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1.
J Ethnopharmacol ; 247: 112283, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31605736

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bulbus Fritillaria cirrhosa D. Don (BFC) is a Chinese traditional herbal medicine that has long been used as an indispensable component in herbal prescriptions for bronchopulmonary diseases due to its well-established strong anti-inflammation and pulmonary harmonizing effects. Interestingly, there are few case reports in traditional Chinese medicine available where they found it to contribute in anti-tumor therapies. Imperialine is one of the most favored active substances extracted from BFC and has been widely recognized as an anti-inflammatory agent. AIM OF THE STUDY: The aim of the current work is to provide first-hand evidences both in vitro and in vivo showing that imperialine exerts anti-cancer effects against non-small cell lung cancer (NSCLC), and to explore the molecular mechanism of this anti-tumor activity. It is also necessary to examine its systemic toxicity, and to investigate how to develop strategies for feasible clinical translation of imperialine. MATERIALS AND METHODS: To investigate anti-NSCLC efficacy of imperialine using both in vitro and in vivo methods where A549 cell line were chosen as in vitro model NSCLC cells and A549 tumor-bearing mouse model was constructed for in vivo study. The detailed underlying anti-cancer mechanism has been systematically explored for the first time through a comprehensive set of molecular biology methods mainly including immunohistochemistry, western blot and enzyme-linked immunosorbent assays. The toxicity profile of imperialine treatments were evaluated using healthy nude mice by examining hemogram and histopathology. An imperialine-loaded liposomal drug delivery system was developed using thin film hydration method to evaluate target specific delivery. RESULTS: The results showed that imperialine could suppress both NSCLC tumor and associated inflammation through an inflammation-cancer feedback loop in which NF-κB activity was dramatically inhibited by imperialine. The NSCLC-targeting liposomal system was successfully developed for targeted drug delivery. The developed platform could favorably enhance imperialine cellular uptake and in vivo accumulation at tumor sites, thus improving overall anti-tumor effect. The toxicity assays revealed imperialine treatments did not significantly disturb blood cell counts in mice or exert any significant damage to the main organs. CONCLUSIONS: Imperialine exerts anti-cancer effects against NSCLC both in vitro and in vivo, and this previously unknown function is related to NF-κB centered inflammation-cancer feedback loop. Imperialine mediated anti-cancer activity is not through cytotoxicity and exhibit robust systemic safety. Furthermore, the liposome-based system we commenced would dramatically enhance therapeutic effects of imperialine while exhibiting extremely low side effects both on cellular and in NSCLC model. This work has identified imperialine as a promising novel anti-cancer compound and offered an efficient target-delivery solution that greatly facilitate practical use of imperialine.

2.
Clin Neuroradiol ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696281

RESUMO

PURPOSE: To investigate the long-term clinical and angiographic outcomes and their related predictors in endovascular treatment (EVT) of small (<5 mm) ruptured intracranial aneurysms (SRA). METHODS: The study retrospectively reviewed patients with SRAs who underwent EVT between September 2011 and December 2016 in two Chinese stroke centers. Medical charts and telephone call follow-up were used to identify the overall unfavorable clinical outcomes (OUCO, modified Rankin score ≤2) and any recanalization or retreatment. The independent predictors of OUCO and recanalization were studied using univariate and multivariate analyses. Multivariate Cox proportional hazards models were used to identify the predictors of retreatment. RESULTS: In this study 272 SRAs were included with a median follow-up period of 5.0 years (interquartile range 3.5-6.5 years) and 231 patients with over 1171 aneurysm-years were contacted. Among these, OUCO, recanalization, and retreatment occurred in 20 (7.4%), 24 (12.8%), and 11 (7.1%) patients, respectively. Aneurysms accompanied by parent vessel stenosis (AAPVS), high Hunt-Hess grade, high Fisher grade, and intraoperative thrombogenesis in the parent artery (ITPA) were the independent predictors of OUCO. A wide neck was found to be a predictor of recanalization. The 11 retreatments included 1 case of surgical clipping, 6 cases of coiling, and 4 cases of stent-assisted coiling. A wide neck and AAPVS were the related predictors. CONCLUSION: The present study demonstrated relatively favorable clinical and angiographic outcomes in EVT of SRAs in long-term follow-up of up to 5 years. THE AAPVS, as a morphological indicator of the parent artery for both OUCO and retreatment, needs further validation.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31668374

RESUMO

Apoptosis is associated with various cardiovascular diseases. CGRP exerts a variety of effects within the cardiovascular system, and protects against the onset and development of angiotensin (Ang) II-induced vascular dysfunction and remodelling. However, it is not known whether CGRP has a direct effect on Ang II-induced apoptosis in vascular smooth muscle cells (VSMCs), and the mechanism underlying the anti-apoptotic role remains unclear. In this study, CGRP significantly suppressed reactive oxygen species (ROS) and apoptosis in Ang II-induced VSMCs. In VSMCs pre-treated with a CGRP receptor antagonist (CGRP8-37), the CGRP-mediated inhibition of Ang II-induced ROS and apoptosis was completely abolished. Moreover, pre-treatment with N-acetyl-L cysteine (NAC), an ROS scavenger, blocked the effects of CGRP on Ang II-induced apoptosis. In addition, the activation of CaMKII and the downstream transcription factor CREB stimulated by Ang II was abrogated by CGRP. Importantly, in both CGRP and NAC-treated VSMCs, CGRP failed to further attenuate CaMKII and CREB activation. The results demonstrate that CGRP attenuated Ang II-induced ROS-dependent apoptosis in VSMCs by inhibiting the CaMKII/CREB signalling pathway.

4.
Life Sci ; : 117008, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669240

RESUMO

OBJECTIVE: We aimed to explore the expression level and biological function of miR-145-5p in preeclampsia (PE). METHODS: The differentially expressed miRNA/mRNA between normal placentas and PE placentas were screened using the GSE84260 and GSE73374 datasets from the Gene Expression Omnibus Database. The expression of miR-145-5p in PE placentas was detected by qRT-PCR. The CCK-8 assay, wound healing and transwell were carried out to determine the cell growth, migration and invasion when miR-145-5p was overexpressed or inhibited. The real-time quantitative PCR (qRT-PCR), Western Blot and dual-luciferase reporter assays were conducted to preliminarily explore possible mechanisms. RESULTS: A total of 33 miRNAs were found significantly differentially expressed in PE patients, 19 were significantly upregulated and 14 were significantly downregulated. The relative miR-145-5p expression was lower in PE placentas than normal placentas. The viability and invasion were suppressed when miR-145-5p was inhibited in trophoblasts cells, while miR-145-5p overexpression promoted the effectiveness. In addition, mRNA and protein expression of FLT1 in HTR-8/SVneo cell was also downregulated with miR-145-5p overexpression, suggesting that FLT1 is the target gene of miR-145-5p. Consistent with miR-145-5p overexpression, the mRNA and protein expression of FLT1 also were upregulated with miR-145-5p interference. Furthermore, the expression of mir-145-5p was regulated by the Hypoxic conditions. CONCLUSIONS: In conclusion, the results showed miR-145-5p may participate in PE development by affecting the proliferation and invasion of trophoblast cells. This is a new perspective to understand the etiology and pathogenesis of PE, which may provide a new breakthrough for the early prediction and diagnosis of PE.

5.
Braz Oral Res ; 33: e059, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664357

RESUMO

We recently demonstrated that a co-culture system of human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs) could enhance angiogenesis ability in vitro. However, whether tumor necrosis factor α (TNF-α) could promote blood vessel formation during pulp regeneration remained unknown. The aim of this study was to investigate the effects of TNF-α on the formation of endothelial tubules and vascular networks in a co-culture system of hDPSCs and HUVECs. hDPSCs were co-cultured with HUVECs at a ratio of 1:5. The Matrigel assay was performed to detect the total tubule branching lengths and numbers of branches, and the Cell-Counting Kit 8 assay was performed to examine the effect of TNF-α on cell proliferation. Real-time polymerase chain reactions and western blot were used to detect vascular endothelial growth factor (VEGF) mRNA and protein expression. The Matrigel assay showed significantly greater total branching lengths and numbers of branches formed in the experimental groups treated with different concentrations of TNF-α compared with the control group. The decomposition times of the tubule structures were also significantly prolonged (P < 0.05). Treatment with 50 ng/ml TNF-α did not significantly change the proliferation of co-cultured cells, but it significantly increased the VEGF mRNA and protein expression levels (p < 0.05). In addition, the migration abilities of HUVECs and hDPSCs increased after co-culture with TNF-α (p < 0.05). TNF-α enhanced angiogenic ability in vitro in the co-culture system of hDPSCs and HUVECs.

6.
Biomed Pharmacother ; 120: 109501, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31627090

RESUMO

OBJECTIVE: We aimed to explore the expression level and biological function of lncRNA PVT1 in human trophoblast cells. METHODS: The expression levels of PVT1 in cancer cell lines, HTR8/SVneo cell, HUVEC cell, the maternal placenta of GDM patients, PE patients and normal pregnancy were detected by qRT-PCR. The cell culture, cell transfection, CCK-8 assay, flow cytometry, wound scratch assay and transwell were carried out to determine the effects of silencing and overexpression of PVT1 on the HTR8/SVneo trophoblast cell line. Nuclear and chromatin RNA fraction assay, RNA-sequencing, western blot and qRT-PCR were conducted to preliminarily explore possible mechanisms. RESULTS: The relative PVT1 expression level in HTR-8/Svneo cells was higher compared to other cancer cells and HUVEC, and was lower in the GDM and PE placentas than in the normal placentas. The results showed that PVT1 knockdown notably inhibited the proliferation, migration and invasiveness abilities of trophoblast cells, and significantly promoted the apoptosis. Furthermore, overexpression of PVT1 showed the opposite results. We identified 105 differentially expressed genes after PVT1 knockdown, 23 were up-regulated and 82 were down-regulated. GO enrichment analysis and pathway enrichment analysis showed that the DEGs were closely related to the functional changes of trophoblast cells. Because of the enrichment of 7 DEGs and less Q value, PI3K/AKT pathway was prominent and attracted our attention. More importantly, we confirmed that knockdown of PVT1 obviously decreased AKT phosphorylation and decreased the expression of DEGs (GDPD3, ITGAV and ITGB8) while overexpression of PVT1 promoted the AKT phosphorylation and increased the expression of DEGs (GDPD3, ITGAV and ITGB8). PVT1 was primarily distributed in the nuclear compartment and also distributed in the cytoplasmic of HTR-8/Svneo cells. CONCLUSIONS: This study provided the evidence that PVT1 played a vital role in trophoblast cells, and it is important for maintaining the normal physiological function of trophoblast cells. The PVT1 expression was lower in the GDM and PE placentas than the normal placentas, which might disrupt the function of trophoblast cells through PI3K/AKT pathway.

7.
Nano Lett ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31558022

RESUMO

Though plastic nanoparticles have already raised much concern for their potential impact on health, our understanding of their biological effects is still utterly limited. Here we demonstrate for the first time that carboxyl-modified polystyrene nanoparticles (CPS) could effectively inhibit ferroptosis as a result of reduced cellular ROS which was triggered by transcription factor EB (TFEB) nucleus translocation. In this process, CPS first entered cells via macropinocytosis, then CPS-containing macropinosomes fused with lysosomes and expanded into abnormal lysosome-like large vacuoles in vacuolar-type H+-ATPase (V-ATPase) and aquaporins (AQPs) in a dependent way. These large vacuoles were detected both in vitro and in vivo, which was found to be a sign of lysosome stress. The lysosome stress induced deactivation of mammalian target of rapamycin (mTOR) which led to nucleus translocation of TFEB. Then, TFEB-dependent enhanced expression of lysosomal proteins and superoxide dismutase (SOD) which ultimately led to ROS reduction and inhibition of ferroptosis. Knockout of TFEB-enhanced ferroptosis was triggered by Erastin and abolished the effect of CPS on ROS and ferroptosis. In summary, our results reveal a novel mechanism whereby CPS reduced ROS and inhibited ferroptosis in a TFEB-dependent way. These findings have important implications for understanding the biological effects of polystyrene nanoparticles and searching for new anti-ROS and antiferroptosis particles or reagents.

8.
Biol Trace Elem Res ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31473898

RESUMO

Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density of bone can be weakened by the disordered iron metabolism, which increases the incidence of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide ideas for clinical treatment and development of new drugs.

9.
Int Immunopharmacol ; 75: 105761, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325726

RESUMO

The present study was aimed to investigate the effects of the long non-coding RNA DQ786243 in the regulation of Treg cells in oral lichen planus (OLP), as well as to evaluate its potential molecular mechanisms. Here we found that the expression of DQ786243 and Foxp3 were both overexpressed in the CD4+ cells from the peripheral blood of OLP patients, and their expression was positively correlated. Meanwhile, compared with the normal CD4+ cells, the frequency of Foxp3+ Treg cells in the OLP CD4+ cells was significantly higher. DQ786243 overexpression in normal CD4+ cells resulted in the upregulation of Foxp3 and the higher frequency of Foxp3+ Treg cells. Furthermore, we found that the induction of Foxp3+ Treg cells by DQ786243 significantly increased its suppressive function, and suppressed the function of other CD4+ T cells such as Th1 and Th17 by decreasing the levels of IFN-γ and IL-17. Moreover, we found that DQ786243 overexpression markedly elevated the expression of miR-146a via regulating Foxp3, and thus inhibiting the NF-κB signaling. In conclusion, these findings indicate that DQ786243 may regulate the induction and function of CD4+ Treg cells through Foxp3-miR-146a-NF-κB axis, implicating a novel insight into understanding the progression of OLP.

10.
Stroke ; 50(7): 1850-1858, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31167620

RESUMO

Background and Purpose- Ischemic stroke is one of the leading causes of morbidity and mortality worldwide and a major cause of long-term disability. Recently, long noncoding RNAs have been revealed, which are tightly associated with several human diseases. However, the functions of long noncoding RNAs in ischemic stroke still remain largely unknown. In the current study, for the first time, we investigated the role of long noncoding RNA Nespas in ischemic stroke. Methods- We used in vivo models of middle cerebral artery occlusion and in vitro models of oxygen-glucose deprivation to illustrate the effect of long noncoding RNA Nespas on ischemic stroke. Results- We found expression of Nespas was significantly increased in ischemic cerebral tissues and oxygen-glucose deprivation-treated BV2 cells in a time-dependent manner. Silencing of Nespas aggravated middle cerebral artery occlusion operation-induced IR injury and cell death. In addition, proinflammatory cytokine production and NF-κB (nuclear factor-κB) signaling activation were inhibited by Nespas overexpression. TAK1 (transforming growth factor-ß-activated kinase 1) was found to directly interact with Nespas, and TAK1 activation was significantly suppressed by Nespas. At last, we found Nespas-inhibited TRIM8 (tripartite motif 8)-induced K63-linked polyubiquitination of TAK1. Conclusions- We showed that Nespas played anti-inflammatory and antiapoptotic roles in cultured microglial cells after oxygen-glucose deprivation stimulation and in mice after ischemic stroke by inhibiting TRIM8-related K63-linked polyubiquitination of TAK1.

11.
Int Immunopharmacol ; 74: 105695, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254958

RESUMO

NK cells may have great potential in tumor immunotherapy because they can kill tumor cells directly and quickly. Chimeric antigen receptor is a fusion protein composed of extracellular antigen recognition domain, transmembrane domain and intracellular signal domain. Rapid development of CAR-modified T cells has made tremendous achievements in the treatment of malignancies, especially hematological malignancies. However, there are many deficiencies in clinical application of CAR-T cell therapy. Car-modified NK cells have attracted much attention because they may avoid these shortcomings. At present, preclinical and clinical studies have shown that CAR-NK cell therapy may play significant anti-tumor role and it is safer than CAR-T cell therapy. Nevertheless, CAR-NK cell therapy still faces some challenges, such as the expansion and activation of primary NK cells in vitro, the difficulty to store and ship NK cell products and the low transduction efficiency. Thus further research is still needed to optimize CAR-NK cell therapy. Building better CAR-NK cells is important to improve the treatment efficacy and combination therapy offers a novel direction of NK-cell based immunotherapy.

12.
J Food Sci ; 84(6): 1646-1650, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31116433

RESUMO

Pepino (Solanum muricatum), which is an evergreen plant native to South America, is well-known for its effects in antioxidation, antidiabetic activity, anti-inflammation, and antitumor activity. A previous study in our lab indicated that Solanum muricatum (SM) extract promoted osteogenic differentiation by upregulating Wnt and BMP signaling pathway in rat bone marrow stromal cells. The osteogenesis imperfecta (OI) mouse model was used in order to further discover the osteogenic properties of SM extract in the present research. We utilized microCT analysis to collect bone mass and microarchitectural parameters at vertebrae and at femur metaphysis in OI mice. Raman spectrometry was applied to identify change of bone mineral and matrix composition during SM treatment. Finally, collagen synthesis marker PINP and collagen degradation marker CTX were detected using enzyme immunoassay. SM extract could improve the bone mass and microarchitectural parameters both at vertebrae and at femur metaphysis. It also significantly increased the collagen content by promoting its biosynthesis and inhibiting its degradation. By using heterozygous Col1a1Jrt /+ mice as a model of OI, 6 weeks treatment of SM extract could significantly ameliorate the symptoms in OI mice. Thus, SM holds potential for developing new drugs of bone formation and bone remodeling.


Assuntos
Osteogênese Imperfeita/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Solanum/química , Animais , Densidade Óssea/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/fisiopatologia , Microtomografia por Raio-X
13.
Future Oncol ; 15(13): 1535-1543, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31066301

RESUMO

YAP, acting as a crucial transcription factor in nucleus, regulates the organ size, tissue homeostasis and tumorigenesis. Dysregulation of Hippo-YAP pathway brings a significant impact on the occurrence and development of various tumor types. Moreover, regulation of YAP/TAZ far exceeds the core kinase of the Hippo pathway, and gradually opens up new therapeutic targets. For the moment, chemotherapy together with radiotherapy act as routine methods to prolong the lives of cancer patients. Seeking more effective anti-neoplastic agents seems to be the urgent problem. This brief review focuses on the research progress of YAP inhibitors as the antineoplastic targets. Small molecule inhibitors or drugs have been discovered including verteporfin, dasatinib, statins, A35, JQ1, norcantharidin, agave, MLN8237, dobutamine and peptide-based YAP inhibitors. We are trying to seek novel therapies from the relationship between known drugs and potential mechanisms.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Fosfoproteínas/antagonistas & inibidores , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico
14.
Toxicol Appl Pharmacol ; 376: 9-16, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31108107

RESUMO

Osteoporosis is manifested by reduced bone mass. Tanshinone has been shown to affect osteoclast differentiation, but its role in osteoporosis remains less clear. This study aimed to investigate the effects and molecular mechanisms of tanshinone on osteoporosis. Osteoporosis was induced by bilateral ovariectomy (OVX) in adult female rats treated with or without tanshinone. Trabecular bone structure was assessed by micro-computed tomography (micro-CT). Bone marrow stromal cells (BMSCs) were isolated for analysis of stemness and senescence. mRNA levels of age related genes were examined and the role of the gene that was upregulated by tanshinone treatment was suppressed to determine its involvement in tanshinone mediated effects. Finally, the mechanism underlying tanshinone induced gene upregulation was explored. We found that tanshinone treatment restored alveolar bone structure in OVX rats as well as the stemness and senescence status of BMSCs isolated from OVX rats. Tanshinone upregulated Phgdh mRNA levels and inhibition of phosphoglycerate dehydrogenase Phgdh, the protein encoded by the Phgdh gene, abolished the effects of tanshinone on BMSC stemness and senescence. Finally, we found that OVX lead to hypermethylation of the promoter region of Phgdh which was suppressed by tanshinone treatment. Our study shows that tanshinone potently suppress OVX induced osteoporosis and BMSC senescence through upregulation of PHGDH.

15.
Technol Health Care ; 27(S1): 185-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31045538

RESUMO

BACKGROUND: For a protein to execute its function, ensuring its correct subcellular localization is essential. In addition to biological experiments, bioinformatics is widely used to predict and determine the subcellular localization of proteins. However, single-feature extraction methods cannot effectively handle the huge amount of data and multisite localization of proteins. Thus, we developed a pseudo amino acid composition (PseAAC) method and an entropy density technique to extract feature fusion information from subcellular multisite proteins. OBJECTIVE: Predicting multiplex protein subcellular localization and achieve high prediction accuracy. METHOD: To improve the efficiency of predicting multiplex protein subcellular localization, we used the multi-label k-nearest neighbors algorithm and assigned different weights to various attributes. The method was evaluated using several performance metrics with a dataset consisting of protein sequences with single-site and multisite subcellular localizations. RESULTS: Evaluation experiments showed that the proposed method significantly improves the optimal overall accuracy rate of multiplex protein subcellular localization. CONCLUSION: This method can help to more comprehensively predict protein subcellular localization toward better understanding protein function, thereby bridging the gap between theory and application toward improved identification and monitoring of drug targets.

16.
Int Immunopharmacol ; 70: 498-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30875561

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/fisiologia , Animais , Anticorpos Monoclonais/uso terapêutico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Terapia Combinada , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Interleucina-1/antagonistas & inibidores , Neoplasias/imunologia , Terapia Viral Oncolítica , Inibidores de Proteínas Quinases/uso terapêutico , Radioimunoterapia , Linfócitos T/transplante
17.
Proc Natl Acad Sci U S A ; 116(10): 4716-4721, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765516

RESUMO

Seed germination is an energy demanding process that requires functional mitochondria upon imbibition. However, how mitochondria fine tune seed germination, especially in response to the dynamics of environmental temperature, remains largely unknown at the molecular level. Here, we report a mitochondrial matrix-localized heat shock protein GhHSP24.7, that regulates seed germination in a temperature-dependent manner. Suppression of GhHSP24.7 renders the seed insensitive to temperature changes and delays germination. We show that GhHSP24.7 competes with GhCCMH to bind to the maturation subunit protein GhCcmFc to form cytochrome C/C1 (CytC/C1) in the mitochondrial electron transport chain. GhHSP24.7 modulates CytC/C1 production to induce reactive oxygen species (ROS) generation, which consequently accelerates endosperm rupture and promotes seed germination. Overexpression of GhHSP24.7's homologous genes can accelerate seed germination in Arabidopsis and tomato, indicating its conserved function across plant species. Therefore, HSP24.7 is a critical factor that positively controls seed germination via temperature-dependent ROS generation.

18.
J Cell Mol Med ; 23(5): 3417-3428, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30784180

RESUMO

Diabetic nephropathy (DN) is characterized by inflammation of renal tissue. Glomerular endothelial cells (GEnCs) play an important role in inflammation and protein leakage in urine in DN patients. Chemerin and its receptor ChemR23 are inducers of inflammation. The aim of this study was to investigate the function of chemerin/ChemR23 in GEnCs of DN patients. Immunohistochemical staining and qRT-PCR were used to measure the expression of chemerin, ChemR23 and inflammatory factors in renal tissues of DN patients. Db/db mice were used as animal model. ChemR23 of DN mice was knocked down by injecting LV3-shRNA into tail vein. Inflammation, physiological and pathological changes in each group was measured. GEnCs were cultured as an in vitro model to study potential signalling pathways. Results showed that expression of chemerin, ChemR23 and inflammatory factors increased in DN patients and mice. LV3-shRNA alleviated renal damage and inflammation in DN mice. GEnCs stimulated by glucose showed increased chemerin, ChemR23 and inflammatory factors and decreased endothelial marker CD31. Both LV3-shRNA and SB203580 (p38 MAPK inhibitor) attenuated chemerin-induced inflammation and injury in GEnCs. Taken together, chemerin/ChemR23 axis played an important role in endothelial injury and inflammation in DN via the p38 MAPK signalling pathway. Suppression of ChemR23 alleviated DN damage.

19.
Enzyme Microb Technol ; 124: 79-83, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30797482

RESUMO

Pullulanase is a starch-debranching enzyme that is generally employed to efficiently break down starch for the production of high-glucose syrup. Acidic adaptation of pullulanases is of special interest. In this study, we conducted protein engineering to improve the acidic adaptation of Bacillus acidopullulyticus pullulanase (BaPul) and used a hydrogen-bond-based approach to identify promising residues that may change the deprotonation constants (pKa) of the catalytic residues. A total of 19 amino acids were selected for mutation according to the crystal structure of BaPul. The pH optimum of the L627R mutant shifted from 5.0 to 4.0, and its relative activity at pH 4.0 was 117% that of the wide-type enzyme. The improved efficacy of the L627R mutant at pH 4.0 was confirmed by kinetic parameters and pKa prediction. Moreover, the L627R mutant exhibited increased tolerance against acid-mediated denaturation, and its maximum d-glucose content (97.4%) was obtained after 40 h incubation, which is shorter by 10 h compared with the time required by the wide-type enzyme to produce a comparable amount of the monosaccharide. The L627R mutant may be suitable for industrial application because its shortened reaction time translates to reduced energy consumption.


Assuntos
Bacillus/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Engenharia de Proteínas , Adaptação Fisiológica/genética , Aminoácidos/genética , Bacillus/genética , Proteínas de Bactérias/genética , Catálise , Estabilidade Enzimática , Glicosídeo Hidrolases/genética , Ligações de Hidrogênio , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Amido/metabolismo , Relação Estrutura-Atividade , Temperatura Ambiente
20.
Sci Rep ; 9(1): 2089, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765762

RESUMO

Falls in late postmenopausal women with osteopenia usually cause fractures with severe consequences. This 36-month randomized, double-blind and placebo-controlled trial with a 10-year observational follow-up study aimed to investigate the long-term effect of herbal formula Bushen Yijing Fang (BSYJF) on fall risk in the late postmenopausal women with osteopenia. 140 late postmenopausal women (Femoral neck T-score, -2.5~-2 SD) were recruited and randomized to orally receive calcium carbonate 300 mg daily with either BSYJF or placebo for 36 months. The effect was further investigated for another 10-year follow-up. During the 36-month administration, there were 12 falls in BSYJF group and 28 falls in placebo group, respectively, indicating 64% lower risk of falls (RR 0.36 [95% CI, 0.18 to 0.71]; P = 0.004) in BSYJF group. During the 10-year follow-up, 36% lower fall risk (RR 0.64 [95% CI, 0.46 to 0.89]; P = 0.009) was observed in BSYJF group. No significant difference was found in safety profile between two groups. Thirty-six-month administration of BSYJF reduced fall risk with an increase in bone mass, and its latent effect on fall risk was continually observed in the 10-year follow-up in late postmenopausal women with osteopenia. This clinical trial was registered at Chinese clinical trial registry (ChiCTR-IOR-16008942).

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