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1.
Drug Deliv ; 28(1): 2071-2084, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34595970

RESUMO

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality worldwide. Nowadays, liver-targeting drug delivery system has been proven as a promising strategy for overcoming HCC. Asialoglycoprotein receptor (ASGPR) is an ideal receptor for liver targeting, which is mainly expressed on hepatocytes. In this study, we developed several novel liver-targeting chitosan nanoparticles to selectively overcome HCC via ASGPR. Chitosan nanoparticles (Gly-CS-VE, Gal-Gly-CS-VE, Gly-CS-DCA, and Gal-Gly-CS-DCA) were prepared by grafting hydrophilic group (glycidol, Gly), hydrophobic group (deoxycholic acid, DCA or vitamin E succinate, VE), and ASGPR recognizing group (galactose, Gal). Subsequently, their characterizations were measured by 1H NMR, FT-IR, TEM, and DLS. Doxorubicin (DOX) was loaded in nanoparticles and released out in a pH-dependent manner. Most importantly, the galactosylated Gal-Gly-CS-VE and Gal-Gly-CS-DCA nanoparticles exhibited significantly stronger in vitro cell internalization, cytotoxicity, anti-migration capabilities and in vivo anticancer efficacies than the corresponding Gly-CS-VE and Gly-CS-DCA nanoparticles, as well as free DOX. Finally, the four chitosan nanoparticles exhibited good biocompatibility without causing any obvious histological damage to the major organs. Overall, the galactosylated chitosan nanoparticles were proven to be promising pharmaceutical formulations for selectively overcoming HCC, with great potential for clinical applications.

2.
Crit Care Med ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34582411

RESUMO

OBJECTIVES: Sepsis remains a highly lethal disease, whereas the precise reasons for death remain poorly understood. Prokineticin2 is a secreted protein that regulates diverse biological processes. Whether prokineticin2 is beneficial or deleterious to sepsis and the underlying mechanisms remain unknown. DESIGN: Prospective randomized animal investigation and in vitro studies. SETTING: Research laboratory at a medical university hospital. SUBJECTS: Prokineticin2 deficiency and wild-type C57BL/6 mice were used for in vivo studies; sepsis patients by Sepsis-3 definitions, patient controls, and healthy controls were used to obtain blood for in vitro studies. INTERVENTIONS: Prokineticin2 concentrations were measured and analyzed in human septic patients, patient controls, and healthy individuals. The effects of prokineticin2 on sepsis-related survival, bacterial burden, organ injury, and inflammation were assessed in an animal model of cecal ligation and puncture-induced polymicrobial sepsis. In vitro cell models were also used to study the role of prokineticin2 on antibacterial response of macrophages. MEASUREMENTS AND MAIN RESULTS: Prokineticin2 concentration is dramatically decreased in the patients with sepsis and septic shock compared with those of patient controls and healthy controls. Furthermore, the prokineticin2 concentration in these patients died of sepsis or septic shock is significantly lower than those survival patients with sepsis or septic shock, indicating the potential value of prokineticin2 in the diagnosis of sepsis and septic shock, as well as the potential value in predicting mortality in adult patients with sepsis and septic shock. In animal model, recombinant prokineticin2 administration protected against sepsis-related deaths in both heterozygous prokineticin2 deficient mice and wild-type mice and alleviated sepsis-induced multiple organ damage. In in vitro cell models, prokineticin2 enhanced the phagocytic and bactericidal functions of macrophage through signal transducers and activators of transcription 3 pathway which could be abolished by signal transducers and activators of transcription 3 inhibitors S3I-201. Depletion of macrophages reversed prokineticin2-mediated protection against polymicrobial sepsis. CONCLUSIONS: This study elucidated a previously unrecognized role of prokineticin2 in clinical diagnosis and treatment of sepsis. The proof-of-concept study determined a central role of prokineticin2 in alleviating sepsis-induced death by regulation of macrophage function, which presents a new strategy for sepsis immunotherapy.

3.
Pediatr Infect Dis J ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34508026

RESUMO

BACKGROUND: China has a high burden of tuberculosis and latent tuberculosis infection (LTBI). The aim of this study was to estimate the prevalence of LTBI among healthy young children and adolescents and test a 2-step approach to explore the threshold for the diagnosis of tuberculosis infection in Chengdu, China. METHODS: Healthy preschool children and school-going children in Chengdu, Sichuan Province, were screened for LTBI using the tuberculin skin test (TST). Preschool children with TST ≥ 5 mm also underwent interferon-γ release assay (IGRA) to explore the threshold of this 2-step approach. RESULTS: In total, 5667 healthy young children and adolescents completed TST test between July 2020 and January 2021 and were included in the present analysis. The age of the participants ranged from 2.4 to 18 years (median 7.25 ± 4.514 years), of which 2093 (36.9%) were younger than 5 years. The overall prevalence of LTBI was 6.37% and 6.64% in children younger than 5 years old. Fourteen of the 341 preschool children with TST ≥5 mm were interferon-γ release assay positive, of which 4 showed a TST result of 5-10 mm, and 6 preschool children received preventive treatment for LTBI. CONCLUSIONS: Healthy young children and adolescents should also be considered as important target populations for LTBI screening. TST can be recommended for first-line screening as part of a 2-step approach for LTBI screening using a positive threshold of 5 mm.

4.
Pediatr Pulmonol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559474

RESUMO

OBJECTIVE: Few studies have explored the clinical features in children infected with SARS-CoV-2 and other common respiratory viruses, including respiratory syncytial virus (RSV), influenza virus (IV), and adenovirus (ADV). Herein, we reported the clinical characteristics and cytokine profiling in children with COVID-19 or other acute respiratory tract infections (ARTI). METHODS: We enrolled 20 hospitalized children confirmed as COVID-19 positive, 58 patients with ARTI, and 20 age and sex-matched healthy children. The clinical information and blood test results were collected. A total of 27 cytokines and chemokines were measured and analyzed. RESULTS: The median age in the COVID-19 positive group was 14.5 years, which was higher than that of the ARTI groups. Around one-third of patients in the COVID-19 group experienced moderate fever, with a peak temperature of 38.27 ℃. None of the patients displayed wheezing or dyspnea. In addition, patients in the COVID-19 group had lower white blood cells, platelet counts as well as a neutrophil-lymphocyte ratio. Lower serum concentrations of 14 out of 27 cytokines were observed in the COVID-19 group than in healthy individuals. Seven cytokines (IL-1Ra, IL-1ß, IL-9, IL-10, TNF-α, MIP-1α, and VEGF) changed serum concentration in COVID-19 compared with other ARTI groups. CONCLUSION: Patients with COVID-19 were older and showed milder symptoms and a favorable prognosis than ARTI caused by RSV, IV, and ADV. There was a low grade or constrained innate immune reaction in children with mild COVID-19. This article is protected by copyright. All rights reserved.

5.
J Pharmacol Exp Ther ; 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400527

RESUMO

Intestinal mucositis, resulting from 5-fluorouracil (5-FU)-based chemotherapy, subjects patients to great pain and hampers cancer treatment progress. Puerarin, the major active ingredient in Pueraria lobata, exerts anti-inflammatory and anti-oxidative effects. However, whether puerarin has an effect on 5-FU-induced intestinal mucositis remains unknown. We established a mice model of intestinal mucositis through the intraperitoneal injection of 5-FU, and then injected puerarin (50 and 100 mg/kg) intraperitoneally for 7 consecutive days. Routine parameters, such as body weight, food intake, and diarrheal incidence, were examined to evaluate the effects of puerarin on intestinal mucositis in mice. The intestinal barrier's functions were also evaluated by measuring the serum recovery of fluorescein isothiocyanate-4kD dextran in this study. The expression levels of inflammatory cytokines, inflammatory mediators, oxidative reactions, as well as apoptotic marker proteins, were determined to elucidate the underlying mechanisms of puerarin on intestinal mucositis. The model mice presented symptoms and histopathological changes typical of 5-FU-induced intestinal mucositis. In addition to vigorous inflammatory reactions, oxidative reactions and cell apoptosis, Janus kinase (JAK) was markedly activated. Puerarin decreased the expression levels of those of inflammatory mediators, oxidative reactions, and apoptosis-related proteins in 5-FU-induced mucositis by blocking the activation of JAK. Puerarin decreased inflammation, oxidative reactions and apoptosis, and protected intestinal barrier functions, to ameliorate 5-FU-induced intestinal mucositis by inhibiting the activation of JAK. This study provides novel insights into the pathological mechanisms of, and treatment alternatives for, 5-FU-induced intestinal mucositis. Significance Statement This study reveals the mechanism responsible for the protective effects of puerarin in 5-fluorouracil-induced intestinal mucositis. Puerarin inhibits the activation of JAK, thereby suppressing inflammation, oxidative reactions, cell apoptosis, and protected intestinal barrier functions, to ameliorate 5-FU-induced intestinal mucositis. Overall, our results suggest that puerarin can serve as a potential natural JAK inhibitor in the treatment of 5-FU-induced intestinal mucositis.

6.
Inflamm Res ; 70(7): 753-764, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34212215

RESUMO

Janus kinase/signal transduction and transcriptional activator (JAK/STAT) signaling pathway is a transport hub for cytokine secretion and exerts its effects. The activation of JAK/STAT signaling pathway is essential for the regulation of inflammatory responses. Inappropriate activation or deletion of JAK/STAT signaling pathway is the initiator of the inflammatory response. JAK/STAT signaling pathway has been demonstrated to be involved in the process of innate and adaptive immune response to inflammatory bowel disease (IBD). In this review, we discuss the role of the JAK/STAT signaling pathway in the regulation of different cells in IBD, as well as new findings on the involvement of the JAK/STAT signaling pathway in the regulation of the intestinal immune response. The current status of JAK inhibitors in the treatment of IBD is summarized as well. This review highlights natural remedies that can serve as potential JAK inhibitors. These phytochemicals may be useful in the identification of precursor compounds in the process of designing and developing novel JAK inhibitors.

7.
Small ; 17(31): e2006742, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34038611

RESUMO

Photodynamic therapy (PDT) has shown great potential for tumor treatment with merits of non-invasiveness, high selectivity, and minimal side effects. However, conventional type II PDT relying on 1 O2 presents poor therapeutic efficacy for hypoxic tumors due to the oxygen-dependent manner. Alternatively, emerging researches have demonstrated that type I PDT exhibits superiority over type II PDT in tumor treatment owing to its diminished oxygen-dependence. In this review, state-of-the-art studies concerning recent progress in type I photosensitizers are scrutinized, emphasizing the strategies to construct highly effective type I photosensitizers. As the foundation, basic principles of type I PDT are presented, and up-to-date type I photosensitizers are summarized and classified based on their attributes. Then, a literature review of representative type I photosensitizers (including nanomaterials and small molecules) is presented with impetus to delineate their novel designs, action mechanisms, as well as anticancer PDT applications. Finally, the remaining challenges and development directions of type I photosensitizers are outlined, highlighting key scientific issues toward clinical translations.

8.
Pharmacol Ther ; 226: 107859, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33895184

RESUMO

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification "soluble ligands" that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible than receptors, which are embedded in the cell membrane and have complex tertiary membrane structures. Lastly, certain potential target proteins that are present in membrane-bound forms can become soluble following cleavage, providing further opportunities for intervention in the treatment of IBD. In this review, 49 drugs targeting 25 distinct ligands have been evaluated, including consideration of the characteristics of the ligands and drugs in respect of IBD treatment. In addition to approved drugs targeting soluble ligands, we have also assessed drugs that are in preclinical research and drugs inhibiting ligand-receptor binding. Some new types of targetable soluble ligands/proteins, such as epoxide hydrolase and p-selectin glycoprotein ligand-1, are also introduced. Targeting soluble ligands not only opens a new field of anti-IBD drug development, but the circulating soluble ligands also provide diagnostic insights for early prediction of treatment response. In conclusion, soluble ligands serve as the third-largest protein target class in medicine, with much potential for the drugs targeting them.

9.
J Med Chem ; 64(8): 5137-5156, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33797901

RESUMO

The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/química , Fatores Imunológicos/química , Pirrolidinas/química , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Sítios de Ligação , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Cães , Meia-Vida , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Ratos Wistar , Rinite Alérgica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
10.
J Med Chem ; 64(7): 3911-3939, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33755451

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.


Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Nucleosídeos/uso terapêutico , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/metabolismo , Ligação Proteica , Proteína-Arginina N-Metiltransferases/metabolismo , Relação Estrutura-Atividade
11.
J Pharmacol Exp Ther ; 376(3): 464-472, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33397676

RESUMO

Recent studies suggest an important role for RNA, especially noncoding RNA, in inflammatory bowel disease (IBD) and colon cancer. Drug development based on regulating RNA rather than protein is a promising new area. Phytochemicals are naturally occurring plant-derived compounds with chemical diversity, biologic activity, easy availability, and low toxicity. Many phytochemicals have been shown to exert protective effects on IBD and colon cancer through modulation of RNAs. The aim of this study was to summarize the advancements of phytochemicals in regulating RNA for the treatment of IBD and colon cancer. This review involves many phytochemicals, including polyphenols, flavones, and alkaloids, which can influence various types of RNAs, including microRNA, long noncoding RNA, as well as messenger RNA, by influencing a variety of upstream molecules or regulating epigenetic processes. The limitation for many current studies is that the specific mechanisms of phytochemicals regulating RNA have not been fully uncovered. Accompanied by more identified functions of RNAs, especially noncoding RNA functions, the screening of RNA-regulating phytochemicals has presented challenges as well as opportunities for the prevention and treatment of IBD and colon cancer. SIGNIFICANCE STATEMENT: Noncoding RNAs, which constitute the majority of the human transcriptional genome, play a key role in the disease state and are considered as important therapeutic targets in inflammatory bowel disease (IBD) and colon cancer. Recent studies have shown that phytochemicals regulate the expression of many noncoding RNAs involved in IBD and colon cancer. Therefore, identifying the specific molecular mechanism of phytochemicals regulating noncoding RNA in disease models may result in novel and effective therapeutic opportunities.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Terapia de Alvo Molecular/métodos , Compostos Fitoquímicos/farmacologia , RNA/genética , Animais , Humanos , Compostos Fitoquímicos/uso terapêutico
12.
IEEE Trans Biomed Eng ; 68(2): 556-567, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32746053

RESUMO

Tactile information about an object can only be extracted from population responses of tactile receptors and their afferents. Thus, to best control tactile information in robots, neuroprostheses or haptic devices, inputs should represent responses from full populations of afferents. Here, we describe a simplified model that recreates afferent population responses of thousands of tactile afferents in a personal computer. The whole model includes a resistance network model to simplify the skin mechanics and an improved version of a single unit model that we have previously described. The whole model was implemented by short and efficient python code. The parameters of the model were fit based on a simple vibrating stimulus, but the simulated outputs generalize to match receptive field sizes, edge enhancement, and neurophysiological responses to dot textures, embossed letters and curved surfaces. We discuss how to use this work to model haptic perception and provide guidance in designing and controlling highly realistic tactile interfaces in robots, neural prostheses and haptic devices.


Assuntos
Pele , Tato
13.
IEEE Trans Pattern Anal Mach Intell ; 43(5): 1649-1665, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31751224

RESUMO

Person re-identification (re-ID) aims to robustly measure visual affinities between person images. It has wide applications in intelligent surveillance by associating same persons' images across multiple cameras. It is generally treated as an image retrieval problem: given a probe person image, the affinities between the probe image and gallery images (P2G affinities) are used to rank the retrieved gallery images. There exist two main challenges for effectively solving this problem. 1) Person images usually show significant variations because of different person poses and viewing angles. The spatial layouts and correspondences between person images are therefore vital information for tackling this problem. State-of-the-art methods either ignore such spatial variation or utilize extra pose information for handling the challenge. 2) Most existing person re-ID methods rank gallery images considering only P2G affinities but ignore the affinities between the gallery images (G2G affinity). Such affinities could provide important clues for accurate gallery image ranking but were only utilized in post-processing stages by current methods. In this article, we propose a unified end-to-end deep learning framework to tackle the two challenges. For handling viewpoint and pose variations between compared person images, we propose a novel Kronecker Product Matching operation to match and warp feature maps of different persons. Comparing warped feature maps results in more accurate P2G affinities. To fully utilize all available P2G and G2G affinities for accurately ranking gallery person images, a novel group-shuffling random walk operation is proposed. Both Kronecker Product Matching and Group-shuffling Random Walk operations are end-to-end trainable and are shown to improve the learned visual features if integrated in the deep learning framework. The proposed approach outperforms state-of-the-art methods on Market-1501, CUHK03 and DukeMTMC datasets, which demonstrates the effectiveness and generalization ability of our proposed approach. Code is available at https://github.com/YantaoShen/kpm_rw_person_reid.

14.
J Drug Target ; 29(5): 507-519, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33307848

RESUMO

The Wnt and Notch signalling pathways are important for maintenance of intestinal epithelial barrier integrity by intestinal stem cells (ISCs). Dysfunction of these pathways is implicated in inflammatory bowel disease (IBD) and colon cancer. The objective of this review is to summarise advancements of drugs that regulate Wnt and Notch in the treatment of IBD and colon cancer. The compositions and biological effects of Wnt and Notch modulators in both ISCs and non-ISCs are discussed. The drugs, including phytochemicals, plant extracts, probiotics and synthetic compounds, have been found to regulate Wnt and Notch signalling pathways by targeting regulatory factors (including secreted frizzled-related proteins or pathway proteins such as ß-catenin and γ-secretase) to alleviate IBD and colon cancer. This review highlights the potential for targeting Wnt and Notch pathways to treat IBD and colon cancer.

15.
Acta Pharmacol Sin ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268823

RESUMO

Endoplasmic reticulum (ER) homeostasis is regulated by ER-resident E3 ubiquitin ligase Hrd1, which has been implicated in inflammatory bowel disease (IBD). Ginsenoside Rb1 (GRb1) is the major ginsenoside in ginseng with multiple pharmacological activities. In this study we investigated the role of Hrd1 in IBD and its regulation by GRb1. Two mouse colitis models were established to mimic human IBD: drinking water containing dextran sodium sulfate (DSS) as well as intra-colonic infusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Colitis mice were treated with GRb1 (20, 40 mg·kg-1·d-1, ig) or a positive control drug sulfasalazine (500 mg·kg-1·d-1, ig) for 7 days. The model mice showed typical colitis symptoms and pathological changes in colon tissue. In addition to significant inflammatory responses and cell apoptosis in colon tissue, colon epithelial expression of Hrd1 was significantly decreased, the expression of ER stress markers GRP78, PERK, CHOP, and caspase 12 was increased, and the expression of Fas was increased (Fas was removed by Hrd1-induced ubiquitination). These changes were partially, or completely, reversed by GRb1 administration, whereas injection of Hrd1 inhibitor LS102 (50 mg·kg-1· d-1, ip, for 6 days) exacerbated colitis symptoms in colitis mice. GRb1 administration not only normalized Hrd1 expression at both the mRNA and protein levels, but also alleviated the ER stress response, Fas-related apoptosis, and other colitis symptoms. In intestinal cell line IEC-6, the expression of Hrd1 was significantly decreased by LPS treatment, but was normalized by GRb1 (200 µM). GRb1 alleviated LPS-induced ER stress and cell apoptosis in IEC-6 cells, and GRb1 action was inhibited by knockdown of Hrd1 using small interfering RNA. In summary, these results reveal a pathological role of Hrd1 in colitis, and provide a novel insight into alternative treatment of colitis using GRb1 activating Hrd1 signaling pathway.

16.
Oxid Med Cell Longev ; 2020: 4196548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381264

RESUMO

The aim of this study was to characterize and reveal the protective effects of cinnamaldehyde (CA) against mesenteric ischemia-reperfusion- (I/R-) induced lung and liver injuries and the related mechanisms. Sprague-Dawley (SPD) rats were pretreated for three days with 10 or 40 mg/kg/d, ig of CA, and then induced with mesenteric ischemia for 1 h and reperfusion for 2 h. The results indicated that pretreatment with 10 or 40 mg/kg of CA attenuated morphological damage in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly restored the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mesenteric I/R-injured liver tissues, indicating the improvement of hepatic function. CA also significantly attenuated the inflammation via reducing myeloperoxidase (MOP) activity and downregulating the expression of inflammation-related proteins, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (Cox-2), and tumor necrosis factor receptor type-2 (TNFR-2) in both lung and liver tissues of mesenteric I/R-injured rats. Pretreatment with CA significantly downregulated nuclear factor kappa B- (NF-κB-) related protein expressions (NF-κB p65, NF-κB p50, I kappa B alpha (IK-α), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß)) in both lung and liver tissues of mesenteric I/R-injured rats. CA also significantly downregulated the protein expression of p53 family members, including caspase-3, caspase-9, Bax, and p53, and restored Bcl-2 in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly reduced TUNEL-apoptotic cells and significantly inhibited p53 and NF-κB p65 nuclear translocation in both lung and liver tissues of mesenteric I/R-injured rats. CA neither induced pulmonary and hepatic histological alterations nor affected the parameters of inflammation and apoptosis in sham rats. We conclude that CA alleviated mesenteric I/R-induced pulmonary and hepatic injuries via attenuating apoptosis and inflammation through inhibition of NF-κB and p53 pathways in rats, suggesting the potential role of CA in remote organ ischemic injury protection.


Assuntos
Acroleína/análogos & derivados , Isquemia Mesentérica/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Acroleína/farmacologia , Acroleína/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Hepatopatias/prevenção & controle , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Masculino , Isquemia Mesentérica/complicações , Isquemia Mesentérica/patologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
17.
J Breath Res ; 15(1): 016001, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084605

RESUMO

Characterization of nonvolatile molecules in exhaled breath particles can be used for respiratory disease monitoring and diagnosis. Conventional methods for the collection of nonvolatile molecules in breath heavily rely on the physical properties of exhaled breath particles. Strategies taking advantage of their chemical properties have not yet been explored. In the present study, we developed a column system in which the surface chemistry between organic nonvolatile molecules and octadecyl carbon chain was exploited for the comprehensive collection of metabolites, lipids, and proteins. We demonstrated that the collection system had the capture efficiency of 99% and the capacity to capture representative nonvolatile molecules. The collection system was further evaluated using human subjects and proteins collected from human exhaled breath were characterized and identified using gel electrophoresis and bottom-up proteomics. The identified 303 proteins from mass spectrometry were further searched against reported bronchoalveolar lavage fluid proteomes and it was shown that 60 proteins have the tissue origin of lower respiratory airways. In summary, we demonstrate that our collection system can collect nonvolatile molecules from human exhaled breath in an efficient and comprehensive manner and has the potential to be used for the study of respiratory diseases.


Assuntos
Testes Respiratórios/métodos , Expiração , Manejo de Espécimes/métodos , Adulto , Líquido da Lavagem Broncoalveolar , Cromatografia Líquida , Humanos , Espectrometria de Massas , Proteínas/análise
18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(4): 431-435, 2020 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895093

RESUMO

Objective To investigate the differences in energy spectrum CT findings between anterior mediastinal lymphoma and thymic carcinoma. Methods Twenty-two cases of anterior mediastinal lymphoma and 28 cases of thymic carcinoma confirmed by biopsy in Tangshan People's Hospital were selected.The CT values and changes of iodine content and water content in lesion sites were measured by energy spectrum analysis software.The differences between anterior mediastinal lymphoma and thymic carcinoma were compared. Results The single-energy CT value of 40-80 keV in thymus carcinoma was higher than that in anterior mediastinal lymphoma(P=0.001,P=0.037,P=0.042,P=0.034,P=0.002;P=0.016,P=0.013,P=0.018,P=0.024,P=0.012).The difference in the single-energy CT value of 90-110 keV between anterior mediastinal lymphoma and thymic carcinoma showed no statistical significance(all P>0.05).The concentrations of water in the arterial and venous stages of thymic carcinoma were significantly lower than those in the anterior mediastinal lymphoma(P=0.030,P=0.037),whereas the iodine concentrations were significantly higher(P=0.026,P=0.000). Conclusion Anterior mediastinal lymphoma and thymic carcinoma have remarkably different 40-80 keV single energy CT value and iodine concentration in arterial and venous phases,which may be helpful for the differential diagnosis of these two malignancies.


Assuntos
Linfoma , Neoplasias do Mediastino , Timoma , Neoplasias do Timo , Humanos , Linfoma/diagnóstico por imagem , Neoplasias do Mediastino/diagnóstico por imagem , Timoma/diagnóstico por imagem , Neoplasias do Timo/diagnóstico por imagem , Tomografia Computadorizada por Raios X
19.
Arch Physiol Biochem ; : 1-8, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32970504

RESUMO

Nowadays the most effective way to cure myocardial infarction (MI) is reperfusion, which inevitably leads to cardiomyocyte apoptosis. In this study, we discussed the functions of SNHG15 in regulating cardiomyocyte apoptosis through the modulation of miR-188-5p/PTEN axis. We examined the links between SNHG15 and miR-188-5p/PTEN in mice with MI. Extensive experiments, measurements and comparisons were performed, including RT-PCR, western blotting, luciferase reporter assay, flow cytometry analysis etc. Through a series of comparisons and analysis, we discovered that SNHG15 could interact with the miR-188-5p/PTEN axis and impact the cellular physiology of cardiomyocyte apoptosis. PTEN was upregulated in hypoxia cells, but this effect was attenuated by miR-188-5p. MiR-188-5p could combine with SNHG15 and PTEN, and form a SNHG15-miR-188-5p-PTEN axis, which regulated the apoptosis of MCs. These results suggest that LncRNA SNHG15 regulates cardiomyocyte apoptosis induced by hypoxia or reperfusion injury through modulating of miR-188-5p/PTEN axis.

20.
ACS Sens ; 5(11): 3420-3431, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32929960

RESUMO

In this work, a surface-enhanced Raman scattering (SERS)-active droplet with three-dimensional (3D) hot spots prepared from a superhydrophobic SERS substrate, which is inspired by the nut wizard strategy, was developed for ultrasensitive detection in complex liquid environments. The SERS substrate was composed of silver-capped parylene C-coated carbon nanoparticles (Ag-PC@CNPs). Such a SERS substrate was prepared by candle-soot deposition to provide a porous carbon nanoparticle layer followed by deposition of a parylene C film to protect the CNPs and then sputtering of silver nanoparticles. Similar to a nut wizard, a droplet rolling on the Ag-PC@CNP-coated substrate picked up the Ag-PC@CNPs. In this way, a self-concentrated and extremely sensitive SERS-active droplet sensor with 3D hot spots was formed. The sensor did not require precise laser focusing and showed relatively high repeatability and much higher sensitivity than those of a corresponding SERS substrate with two-dimensional hot spots. The sensor also achieved high sensitivity and specificity in complex liquid environments; in addition, bovine serum albumin with a concentration as low as 1 pM can be achieved. Consequently, an extremely simple, flexible, and highly sensitive SERS detection technique applicable to liquid biopsy analysis is anticipated.


Assuntos
Nanopartículas Metálicas , Análise Espectral Raman , Carbono , Luz , Prata
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