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1.
Bioact Mater ; 19: 251-267, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35510173

RESUMO

Inflammatory bowel disease (IBD) is a chronic, immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier. Due to the poor remission effect and severe adverse events associated with current clinical medications, IBD remains an incurable disease. Here, we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating. The molecular coating is composed of o-nitrobenzaldehyde (NB)-modified Gelatin (GelNB), which can strongly bond with -NH2 on the intestinal surface of tissue to form a thin biophysical barrier. We found that this molecular coating was able to stay on the surface of the intestine for long periods of time, effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora. In addition, our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration, but also achieved a better outcome of IBD by reducing intestinal inflammation. Moreover, the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine. Therefore, our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.

2.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144486

RESUMO

Secoatractylohexone A (1), an unprecedented secoguaiane lactone glycoside featuring 6/7 cores and dihydroxy-9-guaine-3-one 11-O-ß-d-glucopyranoside (2), a 9,10-unsaturated guaiene-type glycoside possessing an uncommon scaffold, were isolated from the water-soluble portion of the ethanolic extract of Atractylodes lancea rhizomes together with five known compounds (3-7). The structures of 1 and 2 were elucidated on the basis of extensive spectroscopic data and application of the CD technique. The potential biological activities of secoatractylohexone A were predicted by network pharmacology in silico, the result of which indicated that secoatractylohexone A may be used to treat type II diabetes.

3.
Front Chem ; 10: 975559, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110131

RESUMO

We have synthesized Rhopaladins' analog (2E,4E)-4-chlorobenzylidene-2-(4-chlorostyryl)-N-cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (RPDPRH) via a highly facile, inexpensive and green approach and verified the structural superiority of compound RPDPRH through molecular docking. Moreover, we further detected the anti-proliferation, apoptosis and HPV E6/E7 effects of RPDPRH on CaSki cells. Finally, we confirmed that compared with the previous compound (E)-N-(tert-butyl)-2-(4-chlorobenzoyl)-4-(4-fluorobenzylidene)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (RPDPB), RPDPRH could better inhibit proliferation, induce apoptosis, and down-regulate HPV E6/E7 mRNA expression on Caski cells. And preliminary RT-PCR experiments have demonstrated that RPDPRH also could affect the expression of Bcl-2, Bax and Caspase-3 mRNA in Caski cells. In summary, RPDPRH has potential as an effective agent against cervical cancer and will play an important role in our subsequent research.

4.
Front Endocrinol (Lausanne) ; 13: 899731, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060945

RESUMO

Non-alcoholic fatty liver disease (NAFLD), hallmarked by liver steatosis, is becoming a global concern, but effective and safe drugs for NAFLD are still lacking at present. Parathyroid hormone (PTH), the only FDA-approved anabolic treatment for osteoporosis, is important in calcium-phosphate homeostasis. However, little is known about its potential therapeutic effects on other diseases. Here, we report that intermittent administration of PTH ameliorated non-alcoholic liver steatosis in diet-induced obese (DIO) mice and db/db mice, as well as fasting-induced hepatic steatosis. In vitro, PTH inhibits palmitic acid-induced intracellular lipid accumulation in a parathyroid hormone 1 receptor (PTH1R)-dependent manner. Mechanistically, PTH upregulates the expression of genes involved in lipid ß-oxidation and suppresses the expression of genes related to lipid uptake and de novo lipogenesis by activating the cAMP/PKA/CREB pathway. Taken together, our current finding proposes a new therapeutic role of PTH on NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Hormônio Paratireóideo , Animais , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lipídeos , Lipogênese , Camundongos , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/uso terapêutico , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo
5.
J Am Chem Soc ; 144(36): 16287-16291, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36037095

RESUMO

We report the first experimental characterization of isomerically pure and pristine C120 fullertubes, [5,5] C120-D5d(1) and [10,0] C120-D5h(10766). These new molecules represent the highest aspect ratio fullertubes isolated to date; for example, the prior largest empty cage fullertube was [5,5] C100-D5d(1). This increase of 20 carbon atoms represents a gigantic leap in comparison to three decades of C60-C90 fullerene research. Moreover, the [10,0] C120-D5d(10766) fullertube has an end-cap derived from C80-Ih and is a new fullertube whose C40 end-cap has not yet been isolated experimentally. Theoretical and experimental analyses of anisotropic polarizability and UV-vis assign C120 isomer I as a [5,5] C120-D5d(1) fullertube. C120 isomer II matches a [10,0] C120-D5h(10766) fullertube. These structural assignments are further supported by Raman data showing metallic character for [5,5] C120-D5d(1) and nonmetallic character for C120-D5h(10766). STM imaging reveals a tubular structure with an aspect ratio consistent with a [5,5] C120-D5d(1) fullertube. With microgram quantities not amenable to crystallography, we demonstrate that DFT anisotropic polarizability, augmented by long-accepted experimental analyses (HPLC retention time, UV-vis, Raman, and STM) can be synergistically used (with DFT) to down select, predict, and assign C120 fullertube candidate structures. From 10 774 mathematically possible IPR C120 structures, this anisotropic polarizability paradigm is quite favorable to distinguish tubular structures from carbon soot. Identification of isomers I and II was surprisingly facile, i.e., two purified isomers for two possible structures of widely distinguishing features. These metallic and nonmetallic C120 fullertube isomers open the door to both fundamental research and application development.


Assuntos
Fulerenos , Fulerenos/química , Isomerismo
6.
J Belg Soc Radiol ; 106(1): 73, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36042789

RESUMO

Magnetic resonance images (MRI) of migrated nucleus pulposus after collagenase treatment of lumbar disc herniation are rarely published. Here, we describe a 65-year-old woman with L5-S1 intervertebral disc herniation on the rear left. The patient was treated with a lumbar disc collagenase injection, and the pain was relieved. Two weeks later, the patient suddenly developed pain again after engaging in weight-bearing activity. Lumbar MRI showed a nodule in the spinal canal at the L5-S1 level. The patient underwent surgical treatment two days later. Pathology showed that the nodule was nucleus pulposus tissue. Teaching point: It is important to understanding the MR manifestations of migrated nucleus pulposus after collagenase treatment to prevent such misdiagnosis.

7.
Eur J Med Chem ; 241: 114654, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35961071

RESUMO

Several secondary tropomyosin receptor kinase (TRK) mutations located in the solvent front, xDFG, and gatekeeper regions, are a common cause of clinical resistance. Mutations in the xDFG motif in particular limit sensitivity to second-generation TRK inhibitors, which represent an unmet clinical need. We designed a series of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives toward these secondary mutations using ring-opening and scaffold-hopping strategies. Compound 5n was the most potent, with IC50 values of 2.3 nM, 0.4 nM, and 0.5 nM against TRKAG667C, TRKAF589L, and TRKAG595R, compared to selitrectinib with IC50 values of 12.6 nM, 5.8 nM, and 7.6 nM, respectively (approximately 5.4, 14.5, and 15.2-fold increases). Furthermore, 5n displayed favorable pharmacokinetic properties and satisfactory antitumor efficacy (tumor growth inhibition of 97% at 30 mg/kg and 73% at 100 mg/kg) in TRKAWT and TRKAG667C xenograft mouse models. Collectively, 5n is a promising TRK inhibitor lead compound for overcoming clinically acquired resistance to second-generation inhibitors, particularly for resistant tumors harboring the TRKAG667C mutation in the xDFG motif.


Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor trkA
8.
Mult Scler Relat Disord ; 66: 104070, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35914471

RESUMO

OBJECTIVES: This study aimed to explore the microstructural heterogeneity of different white matter (WM) tissues in relapsing-remitting multiple sclerosis (RRMS) patients by diffusion magnetic resonance imaging (dMRI) and its correlation with disability and cognitive status. MATERIALS AND METHODS: A total of 337 iron rim lesions (IRLs), 337 perilesional white matters of IRLs (IRLs-PLWMs), 330 non-iron rim lesions (non-IRLs), 330 non-IRLs-PLWMs, 42 normal-appearing white matters (NAWMs) in 42 RRMS patients, and 30 white matters in healthy controls (WMs in HCs) were enrolled in the lesion-wise analysis. Diffusion kurtosis imaging (DKI) parameters including kurtosis fractional anisotropy (KFA) and mean kurtosis (MK), and diffusion tensor imaging (DTI) parameters including fractional anisotropy (FA) and mean diffusivity (MD) were measured in the six types of tissues. Subgroup analysis was performed between non-IRLs with QSM hyperintense (non-IRLs-H) and non-IRLs with QSM isointense or hypointense (non-IRLs-I), as well as between non-IRLs-H-PLWMs and non-IRLs-I-PLWMs. Thirty-four out of forty-two patients were enrolled in patient-wise analysis. The relationships between these diffusion metrics of patients and their Kurtzke Expanded Disability Status Scale (EDSS) score and Symbol Digit Modalities Test (SDMT) score were analyzed separately by partial correlation analysis with age and disease duration (DD) as covariates. RESULTS: The KFA, FA, MK, and MD values were significantly different among the six types of tissues. The lowest KFA, FA, and MK values and the highest MD values were revealed in IRLs. There were significant differences in all the enrolled diffusion metrics between IRLs and non-IRLs, as well as between IRLs-PLWMs and non-IRLs-PLWMs (p < 0.05). There were no significant differences between NAWMs and WMs in HCs (p = 1.000 for all enrolled diffusion metrics). For all the enrolled diffusion metrics, no significant differences were found in the subgroup analysis. The FA, MK, and MD values of total lesions (including IRLs and non-IRLs) (r = -0.420, p = 0.017; r = -0.472, p = 0.006; r = -0.475, p = 0.006) and the MK values of IRLs (r = -0.438, p = 0.012) were correlated with the EDSS scores. There was no significant correlation between the diffusion parameter values and the SDMT scores. CONCLUSION: Our findings demonstrate that IRLs are more destructive than non-IRLs. Similarly, IRLs-PLWMs are more destructive than non-IRLs-PLWMs. Additionally, diffusion parameter values of MS lesions can reflect the disability degree. These findings contribute to a better understanding of the different evolution of MS lesions and the relationship between the disability level of patients and focal lesion damage degree.

9.
Biomed Res Int ; 2022: 8638085, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35978634

RESUMO

Objective: Natural and synthetic chalcones played roles in inflammation and cancers. Chalcone 9X was an aromatic ketone that was found to inhibit cell growth of hepatic cancer and lung cancer cells. In this study, we wanted to investigate the functions of Chalcone 9X in glioma. Materials and Methods: Chemical Chalcone 9X was added in human glioma cell lines (U87 and T98G cells) and normal astrocyte cell lines (HA1800) with various concentrations (0 µmol/L, 20 µmol/L, 50 µmol/L, and 100 µmol/L). CCK-8 assay was used to measure cell viability. Flow cytometric assay was used to measure cell apoptotic rates. Wound healing assay and transwell assay were used to measure cell invasion. RT-PCR was used to detect relative mRNA expressions, and the protein expressions were detected by western blot (WB) and immunohistochemical staining (IHC). Finally, nude mouse xenograft assay was performed to prove the effects of Chalcone 9X in vivo. Results: Results revealed that Chalcone 9X treatment suppressed cell viability and cell migration capacity; it could also induce cell apoptosis in U87 and T98G cells with dose dependence. However, it had little cytotoxicity to normal astrocyte HA1800 cells. Moreover, Chalcone 9X treatment could repress the mRNA and protein expressions of FOXM1 in human glioma cell lines, which was an oncogene that could promote the progression and malignancy of glioma. In addition, FOXM1 overexpression dismissed the Chalcone 9X effects on cell proliferation, apoptosis, and migration in human glioma cell lines. Finally, in vivo assay showed that Chalcone 9X treatment repressed the expression of FOXM1, which inhibited the tumor growth of a xenograft model injected with U87 in nude mice. Conclusions: In all, we found that Chalcone 9X could suppress cell proliferation and migration and induce cell apoptosis in human glioma cells, while it has little cytotoxicity to normal astrocyte cells. Therefore, we uncovered a novel way that Chalcone 9X could inhibit FOXM1 expression and repress the progression and biofunctions of glioma cells, which might be a potential therapeutic drug for treating human glioma.


Assuntos
Chalcona , Chalconas , Glioma , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Chalcona/farmacologia , Chalconas/farmacologia , Chalconas/uso terapêutico , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Humanos , Camundongos , Camundongos Nus , RNA Mensageiro
10.
Prep Biochem Biotechnol ; : 1-12, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35816458

RESUMO

Photosynthetic bacteria wastewater treatment is an efficient water pollution treatment method, but photosynthetic bacteria fermentation is a multivariable, non-linear, and time-varying process. So it is difficult to establish an accurate model. Aiming at the difficulty of online measurement of key parameters, such as bacterial concentration and matrix concentration in photosynthetic bacteria fermentation process, an improved ant colony algorithm least squares support vector machine (AC-LSSVM) soft sensing model method is proposed in this paper. Firstly, the virtual sensing subsystem of the photosynthetic bacteria fermentation process is proposed, with measurable parameters as input and unmeasurable key parameters as output, and the left inverse soft sensing model of virtual sensing is constructed. Then, the ant colony algorithm can quickly find the shortest path to optimize the parameters of the traditional PI regulation, to improve the dynamic performance and accuracy of parameter measurement in the fermentation process. After that, the ant colony algorithm is used to optimize penalty parameters C and kernel parameters σ of LSSVM, which effectively avoids the local optimization and improves the computing power and global optimization ability. Finally, the soft sensing prediction model of the photosynthetic bacteria fermentation process based on AC-LSSVM is established. Compared with SVM and LSSVM prediction models, the root mean square error of bacterial concentration and matrix concentration based on the AC-LSSVM model are 0.468 and 0.126, respectively. The simulation analysis shows that this model has less error and better prediction ability, and it can meet the needs of online prediction of key parameters of photosynthetic bacteria fermentation.

11.
Nat Commun ; 13(1): 4240, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869071

RESUMO

Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 KO cells. APEX1/2 are synthetic lethal with TDP1. However, deficiency of APEX1/2 does not reduce DSB formation in TDP1 KO cells. Together, our data suggest that TOP1cc can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination (HR) pathway.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I , Camptotecina/farmacologia , Dano ao DNA , Reparo do DNA , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/metabolismo , Diester Fosfórico Hidrolases/metabolismo
12.
Front Public Health ; 10: 903183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35801249

RESUMO

A decline in the fertility rate has been observed worldwide, which hampers social development severely. Given the impacts of COVID-19 on individuals and society, it is of great significance to investigate the fertility intention of reproductive couples under COVID-19. The convenience sampling method was used to obtain our study sample. The self-administered questionnaire included the following components: sociodemographic characteristics (age, residence, education, occupation, characteristics of the couples, and annual household income), reproductive history (parity, number of children, child gender, and duration of preparing pregnancy), and attitudes toward COVID-19, was distributed online via an applet of WeChat. The results showed that among 4,133 valid questionnaires, 1,091 had fertility intention before COVID-19, whereas 3,042 did not, indicating a fertility intention rate of 26.4% among participating couples. Of the 1,091 couples who had fertility intention before COVID-19, 520 (47.7%) were affected by the outbreak, whereas 571 (52.3%) were not. By multivariable logistic regression analysis, we further found that couples living in Hubei Province, the epicenter in China (OR 2.20, 95% CI 1.35-3.60), and couples who prepared for pregnancy longer before COVID-19 (OR 1.19, 95% CI 1.06-1.33) were more likely to change their fertility intention under the pandemic. In addition, most of the participants reported their fertility intention was affected by the inconvenience of seeking medical service under COVID-19. Therefore, more forms of medical services to provide convenience for patients might be effective ways to reverse the declined fertility intention rate in facing COVID-19.


Assuntos
COVID-19 , Intenção , COVID-19/epidemiologia , Criança , China/epidemiologia , Estudos Transversais , Surtos de Doenças , Feminino , Fertilidade , Humanos , Gravidez
13.
J Biomed Opt ; 27(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35773774

RESUMO

SIGNIFICANCE: Raman spectroscopy (RS) provides an automated approach for assisting Mohs micrographic surgery for skin cancer diagnosis; however, the specificity of RS is limited by the high spectral similarity between tumors and normal tissues structures. Reflectance confocal microscopy (RCM) provides morphological and cytological details by which many features of epidermis and hair follicles can be readily identified. Combining RS with deep-learning-aided RCM has the potential to improve the diagnostic accuracy of RS in an automated fashion, without requiring additional input from the clinician. AIM: The aim of this study is to improve the specificity of RS for detecting basal cell carcinoma (BCC) using an artificial neural network trained on RCM images to identify false positive normal skin structures (hair follicles and epidermis). APPROACH: Our approach was to build a two-step classification model. In the first step, a Raman biophysical model that was used in prior work classified BCC tumors from normal tissue structures with high sensitivity. In the second step, 191 RCM images were collected from the same site as the Raman data and served as inputs for two ResNet50 networks. The networks selected the hair structure and epidermis images, respectively, within all images corresponding to the positive predictions of the Raman biophysical model with high specificity. The specificity of the BCC biophysical model was improved by moving the Raman spectra corresponding to these selected images from false positive to true negative. RESULTS: Deep-learning trained on RCM images removed 52% of false positive predictions from the Raman biophysical model result while maintaining a sensitivity of 100%. The specificity was improved from 84.2% using Raman spectra alone to 92.4% by integrating Raman spectra with RCM images. CONCLUSIONS: Combining RS with deep-learning-aided RCM imaging is a promising tool for guiding tumor resection surgery.


Assuntos
Carcinoma Basocelular , Aprendizado Profundo , Neoplasias Cutâneas , Carcinoma Basocelular/diagnóstico por imagem , Dermoscopia/métodos , Humanos , Microscopia Confocal/métodos , Neoplasias Cutâneas/patologia
14.
Cell Metab ; 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35705079

RESUMO

Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.

15.
Cancer Res ; 82(17): 3088-3101, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35771632

RESUMO

Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies. SIGNIFICANCE: CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.


Assuntos
Aurora Quinase A , Proteínas de Ciclo Celular , DNA Helicases , Proteínas de Ligação a DNA , Proteínas Associadas aos Microtúbulos , Neoplasias da Próstata , Animais , Antineoplásicos , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Inibidores de Proteínas Quinases/farmacologia
17.
Proc Natl Acad Sci U S A ; 119(25): e2121779119, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35704761

RESUMO

Cell surface proteins play essential roles in various biological processes and are highly related to cancer development. They also serve as important markers for cell identity and targets for pharmacological intervention. Despite their great potentials in biomedical research, comprehensive functional analysis of cell surface proteins remains scarce. Here, with a de novo designed library targeting cell surface proteins, we performed in vivo CRISPR screens to evaluate the effects of cell surface proteins on tumor survival and proliferation. We found that Kirrel1 loss markedly promoted tumor growth in vivo. Moreover, KIRREL was significantly enriched in a separate CRISPR screen based on a specific Hippo pathway reporter. Further studies revealed that KIRREL binds directly to SAV1 to activate the Hippo tumor suppressor pathway. Together, our integrated screens reveal a cell surface tumor suppressor involved in the Hippo pathway and highlight the potential of these approaches in biomedical research.


Assuntos
Genes Supressores de Tumor , Via de Sinalização Hippo , Proteínas de Membrana , Neoplasias , Animais , Proliferação de Células/genética , Via de Sinalização Hippo/genética , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais
18.
Org Lett ; 24(27): 4992-4997, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35771975

RESUMO

A successful Cu-catalyzed addition of both Cl and SO2OCF2H groups into alkenes allows us to discover the unusual reactivity of the SO2OCF2H group. As opposed to common sulfonic esters (RSO2-O-R'), in which the R' group is highly electrophilic, the SO2 moiety demonstrates higher electrophilicity in RSO2-OCF2H. The unexpected reactivity is further developed not only as a synthetic tool for well-functionalized alkenyl sulfonyl fluorides but also for the first 18F labeling of alkenyl sulfonyl fluorides.


Assuntos
Fluoretos , Ácidos Sulfínicos , Alcenos , Ésteres
19.
Phys Rev Lett ; 128(17): 172002, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35570428

RESUMO

We develop a method for lattice QCD calculation of the two-photon exchange contribution to the muonic-hydrogen Lamb shift. To demonstrate its feasibility, we present the first lattice calculation with a gauge ensemble at m_{π}=142 MeV. By adopting the infinite-volume reconstruction method along with an optimized subtraction scheme, we obtain with statistical uncertainty ΔE_{TPE}=-28.9(4.9) µeV+93.72 µeV/fm^{2}·⟨r_{p}^{2}⟩, or ΔE_{TPE}=37.4(4.9) µeV, which is consistent with the previous theoretical results in a range of 20-50 µeV.

20.
Cell Death Dis ; 13(5): 494, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35610206

RESUMO

A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin ß3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.


Assuntos
MicroRNAs , Osteogênese , Envelhecimento/genética , Animais , Células Endoteliais/metabolismo , Endotélio , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica , Osteogênese/genética
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