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1.
Quant Imaging Med Surg ; 12(4): 2378-2384, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35371957

RESUMO

Background: To investigate the value of intraoperative frozen section examination (IFSE) in multiparametric magnetic resonance imaging/transrectal ultrasound (mpMRI/TRUS) fusion prostate biopsy in a major pandemic. Methods: A total of 35 patients were prospectively enrolled in our hospital from March 2020 to January 2021. The mpMRI/TRUS fusion system was used to perform a targeted biopsy, and the collected specimens were examined by IFSE (Observation Group 1). Then, a targeted biopsy was performed again for routine pathological examination (Observation Group 2). Finally, a systemic biopsy was performed, and the obtained specimens were routinely examined (Control Group). The positive rate, single core positive rate, Gleason score, and time to obtain pathological reports were compared between the groups. Results: The positive rate was 48.6% (17/35) in the control group, 48.6% (17/35) in Observation Group 1, and 51.4% (18/35) in Observation Group 2, showing no significant difference (P>0.05). The single core positive rates were 17.8%, 44.6%, and 47.1% in the Control Group, Observation Group 1, and Observation Group 2, respectively. Observation Group 1 and Observation Group 2 were significantly different from the Control Group (P<0.001). No participants in Observation Group 1 had increased or decreased Gleason scores compared with those in Observation Group 2. The time to obtain the pathological report was 0.025±0.014 days and 4.216±1.073 days for Observation Group 1 and Observation Group 2, respectively, showing a significant difference (P<0.001). Conclusions: This study showed that IFSE can not only rapidly obtain the pathological report of an mpMRI/TRUS biopsy, but can also ensure the accuracy of the pathological diagnosis. Trial Registration: CHICTR, Identifier: ChiCTR2000040789. Registered 10 December 2020 - Retrospectively registered, http://www.chictr.org.cn/edit.aspx?pid=63252&htm=4.

2.
Macromol Rapid Commun ; : e2200705, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36461768

RESUMO

Hydrogel shape memory and actuating functionalities are heavily pursued and have found great potential in various application fields. However, their combination for more flexible and complicated morphing behaviors is still challenging. Here we report that by controlling the light-initiated polymerization of active hydrogel layers on shape memory hydrogel substrates, advanced morphing behaviors based on programmable hydrogel shapes and actuating trajectories are realized. The formation and photo-reduction-induced dissociation of Fe3+ -carboxylate coordination endow the hydrogel substrates with shape memory functionality. The photo-reduced Fe2+ ions can diffuse from the substrates into the monomer solutions to initiate the polymerization of the thermally responsive active layers, whose actuating temperatures and amplitudes can be facially tuned by controlling their thicknesses and compositions. One potential application, a shape-programmable 3D hook that can lift an object with a specific shape, is also unveiled. The demonstrated strategy is extendable to other hydrogel systems to realize more versatile and complicated actuating behaviors. This article is protected by copyright. All rights reserved.

3.
BMC Plant Biol ; 22(1): 557, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36456919

RESUMO

Containing the largest number of species, the orchid family provides not only materials for studying plant evolution and environmental adaptation, but economically and culturally important ornamental plants for human society. Previously, we collected genome and transcriptome information of Dendrobium catenatum, Phalaenopsis equestris, and Apostasia shenzhenica which belong to two different subfamilies of Orchidaceae, and developed user-friendly tools to explore the orchid genetic sequences in the OrchidBase 4.0. The OrchidBase 4.0 offers the opportunity for plant science community to compare orchid genomes and transcriptomes and retrieve orchid sequences for further study.In the year 2022, two whole-genome sequences of Orchidoideae species, Platanthera zijinensis and Platanthera guangdongensis, were de novo sequenced, assembled and analyzed. In addition, systemic transcriptomes from these two species were also established. Therefore, we included these datasets to develop the new version of OrchidBase 5.0. In addition, three new functions including synteny, gene order, and miRNA information were also developed for orchid genome comparisons and miRNA characterization.OrchidBase 5.0 extended the genetic information to three orchid subfamilies (including five orchid species) and provided new tools for orchid researchers to analyze orchid genomes and transcriptomes. The online resources can be accessed at https://cosbi.ee.ncku.edu.tw/orchidbase5/.

4.
J Aging Health ; : 8982643221143828, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459693

RESUMO

ObjectivesTo investigate how indicators of psychological stress and physical health differentially influence subjective and objective memory in older adults. Methods: 404 adults aged ≥55 without cognitive impairment participated in remote assessment of physical health (PHY; multimorbidity, body-mass-index), psychological distress (PDS; perceived stress, anxiety, depression), subjective memory complaints (SM), and task-based objective memory performance (OM). Results: Separately, both PHY and PDS significantly predicted SM (p < 0.01), but only PHY was associated with OM (p = 0.05). Combined models showed that PHY and PDS maintained significant association with SM (p < 0.01, R2 = 0.30), while only PHY was associated with OM (p = .07, R2 = 0.03; for associative OM, p = 0.04). Discussion: SM is associated with participants' psychological profile, highlighting the importance of addressing these factors when assessing SM. The results also reveal that remotely-administered OM tasks are more immune to participants' psychological profile, and support previously-established links between physical health and objective and subjective memory function.

5.
Theranostics ; 12(18): 7788-7803, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36451856

RESUMO

Rationale: T-cell-redirecting bispecific antibodies (bsAbs) and trispecific antibodies (tsAbs) designed to recognize different epitopes or antigens have emerged as promising cancer therapies. Current approaches are all designed to include another antibody specific to the site of the primary antibody, and the molecular structures are generally established. However, the dimensions of target molecule and epitope location play a key role in the efficiency of the immunological synapse (IS) formation and subsequent T-cell-redirecting activities, therefore the connection flexibility of these antibodies determines the geometries of different formats of these molecules and will have a major impact on the efficacy. Methods: We describe a novel recombination strategy using various linker designs to site-specifically fuse anti-Her2 (2Rs15) or anti-VEGFR2 (3VGR19) nanobodies to different positions of the anti-CD3 antibody fragment (Fab, SP34). Based on the comparison among the various antigen-specific bsAbs, we could determine the desired fusion site of each nanobody to SP34, and further ensure the optimal structure of tsAbs with synergistic dual-antigen enhanced T-cell-redirecting activities. Results: This approach allows precise control of the formation of IS between Her2- and/or VEGFR2-expressing cancer cells and T cells, to obtain the optimal structure of the Her2/VEGFR2/CD3 tsAb without the need to map antibody-binding epitopes. Optimization of Her2/VEGFR2/CD3 tsAb results in enhanced T-cell-redirecting in vitro and in vivo antitumor efficacy compared with the corresponding bsAbs alone or in combination, and the potency to overcome tumor relapse due to antigen escape or resistance to Herceptin and Cyramza therapy. Conclusion: The novel design strategy for developing tsAbs using a site-specific recombination approach represents a promising platform for immuno-oncology and in applications other than cancer therapy.


Assuntos
Anticorpos Biespecíficos , Linfócitos T , Anticorpos Biespecíficos/farmacologia , Ativação Linfocitária , Epitopos , Especificidade de Anticorpos
6.
J Colloid Interface Sci ; 633: 275-283, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36455435

RESUMO

Constructing highly active electrocatalysts towards hydrogen evolution reaction (HER) in both alkaline and acidic media is essential for achieving a sustainable energy economy. Here, a facile ethylene glycol reduction strategy was employed to design the nickel-ruthenium nanocrystals (Ni-Ru NC) with an exposed highly active Ru (101) facet as an efficient electrocatalyst for HER. Testings show Ni-Ru NC outperforms the benchmark catalyst Pt/C by delivering extraordinarily low overpotentials of 21.1 and 70.9 mV to drive 10 mA cm-2 in acidic and alkaline solutions, respectively. The results of experimental and theoretical studies suggest that Ni can modulate the electronic structure of the Ru NC and optimize the hydrogen adsorption free energy on Ru's surface, which accelerates the charge transfer kinetics and enhances the HER performance. The study support the potential application of facet-modulated Ru-based HER eleccatalyst in an alkaline environment.

7.
Int J Nanomedicine ; 17: 5049-5061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325149

RESUMO

Background: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro. Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs. Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration. Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.


Assuntos
Colite , Neoplasias Colorretais , Camundongos , Animais , Azoximetano/toxicidade , Azoximetano/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Lipossomos/uso terapêutico , Sulfato de Dextrana/toxicidade , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Lipopolissacarídeos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colite/induzido quimicamente
8.
Front Plant Sci ; 13: 1012741, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330263

RESUMO

Although the effects of girdling on grape berry development have been widely studied, the underlying mechanisms are poorly understood, especially at the molecular level. This study investigated the effect of trunk girdling on grape (Vitis L.) berry maturation. Girdling was performed on 5-year-old 'Summer Black' grapevines at early veraison, and transcriptional and physiologic analyses were performed. Trunk girdling promoted sugar accumulation and color development in berries and accelerated berry ripening by 25 days. Genes related to sucrose cleavage and polysaccharide degradation were upregulated at the transcriptional level, which was associated with increased monosaccharide accumulation and berry softening. Anthocyanin biosynthesis and accumulation were also enhanced by trunk girdling through the upregulation of anthocyanin biosynthesis genes including phenylalanine ammonia-lyase and UDP-glucose:flavonoid 3-O-glucosyltransferase (UFGT). The increased expression of two VvUFGT genes was accompanied by the upregulation of VvMYBA2 under girdling. The upregulation of genes involved in ethylene biosynthesis and hormone (abscisic acid and brassinosteroid) responses and downregulation of genes involved in indoleacetic acid biosynthesis and response may have also promoted berry ripening in the girdling group. A total of 120 differentially expressed transcription factor genes from 29 gene families including MYB, ERF, and MYB-related were identified in the girdling group, which may participate in the regulation of berry development and ripening. These results provide molecular-level insight into the positive effects of trunk girdling on berry development in grapes.

9.
ACS Appl Mater Interfaces ; 14(45): 51244-51252, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36397310

RESUMO

Thermal-responsive hydrogel actuators have aroused a wide scope of research interest and have been extensively studied. However, their actuating behaviors are usually monotonous due to their unchangeable shapes and structures. Here, we report thermal-responsive poly(isopropylacrylamide-co-2-(dimethylamino)ethyl methacrylate)/alginate hydrogels with programmable external shapes and internal actuating trajectories. The volume phase transition temperatures of the resulting hydrogels can be tuned in a wide temperature range from 32 to above 50 °C by adjusting the monomer composition. While the formation and photo-dissociation of Fe3+-carboxylate tri-coordinates within the entire hydrogel network enable photo-responsive shape memory property, the insufficient dissociation of the tri-coordinates along the irradiation path gives rise to gradient crosslinking for realizing thermal-responsive actuation. Controlling the evolution of the gradient structure facilitates the regulation of the actuating amplitude. Furthermore, we show that the combination of these two types of shape-changing functionalities leads to more flexible and intricate shape-changing behaviors. One interesting application, a programmable hook with changeable actuating behaviors for lifting different objects with specific shapes, is also demonstrated. The proposed strategy can be extended to other types of actuating hydrogels with more advanced actuating behaviors.

10.
Mediators Inflamm ; 2022: 1875736, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387933

RESUMO

Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RARγ) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RARγ in cartilage destruction caused by inflammation in OA are still unknown. Here, we demonstrated that the RARγ was highly expressed in chondrocytes of OA patients compared with healthy people and was positively correlated with the damage degree of cartilage in OA. Cytokine TNF-α promoted the transcription and expression of RARγ through activating the NF-κB pathway in OA cartilage. In addition, the overexpression of RARγ resulted in the upregulation of matrix degradation and inflammation associated genes and downregulation of differentiation and collagen production genes in human normal chondrocyte C28/I2 cells. Mechanistically, overexpression of RARγ could increase the level of p-IκBα and p-P65 to regulate the expression of downstream genes. RARγ and IκBα also could interact with each other and had the same localization in C28/I2 cells. Moreover, the SD rats OA model induced by monosodium iodoacetate indicated that CD437 (RARγ agonist) and TNF-α accelerated the OA progression, including more severe cartilage layer destruction, larger knee joint diameter, and higher serum ALP levels, while LY2955303 (RARγ inhibitor) showed the opposite result. RARγ was also highly expressed in OA group and even higher in TNF-α group. In conclusion, RARγ/NF-κB positive feedback loop was activated by TNF-α in chondrocyte to promote cartilage destruction. Our data not only propose a novel and precise molecular mechanism for OA disease but also provide a prospective strategy for the treatment.


Assuntos
NF-kappa B , Osteoartrite , Humanos , Ratos , Animais , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Retroalimentação , Ratos Sprague-Dawley , Osteoartrite/genética , Osteoartrite/metabolismo , Cartilagem/metabolismo , Inflamação/metabolismo
12.
J Virol ; : e0087922, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36377874

RESUMO

The glycan loop of Zika virus (ZIKV) envelope protein (E) contains the glycosylation site and has been well documented to be important for viral pathogenesis and transmission. In the present study, we report that deletions in the E glycan loop, which were recorded in African ZIKV strains previously, have re-emerged in their contemporary Asian lineages. Here, we generated recombinant ZIKV containing specific deletions in the E glycan loop by reverse genetics. Extensive in vitro and in vivo characterization of these deletion mutants demonstrated an attenuated phenotype in an adult A129 mouse model and reduced oral infections in mosquitoes. Surprisingly, these glycan loop deletion mutants exhibited an enhanced neurovirulence phenotype, and resulted in a more severe microcephalic brain in neonatal mouse models. Crystal structures of the ZIKV E protein and a deletion mutant at 2.5 and 2.6 Å, respectively, revealed that deletion of the glycan loop induces encephalitic flavivirus-like conformational alterations, including the appearance of perforations on the surface and a clear change in the topology of the loops. Overall, our results demonstrate that the E glycan loop deletions represent neonatal mouse neurovirulence markers of ZIKV. IMPORTANCE Zika virus (ZIKV) has been identified as a cause of microcephaly and acquired evolutionary mutations since its discovery. Previously deletions in the E glycan loop were recorded in African ZIKV strains, which have re-emerged in the contemporary Asian lineages recently. The glycan loop deletion mutants are not glycosylated, which are attenuated in adult A129 mouse model and reduced oral infections in mosquitoes. More importantly, the glycan loop deletion mutants induce an encephalitic flavivirus-like conformational alteration in the E homodimer, resulting in a significant enhancement of neonatal mouse neurovirulence. This study underscores the critical role of glycan loop deletion mutants in ZIKV pathogenesis, highlighting a need for global virological surveillance for such ZIKV variants.

13.
Br J Anaesth ; 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36347723

RESUMO

BACKGROUND: Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts. METHODS: Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified. RESULTS: The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues. CONCLUSIONS: Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

14.
Cancer Gene Ther ; 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369341

RESUMO

The enhancer of zeste homolog 2 (EZH2) and its highly related homolog EZH1 are considered to be epigenetic silencing factors, and they play key roles in the growth and differentiation of cells as the core components of polycomb repressive complex 2 (PRC2). EZH1 and EZH2 are known to have a role in human malignancies, and alterations in these two genes have been implicated in transformation of human malignancies. Inhibition of EZH1/2 has been shown to result in tumor regression in humans and has been studied and evaluated in the preclinical setting and in multiple clinical trials at various levels. Our work thus contributes to the understanding of the relationship between regulatory molecules associated with EZH1/2 proteins and tumor progression, and may provide new insights for mechanism-based EZH1/2-targeted therapy in tumors.

15.
Ann Transl Med ; 10(20): 1131, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36388784

RESUMO

Background: Since the first case reported in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of coronavirus disease 2019 (COVID-19) worldwide. The global case count continued to rise and the WHO declared a Public Health Emergency of International Concern (PHEIC), causing a growing risk of imported COVID-19 infection. This study aimed to provide descriptive and quantitative epidemiological characteristics of imported COVID-19 cases in China. Methods: This cross-sectional study examined all imported COVID-19 cases in Mainland China from 22 January to 21 April 2020. Ratios, Median and percentile were used for descriptive analysis. Spearman's correlation analysis was performed between daily new imported cases in Mainland China and the country of origin. The chi-square test was used to evaluate the difference between home quarantine and compulsory centralized quarantine on native transmission. Results: A total of 1,610 cases of COVID-19 were imported from 49 countries to 27 provincial administrative regions in China; 79.8% were from European countries and the United States of America (the USA). Before 29 March 2020, the imported cases were mainly from the USA (27.7%) and United Kingdom (UK; 42.6%). After 29 March 2020, the daily newly imported cases from Russia rapidly grew. After 12 April 2020, the number of daily newly imported cases gradually decreased and remained at a low level (12±7 cases per day). Airport entry was encouraged, and ground border crossing was limited. Among the 1,610 cases, 54.0% were in the asymptomatic incubation period on arrival in Mainland China. Conclusions: The transmissions by imported COVID-19 were gradually and effectively curbed in Mainland China, despite a disproportionally high number of cases worldwide. Entry screening measures must be implemented universally to all inbound travelers at a point of entry or targeted to specific travel routes or to specific travelers. Compulsory centralized quarantine should be recommended in the prevention of the imported COVID-19 epidemic.

16.
Front Microbiol ; 13: 1040846, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406423

RESUMO

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage. Epidemiological data demonstrated that the high morbidity of T2DM occurs as a result of obesity and gradually develops into serious complications. To date, the mechanisms that underlie this observation are still ill-defined. In view of the effect of obesity on the gut microflora, Leprdb/db mice underwent antibiotic treatment and microbiota transplants to modify the gut microbiome to investigate whether microbes are involved in the development of diabetic nephropathy (DN) and/or diabetic retinopathy (DR). The mouse feces were collected for bacterial 16S ribosomal RNA gene sequencing. Cytokines including TNF-α, TGF-ß1, IFN-γ, IL-1ß, IL-6, IL-17A, IL-10, and VEGFA were detected by enzyme-linked immunosorbent assay (ELISA), flow cytometry, real-time PCR and immunofluorescent assay. Eyes and kidney were collected for histopathological assay. Intestinal permeability was also detected using Evans Blue. The results showed that obesity influenced metabolic variables (including fast/fed glucose, insulin, and triglyceride), retinopathy and nephropathy, and the gut microbiota. Obesity mainly reduced the ratio of Bacteroidetes/Firmicutes and influenced relative abundance of Proteobacteria, Actinobacteria, and Spirochetes. Obesity also increased intestinal permeability, metabolic endotoxemia, cytokines, and VEGFA. Microbiota transplants confirm that obesity aggravates retinopathy and nephropathy through the gut microbiota. These findings suggest that obesity exacerbates retinopathy and nephropathy by inducing gut microbiota dysbiosis, which further enhanced intestinal permeability and chronic low-grade inflammation.

17.
Org Biomol Chem ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36448655

RESUMO

A palladium-catalyzed ß-C(sp3)-H nitrooxylation of aliphatic alcohols with AgNO2 is reported. An 8-formylquinoline-derived oxime is installed as an exo-type directing group for sp3 C-H activation and selectfluor acts as the oxidant. The reaction tolerates a variety of functional groups and shows good selectivity for ß-C-H nitrooxylation of alcohols.

19.
J Virol ; : e0145322, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36416586

RESUMO

Phosphoinositide-3 kinase (PI3K) signaling regulates many cellular processes, including cell survival, differentiation, proliferation, cytoskeleton reorganization, and apoptosis. The actin cytoskeleton regulated by PI3K signaling plays an important role in plasma membrane rearrangement. Currently, it is known that respiratory syncytial virus (RSV) infection requires PI3K signaling. However, the regulatory pattern or corresponding molecular mechanism of PI3K signaling on cell-to-cell fusion during syncytium formation remains unclear. This study synthesized a novel PI3K inhibitor PIK-24 designed with PI3K as a target and used it as a molecular probe to investigate the involvement of PI3K signaling in syncytium formation during RSV infection. The results of the antiviral mechanism revealed that syncytium formation required PI3K signaling to activate RHO family GTPases Cdc42, to upregulate the inactive form of cofilin, and to increase the amount of F-actin in cells, thereby causing actin cytoskeleton reorganization and membrane fusion between adjacent cells. PIK-24 treatment significantly abolished the generation of these events by blocking the activation of PI3K signaling. Moreover, PIK-24 had an obvious binding activity with the p85α regulatory subunit of PI3K. The anti-RSV effect similar to PIK-24 was obtained after knockdown of p85α in vitro or knockout of p85α in vivo, suggesting that PIK-24 inhibited RSV infection by targeting PI3K p85α. Most importantly, PIK-24 exerted a potent anti-RSV activity, and its antiviral effect was stronger than that of the classic PI3K inhibitor LY294002, PI-103, and broad-spectrum antiviral drug ribavirin. Thus, PIK-24 has the potential to be developed into a novel anti-RSV agent targeting cellular PI3K signaling. IMPORTANCE PI3K protein has many functions and regulates various cellular processes. As an important regulatory subunit of PI3K, p85α can regulate the activity of PI3K signaling. Therefore, it serves as the key target for virus infection. Indeed, p85α-regulated PI3K signaling facilitates various intracellular plasma membrane rearrangement events by modulating the actin cytoskeleton, which may be critical for RSV-induced syncytium formation. In this study, we show that a novel PI3K inhibitor inhibits RSV-induced PI3K signaling activation and actin cytoskeleton reorganization by targeting the p85α protein, thereby inhibiting syncytium formation and exerting a potent antiviral effect. Respiratory syncytial virus (RSV) is one of the most common respiratory pathogens, causing enormous morbidity, mortality, and economic burden. Currently, no effective antiviral drugs or vaccines exist for RSV infection. This study contributes to understanding the molecular mechanism by which PI3K signaling regulates syncytium formation and provides a leading compound for anti-RSV infection drug development.

20.
J Vet Sci ; 23(6): e90, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36448436

RESUMO

BACKGROUND: Insulin regulates glucose homeostasis and has important effects on metabolism, cell growth, and differentiation. Depending on the cell type and physiological context, insulin signal has specific pathways and biological outcomes in different tissues and cells. For studying the signal pathway of insulin on glycolipid metabolism in porcine embryonic fibroblast (PEF), we used high-throughput sequencing to monitor gene expression patterns regulated by insulin. OBJECTIVES: The goal of our research was to see how insulin affected glucose and lipid metabolism in PEFs. METHODS: We cultured the PEFs with the addition of insulin and sampled them at 0, 48, and 72 h for RNA-Seq analysis in triplicate for each time point. RESULTS: At 48 and 72 h, 801 and 1,176 genes were differentially expressed, respectively. Of these, 272 up-regulated genes and 264 down-regulated genes were common to both time points. Gene Ontology analysis was used to annotate the functions of the differentially expressed genes (DEGs), the biological processes related to lipid metabolism and cell cycle were dominant. And the DEGs were significantly enriched in interleukin-17 signaling pathway, phosphatidylinositol-3-kinase-protein kinase B signaling pathway, pyruvate metabolism, and others pathways related to lipid metabolism by Kyoto Encyclopedia of Genes and Genomes enrichment analysis. CONCLUSIONS: These results elucidate the transcriptomic response to insulin in PEF. The genes and pathways involved in the transcriptome mechanisms provide useful information for further research into the complicated molecular processes of insulin in PEF.


Assuntos
Fibroblastos , Insulinas , Animais , Suínos , RNA-Seq/veterinária , Metabolismo dos Lipídeos , Glucose
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