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1.
Am J Transl Res ; 14(4): 2231-2243, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35559417

RESUMO

OBJECTIVES: Paraneoplastic antigen Ma family (PNMA) is dysregulated in the pathological development of various cancers. However, the actions of PNMA member 5 (PNMA5) in cancers are still unknown. The aim of this study was to explore the biological actions of PNMA5 and its implication in epithelial-mesenchymal transition (EMT) during the progression of colorectal cancer (CRC). METHODS: Immunohistochemical staining, western blot and qPCR were used to explore PNMA5 expression in colorectal cancer tissues and cells. In addition, western blot, MTT assays, Colony formation assay, wound-healing, and transwell cell invasion assays were used to investigate the effects of PNMA5 on EMT in colorectal cancer. The lung metastasis models and xenografts in nude mice were established to explore the roles of PNMA5 in vivo. RESULTS: It was found that the expression level of PNMA5 in colorectal cancer tissues was significantly up regulated compared to that in the adjacent tissues. The overall survival rates of patients with a higher PNMA5 expression were markedly decreased. In addition, knockdown of PNMA5 expression decreased the proliferation, invasion and migration of both HCT-15 and HCT-116 cells. PNMA5 expression was found to be positively associated with the expression of C-myc, CyclinD1, Ki67, N-cadherin, zinc finger E-box binding homeobox 1 and vimentin, and negatively associated with E-cadherin. It was also found that PNMA5 knockdown attenuated TGF-ß-induced EMT in colorectal cancer cells. Finally, it was demonstrated that PNMA5 accelerated colorectal cancer cell proliferation, invasion and migration in vivo. CONCLUSION: The results revealed that PNMA5 increased cellular proliferation, invasion and migration in colorectal cancer. PNMA5 plays a key role in promoting CRC carcinogenesis and progression for patients with CRC.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35571733

RESUMO

Background: Primary bone diffuse large B-cell lymphoma (PD-DLBCL) accounts for more than 80% of primary bone lymphoma. We created two nomograms to predict overall survival (OS) and cancer-specific survival (CSS) in patients with PD-DLBCL for this rare disease. Methods: In total, 891 patients diagnosed with PB-DLBCL between 2007 and 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to explore independent prognostic factors and create nomograms for OS and CSS. The area under the curve (AUC), the calibration curve, decision curve analysis (DCA), and Kaplan-Meier (K-M) curve analysis were used to evaluate the nomograms. Results: Four variables were identified as independent prognostic factors for OS, and three variables were identified as independent prognostic factors for CSS. The receiver operating characteristic (ROC) curves demonstrated the strong discriminatory power of the nomograms. The calibration and DCA curves showed that the nomograms had a satisfactory ability to predict OS and CSS. The K-M curves showed that age, gender, primary site, chemotherapy, and tumor stage affected patient survival. Conclusions: In patients with PD-DLBCL, age, race, primary site, and chemotherapy affected OS, while age, race, and chemotherapy affected CSS. The two nomograms created based on the aforementioned variables provided more accurate individual survival predictions for PD-DLBCL patients and can help physicians make appropriate clinical decisions.

3.
Front Microbiol ; 13: 884034, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572668

RESUMO

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), public health worldwide has been greatly threatened. The development of an effective treatment for this infection is crucial and urgent but is hampered by the incomplete understanding of the viral infection mechanisms and the lack of specific antiviral agents. We previously reported that teicoplanin, a glycopeptide antibiotic that has been commonly used in the clinic to treat bacterial infection, significantly restrained the cell entry of Ebola virus, SARS-CoV, and MERS-CoV by specifically inhibiting the activity of cathepsin L (CTSL). Here, we found that the cleavage sites of CTSL on the spike proteins of SARS-CoV-2 were highly conserved among all the variants. The treatment with teicoplanin suppressed the proteolytic activity of CTSL on spike and prevented the cellular infection of different pseudotyped SARS-CoV-2 viruses. Teicoplanin potently prevented the entry of SARS-CoV-2 into the cellular cytoplasm with an IC50 of 2.038 µM for the Wuhan-Hu-1 reference strain and an IC50 of 2.116 µM for the SARS-CoV-2 (D614G) variant. The pre-treatment of teicoplanin also prevented SARS-CoV-2 infection in hACE2 mice. In summary, our data reveal that CTSL is required for both SARS-CoV-2 and SARS-CoV infection and demonstrate the therapeutic potential of teicoplanin for universal anti-CoVs intervention.

4.
Ying Yong Sheng Tai Xue Bao ; 33(4): 894-900, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35543039

RESUMO

With continuous increases in the amount and duration of plastic film used, the residual film in farmland soil is accumulated and tended to be fragmented, which affects soil water infiltration. We carried out an experiment of one-dimensional vertical infiltration of soil moisture. We examined the effects of different residual film density and area on soil water cumulative infiltration under 21 experimental treatments with 5 residual film area levels (0.25, 0.5, 1, 2, 8 cm2) and 5 residual film density levels (0, 60, 180, 300, 420 kg·hm-2). The results showed that soil water infiltration rate was accelerated and the total infiltration amount was increased by adding a certain amount of residual film into the clay loam soil with bulk density of 1.53 g·cm-3. The total infiltration amount of different residual film area always appeared mutation or turning point when the single residual film area was 1 cm2. When the residual film area and density were larger or smaller than that, the cumulative infiltration amount would be significantly affected, with the treatment of 0.5 cm2 residual film area and 200 kg·hm-2 residual film density being obvious demarcation. When the residual film area was 0.25 cm2, the cumulative infiltration reached the maximum. When the residual film with a single area ≤0.25 cm2 was uniformly mixed into the soil, the slope of soil water cumulative infiltration curve was significantly different from that of other residual film treatments, forming a "new structure" soil with unique water infiltration characteristics.


Assuntos
Solo , Água , Agricultura/métodos , China , Plásticos , Água/análise
5.
Adv Mater ; : e2201880, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35557021

RESUMO

With the advent of the Internet of Things and big data, massive data must be rapidly processed and stored within a short timeframe. This imposes stringent requirements on the memory hardware implementation in terms of operation speed, energy consumption, and integration density. To fulfil these demands, two-dimensional (2D) materials, which are excellent electronic building blocks, provide numerous possibilities for developing advanced memory device arrays with high performance, smart computing architectures, and desirable downscaling. Over the past few years, 2D material-based memory device arrays with different working mechanisms including defects, filaments, charges, ferroelectricity, and spins, have been increasingly developed. These arrays can be used to implement brain-inspired computing or sensing with extraordinary performance, architectures, and functionalities. In this review, we survey recent research into integrated, state-of-the-art memory devices made from 2D materials, as well as their implications for brain-inspired computing. We discuss the existing challenges at the array level, and present the scope for future research. This article is protected by copyright. All rights reserved.

6.
Nat Commun ; 13(1): 2835, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595767

RESUMO

Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.


Assuntos
Quinases relacionadas a CDC2 e CDC28 , Leucemia , Animais , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Camundongos
7.
Nat Commun ; 13(1): 2863, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35606357

RESUMO

Searching for superconductivity with Tc near room temperature is of great interest both for fundamental science & many potential applications. Here we report the experimental discovery of superconductivity with maximum critical temperature (Tc) above 210 K in calcium superhydrides, the new alkali earth hydrides experimentally showing superconductivity above 200 K in addition to sulfur hydride & rare-earth hydride system. The materials are synthesized at the synergetic conditions of 160~190 GPa and ~2000 K using diamond anvil cell combined with in-situ laser heating technique. The superconductivity was studied through in-situ high pressure electric conductance measurements in an applied magnetic field for the sample quenched from high temperature while maintained at high pressures. The upper critical field Hc(0) was estimated to be ~268 T while the GL coherent length is ~11 Å. The in-situ synchrotron X-ray diffraction measurements suggest that the synthesized calcium hydrides are primarily composed of CaH6 while there may also exist other calcium hydrides with different hydrogen contents.

8.
Poult Sci ; 101(7): 101821, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35537342

RESUMO

Heat stress is one of the major environmental stressors challenging the global poultry industry. Identifying the genes responsible for heat tolerance is fundamentally important for direct breeding programs. To uncover the genetic basis underlying the ambient temperature adaptation of chickens, we analyzed a total of 59 whole genomes from indigenous chickens that inhabit South Asian tropical regions and temperate regions from Northern China. We applied FST and π-ratio to scan selective sweeps and identified 34 genes with a signature of positive selection in chickens from tropical regions. Several of these genes are functionally implicated in metabolism (FABP2, RAMP3, SUGCT, and TSHR) and vascular smooth muscle contractility (CAMK2), and they may be associated with adaptation to tropical regions. In particular, we found a missense mutation in thyroid-stimulating hormone receptor (41020238:G>A) that shows significant differences in allele frequency between the chicken populations of the two regions. To evaluate whether the missense mutation in TSHR could enhance the heat tolerance of chickens, we constructed segregated chicken populations and conducted heat stress experiments using homozygous mutations (AA) and wild-type (GG) chickens. We found that GG chickens exhibited significantly higher concentrations of alanine aminotransferase, lactate dehydrogenase, and creatine kinase than AA chickens under heat stress (35 ± 1°C) conditions (P < 0.05). These results suggest that TSHR (41020238:G>A) can facilitate heat tolerance and adaptation to higher ambient temperature conditions in tropical climates. Overall, our results provide potential candidate genes for molecular breeding of heat-tolerant chickens.

9.
Zhen Ci Yan Jiu ; 47(4): 290-7, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35532365

RESUMO

OBJECTIVE: To observe the effect of mild moxibustion on monocyte chemotaxis protein 1 (MCP-1)/matrix metalloproteinase 2 (MMP-2)/transforming growth factor ß1 (TGF-ß1) pro-inflammatory signal loop in senile rats, so as to explore its mechanisms underlying improving vascular aging (VA). METHODS: Twenty-four male VA SD rats were randomized into senium (VA) control, medication and moxibustion groups, and other 8 young SD rats (aged 2 months) were used as the young control group. The VA model was established by intraperitoneal injection of D-galactose (300 mg·kg-1·d-1) once daily for 4 weeks, and verified by serum total testosterone (TT) and free testosterone (FT) levels. For rats of the moxibustion group, mild moxibustion was applied to bilateral "Shenshu"(BL23) and "Guanyuan"(CV4) for 20 min, once a day, 5 days a week for 8 weeks. Rats of the medication group were treated by intraperitoneal injection of testosterone propionate (7 mg·kg-1·[3 d]-1) once daily for 8 weeks except weekends, and rats of the senium control and young control groups treated by intraperitoneal injection of the same dose of normal saline, once daily for 8 weeks except weekends. The duration of exhausted swimming (DES) before and after the treatment was recorded. H.E. staining and Masson staining were used to observe histopathological changes and collagen fiber content of the thoracic aortic tissue, respectively. The contents of serum TT, FT and angiotensin 2 (Ang Ⅱ) were determined by ELISA. The immunoactivity of aortic MCP-1 was detected by immunohistochemistry, and the expression levels of aortic MCP-1, MMP-2 and TGF-ß1 were detected by Western blot. RESULTS: Compared with the young control group, the levels of DES, serum TT and FT contents were significantly decreased (P<0.01), while those of serum AngⅡ and collagen fiber contents, aortic MCP-1 immunoactivity and MMP-2, TGF-ß1 and MCP-1 protein expression considerably increased in the senium control group (P<0.01). After the interventions, the decreased levels of DES, serum TT and FT contents and the increased levels of serum AngⅡ, collagen fiber contents, aortic MCP-1 immunoactivity and MMP-2, TGF-ß1 and MCP-1 protein expression were reversed in both medication and moxibustion groups (P<0.01, P<0.05). The therapeutic effect of mild moxibustion was significantly superior to that of medication in down-regulating the aortic collagen fiber, serum AngⅡ contents and MCP-1 immunoactivity and protein expression (P<0.05). H.E. staining showed thickened endometrium and disordered arrangement of vascular smooth muscles of the aorta in the senium group, and thinner endometrium and regular and ordered arrangement of aortic vascular smooth muscles in both moxibustion and medication groups. CONCLUSION: Mild moxibustion may improve vascular aging in senescence rats, which is possibly by suppressing vascular MCP-1/MMP-2/TGF-ß1 pro-inflammatory signal loop.


Assuntos
Moxibustão , Envelhecimento , Animais , Colágeno , Feminino , Masculino , Metaloproteinase 2 da Matriz/genética , Ratos , Ratos Sprague-Dawley , Testosterona , Fator de Crescimento Transformador beta1/genética
10.
J Biochem Mol Toxicol ; : e23091, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35543488

RESUMO

Nuclear receptor subfamily 6 group A member 1 (NR6A1) is involved in promoting the apoptotic process of vascular smooth muscle cells (VSMCs) which is a critical process involved in atherosclerosis, but the action mechanism remains to be determined. Therefore, we studied the underlying mechanisms by which NR6A1 accelerated VSMC apoptosis in atherosclerosis. An atherosclerosis model has been established in apolipoprotein E-deficient rats with a high-fat diet for 12 weeks, which was characterized by pathological aortic plaques, increased lipid deposition and collagen content in aortic tissues, and high cholesterol and triglycerides levels in the serum. NR6A1 was experimentally shown to increase at protein level rather than messenger RNA level in atherosclerotic rats. Immunofluorescence exhibited the main location of NR6A1 in the cell nucleus of rat aortic tissues. By performing ectopic expression experiments, NR6A1 was demonstrated to suppress the viability and expedite the apoptosis of VSMCs, corresponding to augmented caspase-3, caspase-8, and caspase-9 activities. It was further unraveled that NR6A1 could activate receptor-interacting serine/threonine-protein kinase 3 (RIPK3) by inducing its phosphorylation. Conversely, RIPK3 inhibitor GSK872 undermined the proapoptotic effect of NR6A1 on VSMCs. The co-immunoprecipitation assay identified that linear ubiquitin chain assembly complex (LUBAC) can be pulled down by NR6A1. Furthermore. LUBAC inhibited the expression of NR6A1 by promoting its linear ubiquitination, thereby dephosphorylating RIPK3 and consequently inhibiting the VSMC apoptosis. Overall, LUBAC-induced linear ubiquitination of NR6A1 can potentially arrest the apoptosis of VSMCs in atherosclerosis by downregulating RIPK3 and attenuating caspase activity. This finding suggests promising athero-protective targets by limiting VSMC apoptosis.

11.
PLoS Comput Biol ; 18(5): e1010011, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35576194

RESUMO

Genomewide association studies (GWAS) have identified a large number of loci associated with neuropsychiatric traits, however, understanding the molecular mechanisms underlying these loci remains difficult. To help prioritize causal variants and interpret their functions, computational methods have been developed to predict regulatory effects of non-coding variants. An emerging approach to variant annotation is deep learning models that predict regulatory functions from DNA sequences alone. While such models have been trained on large publicly available dataset such as ENCODE, neuropsychiatric trait-related cell types are under-represented in these datasets, thus there is an urgent need of better tools and resources to annotate variant functions in such cellular contexts. To fill this gap, we collected a large collection of neurodevelopment-related cell/tissue types, and trained deep Convolutional Neural Networks (ResNet) using such data. Furthermore, our model, called MetaChrom, borrows information from public epigenomic consortium to improve the accuracy via transfer learning. We show that MetaChrom is substantially better in predicting experimentally determined chromatin accessibility variants than popular variant annotation tools such as CADD and delta-SVM. By combining GWAS data with MetaChrom predictions, we prioritized 31 SNPs for Schizophrenia, suggesting potential risk genes and the biological contexts where they act. In summary, MetaChrom provides functional annotations of any DNA variants in the neuro-development context and the general method of MetaChrom can also be extended to other disease-related cell or tissue types.

12.
J Immunol Res ; 2022: 1951620, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509981

RESUMO

Lung adenocarcinoma (LUAD) is still one of the illnesses with the greatest mortality and morbidity. As a recently identified mode of cellular death, the activation of ferroptosis may promote the effectiveness of antitumor therapies in several types of tumors. However, the expression and clinical significance of Ferroptosis-associated genes in LUAD are still elusive. The RNA sequencing data of LUAD and relevant clinical data were downloaded from The Cancer Genome Atlas (TCGA) datasets. Subsequently, potential prognostic biomarkers were determined by the use of biological information technology. The R software package "ggalluvial" was applied to structure Sanguini diagram. Herein, our team screened 14 dysregulated ferroptosis-associated genes in LUAD. Among them, only four genes were associated with clinical outcome of LUAD patients, including ATP5MC3, FANCD2, GLS2, and SLC7A11. In addition, we found that high SLC7A11 expression predicted an advanced clinical progression in LUAD patients. Additionally, 8 immune checkpoint genes and 7 immune cells for LUAD were recognized to be related to the expression of SLC7A11. KEGG assays indicated that high expression of SLC7A11 might participate in the modulation of intestinal immune network for IgA generation and Staphylococcus aureus infection. Overall, our findings revealed that SLC7A11 might become a potentially diagnostic biomarker and SLC7A11 might serve as an independent prognosis indicator for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Ferroptose , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Sistema y+ de Transporte de Aminoácidos/genética , Biomarcadores , Ferroptose/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Prognóstico
13.
Front Pharmacol ; 13: 868203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431936

RESUMO

Background: Cisplatin is the basis of the primary treatment for SCLC chemotherapy. However, the limited objective response rate and definite drug resistance greatly restrict the clinical potential and therapeutic benefits of cisplatin use. Therefore, it is essential to identify biomarkers that can discern the sensitivity of SCLC patients to cisplatin treatment. Methods: We collected two SCLC cohorts treated with cisplatin that included mutation data, prognosis data and expression data. The sensitivity of cisplatin was evaluated by the pRRophetic algorithm. MCPcounter, quanTIseq, and xCell algorithms were used to evaluate immune cell score. GSEA and ssGSEA algorithms were used to calculate immune-related pathway scores. Univariate and multivariate Cox regression models were employed, and survival analysis was used to evaluate the prognostic value of the candidate genes. Results: MMP9-High is related to improved clinical prognoses of patients with SCLC (HR = 0.425, p = 0.0085; HR = 0.365, p = 0.0219). Multivariate results showed that MMP-High could be used as an independent predictor of the prognosis of SCLC after cisplatin treatment (HR = 0.216, p = 0.00153; HR = 0.352; p = 0.0199). In addition, MMP9-High displayed a significantly lower IC50 value of cisplatin and higher immunogenicity than MMP9-Low SCLC. Compared with MMP9-Low SCLC, MMP9-High included significantly increased levels of T-cells, cytoxic lymphocytes, B-cells, NK-cells, and dense cells (DCS). Similarly, the activity of cytokine binding, B-cell, NK-cell mediated immune response chemokine binding, and antigen presentation pathways in MMP9-High was significantly higher than that in MMP9-Low. Conclusion: In this study, we identified that MMP9-High could be potentially considered a novel biomarker used to ascertain the improved prognosis of SCLC patients after cisplatin treatment. Furthermore, we indicated that the tumor immune microenvironment of MMP9-High SCLC is mainly characterized by a large number of infiltrated activated immune cells as well as activated immune-related pathways.

14.
J Phys Chem A ; 126(15): 2437-2444, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35389639

RESUMO

Chemical bonds and noncovalent interactions are extraordinarily important concepts in chemistry and beyond. Using density-based quantities to describe them has a long history in the literature, yet none can satisfactorily describe the entire spectrum of interactions from strong chemical bonds to weak van der Waals forces. In this work, employing Pauli energy as the theoretical foundation, we fill in that knowledge gap. Our results show that the newly established density-based index can describe single and multiple covalent bonds, ionic bonds, metallic bonds, and different kinds of noncovalent interactions, all with unique and readily identifiable signature shapes. Two new descriptors, BNI (bonding and noncovalent interaction) index and USI (ultra-strong interaction) index, have been introduced in this work. Together with NCI (noncovalent interaction) and SCI (strong covalent interaction) indexes already available in the literature, a density-based description of both chemical bonds and noncovalent interactions is accomplished.

15.
Stem Cell Res Ther ; 13(1): 164, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35414044

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSC therapy. This study investigated whether the combination of melatonin and human umbilical cord mesenchymal stem cells (hUC-MSCs) was superior to hUC-MSCs alone in ameliorating high-fat diet and streptozocin (STZ)-induced type II diabetes mellitus (T2DM) in a mouse model. METHODS: Mice were divided into four groups: normal control (NC) group; T2DM group; hUC-MSCs treatment alone (UCMSC) group and pretreatment of hUC-MSCs with melatonin (UCMSC/Mel) group. RESULTS: RNA sequence analysis showed that certain pathways, including the signaling pathway involved in the regulation of cell proliferation signaling pathway, were regulated by melatonin. The blood glucose levels of the mice in the UCMSC and UCMSC/Mel treatment groups were significantly reduced compared with the T2DM group without treatment (P < 0.05). Furthermore, hUC-MSCs enhance the key factor in the activation of the PI3K/Akt pathway in T2DM mouse hepatocytes. CONCLUSION: The pretreatment of hUC-MSCs with melatonin partly boosted cell efficiency and thereby alleviated impaired glycemic control and insulin resistance. This study provides a practical strategy to improve the application of hUC-MSCs in diabetes mellitus and cytotherapy. Overview of the PI3K/AKT signaling pathway. (A) Underlying mechanism of UCMSC/Mel inhibition of hyperglycemia and insulin resistance T2DM mice via regulation of PI3K/AKT pathway. hUC-MSCs stimulates glucose uptake and improves insulin action thus should inhibition the clinical signs of T2DM, through activation of the p-PI3K/Akt signaling pathway and then regulates glucose transport through activating AS160. UCMSC/Mel increases p53-dependent expression of BCL2, and inhibit BAX and Capase3 protein activation. Leading to the decrease in apoptosis. (B) Melatonin modulated PI3K/AKT signaling pathway. Melatonin activated PI3K/AKT response pathway through binding to MT1and MT2 receptor. Leading to the increase in hUC-MSCs proliferation, migration and differentiation. → (Direct stimulatory modification); ┴ ( Direct Inhibitory modification); → ┤ (Multistep inhibitory modification); ↑ (Up regulate); ↓ (Down regulate); PI3K (Phosphoinositide 3-Kinase); AKT ( protein kinase B); PDK1 (Phosphoinositide-dependent protein kinase 1); IR, insulin receptor; GLUT4 ( glucose transporter type 4); ROS (reactive oxygen species); BCL-2 (B-cell lymphoma-2); PDK1 (phosphoinositide-dependent kinase 1) BAX (B-cell lymphoma-2-associated X protein); PCNA (Proliferating cell nuclear antigen); Cell cycle-associated proteins (KI67, cyclin A, cyclin E).


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Melatonina , Transplante de Células-Tronco Mesenquimais , Animais , Diabetes Mellitus Tipo 2/terapia , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Cordão Umbilical , Proteína X Associada a bcl-2
16.
J Mol Model ; 28(5): 122, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35437635

RESUMO

Small atomic clusters with exotic stability, bonding, aromaticity, and reactivity properties can be made use of for various purposes. In this work, we revisit the trapping of noble gas atoms (He-Kr) by the triatomic H3+ and Li3+ species by using some analytical tools from density functional theory, conceptual density functional theory, and the information-theoretic approach. Our results showcase that though similar in geometry, H3+ and Li3+ exhibit markedly different behavior in bonding, aromaticity, and reactivity properties after the addition of noble gas atoms. Moreover, the exchange-correlation interaction and steric effect are key energy components in stabilizing the clusters. This study also finds that the origin of the molecular stability of these species is due to the spatial delocalization of the electron density distribution. Our work provides an additional arsenal towards a better understanding of small atomic clusters capturing noble gases.

17.
Signal Transduct Target Ther ; 7(1): 134, 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35461308

RESUMO

Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Células Endoteliais/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Humanos , RNA/metabolismo , RNA/uso terapêutico , Doadores de Tecidos
18.
Plants (Basel) ; 11(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35406965

RESUMO

Smart Glass Film (SGF) is a glasshouse covering material designed to permit 80% transmission of photosynthetically active light and block heat-generating solar energy. SGF can reduce crop water and nutrient consumption and improve glasshouse energy use efficiency yet can reduce crop yield. The effect of SGF on the postharvest shelf life of fruits remains unknown. Two capsicum varieties, Red (Gina) and Orange (O06614), were cultivated within a glasshouse covered in SGF to assess fruit quality and shelf life during the winter season. SGF reduced cuticle thickness in the Red cultivar (5%) and decreased ascorbic acid in both cultivars (9-14%) without altering the overall morphology of the mature fruits. The ratio of total soluble solids (TSSs) to titratable acidity (TA) was significantly higher in Red (29%) and Orange (89%) cultivars grown under SGF. The Red fruits had a thicker cuticle that reduced water loss and extended shelf life when compared to the Orange fruits, yet neither water loss nor firmness were impacted by SGF. Reducing the storage temperature to 2 °C and increasing relative humidity to 90% extended the shelf life in both cultivars without evidence of chilling injury. In summary, SGF had minimal impact on fruit development and postharvest traits and did not compromise the shelf life of mature fruits. SGF provides a promising technology to block heat-generating solar radiation energy without affecting fruit ripening and marketable quality of capsicum fruits grown during the winter season.

19.
J Agric Food Chem ; 70(16): 4995-5004, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35412829

RESUMO

Punicalagin exerts neuroprotective activity by improving AMP-activated kinase (AMPK) and mitochondrial Krebs cycle. AMPK and Krebs cycle metabolites regulate 5-hydroxymethylcytosine (5hmC) via acting on ten-eleven translocation (TET) enzymes. Therefore, we hypothesized that punicalagin inhibits diabetes-related neuronal apoptosis by upregulating 5hmC in the diabetic mouse brain. C57BL/6J mice aged 8 weeks were randomly separated into five groups (n = 10), normal control (NC), diabetes mellitus (DM), resveratrol (RES), low-dose punicalagin (LPU), and high-dose punicalagin (HPU). Compared with other groups, the neuronal apoptosis rate was significantly higher and the 5hmC level of the cerebral cortex was significantly lower in the DM group. The levels of TET2 and P-AMPKα/AMPKα were significantly lower in the DM group than in both LPU and HPU groups. The ratio of (succinic acid + fumaric acid)/α-ketoglutarate was significantly higher in the DM group than in other groups. The present results suggest that punicalagin upregulates 5hmC via activating AMPK and maintaining Krebs cycle homeostasis, thus inhibiting neuronal apoptosis in the diabetic mouse brain.


Assuntos
Proteínas Quinases Ativadas por AMP , Diabetes Mellitus , 5-Metilcitosina/análogos & derivados , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Encéfalo/metabolismo , Diabetes Mellitus/metabolismo , Taninos Hidrolisáveis , Camundongos , Camundongos Endogâmicos C57BL
20.
Neuroscience ; 492: 1-17, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35405301

RESUMO

Toll-like receptor-4 (TLR4), a member of the TLR family, plays a key role in inflammation-related diseases of the nervous system. TLR4 knockout mice are widely used in various neurological disease studies, and there is a clear correlation between inflammation and behavior. Therefore, elucidating the effect of TLR4 on neurobehavioral function is essential, and the related mechanisms need to be explored. Male TLR4 knockout (TLR4-/-) and wild-type (TLR4+/+) mice of different ages (4, 8, and 16 months) were used for behavioral experiments. Synaptic spine, blood-brain barrier (BBB) integrity, memory regulatory proteins, cortical blood flow, and inflammatory factor examinations were also conducted to explore the possible mechanism by which TLR4 works. Here, we found that compared with 16-m-old TLR4+/+ mice, age-matched TLR4-/- mice had better learning and memory abilities, increased expression of neuronal synaptic spines, and increased memory-related regulatory proteins in the hippocampus. TLR4 knockout significantly attenuated the fear response in 16-m-old mice. The TLR4-/- mice also had better blood-brain barrier integrity, increased expression of tight junction-associated proteins, increased cerebral cortical blood flow and reduced proinflammatory cytokine expression in the cortex and cerebrospinal fluid. Our results suggest that TLR4 deletion ameliorates significant neurobehavioral dysfunction during the aging stage, as well as multiple abnormalities in brain function and structure due to alterations in tight junction-associated proteins and inflammatory factors.


Assuntos
Encéfalo , Receptor 4 Toll-Like , Animais , Encéfalo/metabolismo , Cognição , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Junções Íntimas/metabolismo , Receptor 4 Toll-Like/metabolismo
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