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1.
J Affect Disord ; 296: 233-240, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34619449

RESUMO

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have provided strong evidence of abnormal regional spontaneous brain activities among anxiety-disordered patients. However, the evidence has been divergent and inconclusive. Therefore, it is necessary to perform a meta-analysis identifying a common pattern of altered regional spontaneous brain activity for anxiety disorders. METHOD: Corresponding research of anxiety disorders, namely, whole-brain rs-fMRI studies that measured differences in regional homogeneity, amplitude of low-frequency fluctuations, or fractional amplitude of low-frequency fluctuations, were analyzed in this study. Overall, seven studies with 235 anxiety-disordered patients and 241 healthy controls were ultimately included in the meta-analysis. The meta-analysis was processed by seed-based d mapping. RESULTS: Compared with healthy controls, patients with anxiety disorders showed significantly decreased regional spontaneous brain activities in the right putamen, the right orbital inferior frontal gyrus, and the right temporal pole. No increases in regional spontaneous brain activities were detected in patients relative to the controls. LIMITATION: Limited number of available studies, only Asian samples, and insufficient information of sample characteristics. CONCLUSION: The present study suggests that anxiety disorders are associated with aberrant regional brain activity in areas connected with emotion processing, which extends our understanding of anxiety disorders' pathophysiology.

2.
Food Chem ; : 131572, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34810015

RESUMO

In this work, a natural proanthocyanidin (PA) based magnetic nanoporous organic polymer (named as PA-MOP) was successfully synthesized for the first time. The PA-MOP possessed high hydrophilic-surface, good magnetic responsiveness and high affinity for neonicotinoid insecticides. It was applied as an advanced magnetic sorbent for extraction of four neonicotinoids (thiamethoxam, imidacloprid, acetamiprid and thiacloprid) from environmental water, peach juice and honey samples prior to HPLC analysis. Under optimal conditions, the limits of detection for the analytes at S/N = 3 were 0.02-0.08 ng mL-1 for water, 0.03-0.10 ng mL-1 for peach juice and 0.05-0.16 ng g-1 for honey sample. The method recoveries were 80.0%-114.8%, with the relative standard deviations below 6.8%. The values of matrix effect were from -1.5% to -9.3%. Based on theory calculation, the extraction mechanism can be attributed to multiple interactions between the PA-MOP and the neonicotinoids, in which hydrogen bonding, π-π stacking and electrostatic interactions are the major interactions.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34801999

RESUMO

OBJECTIVES: MicroRNAs were revealed as biomarkers for early detection or prognosis predictors of cancer and were involved in the progression of cancer. The present study investigated the expression pattern, potential clinical, and functional role of miR-885-5p in cervical cancer. DESIGN: A total of 115 pairs of cervical cancer tissue specimens and adjacent non-tumor paracancerous tissue specimens were collected from the cervical cancer patients who underwent surgical resection or biopsy without preoperative systemic therapy at Maternity and Child Health Care of Zaozhuang from 2012 to 2014. Participants/Materials, Setting, Methods: The expression levels of miR-885-5p in cervical cancer were measured using the qRT-PCR assay. A follow-up study was conducted and the Kaplan-Meier method with log-rank test was used to analyze the potential clinical significance of miR-885-5p in cervical cancer. The functional experiments including CCK-8, Transwell migration, and invasion assays were used to investigate the biological function of miR-885-5p in cervical cancer cells. RESULTS: miR-885-5p expression was decreased in tumor tissues and tumor cell lines compared to normal control. Low expression of miR-885-5p was related to lymph node metastasis, late FIGO stage, and shorter overall survival outcome. Ascending expression of miR-885-5p inhibited the proliferative, migratory, and invasive abilities of cervical cancer cells, while downregulation of miR-885-5p promoted these cellular abilities of cervical cancer cells in vitro. LIMITATIONS: The patient population size was limited, thus the clinical significance of miR-885-5p requires further verification. Secondly, the precise mechanism of miR-885-5p in cervical cancer still exclusive. In future studies, a larger sample size will be required to confirm the prognostic value of miR-885-5p in cervical cancer, and the possible targets, as well as the detailed mechanism of miR-885-5p, will be investigated. CONCLUSIONS: miR-885-5p expression was decreased in cervical cancer and downregulation of miR-885-5p promoted the progression of cervical cancer cells. miR-885-5p may be an independent prognostic predictor and therapeutic target for treating cervical cancer.

4.
Adv Healthc Mater ; : e2101761, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34811972

RESUMO

Circulating tumor cells (CTCs) are reported as the precursor of tumor metastases, implying that stifling CTCs would be beneficial for metastasis prevention. However, challenges remain for the application of therapies that aim at CTCs due to lack of effective CTC-targeting strategy and sensitive therapeutic agents. Herein, we propose a general CTC-intervention strategy based on neutrophil cyto-pharmaceuticals for suppressing CTC colonization and metastasis formation. Breast cancer 4T1 cells were infused as the mimic CTCs, and we first elucidate 4T1 cells trapped in neutrophil extracellular traps (NETs) expressing high levels of hypoxia-inducible factor-1α (HIF-1α) due to NET formation and thus promoting tumor cell colonization through enhanced migration, invasion and stemness. After verifying HIF-1α as a potential target for metastasis prevention, living neutrophil cyto-pharmaceuticals (CytPNEs) loaded with HIF-1α inhibitor are fabricated to therapeutically inhibit HIF-1α. We demonstrate that CytPNEs can specially convey the HIF-1α inhibitor to 4T1 cells according to the inflammatory chemotaxis of neutrophils and down-regulate HIF-1α, thereby inhibiting metastasis and prolonging the median survival of mice bearing breast cancer lung metastasis. Our research offers a new perspective for understanding the mechanism of CTC colonization, and puts forward the strategy of targeted intervention of CTCs as a meaningful treatment for tumor metastasis. This article is protected by copyright. All rights reserved.

6.
Oxid Med Cell Longev ; 2021: 3206982, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594474

RESUMO

Fibrosis is defined as the pathological progress of excessive extracellular matrix (ECM), such as collagen, fibronectin, and elastin deposition, as the regenerative capacity of cells cannot satisfy the dynamic repair of chronic damage. The well-known features of tissue fibrosis are characterized as the presence of excessive activated and proliferated fibroblasts and the differentiation of fibroblasts into myofibroblasts, and epithelial cells undergo the epithelial-mesenchymal transition (EMT) to expand the number of fibroblasts and myofibroblasts thereby driving fibrogenesis. In terms of mechanism, during the process of fibrosis, the activations of the TGF-ß signaling pathway, oxidative stress, cellular senescence, and inflammatory response play crucial roles in the activation and proliferation of fibroblasts to generate ECM. The deaths due to severe fibrosis account for almost half of the total deaths from various diseases, and few treatment strategies are available for the prevention of fibrosis as yet. Recently, numerous studies demonstrated that three well-defined bioactive gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), generally exhibited anti-inflammatory, antioxidative, antiapoptotic, and antiproliferative properties. Besides these effects, a number of studies have reported that low-dose exogenous and endogenous gasotransmitters can delay and interfere with the occurrence and development of fibrotic diseases, including myocardial fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, diabetic diaphragm fibrosis, and peritoneal fibrosis. Furthermore, in animal and clinical experiments, the inhalation of low-dose exogenous gas and intraperitoneal injection of gaseous donors, such as SNAP, CINOD, CORM, SAC, and NaHS, showed a significant therapeutic effect on the inhibition of fibrosis through modulating the TGF-ß signaling pathway, attenuating oxidative stress and inflammatory response, and delaying the cellular senescence, while promoting the process of autophagy. In this review, we first demonstrate and summarize the therapeutic effects of gasotransmitters on diverse fibrotic diseases and highlight their molecular mechanisms in the process and development of fibrosis.

8.
ACS Appl Mater Interfaces ; 13(40): 48292-48300, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34607429

RESUMO

A novel integrated bioinspired surface is fabricated by using an innovative capillarity-induced selective oxidation method, to achieve the combination of the fog-collecting characteristics of a variety of creatures, i.e., the micronanostructures of spider silk, the wettable patterns of desert beetle, the conical structure of cactus spine, and the hierarchical microchannel of Sarracenia trichome. The fog is captured effectively via multistructures on the cone tips, and captured droplet is collected and confined in the microchannel to realize rapid transport via the formation of wettable pattern on the surface and the introduction of wettable gradient in the microchannel. Consequently, the fog harvest efficiency reaches 2.48 g/h, increasing to nearly 320% compared to the normal surface. More interestingly, similar to Sarracenia trichome, the surface also presents two transport modes, namely, Mode I (water transport along dry microchannel) and Mode II (succeeding water slippage on the water film). In Mode II, the velocity of 34.10 mm/s is about three times faster than that on the Sarracenia trichome. Such a design of integrated bioinspired surface may present potential applications in high-efficiency water collection systems, microfluidic devices, and others.

9.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639184

RESUMO

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.


Assuntos
Queratinócitos/efeitos dos fármacos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
J Headache Pain ; 22(1): 129, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711175

RESUMO

OBJECTIVES: In this study, we aimed to investigate the spontaneous neural activity in the conventional frequency band (0.01-0.08 Hz) and two sub-frequency bands (slow-4: 0.027-0.073 Hz, and slow-5: 0.01-0.027 Hz) in tension-type headache (TTH) patients with regional homogeneity (ReHo) analyses. METHODS: Thirty-eight TTH patients and thirty-eight healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (RS-fMRI) scanning to investigate abnormal spontaneous neural activity using ReHo analysis in conventional frequency band (0.01-0.08 Hz) and two sub-frequency bands (slow-4: 0.027-0.073 Hz and slow-5: 0.01-0.027 Hz). RESULTS: In comparison with the HC group, patients with TTH exhibited ReHo increases in the right medial superior frontal gyrus in the conventional frequency band (0.01-0.08 Hz). The between group differences in the slow-5 band (0.01-0.027 Hz) highly resembled the differences in the conventional frequency band (0.01-0.08 Hz); even the voxels with increased ReHo were spatially more extensive, including the right medial superior frontal gyrus and the middle frontal gyrus. In contrast, no region showed significant between-group differences in the slow-4 band (0.027-0.073 Hz). The correlation analyses showed no correlation between the ReHo values in TTH patients and VAS scores, course of disease and number of seizures per month in conventional band (0.01-0.08 Hz), slow-4 band (0.027-0.073 Hz), as well as in slow-5 band (0.01-0.027 Hz). CONCLUSIONS: The results showed that the superior frontal gyrus and middle frontal gyrus were involved in the integration and processing of pain signals. In addition, the abnormal spontaneous neural activity in TTH patients was frequency-specific. Namely, slow-5 band (0.01-0.027 Hz) might contain additional useful information in comparison to slow-4 band (0.027-0.073 Hz). This preliminary exploration might provide an objective imaging basis for the understanding of the pathophysiological mechanism of TTH.


Assuntos
Imageamento por Ressonância Magnética , Cefaleia do Tipo Tensional , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Lobo Frontal , Humanos , Cefaleia do Tipo Tensional/diagnóstico por imagem
11.
J Affect Disord ; 295: 1057-1065, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706414

RESUMO

BACKGROUND: Physical exercise has been proved to reduce the risk of major depression in Subthreshold depression (StD) individuals effectively, yet little is known about the spontaneous brain activity changes associated with physical exercise. METHODS: A total of 70 adult subjects, including 38 StD and 32 healthy control (HC) subjects, underwent a resting-state functional magnetic resonance imaging (rs-fMRI) before and after eight-week aerobic exercise respectively. Then, the amplitude of low-frequency fluctuation (ALFF) alterations between the two groups were quantitatively analyzed. RESULTS: Before exercise intervention, the rs-fMRI data showed increased ALFF of the right putamen in the StD group compared with HC group. After exercise intervention, there was no significant ALFF change observed between the StD and HC groups. The longitudinal ALFF differences from pre- to post- exercise intervention showed significantly decreased ALFF in the right middle and inferior occipital gyrus, right middle and inferior temporal gyrus, right fusiform gyrus (FG), while increased ALFF in the right middle cingulate, right superior parietal louble, right inferior parietal lobule (IPL) (inferior parietal gyrus and supramarginal gyrus), and bilateral precuneus in the StD group. As for HC group, the results showed that decreased ALFF in the right FG and right parahippocampus, while increased ALFF in the right precuneus, right middle cingulate, right supplementary motor area, right superior parietal lobule and right paracentral lobule in the HC group. No significant correlation between changes of ALFF and clinical scale scores in the StD group. LIMITATIONS: The definitions of StD are varied in terms of different studies, the final sample size was relatively small, and the age range of the subjects in this study was narrow. Meanwhile, the exercise intervention trial was short-term. CONCLUSIONS: These results further support the standpoint that physical exercise has the potential to reshape the abnormal patterns of spontaneous brain activity in adults with StD.


Assuntos
Depressão , Imageamento por Ressonância Magnética , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Exercício Físico , Humanos
12.
Andrologia ; : e14265, 2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34657331

RESUMO

Asthenozoospermia is detected in 40% of infertile men, and characterised by low sperm motility. MicroRNAs (miRNAs) play essential roles in spermatogenesis, but little is known regarding the function of seminal plasma miRNAs in asthenozoospermia. In this study, we collected seminal plasma samples from patients with asthenospermia and healthy men and employed high-throughput sequence technology to identify differentially expressed miRNAs. Thirteen altered miRNAs were confirmed by qRT-PCR. Six of these miRNAs were upregulated, and seven were downregulated. Five of the miRNAs (hsa-miR-34c-5p, hsa-miR-34b-5p, hsa-miR-146b-5p, hsa-miR-449a and has-miR-765) had been characterised previously, and eight of the others (miR-5000-3p, miR-4289, miR-6514-3p, miR-6882-5p and miR-6739-5p, miR-135a-5p, miR-509-3p and miR-196b-5p) were identified in asthenospermia for the first time in this study. These miRNAs were significantly associated with PI3K-Akt signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway and FoxO signaling pathway. The identified dysregulated miRNA may be the key to the development of new and enhanced diagnosis and prognosis technologies for asthenospermia, and may also provide new therapeutic possibilities in the field of personalised medicine.

13.
Front Cell Infect Microbiol ; 11: 746926, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604118

RESUMO

Due to lacking a proofreading mechanism in their RNA-dependent RNA polymerases (RdRp), RNA viruses generally possess high mutation frequencies, making them evolve rapidly to form viral quasispecies during serial passages in cells, especially treated with mutagens, like ribavirin. Canine distemper virus (CDV) belongs to the genus Morbillivirus. Its L protein functions as an RdRp during viral replication. In this study, a recombinant enhanced green fluorescence protein-tagged CDV (rCDV-eGFP) was rescued from its cDNA clone, followed by viral identification and characterization at passage-7 (P7). This recombinant was independently subjected to extra 40 serial passages (P8 to 47) in ribavirin- and non-treated cells. Two viral progenies, undergoing passages in ribavirin- and non-treated VDS cells, were named rCDV-eGFP-R and -N, respectively. Both progenies were simultaneously subjected to next-generation sequencing (NGS) at P47 for comparing their quasispecies diversities with each other. The rCDV-eGFP-R and -N showed 62 and 23 single-nucleotide mutations (SNMs) in individual antigenomes, respectively, suggesting that the ribavirin conferred a mutagenic effect on the rCDV-eGFP-R. The spectrum of 62 SNMs contained 26 missense and 36 silent mutations, and that of 23 SNMs was composed of 17 missense and 6 silent mutations. Neither the rCDV-eGFP-R nor -N exhibited nonsense mutation in individual antigenomes. We speculate that the rCDV-eGFP-R may contain at least one P47 sub-progeny characterized by high-fidelity replication in cells. If such a sub-progeny can be purified from the mutant swarm, its L protein would elucidate a molecular mechanism of CDV high-fidelity replication.


Assuntos
Vírus da Cinomose Canina , Animais , Vírus da Cinomose Canina/genética , Mutação , RNA Polimerase Dependente de RNA , Ribavirina/farmacologia , Inoculações Seriadas
14.
Phys Chem Chem Phys ; 23(34): 18404-18413, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612381

RESUMO

As a human mitotic kinase, haspin is considered as a promising target for various diseases including cancers. However, no inhibitors targeting haspin have entered clinical trials presently. 5-iTU (5-iodotubercidin) is a useful and classical chemical probe for the investigation of haspin activity, but its inhibitory mechanism remains unclear. In this study, integrated molecular dynamics (MD) of conventional MD, extended adaptive biasing force (eABF), random acceleration MD and well-tempered metadynamics were applied to investigate the thermodynamic and kinetic features of 5-iTU and three derivatives targeting haspin. To emphasize the importance of gatekeeper Phe605, two haspin mutants (F605Y and F605T) were also built. The results showed that the binding affinity of 5-iTU and haspin was highest in all wild type (WT) systems, relying on the strong halogen aromatic π interaction between 5-iTU and gatekeeper Phe605. Gatekeeper mutations, because of damage to this interaction, led to the rearrangement of water distributions at the binding site and the decrease of 5-iTU residence times. Additionally, compared with the smaller 5-fTU, 5-iTU dissociated from WT haspin with more difficulty through distinct unbinding pathways. These findings will provide crucial guidance for the design and development of novel haspin inhibitors and the rational modification of existing inhibitors.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Termodinâmica , Tubercidina/análogos & derivados , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Conformação Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Tubercidina/química , Tubercidina/farmacologia
15.
Opt Express ; 29(16): 25064-25083, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34614846

RESUMO

In inverse design, the design and background areas can be represented by different spatial resolutions; thus, adaptive meshes are more efficient than structured meshes. In this study, a second-order interpolation scheme is introduced to realize an inverse design process on an adaptive mesh. Experiment results show that the proposed scheme yields a 1.79-fold acceleration over that achieved using a structured mesh, aiding design time reduction or design area expansion. As the design area can be divided into multiple areas with different spatial resolutions, in future work, adaptive meshes can be combined with machine learning algorithms to further improve the inverse-design-process efficiency.

16.
Microbiol Spectr ; 9(2): e0050321, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34612694

RESUMO

The aims of this study were to elucidate the role of IS1294 in plasmid reorganization and to analyze biological characteristics of cointegrates derived from different daughter plasmids. The genetic profiles of plasmids in Escherichia coli strain C21 and its transconjugants were characterized by conjugation, S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), Southern hybridization, whole-genome sequencing (WGS) analysis, and PCR. The traits of cointegrates were characterized by conjugation and stability assays. blaCTX-M-55-bearing IncI2 pC21-1 and nonresistant IncI1 pC21-3, as conjugative helper plasmids, were fused with nonconjugative rmtB-bearing IncN-X1 pC21-2, generating cointegrates pC21-F1 and pC21-F2. Similarly, pC21-1 and pC21-3 were fused with nonconjugative IncF33:A-:B- pHB37-2 from another E. coli strain to generate cointegrates pC21-F3 and pC21-F4 under experimental conditions. Four cointegrates were further conjugated into the E. coli strain J53 recipient at high conjugation frequencies, ranging from 2.8 × 10-3 to 3.2 × 10-2. The formation of pC21-F1 and pC21-F4 was the result of host- and IS1294-mediated reactions and occurred at high fusion frequencies of 9.9 × 10-4 and 2.1 × 10-4, respectively. Knockout of RecA resulted in a 100-fold decrease in the frequency of plasmid reorganization. The phenomenon of cointegrate pC21-F2 and its daughter plasmids coexisting in transconjugants was detected for the first time in plasmid stability experiments. IS26-orf-oqxAB was excised from cointegrate pC21-F2 through a circular intermediate at a very low frequency, which was experimentally observed. To the best of our knowledge, this is the first report of IS1294-mediated fusion between plasmids with different replicons. This study provides insight into the formation and evolution of cointegrate plasmids under different drug selection pressures, which can promote the dissemination of MDR plasmids. IMPORTANCE The increasing resistance to ß-lactams and aminoglycoside antibiotics, mainly due to extended-spectrum ß-lactamases (ESBLs) and 16S rRNA methylase genes, is becoming a serious problem in Gram-negative bacteria. Plasmids, as the vehicles for resistance gene capture and horizontal gene transfer, serve a key role in terms of antibiotic resistance emergence and transmission. IS26, present in many antibiotic-resistant plasmids from Gram-negative bacteria, plays a critical role in the spread, clustering, and reorganization of resistance determinant-encoding plasmids and in plasmid reorganization through replicative transposition mechanisms and homologous recombination. However, the role of IS1294, present in many MDR plasmids, in the formation of cointegrates remains unclear. Here, we investigated experimentally the intermolecular recombination of IS1294, which occurred with high frequencies and led to the formation of conjugative MDR cointegrates and facilitated the cotransfer of blaCTX-M-55 and rmtB, and we further uncovered the significance of IS1294 in the formation of cointegrates and the common features of IS1294-driven cointegration of plasmids.

17.
Nature ; 599(7884): 320-324, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34707294

RESUMO

The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters1,2 and to H+-driven transporters of the RND family3,4, enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression5-10. Here we determine a cryo-electron microscopy structure of the mouse protein Dispatched homologue 1 (DISP1), revealing three Na+ ions coordinated within a channel that traverses its transmembrane domain. We find that the rate of Hedgehog export is dependent on the Na+ gradient across the plasma membrane. The transmembrane channel and Na+ binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na+ ions. DISP1-NNN and variants that disrupt single Na+ sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na+-site occupancies, which suggests a mechanism by which transmembrane Na+ flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na+-coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na+ flux powers their conformationally driven activities.

18.
J Cell Mol Med ; 25(21): 10101-10110, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34609056

RESUMO

Thymoquinone (TQ) has been reported as an anti-tumour drug widely studied in various tumours, and its mechanism and effect of which has become a focus of current research. However, previous studies from our laboratory and other groups found that TQ showed weak anti-tumour effects in many cancer cell lines and animal models. Therefore, it is necessary to modify and optimize the structure of TQ to obtain new chemical entities with high efficiency and low toxicity as candidates for development of new drugs in treating cancer. Therefore, we designed and synthesized several TQ derivatives. Systematic analysis, including in vitro and in vivo, was conducted on a panel of triple-negative breast cancer (TNBC) cells and mouse model to demonstrate whether TQFL12, a new TQ derivative, is more efficient than TQ. We found that the anti-proliferative effect of TQFL12 against TNBC cells is significantly stronger than TQ. We also demonstrated TQFL12 affects different aspects in breast cancer development including cell proliferation, migration, invasion and apoptosis. Moreover, TQFL12 inhibited tumour growth and metastasis in cancer cell-derived xenograft mouse model, with less toxicity compared with TQ. Finally, mechanism research indicated that TQFL12 increased AMPK/ACC activity by stabilizing AMPKα, while molecular docking supported the direct interaction between TQFL12 and AMPKα. Taken together, our findings suggest that TQFL12, as a novel chemical entity, possesses a better inhibitory effect on TNBC cells and less toxicity in both in vitro and in vivo studies. As such, TQFL12 could serve as a potential therapeutic agent for breast cancer.

19.
Biomed Pharmacother ; 144: 112252, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34619493

RESUMO

The protein arginine methyltransferase 5 (PRMT5) as the major type II arginine methyltransferase catalyzes the mono- and symmetric dimethylation of arginine residues in both histone and non-histone proteins. Recently, increasing evidence has demonstrated that PRMT5 plays an indispensable role in the occurrence and development of various human cancers by promoting the cell proliferation, invasion, and migration. It has become a promising and valuable target in the cancer epigenetic therapy. This review is to summarize the clinical significance of PRMT5 in the cancers such as lung cancer, breast cancer and colorectal cancer, and the drug discovery targeting PRMT5. Importantly, the existing PRMT5 inhibitors representing different molecular mechanisms, and their pharmacological effect, mechanism of action and biological affinity are analyzed. Clinical status, current problems and future perspective of PRMT5 inhibitors for the treatment of cancers are also discussed, all of which provides crucial help for the future discovery of PRMT5 targeted drugs for cancer treatment.

20.
Inorg Chem ; 60(22): 17151-17160, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34705464

RESUMO

The poor rate and cycle performance rooting from the inferior electrical conductivity and large volume change are bottlenecks for further application of the potential anode material in sodium-ion batteries. To address this problem, homogeneous CoP nanoparticles enwrapped in the N-doped carbon (CoP/NC) microspheres are synthesized by the simultaneous carbonization and phosphorization of Co-salen complex microspheres for the first time. The N-doped carbon enhances its conductivity and diminishes the volume stress, and the dispersed CoP nanoparticles in carbon provide more reaction sites, resulting in a superior sodium storage performance. CoP/NC microspheres exhibit the capacity of 373 mA h g-1 at 0.1 A g-1 after 100 cycles. Even at 2 A g-1 for 2000 cycles, the capacity of 195 mA h g-1 is also achieved. This work provides an excellent reference for the design and synthesis of sulfide, selenide, and other transition-metal composites. It is also beneficial to expand the application of salen complexes in the design and synthesis of catalysts and energy storage materials.

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