Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 128
Filtrar
1.
Biol Pharm Bull ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34719576

RESUMO

With the development of structural biology and data mining, computer-aided drug design (CADD) has been playing an important role in all aspects of new drug development. Reverse docking, a method of virtual screening based on molecular docking in CADD, is widely used in drug repositioning, drug rescue, and traditional Chinese medicine (TCM) research, for it can search for macromolecular targets that can bind to a given ligand molecule. This review revealed the principle of reverse docking, summarized common target protein databases and docking procedures, and enumerated the applications of reverse docking in drug repositioning, adverse drug reactions, traditional Chinese medicine, and COVID-19 treatment. Hope our work can give some inspiration to researchers engaged in drug development.

2.
Mol Metab ; : 101401, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34823066

RESUMO

OBJECTIVE: The paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ connectivity and its role in other physiological regulations are not fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and further test their physiological functions beyond feeding. METHODS: Using a combination of viral tools, we mapped PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. RESULTS: We found that PVNMC4R+ neurons innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue temperature. These physiological changes accompanied an acute transient hyperactivity followed by hypoactivity and resting-like behavior. CONCLUSIONS: Our results clarify the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermoregulation, cardiovascular function and biphasic behavioral activation.

3.
ACS Nano ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34842409

RESUMO

Bottom-up graphene nanoribbons (GNRs) have recently been shown to host nontrivial topological phases. Here, we report the fabrication and characterization of deterministic GNR quantum dots whose orbital character is defined by zero-mode states arising from nontrivial topological interfaces. Topological control was achieved through the synthesis and on-surface assembly of three distinct molecular precursors designed to exhibit structurally derived topological electronic states. Using a combination of low-temperature scanning tunneling microscopy and spectroscopy, we have characterized two GNR topological quantum dot arrangements synthesized under ultrahigh vacuum conditions. Our results are supported by density-functional theory and tight-binding calculations, revealing that the magnitude and sign of orbital hopping between topological zero-mode states can be tuned based on the bonding geometry of the interconnecting region. These results demonstrate the utility of topological zero modes as components for designer quantum dots and advanced electronic devices.

4.
Gastrointest Endosc ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34736933

RESUMO

BACKGROUND AND AIMS: With the increasing incidence of small gastrointestinal stromal tumors (GISTs), endoscopic full-thickness resection (EFR) and cap-assisted EFR (EFR-C) have been suggested as 2 effective resection methods. We aimed to compare the outcomes of EFR and EFR-C for the treatment of small (≤ 1.5 cm) gastric GISTs. METHODS: This retrospective study included 67 patients who underwent EFR and 46 patients who underwent EFR-C at Nanjing Drum Tower Hospital. Clinicopathological features, adverse events and outcomes were compared between the 2 groups. Univariate and multivariate linear and logistic regressions were used to analyze the effects of the procedure on the therapeutic outcomes of patients and adjusted for covariates in multivariate analysis. RESULTS: The tumor size in the EFR group tended to be larger (P = 0.005). The resection time in the EFR-C group was shorter than that in the EFR group (38.3 ± 20.7 min vs 15.0 ± 11.8 min, P < 0.001), which retained statistical significance with adjustment for the covariates (adjusted mean difference: 22.2; 95% CI, 15.0-29.4, P < 0.001). The R0 resection rate of the EFR group was 94.0%, and for the EFR-C group, it was 97.8% (P = 0.355). The EFR-C group was superior to the EFR group in terms of perioperative therapeutic outcomes, adverse events and postoperative recovery. No recurrence occurred in the EFR and EFR-C groups. CONCLUSION: EFR-C was found to be the preferable technique for small (≤1.5 cm) gastric GISTs with shorter operation times, lower adverse events, faster postoperative recovery, and shorter hospitalization times as compared with those with EFR.

5.
Future Oncol ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34787500

RESUMO

Background: The efficacy of PD-1 or PD-L1 inhibitors in patients with brain metastases of non-small-cell lung cancer (BM-NSCLC) is inconclusive. Materials & methods: An electronic search was performed. Randomized controlled trials RCTs that compared the efficacy of PD-1- or PD-L1-inhibitor-based regimens with non-PD-1/L1 inhibitor regimens in patients with NSCLC and reported the data of subgroup patients with brain metastases were eligible for inclusion. The hazard ratios (HRs) for progression-free survival and overall survival were pooled in BM-NSCLC. Results: Seven RCTs with 472 BM-NSCLC cases are included. The pooled HRs indicated that PD-1 or PD-L1 inhibitor-based regimens reduced risk of disease progression by 44% and reduced risk of death of BM-NSCLC patients by 29% compared with non-PD-1/L1 inhibitor regimens. Conclusion: This meta-analysis indicates that PD-1 or PD-L1 inhibitors can reduce risk of both disease progression and death of patients with brain metastases of NSCLC, who have been pretreated with local therapies and/or are asymptomatic for the brain lesions.

6.
Hepatology ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510514

RESUMO

BACKGROUND AND AIMS: Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. APPROACH AND RESULTS: In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate ß-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. CONCLUSIONS: Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.

7.
Hepatology ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435375

RESUMO

BACKGROUND & AIMS: Although the prevalence of nonalcoholic fatty liver disease (NAFLD) has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease due to uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown. APPROACH & RESULTS: Based on expression analysis, we identified a marked downregulation of MAVS in hepatocytes during NAFLD progression. By employing MAVS global knockout and hepatocyte-specific MAVS knockout mice, we found that MAVS is protective against diet-induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N-terminal stretch of voltage-dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis. CONCLUSIONS: In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide new insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent a new avenue for treating NAFLD.

8.
BMC Immunol ; 22(1): 55, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380434

RESUMO

BACKGROUND: Cancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial. RESULTS: In this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro. CONCLUSIONS: Affinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist, providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy.

9.
Clin Transl Gastroenterol ; 12(8): e00393, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346911

RESUMO

INTRODUCTION: This study aims to construct a real-time deep convolutional neural networks (DCNNs) system to diagnose early esophageal squamous cell carcinoma (ESCC) with white light imaging endoscopy. METHODS: A total of 4,002 images from 1,078 patients were used to train and cross-validate the DCNN model for diagnosing early ESCC. The performance of the model was further tested with independent internal and external validation data sets containing 1,033 images from 243 patients. The performance of the model was then compared with endoscopists. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and Cohen kappa coefficient were measured to assess performance. RESULTS: The DCNN model had excellent performance in diagnosing early ESCC with a sensitivity of 0.979, a specificity of 0.886, a positive predictive value of 0.777, a negative predictive value of 0.991, and an area under curve of 0.954 in the internal validation data set. The model also depicted a tremendously generalized performance in 2 external data sets and exhibited superior performance compared with endoscopists. The performance of the endoscopists was markedly elevated after referring to the predictions of the DCNN model. An open-accessed website of the DCNN system was established to facilitate associated research. DISCUSSION: A real-time DCNN system, which was constructed to diagnose early ESCC, showed good performance in validation data sets. However, more prospective validation is needed to understand its true clinical significance in the real world.

10.
Mol Metab ; 53: 101308, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34303879

RESUMO

OBJECTIVES: Endothelial cells that line the entire vascular system play a pivotal role in the control of various physiological processes, including metabolism. Additionally, endothelial dysfunction is associated with many pathological conditions, including obesity. Here, we assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins in endothelial cells. METHODS: We studied the effects of BBSome disruption in endothelial cells on vascular function, body weight, glucose homeostasis, and the liver and retina. For this, we generated mice with selective BBSome disruption in endothelial cells through Bbs1 gene deletion. RESULTS: We found that endothelial cell-specific BBSome disruption causes endothelial dysfunction, as indicated by the impaired acetylcholine-induced vasorelaxation in both the aorta and mesenteric artery. This was associated with an increase in the contractile response to thromboxane A2 receptor agonist (U46619) in the mesenteric artery. Mechanistically, we demonstrated that mice lacking the Bbs1 gene in endothelial cells show elevated vascular angiotensinogen gene expression, implicating renin-angiotensin system activation in the vascular changes evoked by endothelial BBSome deficiency. Strikingly, our data indicate that endothelial BBSome deficiency increases body weight and fat mass and causes hepatosteatosis along with alterations in hepatic expression of lipid metabolism-related genes and metabolomics profile. In addition, electroretinogram and optical coherence tomography analyses revealed functional and structural abnormalities in the retina, evoked by absence of the endothelial BBSome. CONCLUSIONS: Our findings demonstrate that the BBSome in endothelial cells is required for the regulation of vascular function, adiposity, hepatic lipid metabolism, and retinal function.

11.
Biochem Pharmacol ; 190: 114641, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34077738

RESUMO

Hepatocellular carcinoma (HCC), a hypervascular solid tumor, is the most leading cause of cancer mortality worldwide. Microtubule binding agents targeting tumor vasculature have been investigated and employed clinically. C118P is a newly synthesized analog of CA4 with improved water solubility and extended half-life. The current studies investigated the pharmacological effects of C118P and its active metabolite C118. Here, we first confirmed by in vitro assays that C118 exerts microtubule depolymerization activity and by molecular docking revealed that it fits to the colchicine binding site of tubulin. In addition, we found that C118P and C118 altered microtubule dynamics and cytoskeleton in human umbilical vein endothelial cells. Accordingly, we observed that C118P and C118 inhibited angiogenesis and disrupted established vascular networks using tube formation assays and chick chorioallantoic membrane angiogenesis assays. In addition, our data showed that C118P and C118 exhibited board anti-proliferative effect on various cancer cells, including HCC cell lines, in MTT assays or Sulforhodamine B assays. Moreover, we found that C118P induced G2/M phase cell cycle arrest and apoptosis in HCC cell lines BEL7402 and SMMC7721 using flow cytometry analysis and immunoblotting assays. Finally, we confirmed that C118P suppressed HCC growth via targeting tumor vasculature and inducing apoptosis in the SMMC7721 xenograft mouse model. In conclusion, our studies revealed that C118P, as a potent microtubule destabilizing agent, exerts its multiple pharmacological effects against HCC by inducing cell cycle arrest and apoptosis, as well as targeting tumor vasculature. Thus, C118P might be a promising drug candidate for liver cancer treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos , Apoptose , Vasos Sanguíneos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Conformação Proteica , Tubulina (Proteína)/química , Moduladores de Tubulina/química
12.
Artigo em Inglês | MEDLINE | ID: mdl-33971398

RESUMO

The sea cucumber Apostichopus japonicus is an economically important marine organism, and its aquaculture has rapidly developed in China. The very large market demand puts forward higher requirements for the economically efficient breeding of sea cucumbers. Sex and the associated reproductive processes have been reported to affect the physiological characteristics of sea cucumbers. However, little is known about the metabolism differences that related to sex and the associated reproductive processes and their potential effects on the efficiency of A. japonicus aquaculture. In this study, ultra-performance liquid chromatography was applied to investigate the variations in metabolic profiles in cell-free coelomic fluids (CCFs) of sea cucumbers of different sexes and reproductive states. A total of 4435 metabolites were detected, and the metabolic profiles of A. japonicus were significantly affected by both sexes and reproductive process. The differentially abundant metabolites in CCFs of A. japonicus of different sexes and reproductive states were also screened and analyzed. The findings revealed that unsaturated fatty acid synthesis and phenylalanine metabolism were the most significantly changed pathways. Moreover, the weakest ability to synthesize capsaicin using phenylalanine was found in A. japonicus after spawning. Our study provides new insights into the metabolic response of A. japonicus during the reproductive process, and also provides valuable references for the economically efficient breeding of A. japonicus.


Assuntos
Cromatografia Líquida/métodos , Metaboloma , Reprodução , Pepinos-do-Mar/metabolismo , Animais , Fatores Sexuais
13.
Front Immunol ; 12: 625808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841409

RESUMO

B7 family members and their receptors play key roles in regulating T cell responses, and constitute very attractive targets for developing immunotherapeutic drugs. V-Set and Immunoglobulin domain containing 3 (VSIG3), a ligand for the novel B7 family immune checkpoint V-domain immunoglobulin suppressor of T cell activation (VISTA), can significantly inhibit T cell functions. Inhibitors targeting the VISTA/VSIG3 pathway are of great significance in tumor immunology. Here, we show the crystal structure of the extracellular domain (ECD) of the human VSIG3 protein at 2.64 angstrom resolution, and we produce recombinant human VSIG-3 ECD in both CHO cells and E. coli. Furthermore, we demonstrated the interaction of VISTA and VSIG3 by coimmunoprecipitation (Co-IP). Based on protein-protein docking for VISTA and VSIG3, we report a small molecule inhibitor of VSIG3 K284-3046 and evaluate its biological activities in vitro. This study was the first to reveal the crystal structure of VSIG3, and provides the structural basis for designing antibodies or compounds for the unique VSIG3/VISTA coinhibitory pathway in the treatment of cancers, autoimmune diseases and may be beneficial of designing vaccines.


Assuntos
Antígenos B7/metabolismo , Moléculas de Adesão Celular/metabolismo , Imunoglobulinas/metabolismo , Animais , Antígenos B7/química , Antígenos B7/genética , Células CHO , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Proliferação de Células/efeitos dos fármacos , Cricetulus , Cristalografia por Raios X , Citocinas/metabolismo , Desenho de Fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Imunoglobulinas/química , Imunoglobulinas/genética , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ligantes , Ativação Linfocitária/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade
14.
Br J Pharmacol ; 178(6): 1445-1458, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33450048

RESUMO

BACKGROUND AND PURPOSE: The protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune-checkpoint molecule that belongs to the B7 family and regulates a broad spectrum of immune responses. So far, low MW compounds targeting VISTA for the treatment of autoimmune diseases or inflammation, have not been identified. EXPERIMENTAL APPROACH: We developed a homology modelling for VISTA 3D structure and subsequent virtual screening for low MW ligands binding to VISTA. Visualization of the binding postures of docked ligands with protein VISTA indicated that compound M351-0056 targeted VISTA. The biological activities of compound M351-0056 targeting VISTA were investigated in vitro using monocytes and T cells and in vivo, using mice with imiquimod-induced dermatitis. KEY RESULTS: The KD value of M351-0056 for human VISTA-extracellular domain was 12.60 ± 3.84 µM as assessed by microscale thermophoresis. M351-0056 decreased cytokine secretion from PBMCs or human CD4+ T cells, suppressed proliferation of PBMCs and enhanced expression of Foxp3+ T cells. These effects of M351-0056 modulating VISTA involved the JAK2-STAT2 pathway. Daily administration of M351-0056 ameliorated imiquimod-induced psoriasis-like dermatitis. Expression of mRNA and protein of inflammatory cytokines in psoriatic lesions was decreased after M351-0056 treatment. CONCLUSION AND IMPLICATIONS: The compound M351-0056 showed high affinity for VISTA and may modulate its immune function in vitro and in vivo. Our finding provides a lead compound for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune diseases or inflammation.


Assuntos
Dermatite/genética , Proteínas de Checkpoint Imunológico , Ativação Linfocitária , Proteínas de Membrana/antagonistas & inibidores , Animais , Citocinas , Imiquimode , Inflamação , Ligantes , Camundongos
15.
J Cachexia Sarcopenia Muscle ; 12(1): 192-208, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33236534

RESUMO

BACKGROUND: Transforming growth factor-ß-activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation could be exploited to aid the treatment of this disease. METHODS: Muscle biopsies were obtained from control donors or DMD patients for diagnosis (n = 6 per group, male, 2-3 years, respectively). Protein expression of phosphorylated TAK1 was measured by western blot and immunofluorescence analysis. In vivo overexpression of TAK1 was performed in skeletal muscle to assess whether TAK1 is sufficient to induce or aggravate atrophy and fibrosis. To explore whether TAK1 inhibition protects against muscle damage, mdx (loss of dystrophin) mice were treated with adeno-associated virus (AAV)-short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. RESULTS: We found that TAK1 was activated in the dystrophic muscles of DMD patients (n = 6, +72.2%, P < 0.001), resulting in fibrosis ( +65.9% for fibronectin expression, P < 0.001) and loss of muscle fibres (-32.5%, P < 0.01). Moreover, TAK1 was activated by interleukin-1ß, tumour necrosis factor-α, and transforming growth factor-ß1 (P < 0.01). Overexpression of TAK1 by AAV vectors further aggravated fibrosis (n = 8, +39.6% for hydroxyproline content, P < 0.01) and exacerbated muscle wasting (-31.6%, P < 0.01) in mdx mice; however, these effects were reversed in mdx mice by treatment with AAV-short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). The molecular mechanism underlying these effects may be related to the prevention of TAK1-mediated transdifferentiation of myoblasts into fibroblasts, thereby reducing fibrosis and increasing myoblast differentiation. CONCLUSIONS: Our findings show that TAK1 activation exacerbated fibrosis and muscle degeneration and that TAK1 inhibition can improve whole-body muscle quality and the function of dystrophic skeletal muscle. Thus, TAK1 inhibition may constitute a novel therapy for DMD.

16.
Nano Lett ; 21(1): 197-202, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33320677

RESUMO

We apply the topological classification theory using chiral symmetry to graphene nanoribbons (GNRs). This approach eliminates the requirement of time-reversal and spatial symmetry in previous Z2 topology theory, resulting in a Z classification with the conventional Z index in a new vector-formed expression called "chiral phase index" (CPI). Our approach is applicable to GNRs of arbitrary terminations and any quasi one-dimensional chiral structures, including magnetism. It naturally solves a recent experimental puzzle of junction states at a class of asymmetric GNR junctions. We moreover derive a simple analytic formula for the CPI of armchair GNRs. Since this approach enables access to electron spin behavior, based on the CPI, we design a novel GNR with periodic localized moments and strong spin-spin exchange coupling.

17.
Stroke Vasc Neurol ; 5(4): 381-387, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33376199

RESUMO

The discovery of targeted drugs heavily relies on three-dimensional (3D) structures of target proteins. When the 3D structure of a protein target is unknown, it is very difficult to design its corresponding targeted drugs. Although the 3D structures of some proteins (the so-called undruggable targets) are known, their targeted drugs are still absent. As increasing crystal/cryogenic electron microscopy structures are deposited in Protein Data Bank, it is much more possible to discover the targeted drugs. Moreover, it is also highly probable to turn previous undruggable targets into druggable ones when we identify their hidden allosteric sites. In this review, we focus on the currently available advanced methods for the discovery of novel compounds targeting proteins without 3D structure and how to turn undruggable targets into druggable ones.


Assuntos
Inteligência Artificial , Big Data , Desenho Assistido por Computador , Mineração de Dados , Desenho de Fármacos , Descoberta de Drogas , Preparações Farmacêuticas/química , Proteínas/química , Animais , Bases de Dados de Proteínas , Humanos , Ligantes , Estrutura Molecular , Terapia de Alvo Molecular , Conformação Proteica , Relação Estrutura-Atividade
18.
Front Immunol ; 11: 563044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250890

RESUMO

Background: Immunotherapies targeting CTLA-4 and PD-1 have elicited promising responses in a variety of cancers. However, the relatively low response rates warrant the identification of additional immunosuppressive pathways. V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and is a valuable target in cancer immunotherapy. Methods: Here, we used single-cell RNA-seq to analyze the gene expression levels of 14897 cells from a breast cancer sample and its paired 7,320 normal cells. Then, we validated the protein expression of immune checkpoint molecules (VISTA, PD-1, PD-L1, TIGIT, TIM3, and LAG3) in 324 human breast cancer samples by immunohistochemistry and quantitative immunofluorescence (QIF) approaches. Results: Single cell RNA-seq results show a higher level of immune checkpoint VISTA expression in breast cancer tissue compared to adjacent normal tissue. We also found that VISTA expressed highest in breast cancer tissue than other immune-checkpoints. Immunohistochemical results showed that VISTA was detected with a membranous/cytoplasmic staining pattern in intratumoral immune cells and breast cancer cells. Additionally, VISTA was positively correlated with pathological grade, lymph node status and the levels of PD-1 according to the chi-square test or Fisher's test. Furthermore, VISTA expression was higher in CD68+ tumor-associated macrophages (TAMs) than in CD4+ T cells, CD8+ cytotoxic T cells or CD20+ B cells. Conclusions: These findings therefore support the immunoregulatory role of VISTA in breast cancer and indicate that targeting VISTA may benefit breast cancer immunotherapy.


Assuntos
Antígenos B7/genética , Antígenos B7/metabolismo , Neoplasias da Mama/imunologia , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , RNA-Seq , Análise de Célula Única , Evasão Tumoral , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia
19.
Therap Adv Gastroenterol ; 13: 1756284820966929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193812

RESUMO

Aims: Early gastric cardiac cancer (EGCC) has a low risk of lymph node metastasis with the potential for endoscopic therapy. We aimed to evaluate the short- and long-term outcomes of endoscopic submucosal dissection (ESD)-resected EGCCs in a large cohort of Chinese patients and compare endoscopic and clinicopathologic features between EGCC and early gastric non-cardiac cancer (EGNC). Methods: We retrospectively studied 512 EGCCs in 499 consecutive patients and 621 EGNCs in 555 consecutive patients between January 2011 and March 2018 at our center. We investigated clinicopathological characteristics of EGCC tumors, ESD treatment results, adverse events, and postresection patient survival. Results: Compared with EGNC patients, EGCC patients were significantly older (average age: 66 years versus 62 years, p < 0.001). The percentage of the gross 0-IIc pattern was higher in EGCCs (46.1%) than in EGNCs (41.5%), while the frequency of the 0-IIa pattern was lower in EGCCs (14.9%) than in EGNCs (22.4%) (p = 0.001). Compared with EGNCs, EGCCs showed smaller size, deeper invasion, fewer ulcerated or poorly differentiated tumors, but more cases with gastritis cystica profunda. The prevalence of ESD-related complications was higher in EGCCs (6.1%) than in EGNCs (2.3%) (p = 0.001). In EGCCs, the disease-specific survival rate was significantly higher in patients of the noncurative resection group with surgery (100%), compared with that (93.9%) without surgery (p < 0.001). Conclusion: Clinicopathological characteristics were significantly different between EGCCs and EGNCs. ESD is a safe and effective treatment option with favorable outcomes for patients with EGCC. Additional surgery improved survival in patients with noncurative ESD resection.

20.
Am J Physiol Heart Circ Physiol ; 319(5): H1069-H1077, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946297

RESUMO

The arcuate nucleus of the hypothalamus (ARC) plays a key role in linking peripheral metabolic status to the brain melanocortin system, which influences a wide range of physiological processes including the sympathetic nervous system and blood pressure. The importance of the activity of agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons, two molecularly distinct populations of ARC neurons, for metabolic regulation is well established, but their relevance for sympathetic and cardiovascular control remains unclear. We used designer receptors exclusively activated by designer drug (DREADD) technology to study how activation of AgRP and POMC neurons affect renal sympathetic nerve traffic and blood pressure. In addition to the drastic feeding-stimulatory effect, DREADD-mediated activation of AgRP, but not POMC neurons, induced an acute reduction in renal sympathetic nerve activity in conscious mice. Paradoxically, however, DREADD-mediated chronic activation of AgRP neurons caused a significant increase in blood pressure specifically in the inactive light phase. On the other hand, chronic activation of POMC neurons led to a significant reduction in blood pressure. These results bring new insights to a previously unappreciated role of ARC AgRP and POMC neuronal activity in autonomic and cardiovascular regulation.NEW & NOTEWORTHY Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons of the arcuate nucleus are essential components of the brain melanocortin system that controls various physiological processes. Here, we tested the metabolic and cardiovascular effects of direct activation of these two populations of neurons. Our findings show that, in addition to stimulation of food intake, chemogenetic mediated activation of hypothalamic arcuate nucleus AgRP, but not POMC, neurons reduce renal sympathetic traffic. Despite this, chronic activation of AgRP neurons increased blood pressure. However, chronic activation of POMC neurons led to a significant reduction in blood pressure. Our findings highlight the importance of arcuate nucleus AgRP and POMC neuronal activity in autonomic and cardiovascular regulation.


Assuntos
Coração/fisiologia , Hipotálamo/fisiologia , Neurônios/fisiologia , Sistema Nervoso Simpático/fisiologia , Potenciais de Ação , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Pressão Sanguínea , Hipotálamo/citologia , Camundongos , Neurônios/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...