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1.
J Med Chem ; 66(2): 1112-1136, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36645394

RESUMO

The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its role, as its name suggests, is mainly to regulate cell death. The DAPK family comprises five members, including DAPK1, DAPK2, DAPK3, DRAK1 and DRAK2, which show high homology in the common N-terminal kinase domain but differ in the extra-catalytic domain. Notably, previous research has suggested that the DAPK family plays an essential role in both the development and regulation of human diseases. However, only a few small-molecule inhibitors have been reported. In this Perspective, we mainly discuss the structure, biological function, and role of DAPKs in diseases and the currently discovered small-molecule inhibitors, providing valuable information for the development of the DAPK field.


Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Quinases Associadas com Morte Celular/química , Proteínas Quinases Associadas com Morte Celular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Domínio Catalítico , Proteínas Quinases Dependentes de Cálcio-Calmodulina/química
2.
J Chromatogr A ; 1689: 463772, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36610186

RESUMO

Algae toxins pose a severe threat to human health all over the world. In this study, magnetic metal/nitrogen-doped carbon nanotubes (M-NCNTs) were facilely synthesized based on one-step carbonization and applied for magnetic solid-phase extraction of okadaic acid (OA) from seawater followed by high performance liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) analyses. Differences in the physicochemical properties of the three prepared materials (Fe/Co/Ni-NCNTs) were investigated to confirm the best extraction material. Among them, Ni-NCNTs demonstrated a faster extraction rate (10 min) and higher adsorption capacity (223.5 mg g-1), mainly due to the higher specific surface area, suitable pore structure and more abundant pyridine nitrogen ring. Under the optimal conditions, the calibration curve was linear over the range (1.0-800.0 pg mL-1) with good determination coefficients (R) of 0.9992. The limit of detection (LOD) obtained in multiple replicates was 0.4 pg mL-1. Three seawater samples were measured by the developed method, 12.3 pg mL-1 of OA was detected with a satisfying recovery (88.6%-106.7%) and acceptable repeatability (RSD ≤ 4.8%, n = 6). The results demonstrate that M-NCNTs materials are a promising candidate for magnetic solid-phase extraction. Benefiting from its high extraction and interference resistance, the established analytical method is expected to be extended to detect other marine environmental pollutions.


Assuntos
Nanotubos de Carbono , Humanos , Ácido Okadáico/análise , Nanotubos de Carbono/química , Espectrometria de Massas em Tandem/métodos , Nitrogênio , Água do Mar/química , Extração em Fase Sólida/métodos , Cromatografia Líquida de Alta Pressão , Metais , Fenômenos Magnéticos
3.
Clin Transl Oncol ; 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593383

RESUMO

BACKGROUND: Oral squamous carcinoma (OSCC), the most common head and neck malignancy, has a strong propensity for malignant proliferation and metastasis, which will decrease the survival of patients. P21-activated kinase 4 (PAK4), a classical serine/threonine protein kinase with multiple cellular functions, has an essential role in cancer cell migration and invasion. Here, we elucidated the function and possible molecular mechanisms of the effect of PAK4 on the biological behaviors of OSCC. METHODS: The expression of genes and protein was detected by real-time PCR and western blotting. We used oral squamous carcinoma cell lines, Tca8117, Cal 27, SCC 4, and SCC 9 for validation of our cell function data. Flow cytometry, 3D cultures, and clone formation assay were used to detect proliferation of cells. RNA sequencing and bioinformatic analysis was performed to determine the potential function of PAK4. RESULTS: Immunohistochemistry, western blotting and real-time PCR demonstrated that PAK4 expression was up-regulated in OSCC tissues. Overexpression of PAK4 promoted the proliferation, migration and invasion of OSCC cell lines. RNA sequencing (RNA-seq) for the transcriptome-wide analysis of differential gene expression followed by bioinformatic analysis was performed to determine the potential function of PAK4. Based on the KEGG enrichment analysis and GO analysis of differential expression genes (DEGs) we found that PAK4 promotes the cell-cycle machinery, which associated with 44 regulated genes, thereby promoting cancer cell differentiation. CONCLUSIONS: This study demonstrates that the PAK4 regulates the biological behaviors of OSCC by PI3K-AKT signaling pathway, and these findings might provide a novel strategy for OSCC treatment.

4.
J Magn Reson Imaging ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36661350

RESUMO

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI and non-mono-exponential model-based diffusion-weighted imaging (NME-DWI) that does not require contrast agent can both characterize breast cancer. However, which technique is superior remains unclear. PURPOSE: To compare the performances of DCE-MRI, NME-DWI and their combination as multiparametric MRI (MP-MRI) in the prediction of breast cancer prognostic biomarkers and molecular subtypes based on radiomics. STUDY TYPE: Prospective. POPULATION: A total of 477 female patients with 483 breast cancers (5-fold cross-validation: training/validation, 80%/20%). FIELD STRENGTH/SEQUENCE: A 3.0 T/DCE-MRI (6 dynamic frames) and NME-DWI (13 b values). ASSESSMENT: After data preprocessing, high-throughput features were extracted from each tumor volume of interest, and optimal features were selected using recursive feature elimination method. To identify ER+ vs. ER-, PR+ vs. PR-, HER2+ vs. HER2-, Ki-67+ vs. Ki-67-, luminal A/B vs. nonluminal A/B, and triple negative (TN) vs. non-TN, the following models were implemented: random forest, adaptive boosting, support vector machine, linear discriminant analysis, and logistic regression. STATISTICAL TESTS: Student's t, chi-square, and Fisher's exact tests were applied on clinical characteristics to confirm whether significant differences exist between different statuses (±) of prognostic biomarkers or molecular subtypes. The model performances were compared between the DCE-MRI, NME-DWI, and MP-MRI datasets using the area under the receiver-operating characteristic curve (AUC) and the DeLong test. P < 0.05 was considered significant. RESULTS: With few exceptions, no significant differences (P = 0.062-0.984) were observed in the AUCs of models for six classification tasks between the DCE-MRI (AUC = 0.62-0.87) and NME-DWI (AUC = 0.62-0.91) datasets, while the model performances on the two imaging datasets were significantly poorer than on the MP-MRI dataset (AUC = 0.68-0.93). Additionally, the random forest and adaptive boosting models (AUC = 0.62-0.93) outperformed other three models (AUC = 0.62-0.90). DATA CONCLUSION: NME-DWI was comparable with DCE-MRI in predictive performance and could be used as an alternative technique. Besides, MP-MRI demonstrated significantly higher AUCs than either DCE-MRI or NME-DWI. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

5.
ACS Nano ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662033

RESUMO

Ferroptosis is an iron-dependent cell death and is associated with cancer therapy. Can it play a role in resistance of postoperative infection of implants, especially with an extracellular supplement of Fe ions in a non-cytotoxic dose? To answer this, "nanoswords" of Fe-doped titanite are fabricated on a Ti implant surface to resist bacterial invasion by a synergistic action of ferroptosis-like bacteria killing, proton disturbance, and physical puncture. The related antibiosis mechanism is explored by atomic force microscopy and genome sequencing. The nanoswords induce an increased local pH value, which not only weakens the proton motive force, reducing adenosine triphosphate synthesis of Staphylococcus aureus, but also decreases the membrane modulus, making the nanoswords distort and even puncture a bacterial membrane easily. Simultaneously, more Fe ions are taken by bacteria due to increased bacterial membrane permeability, resulting in ferroptosis-like death of bacteria, and this is demonstrated by intracellular iron enrichment, lipid peroxidation, and glutathione depletion. Interestingly, a microenvironment constructed by these nanoswords improves osteoblast behavior in vitro and bone regeneration in vivo. Overall, the nanoswords can induce ferroptosis-like bacterial death without cytotoxicity and have great promise in applications with clinical implants for outstanding antibiosis and biointegration performance.

6.
Exp Dermatol ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36620869

RESUMO

Keratinocytes regulate melanogenesis in a paracrine manner. Previous studies have shown that melatonin can directly inhibit melanin production in the melanocytes. However, it is unclear whether melatonin can also indirectly regulate melanogenesis through the keratinocytes. In this study, we explored the role of melatonin in regulating keratinocyte-mediated melanogenesis using reconstructed human epidermis (RHE). Melatonin showed an inhibitory effect on melanin synthesis in this model. Furthermore, the conditioned media from melatonin-treated HaCaT cells downregulated melanogenesis-related genes, including MITF, TYR, TYRP1, DCT and RAB27A in the pigment MNT1 cells, and decreased levels of phosphorylated ERK, JNK and p38. RNA sequencing further showed that mitochondrial functions and oxidative stress pathway in the MNT1 cells were inhibited by the conditioned medium from melatonin-treated HaCaT cells. Furthermore, melatonin reduced the secretion of ET-1 and PTGS2 from HaCaT cells by inhibiting the JAK2/STAT3 signalling pathway. In conclusion, melatonin downregulates the paracrine factors ET-1 and PTGS2 in the keratinocytes by inhibiting the JAK2/STAT3 pathway, which reduces melanin production in pigment cells. Thus, melatonin has a potential therapeutic effect on skin pigmentation disorders.

7.
ACS Biomater Sci Eng ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36668685

RESUMO

Substrate stiffness has been indicated as an important factor to control stem cell fate, including proliferation and differentiation. To optimize the stiffness for the differentiation process from h-iPSCs (human induced pluripotent stem cells) into h-iCSCs (human corneal stromal cells derived from h-iPSCs) and the phenotypic maintenance of h-iCSCs in vitro, h-iPSCs were cultured on matrigel-coated tissue culture plate (TCP) (106 kPa), matrigel-coated polydimethylsiloxane (PDMS) 184 (1250 kPa), and matrigel-coated PDMS 527 (4 kPa) before they were differentiated to h-iCSCs. Immunofluorescence staining, quantitative real-time polymerase chain reaction (RT-qPCR), and western blot demonstrated that the stiffer substrate TCP promoted the h-iCSCs' differentiation from h-iPSCs. On the contrary, softer PDMS 527 was more effective to maintain the phenotype of h-iCSCs cultured in vitro. Finally, we cultured h-iCSCs on PDMS 527 until P3 and seeded them on a biomimetic collagen membrane to form the single-layer and multiple-layer bioengineered corneal stroma with high transparency properties and cell survival rate. In conclusion, the study is helpful for differentiating h-iPSCs to h-iCSCs and corneal tissue engineering by manipulating stiffness mechanobiology.

8.
Bioorg Chem ; 132: 106355, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36669359

RESUMO

Candida tropicalis is a major non-albicans species that causes invasive candidiasis. CGA-N12, an anti-Candida peptide found by our group, disrupted cell wall architecture by inhibiting the activity of the protein killer-resistant 9 (KRE9), a ß-1,6-glucan synthase specific to Candida spp. and plants. Herein, a set of CGA-N12 analogues were rationally designed based on the interaction networks between CGA-N12 and C. tropicalis KRE9 (CtKRE9). Seven CGA-N12 analogues with significantly improved antifungal activity against C. tropicalis were screened by reducing the docking energy of CGA-N12 and CtKRE9 and increasing the number of positive charges on CGA-N12 based on a stable three-dimensional model of CtKRE9. CGA-N12 and its analogues exhibited antifungal activity against C. tropicalis and its persist cells; they also inhibited biofilm formation and eradicated preformed biofilms. Compared with fluconazole, they displayed higher activities against the growth of persister cells and more effective preformed biofilm eradication. Among them, CGA-N12-0801, CGA-N12-0902 and CGA-N12-1002 displayed much higher activity and anti-proteinase digestion stability than CGA-N12. Specifically, CGA-N12-0801 was the optimal analogue, with a minimum inhibitory concentration of 3.46 µg/mL and a therapeutic index of 158.07. The results of electronic microscopy observations and KRE9 activity inhibition assays showed that CGA-N12 and its analogues killed C. tropicalis by disrupting the architecture of the cell wall and the integrity of the cell membrane. In conclusion, for the first time, we provide a simple and reliable method for the rational design of antimicrobial peptides and ideal candidates for treating Candida infections that not effectively eliminated by azole drugs.

9.
BMC Musculoskelet Disord ; 24(1): 5, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600227

RESUMO

BACKGROUND: Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in patients after surgery. The choice of antithrombotic agents for venous thromboembolism (VTE) prevention after TKA is controversial. Therefore, this study aimed to compare the effects of different antithrombotic agents on patients after primary unilateral TKA in the context of applied TXA. METHODS: A total of 180 patients undergoing primary unilateral TKA from October 2020 to December 2021 were included in this study. All patients were given an intraoperative drip of 60 mg/kg TXA. Thereafter, patients were divided into three groups (n = 60 each). Baseline data were comparable among the three groups. The average follow-up time was 3.02 ± 0.09 months. Group 1 enrolled patients receiving oral rivaroxaban (RA) at 10 mg, Group 2 included patients who received subcutaneous Dalteparin sodium at 2500 IU, while Group 3 included patients taking oral aspirin (ASA) at 100 mg. Patients in all the three groups received treatment once a day for 30 days at 12 h postoperatively. The primary outcomes in this study were post-treatment drainage volume and thrombotic complication rate. The secondary outcomes included hematologic parameters, transfusion rate, intraoperative blood loss, total blood loss (TBL), and bleeding complication rate. RESULTS: The average drainage volume after treatment was significantly lower in Group 3 than in Group 1 and Group 2 (205.2 ± 69.0 vs 243.4 ± 72.5 vs 295.4 ± 72.5 ml, P < 0.001), and there was a significant difference between Group 1 and Group 2 (243.4 ± 72.5 mL vs 295.4 ± 72.5 mL, P < 0.001). The blood transfusion rate of Group 2 dramatically increased compared with Group 1 and Group 3 (20.0% vs 6.7% vs 5.0%, P = 0.01). The bleeding complication rate in Group 1 apparently increased relative to Group 2 and Group 3 (26.7% vs 10.0% vs 8.3%, P = 0.008). Besides, there was no significant difference in the thrombotic complication rate among the three groups. CONCLUSION: Under the background of TXA application, ASA, RA, and Dalteparin sodium were all effective on preventing VTE after TKA. In addition, ASA effectively reduced post-treatment Hemoglobin (Hb) loss, drainage volume, TBL, transfusion rate, and bleeding complications compared with RA and Dalteparin sodium. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200060169). Date of Registration: 21/05/2022.


Assuntos
Antifibrinolíticos , Artroplastia do Joelho , Ácido Tranexâmico , Tromboembolia Venosa , Humanos , Ácido Tranexâmico/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Fibrinolíticos/efeitos adversos , Antifibrinolíticos/efeitos adversos , Dalteparina , Estudos Prospectivos , Perda Sanguínea Cirúrgica/prevenção & controle , Rivaroxabana/efeitos adversos , Anticoagulantes , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle
10.
J Med Virol ; 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36606602

RESUMO

Due to the COVID-19 pandemic, a series of sequelae, such as fatigue, tachypnea and ageusia, appeared in long COVID patients, but the pathological basis was still uncertain. The targeted radiopharmaceuticals were of potentials to systemically and dynamically trace the pathological changes. For the key ACE2 protein in the virus-host interaction, 68 Ga-cyc-DX600 was developed on the basis of DX600 as a PET tracer of ACE2 fluctuation, and maintained the ability in differentiating ACE and ACE2. In the temporary infection model inhaled with the radio-traceable pseudovirus in the upper respiratory of male humanized ACE2 (hACE2) mice, organ-specific ACE2 dysfunction in acute period and the following ACE2 recovery in a relatively long period were visualized and quantified by ACE2 PET, revealing a complex pattern of virus concentration-dependent degree and time period-dependent tendency of ACE2 recovery, mainly a sudden decrease of apparent ACE2 in heart, liver, kidneys, lungs and so on, but liver was of a quick functional compensation on ACE2 expression after a temporary decrease. ACE2 expression of most organs has recovered to a normal level at 15 days P.I., with brain and genitals still of a decreased SUVACE2 , meanwhile, kidneys were of an increased SUVACE2 . These findings on ACE2 PET were further verified by western blot. When compared with high-resolution computed tomography on structural changes and FDG PET on glycometabolism, ACE2 PET was of the superiority on earlier diagnostic window during infection and more comprehensive understanding of functional dysfunction post infection. In the respective ACE2 PET/CT and ACE2 PET/MR scans of a volunteer, the repeatability of SUVACE2 and the ACE2 specificity were further confirmed. In conclusion, 68 Ga-cyc-DX600 was developed as an ACE2-specific tracer, and the corresponding ACE2 PET revealed the dynamic patterns of functional ACE2 recovery and provided a reference and approach to explore the ACE2-related pathological basis of sequelae in long COVID. This article is protected by copyright. All rights reserved.

11.
Artigo em Chinês | MEDLINE | ID: mdl-36597372

RESUMO

Objective:To study the application value of humidified high flow nasal cannula (HHFNC) combined with visual laryngoscopy in the arytenoid cartilage dislocation. Methods:Twenty-nine patients with arytenoid cartilage dislocation were randomly double-blind into HHFNC group and general nasal catheter oxygen suction group, and the intraoperative and postoperative evaluation indicators, anesthesia-related indicators and postoperative vocal cord were compared. Results:There were statistically significant differences in intraoperative blood oxygen saturation, microstream end-tidal carbon dioxide partial pressure EtCO2, respiratory rate and respiratory intervention times between the two groups (P<0.05), and statistically significant differences in postoperative heart rate, oxygen saturation and respiratory rate (P<0.05). After reduction, the voice disturbance index, the degree of voice abnormality, rough voice, breath sound, powerless pronunciation and catatonic pronunciation changed significantly after operation. Conclusion:HHFNC combined with visual laryngoscopy in the arytenoid cartilage dislocation has high anesthetic safety, good cooperation of patients, and good surgical effect.


Assuntos
Laringoscópios , Distúrbios da Voz , Humanos , Cânula , Laringoscopia , Cateterismo , Cartilagem Aritenoide
12.
J Virol ; : e0190022, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36602367

RESUMO

Respiratory syncytial virus (RSV) is a serious human respiratory pathogen, but no RSV vaccine has been licensed. Many vaccine candidates are focused on the viral F protein since the F protein is more conserved than the viral G protein across RSV strains and serotypes; thus, the F protein is thought more likely to induce a broader range of protection from infection. However, it is the G protein that binds the likely receptor, CX3CR1, in lung ciliated epithelial cells, raising the question of the importance of the G protein in vaccine candidates. Using virus-like particle (VLP) vaccine candidates, we have directly compared VLPs containing only the prefusion F protein (pre-F), only the G protein, or both glycoproteins. We report that VLPs containing both glycoproteins bind to anti-F-protein-specific monoclonal antibodies differently than do VLPs containing only the prefusion F protein. In RSV-naive cotton rats, VLPs assembled with only the pre-F protein stimulated extremely weak neutralizing antibody (NAb) titers, as did VLPs assembled with G protein. However, VLPs assembled with both glycoproteins stimulated quite robust neutralizing antibody titers, induced improved protection of the animals from RSV challenge compared to pre-F VLPs, and induced significantly higher levels of antibodies specific for F protein antigenic site 0, site III, and the AM14 binding site than did VLPs containing only the pre-F protein. These results indicate that assembly of pre-F protein with G protein in VLPs further stabilized the prefusion conformation or otherwise altered the conformation of the F protein, increasing the induction of protective antibodies. IMPORTANCE Respiratory syncytial virus (RSV) results in significant disease in infants, young children, and the elderly. Thus, development of an effective vaccine for these populations is a priority. Most ongoing efforts in RSV vaccine development have focused on the viral fusion (F) protein; however, the importance of the inclusion of G in vaccine candidates is unclear. Here, using virus-like particles (VLPs) assembled with only the F protein, only the G protein, or both glycoproteins, we show that VLPs assembled with both glycoproteins are a far superior vaccine in a cotton rat model compared with VLPs containing only F protein or only G protein. The results show that the presence of G protein in the VLPs influences the conformation of the F protein and the immune responses to F protein, resulting in significantly higher neutralizing antibody titers and better protection from RSV challenge. These results suggest that inclusion of G protein in a vaccine candidate may improve its effectiveness.

13.
Int J Biol Sci ; 19(1): 347-361, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594092

RESUMO

Diabetic foot ulcers (DFUs) are among the most frequent complications of diabetes with significant morbidity and mortality. Diabetes can trigger neutrophils to undergo histone citrullination by protein arginine deiminase 4 (encoded by Padi4 in mice) and release neutrophil extracellular traps (NETs). The specific mechanism of NETs-mediated wound healing impairment in diabetes remains unknown. In this study, we show neutrophils are more susceptible to NETosis in diabetic wound environments. Via in vitro experiments and in vivo models of wound healing using wide-type and Padi4 -/- mice, we demonstrate NETs can induce the activation of PAK2 via the membrane receptor TLR-9. Then PAK2 phosphorylates the intracellular protein Merlin/NF2 to inhibit the Hippo-YAP pathway. YAP binds to transcription factor SMAD2 and translocates from the cytoplasm into the nucleus to promote endothelial-to-mesenchymal transition (EndMT), which ultimately impedes angiogenesis and delays wound healing. Suppression of the Merlin/YAP/SMAD2 pathway can attenuate NET-induced EndMT. Inhibition of NETosis accelerates wound healing by reducing EndMT and promoting angiogenesis. Cumulatively, these data suggest NETosis delays diabetic wound healing by inducing EndMT via the Hippo-YAP pathway. Increased understanding of the molecular mechanism that regulates NETosis and EndMT will be of considerable value for providing cellular targets amenable to therapeutic intervention for DFUs.


Assuntos
Diabetes Mellitus , Pé Diabético , Armadilhas Extracelulares , Animais , Camundongos , Armadilhas Extracelulares/metabolismo , Neurofibromina 2/metabolismo , Via de Sinalização Hippo , Cicatrização/genética , Neutrófilos/metabolismo , Pé Diabético/metabolismo , Diabetes Mellitus/metabolismo
14.
Theranostics ; 13(2): 736-766, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632220

RESUMO

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis. In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on. It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases. In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development. Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.


Assuntos
Neoplasias , Doenças Neurodegenerativas , Humanos , Mitofagia/fisiologia , Autofagia/fisiologia , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/patologia , Neoplasias/patologia
15.
Anal Chem ; 95(2): 1498-1504, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36598384

RESUMO

Simultaneous imaging and especially visualizing the association of survivin mRNA and telomerase in living cells are of great value for the diagnosis and prognosis of cancer because their co-expression facilitates the development of cancer and identifies patients at high risk of tumor-related death. The challenge is to develop methods that enable visualizing the association of multiplex targets and avoid the distorted signals due to the different delivery efficiency of probes. Herein, we engineered a DNA triangular prism nanomachine (DTPN) for simultaneous multicolor imaging of survivin mRNA and telomerase and visualizing their association in living cells. Two recognizing probes targeted survivin mRNA and telomerase, and the reporter probe was assembled on the DTP in equal amounts, ensuring the same delivery efficiency of the probes to the living cells. The results showed that this DTPN could quantify intracellular survivin mRNA expression and telomerase activity. Moreover, it also enabled us to visualize the effect of the down-regulation of one target on the expression of another target under different drug stimulations. The results implied that our DTPN provided a promising platform for cancer diagnosis, prognosis, drug screening, and related biological research.


Assuntos
Telomerase , Humanos , Survivina/genética , Survivina/metabolismo , RNA Mensageiro/genética , Telomerase/genética , Telomerase/metabolismo , DNA/genética , Regulação para Baixo
16.
Small ; : e2206265, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470672

RESUMO

Percutaneous implants may experience infection for several times during their servicing periods. They need antibacterial activity and durability to reduce recurrent infection and cytocompatibility to reconstruct biosealing. A novel photoresponse bio-heterojunction (PCT) is developed herein. It consists of TiO2 nanotubes loaded with CuS nanoparticles and wrapped with polydopamine (PDA) layer. In PCT, a built-in electric field directing from TiO2 to CuS and then to PDA is formed, and with near-infrared (NIR) irradiation, it drives photoexcited electrons to transfer in opposite direction, resulting in the separation of electron-hole pairs and formation of reactive oxygen species (ROS). Simultaneously, PCT shows photothermal effect due to nonradiative relaxation of photoexcited electrons and thermal vibration of lattices. The synergic effect of photogenerated ROS and hyperthermia increases bacterial membrane permeability and leakage of cellular components, endowing PCT with outstanding antibacterial performance. More importantly, PCT has good antibacterial durability and cytocompatibility due to the inhibited leaching of CuS by PDA layer. In reinfected models, with NIR irradiation, PCT sterilizes bacteria, reduces inflammatory response and enhances re-integration of soft tissue efficiently. This work provides an outstanding bio-heterojunction for percutaneous implants in treating reinfection by NIR irradiation and rebuilding biosealing.

17.
Eur J Radiol ; 158: 110639, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36463703

RESUMO

BACKGROUND: The histological sub-classes of brain tumors and the Ki-67 labeling index (LI) of tumor cells are major factors in the diagnosis, prognosis, and treatment management of patients. Many existing studies primarily focused on the classification of two classes of brain tumors and the Ki-67LI of gliomas. This study aimed to develop a preoperative non-invasive radiomics pipeline based on multiparametric-MRI to classify-three types of brain tumors, glioblastoma (GBM), metastasis (MET) and primary central nervous system lymphoma (PCNSL), and to predict their corresponding Ki-67LI. METHODS: In this retrospective study, 153 patients with malignant brain tumors were involved. The radiomics features were extracted from three types of MRI (T1-weighted imaging (T1WI), fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced T1-weighted imaging (CE-T1WI)) with three masks (tumor core, edema, and whole tumor masks) and selected by a combination of Pearson correlation coefficient (CORR), LASSO, and Max-Relevance and Min-Redundancy (mRMR) filters. The performance of six classifiers was compared and the top three performing classifiers were used to construct the ensemble learning model (ELM). The proposed ELM was evaluated in the training dataset (108 patients) by 5-fold cross-validation and in the test dataset (45 patients) by hold-out. The accuracy (ACC), sensitivity (SEN), specificity (SPE), F1-Score, and the area under the receiver operating characteristic curve (AUC) indicators evaluated the performance of the models. RESULTS: The best feature sets and ELM with the optimal performance were selected to construct the tri-categorized brain tumor aided diagnosis model (training dataset AUC: 0.96 (95% CI: 0.93, 0.99); test dataset AUC: 0.93) and Ki-67LI prediction model (training dataset AUC: 0.96 (95% CI: 0.94, 0.98); test dataset AUC: 0.91). The CE-T1WI was the best single modality for all classifiers. Meanwhile, the whole tumor was the most vital mask for the tumor classification and the tumor core was the most vital mask for the Ki-67LI prediction. CONCLUSION: The developed radiomics models led to the precise preoperative classification of GBM, MET, and PCNSL and the prediction of Ki-67LI, which could be utilized in clinical practice for the treatment planning for brain tumors.

18.
Thromb Haemost ; 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36462769

RESUMO

Phenotypic switch of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of atherosclerosis. The mRNA expression of the synthetic biomarker Collagen Type I Alpha 1 Chain (COL1A1) gene is upregulated during the switch of VSMCs from the contractile to the synthetic phenotype. The association of noncoding circular RNAs transcribed by the COL1A1 gene with VSMC phenotype alteration and atherogenesis remains unclear. Here we reported a COL1A1 circular RNA (circCOL1A1) which is specifically expressed in VSMCs and is upregulated during phenotype alteration of VSMCs. CircCOL1A1 is also detectable in the serum or plasma. Healthy vascular tissues have a low expression of CircCOL1A1, while it is upregulated in atherosclerosis patients. Through ex vivo and in vitro assays, we found that circCOL1A1 can promote VSMC phenotype switch. Mechanistic analysis showed that circCOL1A1 may exert its function as a competing endogenous RNA of miR-30a-5p. Upregulation of circCOL1A1 ameliorates the inhibitory effect of miR-30a-5p on its target SMAD1, which leads to suppression of transforming growth factor-ß (TGF-ß) signaling. Our findings demonstrate that circCOL1A1 promotes the phenotype switch of VSMCs through the miR-30a-5p/SMAD1/TGF-ß axis and it may serve as a novel marker of atherogenesis or as a therapeutic target for atherosclerosis.

19.
PeerJ ; 10: e14369, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452079

RESUMO

Background: Yaks are animals that have lived in plateau environments for generations. Yaks can adapt to the hypoxic plateau environment and also pass this adaptability on to the next generation. The lungs are the most important respiratory organs for mammals to adapt to their environment. Pulmonary artery smooth muscle cells play an important role in vascular remodeling under hypoxia, but the genetic mechanism underpinning the yak's ability to adapt to challenging plateau conditions is still unknown. Methods: A tandem mass tag (TMT) proteomics study together with an RNA-seq transcriptome analysis were carried out on pulmonary artery smooth muscle cells (PASMCs) that had been grown for 72 hours in both normoxic (20% O2) and hypoxic (1% O2) environments. RNA and TP (total protein) were collected from the hypoxic and normoxic groups for RNA-seq transcriptome sequencing and TMT marker protein quantification, and RT-qPCR validation was performed. Results: A total of 17,711 genes and 6,859 proteins were identified. Further, 5,969 differentially expressed genes (DEGs) and 531 differentially expressed proteins (DEPs) were identified in the comparison group, including 2,924 and 186 upregulated genes and proteins and 3,045 and 345 down-regulated genes and proteins, respectively. The transcriptomic and proteomic analyses revealed that 109 DEGs and DEPs were highly positively correlated, with 77 genes showing the same expression trend. Nine overlapping genes were identified in the HIF-1 signaling pathway, glycolysis / gluconeogenesis, central carbon metabolism in cancer, PPAR signaling pathway, AMPK signaling pathway, and cholesterol metabolism (PGAM1, PGK1, TPI1, HMOX1, IGF1R, OLR1, SCD, FABP4 and LDLR), suggesting that these differentially expressed genes and protein functional classifications are related to the hypoxia-adaptive pathways. Overall, our study offers abundant data for further analysis of the molecular mechanisms in yak PASMCs and their adaptability to different oxygen concentrations.

20.
J Cosmet Dermatol ; 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456176

RESUMO

BACKGROUND: Vitiligo was an autoimmune disease and some guidelines for the management of vitiligo encouraged the use of NB-UVB combination therapies to enhance repigmentation. OBJECTIVES: To compare the effectiveness of current NB-UVB combination regimen at the improvement in repigmentation through a systematic review and network meta-analysis. METHODS: We searched the electronic databases for randomized controlled trials related to NB-UVB combination therapy for vitiligo till October 2022. STATA15.0 software was applied to carrying out data analysis. RESULTS: A total of 28 eligible studies involving 1194 participants were enrolled in the analysis. The NMA results revealed that compared with NB-UVB, carboxytherapy [OR = 32.35, 95% CI (1.79, 586.05)], Er: YAG laser+ topical 5% 5-FU [OR = 10.74, 95% CI (4.05, 28.49)], needling/micro-needling [OR = 3.42, 95% CI (1.18, 9.88)], betamethasone intramuscular injection [OR = 3.08, 95% CI (1.17, 8.13)], topical tacrolimus [OR = 2.54, 95% CI (1.30, 4.94)], and oral Chinese herbal medicine compound [OR = 2.51, 95% CI (1.40, 4.50)] integrated with NB-UVB were more efficacious in excellent to complete repigmentation response rate (≥75%). Besides, NB-UVB+ Er: YAG laser+ topical 5% 5-FU [OR = 0.17, 95% CI (0.04, 0.67)] and NB-UVB+ needling/micro-needling [OR = 0.24, 95% CI (0.06, 0.88)] were less likely evaluated as ineffective repigmentation response (≤25%). CONCLUSIONS: All combination therapies ranked higher than NB-UVB monotherapy in inducing successful repigmentation and avoiding failed treatment in patients with vitiligo. Comprehensive consideration, NB-UVB+ Er: YAG laser+ topical 5% 5-FU and NB-UVB+ needling/microneedling would be the preferred therapeutic approaches.

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