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1.
Funct Integr Genomics ; 24(4): 127, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39014225

RESUMO

Prostate cancer is a major medical problem for men worldwide. Advanced prostate cancer is currently incurable. Recently, much attention was paid to the role of GPC2 in the field of oncology. Nevertheless, there have been no investigations of GPC2 and its regulatory mechanism in prostate cancer. Here, we revealed a novel action of GPC2 and a tumor promoting mechanism in prostate cancer. GPC2 was upregulated in prostate cancer tissues and cell lines. Higher expression of GPC2 was correlated with higher Gleason score, lymphatic metastasis, and worse overall survival in prostate cancer patients. Decreased expression of GPC2 inhibited cell proliferation, migration, and invasion in prostate cancer, whereas GPC2 overexpression promoted these properties. Mechanistically, GPC2 promoted the activation of PI3K/AKT signaling pathway through MDK. The rescue assay results in prostate cancer cells demonstrated that overexpression of MDK could attenuate GPC2 knockdown induced inactivation of PI3K/AKT signaling and partly reverse GPC2 knockdown induced inhibition of cell proliferation, migration, and invasion. In all, our study identified GPC2 as an oncogene in prostate cancer. GPC2 promoted prostate cancer cell proliferation, migration, and invasion via MDK-mediated activation of PI3K/AKT signaling pathway. GPC2 might be a promising prognosis predictor and potential therapeutic target in prostate cancer.


Assuntos
Movimento Celular , Proliferação de Células , Glipicanas , Fosfatidilinositol 3-Quinases , Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Masculino , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Linhagem Celular Tumoral , Glipicanas/metabolismo , Glipicanas/genética , Regulação Neoplásica da Expressão Gênica , Progressão da Doença
2.
J Nanobiotechnology ; 22(1): 95, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448959

RESUMO

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) remains suboptimal, characterized by high recurrence and metastasis rates. Although metalloimmunotherapy has shown potential in combating tumor proliferation, recurrence and metastasis, current apoptosis-based metalloimmunotherapy fails to elicit sufficient immune response for HCC. RESULTS: A smart responsive bimetallic nanovaccine was constructed to induce immunogenic cell death (ICD) through pyroptosis and enhance the efficacy of the cGAS-STING pathway. The nanovaccine was composed of manganese-doped mesoporous silica as a carrier, loaded with sorafenib (SOR) and modified with MIL-100 (Fe), where Fe3+, SOR, and Mn2+ were synchronized and released into the tumor with the help of the tumor microenvironment (TME). Afterward, Fe3+ worked synergistically with SOR-induced immunogenic pyroptosis (via both the classical and nonclassical signaling pathways), causing the outflow of abundant immunogenic factors, which contributes to dendritic cell (DC) maturation, and the exposure of double-stranded DNA (dsDNA). Subsequently, the exposed dsDNA and Mn2+ jointly activated the cGAS-STING pathway and induced the release of type I interferons, which further led to DC maturation. Moreover, Mn2+-related T1 magnetic resonance imaging (MRI) was used to visually evaluate the smart response functionality of the nanovaccine. CONCLUSION: The utilization of metallic nanovaccines to induce pyroptosis-mediated immune activation provides a promising paradigm for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Nanovacinas , Carcinoma Hepatocelular/terapia , Piroptose , Imunoterapia , Microambiente Tumoral
3.
Mar Drugs ; 22(3)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38535465

RESUMO

To improve the survivability of probiotics, Lactobacillus plantarum was microencapsulated using pufferfish skin gelatin (PSG)-based wall materials by spray-drying. This work investigated the protective effect of three different pH-dependent proteins (sodium caseinate (SC), soy protein isolate (SPI), and whey protein isolate (WPI)) combined with PSG on L. plantarum. The experimental results of spray-drying with an inlet temperature of 120 °C and an outlet temperature of 80 °C, storage at 4 °C for 6 months, simulated digestion, and turbidity indicated that PSG/SC had better stability and encapsulation effects and was more suitable to encapsulate L. plantarum than PSG/SPI and PSG/WPI. The optimum preparation conditions for L. plantarum microcapsules were a PSG/SC mass ratio of 2:1, an SC concentration of 20 g/L, and a cell concentration of 10 g/L. The encapsulation efficiency of the obtained microcapsules was 95.0%, and the survival rate was 94.2% in simulated gastric fluid for 2 h and 98.0% in simulated intestinal fluid for 2 h. Amino acid composition analysis exhibited that the imino acid and aspartic acid contents of PSG were 27.98 and 26.16 g/100 g protein, respectively, which was much higher than commercial bovine gelatin. This characteristic was favorable to the high encapsulation efficiency and stability of microcapsules. In vitro release experiments showed that the PSG/SC microcapsules did not disintegrate in simulated gastric fluid for 2 h but could completely release in simulated intestinal fluid for 2 h, which can maintain the high survivability of L. plantarum in simulated digestion. In general, this study demonstrated that microcapsules using PSG/SC as wall materials can effectively improve the survivability of probiotics and have great potential for application in probiotic products.


Assuntos
Lactobacillus plantarum , Probióticos , Tetraodontiformes , Animais , Bovinos , Gelatina , Cápsulas , Cetonas
4.
Gastroenterology ; 162(7): 1948-1961.e7, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35202643

RESUMO

BACKGROUND & AIMS: Hepatocellular nodular lesions (HNLs) constitute a heterogeneous group of disorders. Differential diagnosis among these lesions, especially high-grade dysplastic nodules (HGDNs) and well-differentiated hepatocellular carcinoma (WD-HCC), can be challenging, let alone biopsy specimens. We aimed to develop a deep learning system to solve these puzzles, improving the histopathologic diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma), and background tissues (nodular cirrhosis, normal liver tissue). METHODS: The samples consisting of surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2 to 3 subspecialists. Four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) were used. Their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was further verified by comparing with that of 9 pathologists. RESULTS: We obtained 213,280 patches from 1115 whole-slide images of 738 patients. An optimal model was finally chosen based on F1 score and area under the curve value, named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists' majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. CONCLUSIONS: We first developed a deep learning diagnostic model for HNLs, which performed well and contributed to enhancing the diagnosis rate of early HCC and risk stratification of patients with HNLs. Furthermore, HnAIM had significant advantages in patch-level recognition, with important diagnostic implications for fragmentary or scarce biopsy specimens.


Assuntos
Carcinoma Hepatocelular , Aprendizado Profundo , Hiperplasia Nodular Focal do Fígado , Neoplasias Hepáticas , Inteligência Artificial , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia
5.
Int J Mol Sci ; 23(13)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35805918

RESUMO

S-TGA-1 and PGP-Me are native archaeal lipids associated with the bacteriorhodopsin (bR) trimer and contribute to protein stabilization and native dynamics for proton transfer. However, little is known about the underlying molecular mechanism of how these lipids regulate bR trimerization and efficient photocycling. Here, we explored the specific binding of S-TGA-1 and PGP-Me with the bR trimer and elucidated how specific interactions modulate the bR trimeric structure and proton release and uptake using long-term atomistic molecular dynamic simulations. Our results showed that S-TGA-1 and PGP-Me are essential for stabilizing the bR trimer and maintaining the coherent conformational dynamics necessary for proton transfer. The specific binding of S-TGA-1 with W80 and K129 regulates proton release on the extracellular surface by forming a "Glu-shared" model. The interaction of PGP-Me with K40 ensures proton uptake by accommodating the conformation of the helices to recruit enough water molecules on the cytoplasmic side. The present study results could fill in the theoretical gaps of studies on the functional role of archaeal lipids and could provide a reference for other membrane proteins containing similar archaeal lipids.


Assuntos
Bacteriorodopsinas , Archaea/metabolismo , Bacteriorodopsinas/química , Bacteriorodopsinas/metabolismo , Lipídeos/química , Estrutura Secundária de Proteína , Prótons
6.
Int J Mol Sci ; 22(24)2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34948384

RESUMO

Aromatic residues are highly conserved in microbial photoreceptors and play crucial roles in the dynamic regulation of receptor functions. However, little is known about the dynamic mechanism of the functional role of those highly conserved aromatic residues during the receptor photocycle. Tyrosine 185 (Y185) is a highly conserved aromatic residue within the retinal binding pocket of bacteriorhodopsin (bR). In this study, we explored the molecular mechanism of the dynamic coupling of Y185 with the bR photocycle by automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) calculations and molecular dynamic (MD) simulations based on chemical shifts obtained by 2D solid-state NMR correlation experiments. We observed that Y185 plays a significant role in regulating the retinal cis-trans thermal equilibrium, stabilizing the pentagonal H-bond network, participating in the orientation switch of Schiff Base (SB) nitrogen, and opening the F42 gate by interacting with the retinal and several key residues along the proton translocation channel. Our findings provide a detailed molecular mechanism of the dynamic couplings of Y185 and the bR photocycle from a structural perspective. The method used in this paper may be applied to the study of other microbial photoreceptors.


Assuntos
Bacteriorodopsinas/química , Halobacterium salinarum/química , Sítios de Ligação , Ligação de Hidrogênio , Luz , Simulação de Dinâmica Molecular , Conformação Proteica , Teoria Quântica , Retinaldeído/química , Tirosina/química
7.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921038

RESUMO

Hypericin (Hyp), well-known as an antidepressant, is mainly extracted from Hypericum perforatum. Although Hyp accumulation and biomass are greater at lower compared to higher temperature, the regulation mechanism has not been reported. Here, the physiological characteristics and transcriptome of H. perforatum grown at 15 and 22 °C were determined and analyzed by HPLC and de novo sequencing. The results showed that the stomatal density and opening percentages were 1.1- and 1.4-fold more, and the Hyp content was 4.5-fold greater at 15 °C compared to 22 °C. A total of 1584 differentially expressed genes (DEGs) were observed at 15 versus 22 °C, with 749 characterized genes, 421 upregulated (UR) and 328 downregulated (DR). Based on biological functions, 150 genes were associated with Hyp biosynthesis, plant growth and the stress response, including photosynthesis, carbohydrate metabolism, fatty acids metabolism, cytochrome P450 (CYPs), morpho-physiological traits, heat shock proteins (HSPs), cold-responsive proteins (CRPs) and transcription factors (TFs). The differential expression levels of the master genes were confirmed by qRT-PCR and almost consistent with their Reads Per kb per Million (RPKM) values. This physiological and transcriptomic analyses provided insight into the regulation mechanisms of low temperature enhancing Hyp biosynthesis in H. perforatum.


Assuntos
Hypericum/química , Perileno/análogos & derivados , Transcriptoma/genética , Antracenos , Perfilação da Expressão Gênica , Perileno/metabolismo , Temperatura
8.
Angew Chem Int Ed Engl ; 57(29): 8937-8941, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-29781190

RESUMO

While certain archaeal ion pumps have been shown to contain two chromophores, retinal and the carotenoid bacterioruberin, the functions of bacterioruberin have not been well explored. To address this research gap, recombinant archaerhodopsin-4 (aR4), either with retinal only or with both retinal and bacterioruberin chromophores, was successfully expressed together with endogenous lipids in H. salinarum L33 and MPK409 respectively. In situ solid-state NMR, supported by molecular spectroscopy and functional assays, revealed for the first time that the retinal thermal equilibrium in the dark-adapted state is modulated by bacterioruberin binding through a cluster of aromatic residues on helix E. Bacterioruberin not only stabilizes the protein trimeric structure but also affects the photocycle kinetics and the ATP formation rate. These new insights may be generalized to other receptors and proteins in which metastable thermal equilibria and functions are perturbed by ligand binding.


Assuntos
Proteínas Arqueais/metabolismo , Carotenoides/metabolismo , Halobacterium salinarum/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Proteínas Arqueais/química , Halobacterium salinarum/química , Isomerismo , Cinética , Multimerização Proteica , Estabilidade Proteica , Alinhamento de Sequência
9.
Am J Ther ; 23(4): e1009-15, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-23884077

RESUMO

Gout, an extremely painful arthritis with relapsing inflammatory attacks, is a common inflammatory joint disease in adults. We examined the therapeutic effect of ketotifen, a mast cell stabilizer, on monosodium urate (MSU) crystal-induced acute inflammation. Eight-week-old male Wistar rats were injected with MSU crystals (5 mg per rat) into air pouch. Ketotifen (0, 0.1, 03, and 1 mg/kg) was given 1 hour before MSU crystal injection. Lavage histamine, leukocyte counts, mast cell counts, nitric oxide, and proinflammatory mediator levels were assessed 12 hours after MSU injection. Ketotifen significantly inhibited MSU-induced mast cell activation and histamine concentration in air pouch lavage. Ketotifen dose-dependently inhibited MSU-initiated leukocyte infiltration into the air pouch. Furthermore, ketotifen significantly decreased proinflammatory mediators, including nitric oxide, interleukin-1ß, and interleukin-6, production in MSU-treated rats. Ketotifen may attenuate MSU-induced acute inflammation by inhibiting mast cell activation and leukocyte infiltration in rats. Furthermore, ketotifen has the potential to be a new approach in managing patients with gouty inflammation in the future.


Assuntos
Anti-Inflamatórios/farmacologia , Gota/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Cetotifeno/farmacologia , Mastócitos/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gota/induzido quimicamente , Inflamação/induzido quimicamente , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Cetotifeno/administração & dosagem , Contagem de Leucócitos , Masculino , Óxido Nítrico/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Ácido Úrico/farmacologia
10.
Chin J Traumatol ; 19(1): 31-4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27033270

RESUMO

PURPOSE: To investigate the usefulness of three-dimensional (3D) printing in complex spinal surgery. METHODS: The study was conducted from October 2014 to March 2015 in Shenzhen Second Peoples' Hospital and 4 cases of complex severe spinal disorders were selected from our department. Among them one patient combined with congenital scoliosis, one with atlas neoplasm, one with atlantoaxial dislocation, and the rest one with atlantoaxial fracture-dislocation. The data of the diseased region was collected from computerized tomography scans for 3D digital reconstruction and rapid prototyping to prepare photosensitive resin models, which were applied in the treatment of these cases. RESULTS: The use of 3D models reduced operating time and intraoperative blood loss as well as the risk of postoperative complications. Furthermore, no pedicle penetrations or screw misplacement occurred according to the postoperative planar radiographic images. CONCLUSION: The tactile models from 3D printing allow direct observation and measurement, helping the orthopedists to have accurate morphometric information to provide personalized surgical planning and better communication with the patient and coworkers. Moreover, the photosensitive resin models can also guide the actual surgery with the drilling of pedicle screws and safe resection of tumor.


Assuntos
Impressão Tridimensional , Doenças da Coluna Vertebral/cirurgia , Idoso , Criança , Humanos , Masculino , Medicina de Precisão , Escoliose/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Neoplasias da Coluna Vertebral/cirurgia
11.
Opt Express ; 23(11): 14603-11, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26072820

RESUMO

We demonstrated a laser depth imaging system based on the time-correlated single-photon counting technique, which was incorporated with a low-jitter superconducting nanowire single-photon detector (SNSPD), operated at the wavelength of 1550 nm. A sub-picosecond time-bin width was chosen for photon counting, resulting in a discrete noise of less than one/two counts for each time bin under indoor/outdoor daylight conditions, with a collection time of 50 ms. Because of the low-jitter SNSPD, the target signal histogram was significantly distinguishable, even for a fairly low retro-reflected photon flux. The depth information was determined directly by the highest bin counts, instead of using any data fitting combined with complex algorithms. Millimeter resolution depth imaging of a low-signature object was obtained, and more accurate data than that produced by the traditional Gaussian fitting method was generated. Combined with the intensity of the return photons, three-dimensional reconstruction overlaid with reflectivity data was realized.

12.
J Pineal Res ; 59(2): 190-205, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25975679

RESUMO

Mesenchymal stem cells (MSCs) represent an attractive source for stem cell-based regenerative therapy, but they are vulnerable to oxidative stress-induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSCs against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSCs from premature senescence induced by hydrogen peroxide (H2 O2 ) via the silent information regulator type 1 (SIRT1)-dependent pathway. In response to H2 O2 at a sublethal concentration of 200 µm, human bone marrow-derived MSCs (BM-MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H2 O2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H2 O2 exposure successfully reversed the senescent phenotypes of BM-MSCs in a dose-dependent manner. This result was made evident by improved cell proliferation, decreased senescence-associated ß-galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 µm melatonin restored the osteogenic differentiation potential of BM-MSCs that was inhibited by H2 O2 -induced premature senescence. We also found that melatonin attenuated the H2 O2 -stimulated phosphorylation of p38 mitogen-activated protein kinase, decreased expression of the senescence-associated protein p16(INK) (4α) , and increased SIRT1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin-mediated antisenescence effects. Inhibition of SIRT1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed the senescence in cells through the SIRT1-dependent pathway. Together, these findings lay new ground for understanding oxidative stress-induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell-based regenerative medicine.


Assuntos
Senescência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melatonina/farmacologia , Células-Tronco Mesenquimais/enzimologia , Sirtuína 1/metabolismo , Benzamidas/farmacologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Naftóis/farmacologia , Fase S/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Arch Gynecol Obstet ; 290(5): 943-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24866887

RESUMO

PURPOSE: Study of the molecular variation in pre-eclampsia placenta based on micro-Raman spectroscopy. METHODS: Five pregnant women with pre-eclampsia from Nanfang hospital were selected as study group whose average age is 28.5 years and 38 ± 2 weeks gestation. The same period of healthy pregnant women, whose average age is 27.6 years and pregnant 39 ± 1 weeks, as control group (n = 5). The normal and pre-eclamptic placental tissues are detected by micro-Raman spectroscopy with the spectrum resolution of 1 cm(-1). RESULTS: We find that the protein structure of α-helix, ß-pleated sheet and ß-turn is overlying in pre-eclamptic placenta, which lead to a disorder of protein structure. The Raman peaks assigned to tryptophan indole ring and phenylalanine in pre-eclamptic placental tissue are more higher than that in normal tissue. CONCLUSIONS: Results suggest that the ordered structures of the main chain in protein molecules are reduced significantly, and the amino acid of side chains is damaged obviously. And a principal component analysis is used to classify the Raman spectra between normal and pre-eclamptic placental tissues. This study presents that Raman spectroscopy has a great potential on the mechanism research and diagnosis of placental lesions.


Assuntos
Placenta/química , Pré-Eclâmpsia/diagnóstico , Proteínas da Gravidez/genética , Análise Espectral Raman/métodos , Adulto , Estudos de Casos e Controles , Feminino , Variação Genética , Idade Gestacional , Humanos , Gravidez , Proteínas da Gravidez/metabolismo , Análise de Componente Principal
14.
Macromol Biosci ; 24(2): e2300116, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37677756

RESUMO

The effectiveness of chemotherapy is primarily hindered by drug resistance, and autophagy plays a crucial role in overcoming this resistance. In this project, a human transferrin nanomedicine contains quercetin (a drug to induce excessive autophagy) and doxorubicin is developed (HTf@DOX/Qu NPs). The purpose of this nanomedicine is to enhance mitophagy and combating drug-resistant cancer. Through in vitro studies, it is demonstrated that HTf@DOX/Qu NPs can effectively downregulate cyclooxygenase-2 (COX-2), leading to an excessive promotion of mitophagy and subsequent mitochondrial dysfunction via the PENT-induced putative kinase 1 (PINK1)/Parkin axis. Additionally, HTf@DOX/Qu NPs can upregulate proapoptotic proteins to induce cellular apoptosis, thereby effectively reversing drug resistance. Furthermore, in vivo results have shown that HTf@DOX/Qu NPs exhibit prolonged circulation in the bloodstream, enhanced drug accumulation in tumors, and superior therapeutic efficacy compared to individual chemotherapy in a drug-resistant tumor model. This study presents a promising strategy for combating multidrug-resistant cancers by exacerbating mitophagy through the use of transferrin nanoparticles.


Assuntos
Nanopartículas , Neoplasias , Humanos , Nanomedicina/métodos , Mitofagia , Transferrina , Doxorrubicina/farmacologia
15.
Clin Res Hepatol Gastroenterol ; 48(7): 102388, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38810880

RESUMO

Acute pancreatitis (AP) is a frequent but severe abdominal emergency in general surgery with intestinal barrier dysfunction. Heat shock protein 70 (HSP70) is a ubiquitous molecular chaperone that has been proposed to exert favorable effects on AP. Nonetheless, the detailed impacts of HSP70 on the intestinal barrier function in AP are unknown, which will be investigated here. After the injection of sodium taurocholate into the biliopancreatic duct, the rat models of AP were established. After modeling, HSP70 expression was up-regulated through lentivirus infection. Western blot was used to detect HSP70 expression. H&E staining was used to examine the histological changes in the pancreatic and intestinal tissues. The levels of pancreatic biochemical markers and oxidative stress markers were detected using corresponding assay kits. ELISA was used to detect the levels of inflammatory cytokines and gastrointestinal function indicators. Immunofluorescence staining and Western blot were used to detect the expression of tight junction proteins. DCFH-DA probe and MitoSOX Red probe were used to detect total reactive oxygen species (ROS) and mitochondrial ROS (mtROS), respectively. TUNEL assay and Western blot were used to detect apoptosis. During the model construction, severe pancreatic and abnormal intestinal tissue abnormalities were observed, inflammatory response was activated and the intestinal barrier was disrupted. HSP70 expression was down-regulated in the intestinal tissues AP rat models. HSP70 ameliorated the morphological damage of pancreatic and intestinal tissues of AP rats. In addition, HSP70 significantly reduced intestinal barrier damage, inflammatory response, oxidative stress and apoptosis in the intestinal tissues of AP rat models. Collectively, HSP70 might attenuate AP through exerting anti-inflammatory, anti-oxidant, anti-apoptotic effects and inhibiting intestinal barrier disruption.

16.
J Cancer ; 15(8): 2380-2390, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38495480

RESUMO

Highly activated aerobic glycolysis provides the metabolic requirements for tumor cell growth and proliferation. Erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, has been reported to exert antitumor activity in multiple cancers. However, whether Erianin exerts inhibitory effects on aerobic glycolysis and the inherent mechanism remain poorly defined in non-small cell lung cancer (NSCLC). Here, we showed that Erianin inhibited the cell viability and proliferation, and induced apoptosis in NSCLC cells. Moreover, Erianin overtly suppressed aerobic glycolysis via decreasing HK2 expression. Mechanistically, Erianin dose-dependently curbed the Akt-GSK3ß signaling pathway phosphorylation activation, which afterwards downregulated HK2 expression. Meanwhile, Erianin inhibited HCC827 tumor growth in vivo. Taken together, our results suggest that the natural product Erianin can suppress aerobic glycolysis and exert potent anticancer effects via the Akt-GSK3ß signaling pathway in NSCLC cells.

17.
ACS Appl Bio Mater ; 7(3): 1990-1999, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38363728

RESUMO

The increasing severity of problems posed by drug-resistant pathogens has compelled researchers to explore innovative approaches for infection prevention. Among these strategies, conjugation methods stand out for their convenience and high efficacy. In this study, multiple covalent conjugates were synthesized, incorporating the natural antimicrobial peptide epsilon-poly-l-lysine (EPL) and two commonly used ß-lactam antibiotics: penicillin G or ampicillin. Enhanced antimicrobial efficacy against typical Gram-negative pathogens, along with faster kill kinetics compared to combination approaches, was demonstrated by the EPL-Ampicillin covalent conjugates. Their antimicrobial mechanism was also substantiated through SEM and fluorescence tests in this work, confirming the inheritance of membrane-disrupting properties from EPL. Furthermore, the excellent biocompatibility of the raw materials was reserved in the covalent conjugates. This simplified conjugation method holds promise for the development of infection therapeutic drugs and potentially restores the sensitivity of conventional antibiotics to drug-resistant pathogens by introducing membrane-disrupting mechanisms.


Assuntos
Polilisina , Antibióticos beta Lactam , Polilisina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Ampicilina/farmacologia , Penicilina G , Monobactamas
18.
Adv Mater ; 36(28): e2313212, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38670140

RESUMO

Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and is realized utilizing the developed double-layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug-loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that the DL-HMCON can be used as a generic drug delivery system. ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors are demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu+ from DL-HMCON itself triggers the Fenton-like reaction and glutathione depletion, resulting in ferroptosis of non-CSCs. This CPT3@ATRA3@DL-HMCON@HA is verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety.


Assuntos
Camptotecina , Cobre , Células-Tronco Neoplásicas , Humanos , Porosidade , Camptotecina/química , Camptotecina/farmacologia , Animais , Cobre/química , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/química , Tretinoína/farmacologia , Nanopartículas/química , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Liberação Controlada de Fármacos
19.
Front Plant Sci ; 15: 1297812, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38434433

RESUMO

Introduction: The potato (Solanum tuberosum L.), one of the most vital food crops worldwide, is sensitive to salinity. Brassinosteroids (BRs) are crucial in tolerance to various abiotic stresses. The constitutive photomorphogenesis and dwarf (CPD) gene encodes C-3 oxidase, which is a rate-limiting enzyme that controls the synthesis of BRs. Methods: In this study, we used StCPD gene overexpression (T) and un-transgenic (NT) plants obtained from our former research to illustrate adaptive resistance to salt stress at levels of phenotype; cell ultrastructure, physiology, and biochemistry; hormone; and transcription. Results: Results showed the accumulation of 2,4-epibrassionolide (EBL) in T potatoes. We found that under high salt situations, the changed Na+/K+ transporter gene expression was linked with the prevalent ionic responses in T plants, which led to lower concentrations of K+ and higher concentrations of Na+ in leaves. Furthermore, RNA-sequencing (RNA-seq) data elucidated that gene expressions in NT and T plants were significantly changed with 200-mM NaCl treatment for 24 h and 48 h, compared with the 0-h treatment. Functional enrichment analysis suggested that most of the differentially expressed genes (DEGs) were related to the regulation of BR-related gene expression, pigment metabolism process, light and action, and plant hormone signal transduction. Discussion: These findings suggested that StCPD gene overexpression can alleviate the damage caused by salt stress and enhance the salt resistance of potato plantlets. Our study provides an essential reference for further research on BR regulation of plant molecular mechanisms in potatoes with stress tolerance.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38607711

RESUMO

3D dense captioning requires a model to translate its understanding of an input 3D scene into several captions associated with different object regions. Existing methods adopt a sophisticated "detect-then-describe" pipeline, which builds explicit relation modules upon a 3D detector with numerous hand-crafted components. While these methods have achieved initial success, the cascade pipeline tends to accumulate errors because of duplicated and inaccurate box estimations and messy 3D scenes. In this paper, we first propose Vote2Cap-DETR, a simple-yet-effective transformer framework that decouples the decoding process of caption generation and object localization through parallel decoding. Moreover, we argue that object localization and description generation require different levels of scene understanding, which could be challenging for a shared set of queries to capture. To this end, we propose an advanced version, Vote2Cap-DETR++, which decouples the queries into localization and caption queries to capture task-specific features. Additionally, we introduce the iterative spatial refinement strategy to vote queries for faster convergence and better localization performance. We also insert additional spatial information to the caption head for more accurate descriptions. Without bells and whistles, extensive experiments on two commonly used datasets, ScanRefer and Nr3D, demonstrate Vote2Cap-DETR and Vote2Cap-DETR++ surpass conventional "detect-then-describe" methods by a large margin. We have made the code available at https://github.com/ch3cook-fdu/Vote2Cap-DETR.

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