol, which is a characteristic phenotype of MoTps2. Furthermore, hydrogen/deuterium exchange mass spectrometry assays support the notion that A1-4 binds to the substrate pockets of TPS and TPP. Collectively, A1-4 is a promising hit compound for the development of safe fungicide with dual-target specificity.
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Fungicidas Industriais , Trealose , Animais , Trealose/metabolismo , Fungicidas Industriais/farmacologia , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Metabolismo dos Carboidratos , Glucosiltransferases/químicaRESUMO
OBJECTIVE: In this study, we established an efficient and rapid transient expression system in the protoplasts of Pinellia ternata (Thunb.) Breit. (P. ternata). RESULTS: The protoplasts of P. ternata were prepared from plant leaves as the source material by digesting them with the combination of 20 g·l-1 cellulase and 15 g·l-1 macerozyme for 6 h. Based on the screening of PEG concentration, the conditions for PEG-mediated protoplast transformation were improved, and the highest transformation efficiency was found for 40% PEG 4000. Furthermore, we used the subcellular protein localization technique in P. ternata protoplasts to allow further validation of transient expression system. CONCLUSIONS: We present the method that can be applicable for studying both gene verification and expression in P. ternata protoplasts, thus allowing for engineering the improved varieties of P. ternata through molecular plant breeding techniques. This method can also be widely applicable for analyzing protein interactions, detecting promoter activity, for somatic cell fusion in plant breeding, as well as for other related studies.
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Celulase , Pinellia , Pinellia/genética , Protoplastos , Melhoramento Vegetal , Embaralhamento de DNARESUMO
Given that the pharmaceutical market has experienced severe market failures, it is necessary that we regulate pharmaceutical prices for many countries. Toward ensuring that pharmaceutical price regulation is efficient, this study investigated the antecedents that lead to an unreasonable pharmaceutical price. Based on 33 case-study countries, this study utilized QCA to analyze the conditional configuration of unreasonable pharmaceutical prices from the perspective of medical service provision. The results showed that the causes of unreasonable pharmaceutical prices are configured by medical service provision, especially cost compensation systems and payment mechanism. This study's conclusions contribute to the research on pharmaceutical price regulation and the institution of medical service provision.
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Custos de Medicamentos , Farmacoeconomia , Preparações FarmacêuticasRESUMO
We elucidate grapevine evolution and domestication histories with 3525 cultivated and wild accessions worldwide. In the Pleistocene, harsh climate drove the separation of wild grape ecotypes caused by continuous habitat fragmentation. Then, domestication occurred concurrently about 11,000 years ago in Western Asia and the Caucasus to yield table and wine grapevines. The Western Asia domesticates dispersed into Europe with early farmers, introgressed with ancient wild western ecotypes, and subsequently diversified along human migration trails into muscat and unique western wine grape ancestries by the late Neolithic. Analyses of domestication traits also reveal new insights into selection for berry palatability, hermaphroditism, muscat flavor, and berry skin color. These data demonstrate the role of the grapevines in the early inception of agriculture across Eurasia.
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Evolução Biológica , Domesticação , Vitis , Humanos , Agricultura , Ásia Ocidental , Ecótipo , Fenótipo , Vitis/genética , AclimataçãoRESUMO
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by pruritus and eczema lesions and psychiatric comorbidities. The gut-brain-skin axis plays a pivotal role during AD development, which might suggest a novel therapeutic strategy for AD. The present study aims to uncover the protective effects and underlying mechanisms of fructo-oligofructose (FOS), a type of prebiotic, on AD-like skin manifestations and comorbid anxiety and depression in AD mice. RESULTS: Female Kunming mice were treated topically with 2,4-dinitrofluorobenzene (DNFB) to induce AD-like symptoms and FOS was administered daily for 14 days. The results showed that FOS could alleviate AD-like skin lesions markedly as evidenced by dramatic decreases in severity score, scratching bouts, the levels of immunoglobulin E (IgE) and T helper 1(Th1)/Th2-related cytokines, and the infiltration of inflammatory cells and mast cells to the dermal tissues. The comorbid anxiety and depressive-like behaviors, estimated by the forced swimming test (FST), the tail-suspension test (TST), the open-field test (OFT), and the zero maze test (ZMT) in AD mice, were significantly attenuated by FOS. Fructo-oligofructose significantly upregulated brain neurotransmitters levels of 5-hydroxytryptamine (5-HT) and dopamine (DA). Furthermore, FOS treatment increased the relative abundance of gut microbiota, such as Prevotella and Lactobacillus and the concentrations of short-chain fatty acids (SCFAs), especially acetate and iso-butyrate in the feces of AD mice. The correlation analysis indicated that the reshaped gut microbiome composition and enhanced SCFAs formation are associated with skin inflammation and behavioral alteration. CONCLUSION: Collectively, these data identify FOS as a promising microbiota-targeted treatment for AD-like skin inflammation and comorbid anxiety and depressive-like behaviors. © 2023 Society of Chemical Industry.
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Dermatite Atópica , Camundongos , Feminino , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dinitrofluorbenzeno/efeitos adversos , Pele , Citocinas , Inflamação/tratamento farmacológicoRESUMO
Blast disease caused by Magnaporthe oryzae threatens rice production worldwide, and chemical control is one of the main methods of its management. The high mutation rate of the M. oryzae genome results in drug resistance, which calls for novel fungicide targets. Fungal proteins that function during the infection process might be potential candidates, and Mps1 (M. oryzae mitogen-activated protein kinase 1) is such a protein that plays a critical role in appressorium penetration of the plant cell wall. Here, we report the structure-aided identification of a small-molecule inhibitor of Mps1. High-throughput screening was performed with Mps1 against a DNA-encoded compound library, and one compound, named A378-0, with the best performance was selected for further verification. A378-0 exhibits a higher binding affinity than the kinase cosubstrate ATP and can inhibit the enzyme activity of Mps1. Cocrystallization of A378-0 with Mps1 revealed that A378-0 binds to the catalytic pocket of Mps1, while the three ring-type substructures of A378-0 constitute a triangle that squeezes into the pocket. In planta assays showed that A378-0 could inhibit both the appressorium penetration and invasive growth but not the appressorium development of M. oryzae, which is consistent with the biological function of Mps1. Furthermore, A378-0 exhibits binding and activity inhibition abilities against Mpk1, the Mps1 ortholog of the soilborne fungal pathogen Fusarium oxysporum. Collectively, these results show that Mps1 as well as its orthologs can be regarded as fungicide targets, and A378-0 might be used as a hit compound for the development of a broad-spectrum fungicide. IMPORTANCE M. oryzae is the causal agent of rice blast, one of the most devastating diseases of cultivated rice. Chemical control is still the main strategy for its management, and the identification of novel fungicide targets is indispensable for overcoming existing problems such as drug resistance and food safety. With a combination of structural, biochemical, and in planta assays, our research shows that Mps1 may serve as a fungicide target and confirms that compound A378-0 binds to Mps1 and possesses bioactivity in inhibiting M. oryzae virulence. As fungal orthologs of Mps1 are conserved, A378-0 may serve as a hit for broad-spectrum fungicide development, as evidenced with Mpk1, the Mps1 ortholog of F. oxysporum. Additionally, A378-0 contains a novel chemical scaffold that has not been reported in approved kinase inhibitors, suggesting its potential to be considered the basis for the development of other kinase inhibitors.
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Fungicidas Industriais , Fungicidas Industriais/farmacologia , Fungos/genética , Fungos/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Plantas/microbiologia , Virulência , Doenças das Plantas/microbiologia , Regulação Fúngica da Expressão GênicaRESUMO
PURPOSE: To compare the effectiveness of TiRobot-assisted kyphoplasty with that of the traditional fluoroscopy-assisted approach in treating multilevel osteoporotic vertebral compression fractures. METHODS: In this retrospective study, we collected data from 71 patients (TiRobot-assisted group, n = 39; fluoroscopy-assisted group, n = 32) with multilevel osteoporotic vertebral compression fracture treated with unilateral traditional TiRobot-assisted or fluoroscopy-assisted percutaneous kyphoplasty. The operative time, infusion volume, length of stay (LOS), hospital expenses, visual analog scale (VAS), Oswestry Disability Index (ODI), radiation exposure, puncture deviation, anterior height of diseased vertebrae, local kyphotic angle, bone cement distribution, and bone cement leakage were compared between the TiRobot- and fluoroscopy-assisted groups. RESULTS: Of the 257 treated vertebrae, the average amount of bone cement injected in the TiRobot-assisted (142 vertebrae) and fluoroscopy-assisted (115 vertebrae) groups was 4.6 mL and 4.5 mL, respectively. The VAS score was significantly lower in the TiRobot-assisted group at 24 hours post-operatively (p = 0.006). The X-ray frequency was 34.7 times in the TiRobot-assisted group and 51.7 times in the fluoroscopy-assisted group (p < 0.001). In addition to the operative time, cumulative radiation dose for the surgeon and patient was significantly lower in the TiRobot-assisted group. The hospital expenses of the TiRobot-assisted group were significantly higher (p < 0.001). The puncture deviation and bone cement distribution were better in the TiRobot-assisted group (p < 0.001). Bone cement leakage was found in 18 and 29 cases in the TiRobot- and fluoroscopy-assisted groups, respectively (p = 0.010). One patient in the fluoroscopy-assisted group experienced radiculopathy due to a misplaced puncture but recovered in three months. No radiculopathy was observed in the TiRobot-assisted group. CONCLUSIONS: TiRobot-assisted percutaneous multilevel kyphoplasty is more accurate and has smaller radiometry, a more uniform bone cement distribution, and lower bone cement leakage. This method was therefore accurate and safe.
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Fraturas por Compressão , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Cifoplastia/efeitos adversos , Cifoplastia/métodos , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/cirurgia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Cimentos Ósseos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/cirurgia , Vertebroplastia/métodosRESUMO
Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder. Obesity is associated with increased prevalence and severity of AD for reasons that remain poorly understood. Myricetin, a dietary flavonoid found in fruits and vegetables, is known to have anti-inflammatory effects, but its role in AD is unclear. Thus, we investigated the effects of obesity on exacerbation AD lesions and evaluated the effects of myricetin on obese AD. Mice were fed normal diet (ND) or high-fat diet, and then 2,4-dinitrofluorobenzene was used to induce AD-like lesions. We found that obesity exacerbated AD lesions, and myricetin topical administration ameliorated symptoms and skin lesions of obsess AD mice, such as dermatitis scores, scratching behavior, epidermal thickness, and mast cell infiltration. In addition, myricetin reduced the levels of immunoglobulin E and histamine, inhibited the infiltration of CD4+T cells, and modulated the expression of Th1, Th2, Th17, and Th22 cytokines and pro-inflammatory factors (CCL17, CCL22, IL-1ß, and TGF-ß). Moreover, myricetin restored impaired barrier function by reducing transepidermal water loss, increasing lamellar body secretion, as well as upregulating the mRNA and protein expression of filaggrin. Western blot results showed that significantly increased levels of phosphorylated IκB and NF-κB p65 was observed in the obese AD mice compared with the AD mice fed ND, whereas the myricetin could downregulated the phosphorylations of IκB and NF-κB, and inhibited mRNA expression of iNOS and COX2. Taken together, our results suggest that myricetin treatment exhibits potentially protective effects against the obeseassociated AD by inhibiting inflammatory response and restoring skin barrier function.
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Dermatite Atópica , Flavonoides , Animais , Camundongos , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dinitrofluorbenzeno/toxicidade , Dinitrofluorbenzeno/metabolismo , Flavonoides/uso terapêutico , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Pele , Proteínas Filagrinas/efeitos dos fármacos , Proteínas Filagrinas/metabolismoRESUMO
Purpose: To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation. Methods: TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB). Results: A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin. Conclusion: Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.
Assuntos
Dermatite Atópica , Medicamentos de Ervas Chinesas , Animais , Camundongos , Luteolina/farmacologia , Dermatite Atópica/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , DinitrofluorbenzenoRESUMO
OBJECTIVE: To investigate the clinical effect of Kinesio Taping combined with electroacupuncture in the treatment of Bigliani typeâ subacromial impingement syndrome. METHODS: From January 2019 to June 2021, 82 cases with Bigliani typeâ subacromial impingement syndrome were selected and divided into treatment group and control group. Treatment group included 41 cases, 23 males and 18 females, aged from 20 to 52 years old, with an average of (39.31±5.80)years old. There were 12 cases on left shoulder and 29 cases on right shoulder. The course of disease was from 3.2 to 35.4 months. The treatment group was treated with Kinesio Taping and electroacupuncture. In control group, there were 41 cases, including 22 males and 19 females, aged from 19 to 53 years old with an average of (40.67±6.13) years old, 30 cases on right shoulder, 11 cases on left shoulder. The courses of disease was from 3.0 to 36.0 months. The control group was treated with simple shoulder electroacupuncture. Patients in both groups were treated with electroacupuncture 3 times a week for 3 weeks. After each electroacupuncture treatment in the treatment group, the Kinesio Taping was applied immediately and kept for 2 days. Before treatment, immediately after treatment, and after 1, 3, 8 weeks, the shoulder joint Constant-Murley score, pain visual analogue scale (VAS), and shoulder joint range of motion were used to evaluate the treatment effect. RESULTS: After 1 week of treatment, there was 1 patient in treatment group refused treatment due to hypersensitivity to Kinesio Taping, 1 patient in control group was allergic to the metal needle and refused treatment. And the other 80 patients completed all treatment. Immediately after treatment, and 1, 3, and 8 weeks after treatment, VAS of treatment group were (2.06±1.03), (2.74±1.66), (3.28±1.04), and (3.90±0.12) points, respectively. The Constant-Murley scores of shoulder joint were(86.41±3.52), (82.44±3.14), (80.46±2.54), (76.97±2.01) points. VAS of control group were(3.35±0.41), (3.08±0.92), (3.77±0.67), (3.96±1.04) points, and the Constant-Murley scores of the shoulder joint were(75.82±2.73), (74.72±1.53), (73.66±1.53), (70.68±1.95) points respectively. Immediately after treatment, VAS, Constant-Murley score, and shoulder range of motion between two groups were better than those of before treatment (P<0.05), and the difference was statistically significant between two groups after treatment (P<0.05). One week after treatment, VAS, Constant-Murley score, and shoulder joint range of motion between two groups were better than those of before treatment (P<0.05), but there was no significant difference in VAS between two groups (P>0.05). There were significant differences in the Constant-Murley score and shoulder range of motion between two groups (P<0.05). At 3 and 8 weeks after treatment, VAS, Constant-Murley score, and the range of motion of shoulder joints between two groups were better than those of before treatment (P<0.05), but there was no significant difference between two groups(P>0.05). CONCLUSION: The treatment for bigliani typeâ subacromial impingement syndrome with Kinesio Taping combined with electroacupuncture can reduce pain, effectively improve the function of shoulder joint. In addition, with Kinesio Taping protection when motion, the patients sports ability can be improved obviously, with good immediate effect, and no trauma. If the patients are willing to accept it, it would be an immediate and effective treatment.
Assuntos
Fita Atlética , Eletroacupuntura , Síndrome de Colisão do Ombro , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Síndrome de Colisão do Ombro/terapia , Amplitude de Movimento Articular , Medição da Dor , Resultado do TratamentoRESUMO
Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-ß), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-ß and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.
Assuntos
Interleucina-4 , Interleucina-9 , Animais , Humanos , Camundongos , Diferenciação Celular/genética , Interleucina-4/metabolismo , Proteínas Repressoras/genética , RNA Interferente Pequeno/metabolismo , Serina/metabolismo , Linfócitos T Auxiliares-Indutores , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismoRESUMO
OBJECTIVE: Studies have compared the safety and accuracy of robot-assisted techniques for inserting conventional open pedicle screws for spinal surgery. However, no relevant studies have confirmed that robot-assisted percutaneous screw placement is better than fluoroscopic percutaneous screw placement for the treatment of thoracolumbar fractures. This study compared the accuracy and safety of TiRobot-assisted percutaneous pedicle screw placement with those of the fluoroscopy-assisted percutaneous technique for the treatment of thoracolumbar fractures. METHODS: This retrospective study included 126 patients with thoracolumbar fractures who underwent percutaneous pedicle screw placement. Sixty-five patients were treated with the TiRobot-assisted technique and 61 patients were treated with the fluoroscopy-assisted technique. Patient demographics, accuracy of screw placement (according to the Gertzbein and Robbins scale of grades A to E), screw insertion angle, radiation exposure, surgical time, intraoperative blood loss, length of hospital stay, incision length, hospital expenses, surgical site infection, and neurological injury of the TiRobot-assisted and fluoroscopy-assisted groups were compared using Student's t-test, Pearson χ2 test, or Fisher's exact test. RESULTS: A total of 729 screws were placed (TiRobot-assisted group: 374 screws; fluoroscopy-assisted group: 355 screws). In the TiRobot-assisted group, 82.8% of screws were optimally positioned (grade A); however, the placement grades of the remaining screws were categorized as grade B (13.3%), grade C (3.2%), and grade D (0.5%). In the fluoroscopy-assisted group, 66.7% of the screws were optimally positioned (grade A); however, the placement grades of the remaining screws were categorized as grade B (21.4%), grade C (7.6%), grade D (3.6%), and grade E (0.5%). The proportion of clinically acceptable screws (grade A or B) was greater in the TiRobot-assisted group than in the fluoroscopy-assisted group. Additionally, the TiRobot-assisted group had a significantly larger mean screw insertion angle (22.27° ± 5.48° vs 20.55° ± 5.15°), larger incision length (13.86 ± 1.24 cm vs 12.77 ± 1.43 cm), and higher hospital expenses (69061.55 ± 7166.60 yuan vs 59383.85 ± 5019.64 yuan) than the fluoroscopy-assisted group. There were no significant differences in the intraoperative blood loss, length of hospital stay, and rates of surgical site infection and neurological injury in both groups (p > 0.05). However, the TiRobot-assisted group had significantly better surgical times, radiation times, and radiation exposure than the fluoroscopy-assisted group (p < 0.05). CONCLUSIONS: Percutaneous TiRobot-assisted pedicle screw placement is a safe, useful, and potentially more accurate alternative to the percutaneous fluoroscopy-assisted technique for treating thoracolumbar fractures.