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1.
Calcif Tissue Int ; 114(6): 614-624, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38714533

RESUMO

To construct a nomogram based on clinical factors and paraspinal muscle features to predict vertebral fractures occurring after acute osteoporotic vertebral compression fracture (OVCF). We retrospectively enrolled 307 patients with acute OVCF between January 2013 and August 2022, and performed magnetic resonance imaging of the L3/4 and L4/5 intervertebral discs (IVDs) to estimate the cross-sectional area (CSA) and degree of fatty infiltration (FI) of the paraspinal muscles. We also collected clinical and radiographic data. We used univariable and multivariable Cox proportional hazards models to identify factors that should be included in the predictive nomogram. Post-OVCF vertebral fracture occurred within 3, 12, and 24 months in 33, 69, and 98 out of the 307 patients (10.8%, 22.5%, and 31.9%, respectively). Multivariate analysis revealed that this event was associated with percutaneous vertebroplasty treatment, higher FI at the L3/4 IVD levels of the psoas muscle, and lower relative CSA of functional muscle at the L4/5 IVD levels of the multifidus muscle. Area under the curve values for subsequent vertebral fracture at 3, 12, and 24 months were 0.711, 0.724, and 0.737, respectively, indicating remarkable accuracy of the nomogram. We developed a model for predicting post-OVCF vertebral fracture from diagnostic information about prescribed treatment, FI at the L3/4 IVD levels of the psoas muscle, and relative CSA of functional muscle at the L4/5 IVD levels of the multifidus muscle. This model could facilitate personalized predictions and preventive strategies.


Assuntos
Fraturas por Osteoporose , Músculos Paraespinais , Fraturas da Coluna Vertebral , Humanos , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Músculos Paraespinais/patologia , Músculos Paraespinais/diagnóstico por imagem , Feminino , Masculino , Idoso , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Fraturas por Compressão/diagnóstico por imagem , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Nomogramas
2.
Funct Integr Genomics ; 23(1): 27, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598700

RESUMO

We aimed to investigate the inhibitory effect of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes (hucMSC-Exos) transmitting microRNA-342-5p (miR-342-5p) on the development of preeclampsia (PE) by targeting programmed cell death 4 (PDCD4). The primary hucMSCs were cultured and transfected with miR-342-5p, and the exosomes (Exo) were extracted from the hucMSCs. PE rats were performed with an intraperitoneal injection of L-NAME from days 11 to 19 of gestation, and injection of Exo, Exo-negative control (NC), Exo-miR-342-5p agomir, Exo-miR-342-5p antagomir, and overexpressing PDCD4 (oe-PDCD4) vector into the placenta on the 16th day of pregnancy. HE staining was utilized to observe the pathological changes in placental tissues. TUNEL staining was implemented to evaluate cell apoptosis in placental tissues. Blood pressure and 24-h urinary protein in pregnant rats were measured by a non-invasive rat tail artery blood pressure measurement and protein auto-analyzer. Expressions of miR-342-5p, PDCD4, proinflammatory cytokines (TNF-α and IL-1ß), and anti-inflammatory cytokines (IL-10 and TGF-ß) were detected by RT-qPCR, and PDCD4 protein expression was determined by Western blot. The interaction between miR-342-5p and PDCD4 was analyzed by luciferase activity assay. MiR-342-5p was downregulated while PDCD4 was upregulated in the placental tissues of PE rats. HucMSC-Exo relieved pathology and suppressed inflammatory response, and apoptosis in the placental tissues, as well as reducing blood pressure and 24-h urinary protein of PE rats. Elevated miR-342-5p enhanced the promoting influence of hucMSC-Exo on PE rats, while inhibited miR-342-5p reversed the functions of hucMSC-Exo on PE rats. miR-342-5p targeted PDCD4. Overexpression of PDCD4 worsened the development of PE in rats. HucMSC-Exo conveying elevated miR-342-5p inhibits the development of PE in a rat model through downregulating PDCD4.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Pré-Eclâmpsia , Humanos , Ratos , Feminino , Gravidez , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Placenta/metabolismo , Citocinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo
3.
J Assist Reprod Genet ; 40(1): 201-210, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36471201

RESUMO

BACKGROUND: The mechanisms underlying the pathogenesis of preeclampsia (PE) remains unclear. Exploring the molecular players in PE progression can provide insights into targeted therapy. METHODS: The expression levels of circSTAM in placental chorionic tissues of PE patients and normal pregnant women were compared by RT-qPCR. CircSTAM was knocked down by small interfering RNA to investigate its role in migration, invasion and epithelial-mesenchymal transformation (EMT) of trophoblast HTR-8/SVneo cells. The downstream target of circSTAM was predicted using online bioinformatics resources, and their molecular interaction was examined by luciferase reporter assay. RESULTS: CircSTAM was upregulated in PE placenta tissues in comparison to normal placental tissues. CircSTAM knockdown significantly enhanced cellular invasion, migration, as well as EMT. Mir-148a-5p was identified as a target of circSTAM to regulate cell migration and invasion. Mir-148a-5p negatively regulated PTEN expression in trophoblast HTR-8 /SVneo cells. CONCLUSION: In summary, circSTAM upregulation in PE trophoblasts promoted the invasion, migration and EMT. CircSTAM may modulate trophoblast phenotype by impinging on mir-148a-5p/PTEN axis. These data provided novel insights into the pathogenesis of PE.


Assuntos
MicroRNAs , Pré-Eclâmpsia , Feminino , Humanos , Gravidez , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Interferente Pequeno , Trofoblastos/metabolismo , Regulação para Cima
4.
Chirality ; 34(1): 77-85, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34747045

RESUMO

Chiral amine-squaramide is a kind of effective hydrogen bond donor bifunctional catalyst to promote many asymmetric transformations. In this paper, novel chiral tertiary amine-squaramide derived from the natural product of the stevioside was developed and applied into the asymmetric Michael addition of acetylacetone to nitroolefins. This asymmetric reaction performed well, and a series of enantiomerically enriched compounds were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee).


Assuntos
Alcenos , Diterpenos do Tipo Caurano , Pentanonas , Quinina/análogos & derivados , Estereoisomerismo
5.
Chirality ; 34(2): 325-332, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34904287

RESUMO

A newly tertiary amine-squaramide organocatalyst has been successfully developed and applied into the asymmetric Michael addition of 4-hydroxycoumarin to ß,γ-unsaturated α-ketoesters. The catalyst system performed well with a low catalyst loading of 1 mol% under mild reaction conditions. A series of coumarin derivatives were obtained in good to high yields (up to 97%) with high enantioselectivities (up to 96% ee).


Assuntos
Aminas , Cumarínicos , Catálise , Diterpenos do Tipo Caurano , Quinina/análogos & derivados , Estereoisomerismo
6.
Protein Expr Purif ; 185: 105898, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33962003

RESUMO

Nutraceuticals containing modified starch with increased content of slowly-digestible starch (SDS) may reduce the prevalence of obesity, diabetes and cardiovascular diseases due to its slow digestion rate. Enzymatic methods for the preparation of modified starch have attracted increasing attention because of their low environmental impact, safety and specificity. In this study, the efficient glucan branching enzyme McGBE from Microvirga sp. MC18 was identified, and its relevant properties as well as its potential for industrial starch modification were evaluated. The purified McGBE exhibited the highest specificity for potato starch, with a maximal specific activity of 791.21 U/mg. A time-dependent increase in the content of α-1,6 linkages from 3.0 to 6.0% was observed in McGBE-modified potato starch. The proportion of shorter chains (degree of polymerization, DP < 13) increased from 29.2 to 63.29% after McGBE treatment, accompanied by a reduction of the medium length chains (DP 13-24) from 52.30 to 35.99% and longer chains (DP > 25) from 18.51 to 0.72%. The reduction of the storage modulus (G') and retrogradation enthalpy (ΔHr) of potato starch with increasing treatment time demonstrated that McGBE could inhibit the short- and long-term retrogradation of starch. Under the optimal conditions, the SDS content of McGBE-modified potato starch increased by 65.8% compared to native potato starch. These results suggest that McGBE has great application potential for the preparation of modified starch with higher SDS content that is resistant to retrogradation.


Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/química , Proteínas de Bactérias/química , Suplementos Nutricionais/análise , Methylobacteriaceae/enzimologia , Amido/química , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Enzima Ramificadora de 1,4-alfa-Glucana/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Hidrólise , Cinética , Methylobacteriaceae/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
7.
J Org Chem ; 86(4): 3546-3554, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33538590

RESUMO

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.


Assuntos
Cianamida , Guanidinas , Reação de Cicloadição , Guanidina , Hidrólise
8.
Biochem Biophys Res Commun ; 524(1): 96-102, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980173

RESUMO

Mesothelin (MSLN) has been reported to be overexpressed in ovarian cancer and may be an ideal target for immunotherapy. Recent studies have suggested that natural killer (NK) cells may be better chimeric antigen receptor (CAR) drivers because of their favorable innate characteristics, such as directly recognizing and killing tumor cells, resulting in a graft-versus-tumor effect but irresponsible for graft-versus-host disease (GVHD). The therapeutic effects of CAR-engineered NK cells targeting MSLN in ovarian cancer have not been evaluated. In this study, MSLN- and CD19-targeted CAR NK-92 (MSLN- and CD19-CAR NK) cells were constructed. Both MSLN- and CD19-CAR molecules were highly expressed on the surface of NK-92 cells following lentiviral gene transduction. MSLN-CAR NK cells specifically killed MSLN-positive ovarian cancer cells (OVCAR-3 and SK-OV-3), rather than MSLN-negative cells (SK-HEP-1), in vitro. Moreover, compared with parental NK-92 cells and CD19-CAR NK cells, stronger cytokine secretion was detected in MSLN-CAR NK cells cocultured with OVCAR-3 and SK-OV-3. Furthermore, MSLN-CAR NK cells effectively eliminated ovarian cancer cells in both subcutaneous and intraperitoneal tumor models; these cells also significantly prolonged the survival of intraperitoneally tumor-bearing mice. These results demonstrate that MSLN-CAR NK cells have robust specific antitumor activity, both in vitro and in vivo, suggesting that mesothelin could be a potential target for CAR NK cells and could be applied in the treatment of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Antígenos CD19/metabolismo , Apoptose , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Humanos , Imunoterapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/metabolismo , Lentivirus/genética , Mesotelina , Camundongos , Modelos Biológicos , Neoplasias Experimentais , Transfecção
9.
J Appl Toxicol ; 40(8): 1141-1152, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32187393

RESUMO

T-2 toxin is one of the most toxic trichothecenes and harmful to human health and animal husbandry. The mechanism underlying its growth suppression remains unclear, especially for mitochondrial damage in human gastric epithelial cells. In the present study, we investigated cell death caused by T-2 toxin in a human gastric epithelial cell line (GES-1) and the possible mechanism of T-2-induced cytotoxicity. T-2 strongly reduced the viability of GES-1 cells in a time- and dose-dependent manner within a small range of concentrations. However, when the concentrations of T-2 were >40 nM, there was no concentration dependence, only time dependence. Moreover, T-2 induced apoptosis, with the activation of caspase-3 in GES-1 and mitochondrial membrane potential (MMP) decrease and cytochrome c release. T-2 also resulted in the accumulation of reactive oxygen species (ROS) and DNA damage with a positive signal of p-H2A.X in GES-1 cells. While T-2 caused a MMP decrease, DNA damage and cell death were not blocked by pretreatment with 3 mM glutathione (GSH), a typical scavenger of ROS. The induction of mitochondrial permeability transition pore (mPTP) regulators voltage-dependent anion channel (VDAC1) and cyclophilin D (CypD) were also observed in T-2-treated cells. Interestingly, cyclosporine A (CsA), a CypD inhibitor, significantly reversed the drop in MMP and the DNA damage, as well as ROS accumulation caused by T-2. Additionally, GES-1 cell death could also be protected to some extent by 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), an inhibitor of VDAC1, especially the combination of CsA and DIDS, and 3 mM GSH could further enhance the effect of CsA + DIDS on cell viability. In conclusion, our present findings indicate that the T-2 induced MMP decrease, DNA damage and cell death, as well as ROS accumulation in GES-1 cells, starts with T-2 directly perturbing the mitochondria triggering ROS generation by acting on CypD and VDAC1. This study presents a new viewpoint for evaluating the toxicity of T-2 toxin.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Gástricas/fisiopatologia , Toxina T-2/toxicidade , Carga Tumoral/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Humanos
10.
Org Biomol Chem ; 17(41): 9200-9208, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31596301

RESUMO

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

11.
Zhongguo Zhong Yao Za Zhi ; 39(19): 3846-9, 2014 Oct.
Artigo em Zh | MEDLINE | ID: mdl-25612452

RESUMO

OBJECTIVE: To observe the changes in Aß40, Aß42 and ADDLs in brains of 3 month-old APPswe/PS1dE9 double transgenic mice after six-month intervention with curcumin, in order to discuss the neuroprotective effect of curcumin. METHOD: APPswe/PS1dE9dtg mice were randomly divided into the model group, the Rosiglitazone group (10 mg x kg(-1) x d(-1)) and curcumin high (400 mg x kg9-1) x d(-1)), medium (200 mg x kg(-1) x d(-1)) and low (100 mg x kg(-1) x d(-1)) dosage groups, with C57/BL6J mice of the same age and the same background in the normal control group. After 6 months, the immunohistochemical staining (IHC) and the Western blot method were used to observe the changes in positive cell of Aß40, Aß42 and ADDLs in hippocampal CA1 area, their distribution and protein expressions. RESULT: Both of the immunohistochemical staining and the Western blot method showed more positive cell of Aß40, Aß42 and ADDLs in hippocampal CA1 area and higher protein expressions in the model group than the normal group (P < 0.01). IHC showed a lower result in the Rosiglitazone group than the model group (P < 0.05), while Western blot showed a much lower result (P < 0.01). The number of Aß40, Aß42 and ADDLs positive cells and the protein expressions decreased in the curcumin high group, the medium group showed a significant decrease (P < 0.01), and the low dose group also showed reductions in the protein expressions of Aß40 and Aß42. CONCLUSION: The six-month intervention with curcumin can significantly reduce the expressions of hippocampal Aß40, Aß42 and ADDLs in brains of APPswe/PS1dE9 double transgenic mice. Whether curcumin can impact Aß cascade reaction by down-regulating expressions of Aß40, Aß42 and ADDLs and show the neuroprotective effect needs further studies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcumina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
12.
Zhongguo Zhong Yao Za Zhi ; 38(9): 1310-3, 2013 May.
Artigo em Zh | MEDLINE | ID: mdl-23944058

RESUMO

OBJECTIVE: Through the dynamic detection of the concentration change of the urine Alzheimer-associated neuronal thread protein (AD7C-NTP) in the curcumin treated Alzheimer's disease (AD) model (APP/PS1 double transgenic) mice, the therapeutic effect of curcumin in AD was determined. METHOD: Thirty three-month-old APP /PS1 double transgenic mice were randomly divided into 5 groups, 6 in each group, the model group, rosiglitazone group(10 mg . kg-1 . d-1) , high(400 mg . kg -1 . d-1) , medium(200 mg . kg-1. d-1) and low(100 mg . kg-1 . d-1) dose curcumin groups. Six C57BL/6J mice in the same age and genetic background were used as normal control group. All the 6 groups of mice were intragastrically administered for 6 months. Urine samples were collected on 4 month, 5 month and 6 month after intragastric administration, respectively. The changes of urinary AD7C-NTP concentration were detected by enzyme-linked immunosorbent assay (ELISA). RESULT: The concentration of AD7C-NTP of each group was compared at the same time point, the concentration of model group is higher than normal control group (P <0.05) ; the concentration of other groups is lower than model group. The concentration of high curcumin dose group with 4 months treatment, has no statistical difference compared with model group. The AD7C-NTP concentration of each group was elevated with the age growth, and all concentrations of the treatment groups were lower than the model group at the same period. With the treatment of 4, 5 and 6 months, the concentration of the normal control group has significant difference with the treatment groups(P <0. 01). There have no statistical difference between all the groups with the treatment of 6 months compared with 5 months. CONCLUSION: With the progression of the disease in AD mice, there are fluctuations in urinary AD7C-NTP concentration, the compound curcumin from traditional Chinese medicine can delay the progression of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/urina , Curcumina/uso terapêutico , Proteínas do Tecido Nervoso/urina , Animais , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Transgênicos , Rosiglitazona , Tiazolidinedionas/uso terapêutico
13.
Small Methods ; 7(2): e2201156, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610015

RESUMO

Printed electronics, which fabricate electrical components and circuits on various substrates by leveraging functional inks and advanced printing technologies, have recently attracted tremendous attention due to their capability of large-scale, high-speed, and cost-effective manufacturing and also their great potential in flexible and wearable devices. To further achieve multifunctional, practical, and commercial applications, various printing technologies toward smarter pattern-design, higher resolution, greater production flexibility, and novel ink formulations toward multi-functionalities and high quality have been insensitively investigated. 2D materials, possessing atomically thin thickness, unique properties and excellent solution-processable ability, hold great potential for high-quality inks. Besides, the great variety of 2D materials ranging from metals, semiconductors to insulators offers great freedom to formulate versatile inks to construct various printed electronics. Here, a detailed review of the progress on 2D material inks formulation and its printed applications has been provided, specifically with an emphasis on emerging printed memristors. Finally, the challenges facing the field and prospects of 2D material inks and printed electronics are discussed.

14.
J Agric Food Chem ; 71(13): 5185-5194, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-36943701

RESUMO

Antimicrobial peptides (AMPs) play essential roles in maintaining intestinal health and have been suggested as possible therapeutic strategies against inflammatory bowel disease (IBD). However, the instability of AMPs in the process of transmission in vivo limits their application in the treatment of IBD. In this study, we constructed the mBD14-producing Lactococcus lactis NZ9000 (L. lactis/mBD14) to achieve enteric delivery of mBD14 and evaluated its protective effect on dextran sodium sulfate (DSS)-induced colitis. Mice treated with L. lactis/mBD14 exhibited milder symptoms of colitis (P < 0.01). Additionally, L. lactis/mBD14 treatment reversed DSS-induced epithelial dysfunction and reduced the production of pro-inflammatory cytokines in colon (P < 0.01). Mechanistically, L. lactis/mBD14 significantly inhibited NOD-like receptor pyrin domain containing three inflammasome-mediated pro-inflammatory response (P < 0.05) and regulated microbiota homeostasis by promoting the abundance of probiotic bacteria Akkermansia muciniphila and Faecalibacterium prausnitzii and decreasing the pathogenic Escherichia coli (P < 0.01). Taken together, this study demonstrates the protective effect of L. lactis/mBD14 in DSS-induced colitis, and suggests that oral administration of L. lactis/mBD14 may represent a potential therapeutic strategy for IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Lactococcus lactis , beta-Defensinas , Animais , Camundongos , beta-Defensinas/genética , Doenças Inflamatórias Intestinais/terapia , Lactococcus lactis/genética , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
15.
Nat Commun ; 13(1): 6203, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36261437

RESUMO

The complex immunosuppressive tumour microenvironment (TME) and lack of tumour-specific targets hinder the application of chimeric antigen receptor (CAR) T cells in the treatment of solid tumours. Combining local treatment with CAR T cell immunotherapy may regulate the TME and enhance the killing potency of CAR T cells in solid tumours. Here, we show that AXL, which is highly expressed in non-small cell lung cancer (NSCLC) but not in normal tissues, might be a target for CAR T cell therapy. AXL-CAR T cells alone cause moderate tumour regression in subcutaneous and pulmonary metastatic lung cancer cell-derived xenograft models. Combination of microwave ablation (MWA) and AXL-CAR T cells have superior antitumour efficacy. MWA enhances the activation, infiltration, persistence and tumour suppressive properties of AXL-CAR T cells in AXL-positive NSCLC patient-derived xenograft tumours via TME remodelling. The combination therapy increases the mitochondrial oxidative metabolism of tumour-infiltrating CAR T cells. Combination treatment induces significant tumour suppression without observed toxicities in humanized immunocompetent mice. The synergistic therapeutic effect of MWA and AXL-CAR T cells may be valuable for NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptores de Antígenos Quiméricos , Humanos , Camundongos , Animais , Microambiente Tumoral , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Micro-Ondas , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Imunoterapia , Fatores Imunológicos/metabolismo , Linfócitos T
16.
Front Genet ; 12: 779186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899863

RESUMO

Diabetes mellitus is a group of complex metabolic disorders which has affected hundreds of millions of patients world-widely. The underlying pathogenesis of various types of diabetes is still unclear, which hinders the way of developing more efficient therapies. Although many genes have been found associated with diabetes mellitus, more novel genes are still needed to be discovered towards a complete picture of the underlying mechanism. With the development of complex molecular networks, network-based disease-gene prediction methods have been widely proposed. However, most existing methods are based on the hypothesis of guilt-by-association and often handcraft node features based on local topological structures. Advances in graph embedding techniques have enabled automatically global feature extraction from molecular networks. Inspired by the successful applications of cutting-edge graph embedding methods on complex diseases, we proposed a computational framework to investigate novel genes associated with diabetes mellitus. There are three main steps in the framework: network feature extraction based on graph embedding methods; feature denoising and regeneration using stacked autoencoder; and disease-gene prediction based on machine learning classifiers. We compared the performance by using different graph embedding methods and machine learning classifiers and designed the best workflow for predicting genes associated with diabetes mellitus. Functional enrichment analysis based on Human Phenotype Ontology (HPO), KEGG, and GO biological process and publication search further evaluated the predicted novel genes.

17.
Cell Death Dis ; 12(3): 237, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664249

RESUMO

Cucurbitacin B (CuB) is a widely available triterpenoid molecule that exhibits various biological activities. Previous studies on the anti-tumour mechanism of CuB have mostly focused on cell apoptosis, and research on the ferroptosis-inducing effect has rarely been reported. Herein, we first discovered the excellent cytotoxicity of CuB towards human nasopharyngeal carcinoma cells and elucidated its potential ferroptosis-inducing mechanisms. Morphology alterations of mitochondrial ultrastructure, as observed via transmission electron microscopy, showed that CuB-treated cells undergo ferroptosis. CuB caused intracellular accumulation of iron ions and depletion of glutathione. Detailed molecular mechanism investigation confirmed that CuB both induced widespread lipid peroxidation and downregulated the expression of GPX4, ultimately initiating a multipronged mechanism of ferroptosis. Furthermore, CuB exhibited anti-tumour effects in vitro by inhibiting cellular microtubule polymerization, arresting cell cycle and suppressing migration and invasion. Finally, CuB significantly inhibited tumour progression without causing obvious side effects in vivo. Altogether, our study highlighted the therapeutic potential of CuB as a ferroptosis-inducing agent for nasopharyngeal cancer, and it provided valuable insights for developing effective anti-tumour agents with novel molecular mechanisms derived from natural products.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ferroptose/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Triterpenos/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Biol Macromol ; 184: 551-557, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171255

RESUMO

Modified potato starch with slower digestion may aid the development of new starch derivatives with improved nutritional values, and strategies to increase nutritional fractions such as resistant starch (RS) are desired. In this study, a correspondence between starch structure and enzymatic resistance was provided based on the efficient branching enzyme AqGBE, and modified starches with different amylose content (Control, 100%; PS1, 90%; PS2, 72%; PS3, 32%; PS4, 18%) were prepared. Through SEM observation, NMR and X-ray diffraction analyses, we identified that an increased proportion of α-1,6-linked branches in potato starch changes its state of granule into large pieces with crystallinity. Molecular weight and chain-length distribution analysis showed a decrease of molecular weight (from 1.1 × 106 to 1.1 × 105 g/mol) without an obvious change of chain-length distribution in PS1, while PS2-4 exhibited an increased proportion of DP 6-12 with a stable molecular weight distribution, indicating a distinct model of structural modification by AqGBE. The enhancement of peak viscosity was related to increased hydrophobic interactions and pieces state of PS1, while the contents of SDS and RS in PS1 increased by 37.7 and 49.4%, respectively. Our result provides an alternative way to increase the RS content of potato starch by branching modification.


Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/metabolismo , Burkholderiales/enzimologia , Solanum tuberosum/química , Amido/química , Amilose/química , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Estrutura Molecular , Peso Molecular , Viscosidade , Difração de Raios X
19.
J Hematol Oncol ; 14(1): 118, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325726

RESUMO

Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7 × 19) and found that these 7 × 19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7 × 19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7 × 19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7 × 19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7 × 19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor. Trial registration: NCT03198546. Registered 26 June 2017, https://clinicaltrials.gov/ct2/show/NCT03198546?term=NCT03198546&draw=2&rank=1.


Assuntos
Quimiocina CCL19/imunologia , Proteínas Ligadas por GPI/análise , Glipicanas/análise , Imunoterapia Adotiva/métodos , Interleucina-7/imunologia , Neoplasias/terapia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Feminino , Proteínas Ligadas por GPI/imunologia , Glipicanas/imunologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Mesotelina , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Linfócitos T/imunologia , Resultado do Tratamento
20.
Chem Asian J ; 15(5): 560-563, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31903670

RESUMO

An efficient preparation of sulfamate-fused 2-aminopyrroles was achieved through an isocyanide-based three-component [1+2+2] annulation of isocyanides, dialkyl acetylenedicarboxylates, and sulfamate-derived cyclic imines in good to excellent yields (up to 99 %). This reaction proceeds smoothly without any activation or modification of substances under neutral and metal-free conditions. The reaction could also be conveniently performed on a gram scale.

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