RESUMO
Chitosan (CS)-based photo-cross-linkable hydrogels have gained increasing attention in biomedical applications. In this study, we grafted CS with gallic acid (GA) by carbodiimide chemistry to prepare the GA-CS conjugate, which was subsequently modified with methacrylic anhydride (MA) modification to obtain the methacrylated GA-CS conjugate (GA-CS-MA). Our results demonstrated that the GA-CS-MA hydrogel not only exhibited improved physicochemical properties but also showed antibacterial, antioxidative, and anti-inflammatory capacity. It showed moderate antibacterial activity and especially showed a more powerful inhibitory effect against Gram-positive bacteria. It modulated macrophage polarization, downregulated pro-inflammatory gene expression, upregulated anti-inflammatory gene expression, and significantly reduced reactive oxygen species (ROS) and nitric oxide (NO) production under lipopolysaccharide (LPS) stimulation. Subcutaneously implanted GA-CS-MA hydrogels induced significantly lower inflammatory responses, as evidenced by less inflammatory cell infiltration, thinner fibrous capsule, and predominately promoted M2 polarization. This study provides a feasible strategy to prepare CS-based photo-cross-linkable hydrogels with improved physicochemical properties for biomedical applications.
Assuntos
Antibacterianos , Anti-Inflamatórios , Antioxidantes , Quitosana , Ácido Gálico , Hidrogéis , Metacrilatos , Quitosana/química , Ácido Gálico/química , Ácido Gálico/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Animais , Hidrogéis/química , Hidrogéis/farmacologia , Hidrogéis/síntese química , Camundongos , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Metacrilatos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Células RAW 264.7 , Reagentes de Ligações Cruzadas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Óxido Nítrico/metabolismoRESUMO
BACKGROUND: In the inflammatory milieu of diabetic chronic wounds, macrophages undergo substantial metabolic reprogramming and play a pivotal role in orchestrating immune responses. Itaconic acid, primarily synthesized by inflammatory macrophages as a byproduct in the tricarboxylic acid cycle, has recently gained increasing attention as an immunomodulator. This study aims to assess the immunomodulatory capacity of an itaconic acid derivative, 4-Octyl itaconate (OI), which was covalently conjugated to electrospun nanofibers and investigated through in vitro studies and a full-thickness wound model of diabetic mice. RESULTS: OI was feasibly conjugated onto chitosan (CS), which was then grafted to electrospun polycaprolactone/gelatin (PG) nanofibers to obtain P/G-CS-OI membranes. The P/G-CS-OI membrane exhibited good mechanical strength, compliance, and biocompatibility. In addition, the sustained OI release endowed the nanofiber membrane with great antioxidative and anti-inflammatory activities as revealed in in vitro and in vivo studies. Specifically, the P/G-CS-OI membrane activated nuclear factor-erythroid-2-related factor 2 (NRF2) by alkylating Kelch-like ECH-associated protein 1 (KEAP1). This antioxidative response modulates macrophage polarization, leading to mitigated inflammatory responses, enhanced angiogenesis, and recovered re-epithelization, finally contributing to improved healing of mouse diabetic wounds. CONCLUSIONS: The P/G-CS-OI nanofiber membrane shows good capacity in macrophage modulation and might be promising for diabetic chronic wound treatment.
Assuntos
Quitosana , Diabetes Mellitus Experimental , Nanofibras , Succinatos , Camundongos , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Macrófagos/metabolismo , Antioxidantes/farmacologia , Cicatrização , Quitosana/metabolismoRESUMO
Lung cancer is a rapidly progressing disease with a poor prognosis. Bone metastasis is commonly found in 40.6% of advanced-stage patients. The mortality rate of lung cancer patients with bone metastasis can be significantly decreased by implementing novel diagnostic techniques, improved staging and classification systems, precise surgical interventions, and advanced treatment modalities. However, it is important to note that there is currently a lack of radical procedures available for these patients due to the development of drug resistance. Consequently, palliative care approaches are commonly employed in clinical practice. Therefore, new understandings of the process of bone metastasis of lung cancer are critical for developing better treatment strategies to improve patient's clinical cure rate and quality of life. Chemokines are cell-secreted small signaling proteins in cancer occurrence, proliferation, invasion, and metastasis. In this study, we review the development of bone metastasis in lung cancer and discuss the mechanisms of specific chemokine families (CC, CXC, CX3C, and XC) in regulating the biological activities of tumors and promoting bone metastasis. We also highlight some preclinical studies and clinical trials on chemokines for lung cancer and bone metastasis.
Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Qualidade de Vida , Quimiocinas/metabolismo , Neoplasias Ósseas/tratamento farmacológicoRESUMO
ABSTRACT: Transthyretincardiac amyloidosis is a rare disease that has gained significant attention in recent years because of misfolding of transthyretin fibrils produced by the liver, leading to their deposition in the myocardium. The disease has an insidious onset, nonspecific clinical manifestations, and historically lacked effective drugs, making early diagnosis and treatment challenging. The survival time of patients largely depends on the extent of heart involvement at the time of diagnosis, and conventional treatments for cardiovascular disease do not provide significant benefits. Effective management of the disease requires treatment of its underlying cause. Orthotopic liver transplantation and combined hepato-heart transplantation have been clinically effective means of treating transthyretin cardiac amyloidosis mutants for many years. However, transplantation has many limitations in clinical practice. In recent years, the development of new drugs has brought new hope to patients. This review presents the latest advances in drug development and clinical application to provide a reference for clinicians managing transthyretin cardiac amyloidosis.
Assuntos
Amiloidose , Cardiomiopatias , Humanos , Cardiomiopatias/diagnóstico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Pré-Albumina/genética , Amiloidose/complicações , Amiloidose/diagnóstico , Amiloidose/terapia , Miocárdio , Miócitos CardíacosRESUMO
BACKGROUND: Gliomas are highly complex and heterogeneous tumors, rendering prognosis prediction challenging. The advent of deep learning algorithms and the accessibility of multi-omic data represent a new approach for the identification of survival-sensitive subtypes. Herein, an autoencoder-based approach was used to identify two survival-sensitive subtypes using RNA sequencing (RNA-seq) and DNA methylation (DNAm) data from The Cancer Genome Atlas (TCGA) dataset. The subtypes were used as labels to build a support vector machine model with cross-validation. We validated the robustness of the model on Chinese Glioma Genome Atlas (CGGA) dataset. DNAm-driven genes were identified by integrating DNAm and gene expression profiling analyses using the R MethylMix package and carried out for further enrichment analysis. RESULTS: For TCGA dataset, the model produced a high C-index (0.92 ± 0.02), low brier score (0.16 ± 0.02), and significant log-rank p value (p < 0.0001). The model also had a decent performance for CGGA dataset (CGGA DNAm: C-index of 0.70, brier score of 0.21; CGGA RNA-seq: C-index of 0.79, brier score of 0.18). Moreover, we identified 389 DNAm-driven genes of survival-sensitive subtypes, which were significantly enriched in the glutathione metabolism pathway. CONCLUSIONS: Our study identified two survival-sensitive subtypes of glioma and provided insights into the molecular mechanisms underlying glioma development; thus, potentially providing a new target for the prognostic prediction of gliomas and supporting personalized treatment strategies.
Assuntos
Aprendizado Profundo , Glioma , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glutationa/metabolismo , Humanos , PrognósticoRESUMO
It is well known that free fatty acids (FFAs) have beneficial effects on the skeletal system, however, which fatty acid sensing GPCR(s) and how the GPCR(s) regulating cartilage development and osteoarthritis (OA) pathogenesis is largely unknown. In this study, we found Gpr84, a receptor for medium-chain FFAs (MCFA), was the only FFA-sensing GPCR in human and mouse chondrocytes that exhibited elevated expression when stimulated by interleukin (IL)-1ß. Gpr84-deficiency upregulated cartilage catabolic regulator expression and downregulated anabolic factor expression in the IL-1ß-induced cell model and the destabilization of the medial meniscus (DMM)-induced OA mouse model. Gpr84-/- mice exhibited an aggravated OA phenotype characterized by severe cartilage degradation, osteophyte formation and subchondral bone sclerosis. Moreover, activating Gpr84 directly enhanced cartilage extracellular matrix (ECM) generation while knockout of Gpr84 suppressed ECM-related gene expression. Especially, the agonists of GPR84 protected human OA cartilage explants against degeneration by inducing cartilage anabolic factor expression. At the molecular level, GPR84 activation inhibited IL-1ß-induced NF-κB signaling pathway. Furthermore, deletion of Gpr84 had little effect on articular and spine cartilaginous tissues during skeletal growth. Together, all of our results demonstrated that fatty acid sensing GPCR (Gpr84) signaling played a critical role in OA pathogenesis, and activation of GPR84 or MCFA supplementation has potential in preventing the pathogenesis and progression of OA without severe cartilaginous side effect.
Assuntos
Osteoartrite/genética , Receptores Acoplados a Proteínas G/genética , Animais , Artralgia/genética , Artralgia/metabolismo , Artralgia/patologia , Cartilagem/metabolismo , Cartilagem/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ácidos Graxos/metabolismo , Homeostase , Humanos , Interleucina-1beta/farmacologia , Articulação do Joelho/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Coluna Vertebral/patologia , Tíbia/patologiaRESUMO
Hepatocellular carcinoma (HCC) is most prevalent tumor in liver and one of the most fatal cancers in the world. Long noncoding RNAs (lncRNAs) have been accepted as important regulators in carcinomas. But there are still many lncRNAs including DLGAP1-AS1 unannotated in HCC. First of all, GEPIA suggested that DLGAP1-AS1 presented high expression in HCC tissue samples relative to the normal tissues. Besides, overexpression of DLGAP1-AS1 was also proved in HCC cell lines. Moreover, DLGAP1-AS1 knockdown efficiently suppressed cell proliferation in HCC. Interestingly, miR-486-5p was predicted and validated to interact with DLGAP1-AS1, while the level of miR-486-5p was significantly increased In HCC after DLGAP1-AS1 knockdown. Moreover, we uncovered that ectopic expression of miR-486-5p induced suppression on HCC cell proliferation and that miR-486-5p inhibition offset the effect of DLGAP1-AS1 silence on HCC cell proliferation and apoptosis. Furthermore, H3F3B was identified as target of miR-486-5p and was therefore positively regulated by DLGAP1-AS1 in HCC. Of note, H3F3B upregulation partly revived the declined cell proliferative capacity in response to DLGAP1-AS1 knockdown. To conclude, DLGAP1-AS1 exerted its oncogenic role in HCC via miR-486-5p/H3F3B axis. Our new findings provided novel theoretical basis for discovery of therapeutic targets of HCC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , MicroRNAs/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Histonas/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Associadas SAP90-PSD95/genética , Células Tumorais CultivadasRESUMO
Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) contain 12 family members(CEACAM1ãCEACAM3ãCEACAM4ãCEACAM5ãCEACAM6ãCEACAM7ãCEACAM8ãCEACAM16ãCEACAM18ãCEACAM19ãCEACAM20 and CEACAM21)and are expressed diversely in different normal and tumor tissues. CEA (CEACAM5) has been used as a tumor biomarker since 1965. Here we review the latest research and development of the structures, expression, and function of CEACAMs in normal and tumor tissues, and their application in the tumor diagnosis, prognosis, and treatment. We focus on recent clinical studies of CEA targeted cancer immunotherapies, including bispecific antibody (BsAb) for radio-immuno-therapy and imaging, bispecific T cell engager (BiTE) and chimeric antigen receptor T cells (CAR-T). We summarize the promising clinical relevance and challenges of these approaches and give perspective view for future research. This review has important implications in understanding the diversified biology of CEACAMs in normal and tumor tissues, and their new role in tumor immunotherapy.
Assuntos
Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Proteínas Ligadas por GPI/imunologia , Imunoterapia , Neoplasias/terapia , Animais , Antígenos CD/química , Moléculas de Adesão Celular/química , Proteínas Ligadas por GPI/química , HumanosRESUMO
Correction is needed to the original version of this article.
RESUMO
BACKGROUND: Herpes simplex virus (HSV) can cause encephalitis. Its infected cell polypeptide 47 (ICP47), encoded by immediate-early gene US12, promotes immune escape. ICP47 was modified in the clinically approved oncolytic HSV (oHSV) T-Vec. However, transcription regulatory sequence (TRS) and transcription regulatory factor (TRF) of HSV US12 are seldom reported. METHODS: Previously, our laboratory isolated a new HSV strain named HSV-1-LXMW from a male patient with oral herpes in Beijing, China. Firstly, the genetic tree was used to analyze its genetic relationship. The US12 TRS and TRF in HSV-1-LXMW were found by using predictive software. Secondly, the further verification by the multi-sequence comparative analysis shown that the upstream DNA sequence of HSV US12 gene contained the conserved region. Finally, the results of literature search shown that the expression of transcription factors was related to the tissue affinity of HSV-1 and HSV-2, so as to increase the new understanding of the transcriptional regulation of HSV biology and oncolytic virus (OVs) therapy. RESULTS: Here we reported the transcriptional regulation region sequence of our new HSV-1-LXMW, and its close relationship with HSV-1-CR38 and HSV-1-17. Importantly we identified eight different kinds of novel TRSs and TRFs of HSV US12 for the first time, and found they are conserved among HSV-1 (c-Rel, Elk-1, Pax-4), HSV-2 (Oct-1, CF2-II, E74A, StuAp) or both HSVs (HNF-4). The TRFs c-Rel and Oct-1 are biologically functional respectively in immune escape and viral replication during HSV infection. CONCLUSIONS: Our findings have important implication to HSV biology, infection, immunity and oHSVs.
Assuntos
Regulação Viral da Expressão Gênica , Herpesvirus Humano 1/genética , Proteínas Imediatamente Precoces/genética , Evasão da Resposta Imune , Transcrição Gênica , China , Herpes Simples/virologia , Herpesvirus Humano 1/classificação , Humanos , Masculino , Filogenia , Replicação ViralRESUMO
Sphingosine kinase 1 (SPHK1) regulates cell proliferation and survival by converting sphingosine to the signaling mediator sphingosine 1-phosphate (S1P). SPHK1 is widely overexpressed in most cancers, promoting tumor progression and is associated with clinical prognosis. Numerous studies have explored SPHK1 as a promising target for cancer therapy. However, due to insufficient knowledge of SPHK1 oncogenic mechanisms, its inhibitors' therapeutic potential in preventing and treating cancer still needs further investigation. In this review, we summarized the metabolic balance regulated by the SPHK1/S1P signaling pathway and highlighted the oncogenic mechanisms of SPHK1 via the upregulation of autophagy, proliferation, and survival, migration, angiogenesis and inflammation, and inhibition of apoptosis. Drug candidates targeting SPHK1 were also discussed at the end. This review provides new insights into the oncogenic effect of SPHK1 and sheds light on the future direction for targeting SPHK1 as cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Carcinogênese/patologia , Neoplasias/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Lisofosfolipídeos/metabolismo , Neoplasias/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismoRESUMO
OBJECTIVE: To propose a novel morphological classification method for notches, which may provide new evidence for notchplasty based on the three-dimensional (3D) features of notches and the risk of anterior cruciate ligament (ACL) injury. MATERIALS AND METHODS: Three hundred individuals in total were included in our study, including 150 patients with ACL ruptures (75 males and 75 females) and 150 age- and gender-matched individuals without ACL ruptures. The notches were divided into four types according to the notch widths at the notch inlet, outlet, and ACL attachment based on the preoperative MRI, the notch volume was calculated, and the risk of ACL injury was compared. The surgical records were reviewed and whether these cases performed notchplasty were collected. RESULTS: The inlet-and-outlet stenosis notch type was associated with smaller notch volume (P = 0.007) and a higher risk of ACL injury (P < 0.001). There were no significant differences in morphological distribution between males and females. The rate of notchplasty in inlet-and-outlet stenosis type was higher than the others. CONCLUSIONS: The new morphological classification method efficiently reflected the association of the notch shape with the 3D notch volume and the risk of ACL injury. The knees with the inlet-and-outlet stenosis notch type and smaller notch volume tended to have a higher risk of ACL injury. Level of evidence Level III, case-control study.
Assuntos
Lesões do Ligamento Cruzado Anterior/diagnóstico por imagem , Constrição Patológica/classificação , Fêmur/diagnóstico por imagem , Articulação do Joelho/diagnóstico por imagem , Adolescente , Adulto , Constrição Patológica/diagnóstico por imagem , Feminino , Fêmur/anormalidades , Fêmur/anatomia & histologia , Humanos , Imageamento Tridimensional , Articulação do Joelho/anatomia & histologia , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Patients receiving brain radiotherapy may suffer acute or chronic side effects. Ionizing radiation induces the production of intracellular reactive oxygen species and pro-inflammatory cytokines in the central nervous system, leading to brain damage. Complementary Chinese herbal medicine therapy may reduce radiotherapy-induced side effects. Flavonoids are a class of natural products which can be extracted from Chinese herbal medicine and have been shown to have neuroprotective and radioprotective properties. Flavonoids are effective antioxidants and can also inhibit regulatory enzymes or transcription factors important for controlling inflammatory mediators, affect oxidative stress through interaction with DNA and enhance genomic stability. In this paper, radiation-induced brain damage and the relevant molecular mechanism were summarized. The radio-neuro-protective effect of flavonoids, i.e., antioxidant, anti-inflammatory and maintaining genomic stability, were then reviewed. We concluded that flavonoids treatment may be a promising complementary therapy to prevent radiotherapy-induced brain pathophysiological changes and cognitive impairment.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Radiação IonizanteRESUMO
PURPOSE: Pernicious placenta previa induces severe hemorrhage during cesarean section. Abdominal aorta balloon occlusion (AABO) is considered as an effective operation for patients with pernicious placenta previa. The aim of this study was to investigate the clinical application of abdominal aortic balloon occlusion in the placenta previa and cesarean section by systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WAN-FANG DATA and CQVIP were searched from inception to Jan. 15th, 2019. Operative time, intraoperative blood loss volume, postoperative hospitalization duration, intraoperative blood transfusion volume, hysterectomy rate, lower extremity thrombosis rate, ICU admission rate, adverse reaction rate, neonatal birth weight, Apgar 1-min and 5-min scores were regarded as the endpoints. Randomized controlled trials (RCT) were used for meta-analysis. RESULTS: Fourteen articles were retrieved from total 650 articles, and the results of meta-analysis showed that application of intraoperative AABO had the ability to reduce the operative time (WMD = - 16.581, 95% CI - 26.690 to - 6.472; P = 0.001), the intraoperative blood loss volume (WMD = - 1202.69, 95% CI - 1732.25 to - 673.12; P < 0.001), the intraoperative blood transfusion volume (WMD = - 1202.69, 95% CI - 1732.25 to - 673.12; P < 0.001). The hysterectomy rate (RR = 0.279, 95% CI 0.164-0.474; P < 0.001), postoperative hospitalization duration (WMD = - 1.423, 95% CI - 2.070 to - 0.776; P < 0.001) and the balloon preset time (WMD = - 13.793, 95% CI - 15.341 to - 12.244; P < 0.001; I2 = 0.0%) were also reduced in AABO group. CONCLUSIONS: Application of AABO in patients with pernicious placenta previa is safe and effective, which is worthy of clinical promotion.
Assuntos
Aorta Abdominal , Oclusão com Balão/métodos , Placenta Prévia/terapia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Transfusão de Sangue , Cesárea/efeitos adversos , Feminino , Humanos , Histerectomia/estatística & dados numéricos , Recém-Nascido , Duração da Cirurgia , Gravidez , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Calcium and integrin-binding protein 1 (CIB1) is an EF-hand calcium binding protein, which is involved in many cellular processes, including calcium signaling, cell survival and proliferation, cell migration, cell adhesion and apoptosis. A number of studies have found that CIB1 is ubiquitously expressed and is related to various human diseases, such as cancer, Alzheimer's disease (AD), cardiac hypertrophy and male infertility. The mechanism of CIB1 in human diseases is still not clear, although multiple functions of CIB1 are modulated by interacting with numerous interacting partners. As a calcium binding protein, the roles of CIB1 in calcium signaling by binding calcium or modulating some key modulators, such as calcineurin, integrin, inositol 1,4,5-trisphosphate receptor (IP3R) and taste 1 receptor member 2 (TAS1R2). The tumor promoting mechanisms of CIB1 have been described in different aspects, including promoting tumor cell cycle and proliferation, inhibiting tumor cell apoptosis, and mediating tumor cell migration and angiogenesis. In addition, multiple functions of CIB1, such as neural development, taste or gustation functions, and virus infection are also elucidated. These recent advances have significantly expanded our understanding of the knowledge of CIB1 and highlighted the potential mechanisms of CIB1 in tumor progression.
Assuntos
Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Proteínas de Ligação ao Cálcio/análise , Movimento Celular , Progressão da Doença , Humanos , Neoplasias/irrigação sanguínea , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Prenilação/efeitos dos fármacos , Quinolinas/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologiaRESUMO
Therapies based on urease inhibition are now seriously considered as the first line of treatment for infections caused by Helicobacter pylori. However, the present inhibitors are ineffective or unstable in highly acidic gastric juice. Here, we report a series of benzylanilines as effective inhibitors of H. pylori urease. Out of the obtained twenty-one compounds, N-(3,4-dihydroxybenzyl)-4-nitroaniline (4) was evaluated in detail and shows promising features for development as anti-H. pylori agent. Excellent potency against urease in both cell-free extract and intact cell was observed at low concentrations of 4 (IC50=0.62 ± 0.04 and 1.92 ± 0.09 µM), which showed over 29- and 54-fold increase in potency with respect to the positive control AHA. The SAR analysis revealed that protection of 3,4-dihydroxy group of 4 as methoxy or changes of 4-NO2 will result in a moderate to dramatic decrease in potency.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Etano/análogos & derivados , Helicobacter pylori/enzimologia , Urease/antagonistas & inibidores , Etano/síntese química , Etano/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The quadriceps-sparing and subvastus approaches are two of the most commonly used minimally-invasive approaches in total knee arthroplasty (TKA). However, the conclusion among studies still remains controversial. The purpose of this meta-analysis was to compare the clinical efficacy of the subvastus and quadriceps-sparing approaches with the standard parapatellar approach in TKA. METHODS: Randomized controlled trials (RCTs) comparing the quadriceps-sparing or subvastus approach with the standard parapatellar approach was identified in the databases of PubMed, the Cochrane library, EMBASE and Web of Science up to July 2014. Two authors extracted the following data: the basic characteristics of patients, the methodological quality and clinical outcomes from the included RCTs independently. RevMan 5.2.7 software was used for meta-analysis. RESULTS: A total of 19 RCTs (1578 patients) were included for meta-analysis. The results suggested that the quadriceps-sparing approach showed better outcomes in knee society score (KSS) and visual analog score (VAS), but this approach required a longer operative time than the standard parapatellar approach. There were no differences in total complications, wound infection, deep vein thrombosis, blood loss and hospital stay between the quadriceps-sparing and standard approaches. The subvastus approach showed better outcomes in VAS, knee range of motion (ROM), straight leg raise and lateral retinacular release than the standard parapatellar approach. There were no differences in KSS, total complication, wound infection, deep vein thrombosis, blood loss and hospital stay between the quadriceps-sparing and standard approaches. CONCLUSIONS: The current evidence showed that, when compared with the standard parapatellar approach, the quadriceps-sparing approach was associated with better outcomes in KSS and VAS but required a longer operative time, and the subvastus approach was associated with better outcomes in VAS, ROM, straight leg raise and lateral retinacular release.
Assuntos
Artroplastia do Joelho/métodos , Artroplastia do Joelho/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: There is no consensus regarding the clinical relevance of gender-speciï¬c prostheses in total knee arthroplasty (TKA). We summarize the current best evidence in a comparison of clinical and radiographic outcomes between gender-speciï¬c prostheses and standard unisex prostheses in female patients. METHODS: We used the PubMed, Embase, Cochrane, Science Citation Index, and Scopus databases. We included randomized controlled trials published up to January 2013 that compared gender-speciï¬c prostheses with standard unisex prostheses in female patients who underwent primary TKAs. RESULTS: 6 trials involving 423 patients with 846 knee joints met the inclusion criteria. No statistically significant differences were observed between the 2 designs regarding pain, range of motion (ROM), knee scores, satisfaction, preference, complications, and radiographic results. The gender-specific design (Gender Solutions; Zimmer Inc, Warsaw, Indiana) reduced the prevalence of overhang. However, it had less overall coverage of the femoral condyles compared to the unisex group. In fact, the femoral prosthesis in the standard unisex group matched better than that in the gender-speciï¬c group. INTERPRETATION: Gender-speciï¬c prostheses do not appear to confer any beneï¬t in terms of clinician- and patient-reported outcomes for the female knee.
Assuntos
Artroplastia do Joelho/métodos , Medicina Baseada em Evidências , Prótese do Joelho , Desenho de Prótese/métodos , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores SexuaisRESUMO
Cardiomyopathy, a heterogeneous pathological condition characterized by changes in cardiac structure or function, represents a significant risk factor for the prevalence and mortality of cardiovascular disease (CVD). Research conducted over the years has led to the modification of definition and classification of cardiomyopathy. Herein, we reviewed seven of the most common types of cardiomyopathies, including Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), diabetic cardiomyopathy, Dilated Cardiomyopathy (DCM), desmin-associated cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), Ischemic Cardiomyopathy (ICM), and obesity cardiomyopathy, focusing on their definitions, epidemiology, and influencing factors. Cardiomyopathies manifest in various ways ranging from microscopic alterations in cardiomyocytes, to tissue hypoperfusion, cardiac failure, and arrhythmias caused by electrical conduction abnormalities. As pleiotropic Transcription Factors (TFs), the Krüppel-Like Factors (KLFs), a family of zinc finger proteins, are involved in regulating the setting and development of cardiomyopathies, and play critical roles in associated biological processes, including Oxidative Stress (OS), inflammatory reactions, myocardial hypertrophy and fibrosis, and cellular autophagy and apoptosis, particularly in diabetic cardiomyopathy. However, research into KLFs in cardiomyopathy is still in its early stages, and the pathophysiologic mechanisms of some KLF members in various types of cardiomyopathies remain unclear. This article reviews the roles and recent research advances in KLFs, specifically those targeting and regulating several cardiomyopathy-associated processes.