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1.
Cell Death Dis ; 12(10): 931, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642304

RESUMO

Studies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) identified Src as the target of matrine. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) provided solid evidences that matrine directly bound to Src. Bioinformatics prediction and pull-down experiment demonstrated that Src kinase domain was required for its interaction with matrine and Ala392 in the kinase domain participated in matrine-Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419 in Src kinase domain. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3, and PI3K/Akt signaling pathways via targeting Src. Collectively, matrine targeted Src, inhibited its kinase activity, and down-regulated its downstream MAPK/ERK, JAK2/STAT3, and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

2.
J Mol Neurosci ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34647267

RESUMO

Following spinal cord injury (SCI), multiple signaling cascades are activated instantaneously in the injured segments of the spinal cord to create a complex and pathogenic microenvironment, making it difficult to treat SCI. Nevertheless, the significance of the integrated stress response (ISR) to the series of physiological and pathological changes that occur after SCI remains unclear. Through western blotting (WB), we determined that the autophosphorylation of stress receptors (GCN2, PERK, PKR, and HRI) was enhanced after SCI, leading to increased phosphorylation of eIF2α at Ser51. Strikingly, we found that eIF2α was highly phosphorylated at 1 day post injury (dpi) and that this hypophosphorylation was maintained thereafter in the spinal cord, especially in neurons, which suggests that intervening with eIF2α phosphorylation may be a treatment strategy for SCI. Therefore, we employed the small molecule ISRIB, which inhibits eIF2α phosphorylation when the ISR is activated at moderate or low levels but not when the ISR is highly activated. Daily intraperitoneal injection of ISRIB significantly inhibited ISR signaling after SCI, reduced the cytosolic localization of RNA-binding proteins, and decreased neuronal apoptosis. Histological and functional experiments further demonstrated that treatment with ISRIB after SCI effectively curbed morphological deterioration and promoted the recovery of locomotor function. In summary, the ISR plays an important role in SCI, and ISRIB is a promising drug for the treatment of SCI.

3.
Oncogene ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615997

RESUMO

Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues (P < 0.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in ApcMin/+ and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545Δ/ΔApcMin/+ mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC.

4.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3886-3892, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472264

RESUMO

This study established high-performance liquid chromatography(HPLC) fingerprints of Chinese medicines derived from Apocynum venetum and Poacynum pictum in Xinjiang and explored their composition differences with the combination of content determination, similarity analysis, cluster analysis and principal component analysis. The HPLC conditions included Phenomenex Kinetex C_(18) column(4.6 mm ×100 mm, 2.6 µm), acetonitrile-0.01% trifluoroacetic acid aqueous solution as mobile phase, gradient elution, flow rate of 0.6 mL·min~(-1), detection wavelength of 281 nm and column temperature of 25 ℃. The content of chlorogenic acid, quercetin-3-O-sophoroside, rutin, hyperin, isoquercitrin, trifolin and astragalin was determined in 31 batches of medicinal materials, and fingerprint research and chemometric analysis were performed with Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine(Version 2004 A) and SPSS 21.0. In the Chinese Pharmacopoeia 2020, the quality of Apocyni Veneti Folium is controlled by character identification, microscopic identification, thin layer chromatography identification and quantitative determination of hyperin. There were 21 common peaks of A. venetum and P. pictum in the HPLC fingerprints, 5 of which were identified as chlorogenic acid, hyperin, isoquercitrin, trifolin and astragalin, with their content also determined. Except for 3 batches of medicinal materials, the similarity of other 28 batches was higher than 0.83, indicating good similarity. Two categories were formed in the cluster analysis based on content determination, which showed that some differences existed in similarities between different regions of Xinjiang. The medicinal materials were ranked by quality with principal component analysis, and the results indicated that the top 15 all came from northern Xinjiang. The quality difference of A. venetum and P. pictum had a correlation with the place of origin. This study provides a reference for the analysis and evaluation of A. venetum and P. pictum from different habitats and the selection of introduction and cultivation areas.


Assuntos
Apocynum , Medicamentos de Ervas Chinesas , China , Cromatografia Líquida de Alta Pressão , Medicina Tradicional Chinesa
5.
Int J Stroke ; : 17474930211045805, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34550833

RESUMO

OBJECTIVE: To determine the influence of renal impairment on clinical outcomes in patients presenting emergent anterior circulation occlusion treated with mechanical thrombectomy. METHODS: Consecutive patients with anterior circulation stroke treated with mechanical thrombectomy at 41 academic tertiary care centers were included. renal impairment was defined as glomerular filtration rate <60 mL/min/1.73 m2 at the time of admission. The primary outcome was the distribution of scores on the modified Rankin scale, and safety outcomes were mortality within 90 days and hemorrhagic complications. Binary and ordinal logistic regression was used to evaluate the associations between renal impairment and categorical outcomes. Linear regression was used to assess continuous outcomes. RESULTS: A total of 607 patients (47 renal impairment and 600 non-renal impairment) who underwent mechanical thrombectomy were included in this study. Multivariate regression analysis showed that renal impairment was independently associated with the increase of the modified Rankin scale at 90 days. The proportion of patients with successful reperfusion was 71.7% in the renal impairment group and 83.3% in the non-renal impairment group. Renal impairment was an independent predictor of 90-day mortality. No significant treatment for the ordinal modified Rankin scale or 90-day mortality was observed by renal impairment interaction. The risk of asymptomatic intracranial hemorrhage was higher in the mechanical thrombectomy plus IVT group (53.6%) than in the mechanical thrombectomy alone group (15.8%) for renal impairment, but was similar between the mechanical thrombectomy plus IVT group (34.6%) and the mechanical thrombectomy alone group (36.4%) for non-renal impairment (p = 0.01). CONCLUSION: These results demonstrated that the outcomes of mechanical thrombectomy alone and mechanical thrombectomy plus IVT group did not differ significantly in acute stroke patients with and without renal impairment. Also, renal impairment was an independent predictor of worse functional independence and higher mortality at 90 days.

6.
Int J Stroke ; : 17474930211047337, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34569866

RESUMO

BACKGROUND: The impact of renal impairment on the outcomes of patients with acute ischemic stroke treated with endovascular thrombectomy was relatively limited and contradictory. We performed a systematic review and meta-analysis to investigate this. AIMS: We registered a protocol in September 2020 and searched MEDLINE, EMBASE, and Google Scholar accordingly. Renal impairment was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Predefined outcomes included functional independence (defined as a modified Rankin Scale of 0, 1, or 2) at three months, successful reperfusion, mortality, and symptomatic intracerebral hemorrhage. SUMMARY OF REVIEW: Eleven studies involving 3453 patients were included. For the unadjusted outcomes, renal impairment was associated with fewer functional independence (odds ratio (OR), 0.49; 95% confidence interval (CI), 0.39-0.62) and higher mortality (OR, 2.55; 95% CI, 2.03-3.21). Renal impairment was not associated with successful reperfusion (OR, 0.80; 95% CI 0.63-1.00) and symptomatic intracerebral hemorrhage (OR, 1.41; 95% CI, 0.95-2.10). For the adjusted outcomes, results derived from a multivariate meta-analysis were consistent with the respective unadjusted outcomes: functional independence (OR, 0.59; 95% CI, 0.45-0.77), mortality (OR, 2.23, 95% CI, 1.45-3.43), and symptomatic intracerebral hemorrhage (OR, 1.34; 95% CI, 0.85-2.10). CONCLUSIONS: We presented the first systematic review to demonstrate that renal impairment is associated with fewer functional independence and higher mortality. Future endovascular thrombectomy studies should publish complete renal estimated glomerular filtration rate data to facilitate prognostic studies and permit estimated glomerular filtration rate to be analyzed in a continuous variable.Systematic Review Registration: PROSPERO CRD42020191309.

7.
J Environ Manage ; 300: 113759, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34543963

RESUMO

Fire is an important disturbance in many wetlands, which are key carbon reservoirs at both regional and global scales. However, the effects of fire on wetland vegetation biomass and plant carbon dynamics are poorly understood. We carried out a burn experiment in a Calamagrostis angustifolia wetland in Sanjiang Plain (Northeast China), which is widespread wetland type in China and frequently exposed to fire. Using a series of replicated experimental annual burns over a three-year period (spring and autumn burns carried out one, two or three times over three consecutive years), together with a control unburned treatment, we assessed the effect of burn seasonality and frequency on aboveground biomass, stem density, and carbon content of aboveground plant parts and ground litter. We found that burning promoted plant growth and hence plant biomass in burned sites compared to the unburned control, with this effect being greatest after three consecutive burn years. Autumn burns promoted higher stem density and more total aboveground biomass than spring burns after three consecutive burn years. Burning increased stem density significantly, especially in twice and thrice burned plots, with stem densities in September over 2000 N/m2, which was much higher than in the control plots (987 ± 190 N/m2). Autumn burns had a larger effect than spring burns on total plant biomass and litter accumulated (e.g. 1236 ± 295 g/m2 after thrice autumn burns compared 796.2 ± 66.6 g/m2 after thrice spring burns), except after two burn treatments. With time since burning, total biomass loads increased in spring-burned plots, while autumn-burned plots showed the opposite trend, declining towards values found at unburned plots in year three. Our results suggest that, at short fire return intervals, autumn burns lead to a more pronounced increase in aboveground biomass and carbon accumulation than spring burns; however, the effects of spring burns on biomass and carbon accumulation are longer lasting than those observed for autumn burns.


Assuntos
Queimaduras , Incêndios , Biomassa , China , Poaceae , Áreas Alagadas
8.
J Biol Chem ; 297(4): 101161, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34480897

RESUMO

Cell migration is an essential physiological process, and aberrant migration of epithelial cells underlies many pathological conditions. However, the molecular mechanisms governing cell migration are not fully understood. We report here that growth factor-induced epithelial cell migration is critically dependent on the crosstalk of two molecular switches, namely phosphorylation switch (P-switch) and transcriptional switch (T-switch). P-switch refers to dynamic interactions of deleted in liver cancer 1 (DLC1) and PI3K with tensin-3 (TNS3), phosphatase and tensin homolog (PTEN), C-terminal tension, and vav guanine nucleotide exchange factor 2 (VAV2) that are dictated by mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated protein kinase 1/2-dependent phosphorylation of TNS3, PTEN, and VAV2. Phosphorylation of TNS3 and PTEN on specific Thr residues led to the switch of DLC1-TNS3 and PI3K-PTEN complexes to DLC1-PTEN and PI3K-TNS3 complexes, whereas Ser phosphorylation of VAV2 promotes the transition of the PI3K-TNS3/PTEN complexes to PI3K-VAV2 complex. T-switch denotes an increase in C-terminal tension transcription/expression regulated by both extracellular signal-regulated protein kinase 1/2 and signal transducer and activator of transcription 3 (STAT3) via interleukin-6-Janus kinase-STAT3 signaling pathway. We have found that, the P-switch is indispensable for both the initiation and continuation of cell migration induced by growth factors, whereas the T-switch is only required to sustain cell migration. The interplay of the two switches facilitated by the interleukin-6-Janus kinase-STAT3 pathway governs a sequence of dynamic protein-protein interactions for sustained cell migration. That a similar mechanism is employed by both normal and tumorigenic epithelial cells to drive their respective migration suggests that the P-switch and T-switch are general regulators of epithelial cell migration and potential therapeutic targets.

9.
J Neuroinflammation ; 18(1): 188, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461942

RESUMO

BACKGROUND: Innate immunity can facilitate early brain injury (EBI) following subarachnoid hemorrhage (SAH). Numerous studies suggest that pyroptosis could exacerbate extracellular immune responses by promoting secretion of inflammatory cytokines. Transforming growth factor-ß-activated kinase 1 (TAK1) is a quintessential kinase that positively regulates inflammation through NF-κB and MAPK signaling cascades. However, the effects of TAK1 on neuroinflammation in EBI following SAH are largely unknown. METHODS: Two hundred and forty-six male C57BL/6J mice were subjected to the endovascular perforation model of SAH. A selective TAK1 inhibitor, 5Z-7-oxozeaenol (OZ) was administered by intracerebroventricular (i.c.v) injection at 30 min after SAH induction. To genetic knockdown of TAK1, small interfering RNA (siRNA) was i.c.v injected at 48 h before SAH induction. SAH grade, brain water content, BBB permeability, neurological score, western blot, real-time PCR, ELISA, transmission electron microscope, and immunofluorescence staining were performed. Long-term behavioral sequelae were evaluated by the rotarod and Morris water maze tests. Furthermore, OZ was added to the culture medium with oxyhemoglobin (OxyHb) to mimic SAH in vitro. The reactive oxygen species level was detected by DCFH-DA staining. Lysosomal integrity was assessed by Lyso-Tracker Red staining and Acridine Orange staining. RESULTS: The neuronal phosphorylated TAK1 expression was upregulated following SAH. Pharmacologic inhibition of TAK1 with OZ could alleviate neurological deficits, brain edema, and brain-blood barrier (BBB) disruption at 24 h after SAH. In addition, OZ administration restored long-term neurobehavioral function. Furthermore, blockade of TAK1 dampened neuronal pyroptosis by downregulating the N-terminal fragment of GSDMD (GSDMD-N) expression and IL-1ß/IL-18 production. Mechanistically, both in vivo and in vitro, we demonstrated that TAK1 can induce neuronal pyroptosis through promoting nuclear translocation of NF-κB p65 and activating nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. TAK1 siRNA treatment mitigated SAH-induced neurobehavioral deficits and restrained phosphorylated NF-κB p65 expression and NLRP3 inflammasome activation. TAK1 blockade also ameliorated reactive oxygen species (ROS) production and prevented lysosomal cathepsin B releasing into the cytoplasm. CONCLUSIONS: Our findings demonstrate that TAK1 modulates NLRP3-mediated neuronal pyroptosis in EBI following SAH. Inhibition of TAK1 may serve as a potential candidate to relieve neuroinflammatory responses triggered by SAH.

10.
Drug Deliv ; 28(1): 1709-1721, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34463174

RESUMO

Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (-18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.

11.
Arch Virol ; 166(10): 2881-2885, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34338875

RESUMO

Here, we describe a novel mycovirus, tentatively designated as "Botryosphaeria dothidea mitovirus 3" (BdMV3), isolated from Botryosphaeria dothidea strain FJ, which causes pear ring rot disease in Fujian Province, China. The complete genome nucleotide sequence of BdMV3 is 2538 nt in length and contains a single 2070-nt open reading frame (ORF) encoding a putative RNA-dependent RNA polymerase (RdRp) of 689 amino acids (aa) using the fungal mitochondrial genetic code. BLASTp analysis revealed that the RdRp of BdMV3 shares 28.91%-69.36% sequence identity (query sequence coverage more than 90%) with those of members of the genus Mitovirus, with the highest sequence identity of 69.36% and 68.79% to the corresponding RdRp aa sequences of Rhizoctonia solani mitovirus 10 and Macrophomina phaseolina mitovirus 4, respectively. Phylogenetic analysis based on RdRp aa sequences indicated that BdMV3 is a new member of the genus Mitovirus in the family Mitoviridae.


Assuntos
Ascomicetos/virologia , Genoma Viral/genética , Doenças das Plantas/microbiologia , Pyrus/microbiologia , Vírus de RNA/genética , Sequência de Aminoácidos , China , Micovírus/classificação , Micovírus/genética , Fases de Leitura Aberta/genética , Filogenia , Vírus de RNA/classificação , RNA Viral/genética , RNA Polimerase Dependente de RNA/genética
12.
Oncoimmunology ; 10(1): 1955545, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34377592

RESUMO

The past decade has witnessed the gradual and steady progress of adoptive T cell therapy in treating various types of cancer. In combination with gemcitabine and carboplatin chemotherapy, we previously conducted a clinical trial, NCT00690872, to treat Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) patients with autologous EBV-expanded cytotoxic T lymphocytes (CTLs). While achieving a 2-year overall survival rate of 62.9%, this trial failed to induce an anti-tumor response in a sizable fraction of patients. Thus, the identification of benchmarks capable of evaluating CTL products and predicting clinical immunotherapeutic efficacy remains an urgent need. We conducted T cell receptor (TCR) repertoire sequencing to assess EBV-expanded infusion-ready CTL products. To depict the overall repertoire landscape, we evaluated the individual repertoire diversity by Shannon entropy, and, compared the inter-patient CDR3 similarity to estimate T cells expanded by common antigens. With a recently developed bioinformatics algorithm, termed Motif Analysis, we made a machine-learning prediction of structural regions within the CDR3 of TCRß that associate with CTL therapy prognosis. We found that long term survivors, defined as patients surviving longer than two years, had a higher CTL repertoire diversity with reduced inter-patient similarity. Furthermore, TCR Motif Analysis identified 11 structural motifs distinguishing long term survivors from short term survivors. Specifically, two motifs with a high area under the curve (AUC) values were identified as potential predictive benchmarks for efficacious CTL production. Together, these results reveal that the presence of diverse TCR sequences containing a common core motif set is associated with a favorable response to CTL immunotherapy against EBV-positive NPC.

13.
Andrologia ; 53(10): e14201, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34350635

RESUMO

Copy number variations (CNVs), including deletions and duplications on the Y chromosome, are known genetic factors in azoospermia. Therefore, it is important to identify novel pathogenic CNVs related to azoospermia. In this study, we compared CNVs detected by STS-PCR and NGS in 107 individuals with nonobstructive azoospermia (NOA). STS-PCR analysis revealed that 8.14% (9/107) of patients had AZF deletions. The highest percentage of deletions was located in the AZFc region, followed by AZFa and AZFb+c. Positive CNVs, including four duplications, six deletions and three complex CNVs, were detected using NGS methods in 12.15% (13/107) of NOA patients. Both the duplications and deletions detected in q11.223 were confirmed to increase the genetic risk for NOA. A comparison between the STS-PCR results and NGS methods revealed concordant CNV-positive results in 4 of 107 cases (3.74%). The discrepancies included 6 cases with CNVs identified by NGS but not detected by STS-PCR, and two cases were detected by STS-PCR but not by NGS. Notably, four duplications were not identified and three complex CNVs were detected as simple deletions using STS-PCR analysis. The NGS method provides comprehensive results in detecting Y chromosome-linked CNVs, including deletions and duplications, which might broaden our understanding of NOA.


Assuntos
Azoospermia , Oligospermia , Azoospermia/genética , Deleção Cromossômica , Cromossomos Humanos Y/genética , Variações do Número de Cópias de DNA , Humanos , Masculino , Oligospermia/genética , Reação em Cadeia da Polimerase
14.
Mol Plant Pathol ; 22(10): 1271-1287, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34288324

RESUMO

A novel cytorhabdovirus, tentatively named Actinidia virus D (AcVD), was identified from kiwifruit (Actinidia chinensis) in China using high-throughput sequencing technology. The genome of AcVD consists of 13,589 nucleotides and is organized into seven open reading frames (ORFs) in its antisense strand, coding for proteins in the order N-P-P3-M-G-P6-L. The ORFs were flanked by a 3' leader sequence and a 5' trailer sequence and are separated by conserved intergenic junctions. The genome sequence of AcVD was 44.6%-51.5% identical to those of reported cytorhabdoviruses. The proteins encoded by AcVD shared the highest sequence identities, ranging from 27.3% (P6) to 44.5% (L), with the respective proteins encoded by reported cytorhabdoviruses. Phylogenetic analysis revealed that AcVD clustered together with the cytorhabdovirus Wuhan insect virus 4. The subcellular locations of the viral proteins N, P, P3, M, G, and P6 in epidermal cells of Nicotiana benthamiana leaves were determined. The M protein of AcVD uniquely formed filament structures and was associated with microtubules. Bimolecular fluorescence complementation assays showed that three proteins, N, P, and M, self-interact, protein N plays a role in the formation of cytoplasm viroplasm, and protein M recruits N, P, P3, and G to microtubules. In addition, numerous paired proteins interact in the nucleus. This study presents the first evidence of a cytorhabdovirus infecting kiwifruit plants and full location and interaction maps to gain insight into viral protein functions.

15.
Drug Des Devel Ther ; 15: 2843-2855, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234415

RESUMO

Purpose: A novel folate receptor-targeted ß-cyclodextrin (ß-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA). Methods: Folate-conjugated ß-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied. Results: The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity. Conclusion: These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.

16.
Invest Ophthalmol Vis Sci ; 62(9): 38, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311469

RESUMO

Purpose: To investigate the molecular mechanism underlying the Leber's hereditary optic neuropathy (LHON)-linked MT-ND1 3460G>A mutation. Methods: Cybrid cell models were generated by fusing mitochondrial DNA-less ρ0 cells with enucleated cells from a patient carrying the m.3460G>A mutation and a control subject. The impact of m.3460G>A mutations on oxidative phosphorylation was evaluated using Blue Native gel electrophoresis, and measurements of oxygen consumption were made with an extracellular flux analyzer. Assessment of reactive oxygen species (ROS) production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Assays for apoptosis and mitophagy were undertaken via immunofluorescence analysis. Results: Nineteen Chinese Han pedigrees bearing the m.3460G>A mutation exhibited variable penetrance and expression of LHON. The m.3460G>A mutation altered the structure and function of MT-ND1, as evidenced by reduced MT-ND1 levels in mutant cybrids bearing the mutation. The instability of mutated MT-ND1 manifested as defects in the assembly and activity of complex I, respiratory deficiency, diminished mitochondrial adenosine triphosphate production, and decreased membrane potential, in addition to increased production of mitochondrial ROS in the mutant cybrids carrying the m.3460G>A mutation. The m.3460G>A mutation mediated apoptosis, as evidenced by the elevated release of cytochrome c into the cytosol and increasing levels of the apoptotic-associated proteins BAK, BAX, and PARP, as well as cleaved caspases 3, 7, and 9, in the mutant cybrids. The cybrids bearing the m.3460G>A mutation exhibited reduced levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PTEN-induced kinase 1/parkin-dependent mitophagy. Conclusions: Our findings highlight the critical role of m.3460G>A mutation in the pathogenesis of LHON, manifested by mitochondrial dysfunction and alterations in apoptosis and mitophagy.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/metabolismo , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Apoptose , Células Cultivadas , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Mitocôndrias/patologia , Mitofagia , NADH Desidrogenase/metabolismo , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/metabolismo , Linhagem
17.
World J Gastroenterol ; 27(20): 2507-2520, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34092972

RESUMO

The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.


Assuntos
Imunoconjugados , Neoplasias Pancreáticas , Anticorpos Monoclonais , Glucanos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais
18.
Mov Disord ; 36(8): 1911-1918, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33876851

RESUMO

BACKGROUND: The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (PD) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of PD. OBJECTIVE: This study investigated appendix abnormality in patients with PD. METHODS: We assessed appendix morphology in 100 patients with PD and 50 control subjects by multislice spiral computed tomography. We analyzed the clinical characteristics of patients with PD with diseased appendices, which was confirmed in seven patients by histopathological analysis. RESULTS: Chronic appendicitis-like lesions were detected in 53% of patients with PD, but these were not associated with the duration of motor symptoms. Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder were risk factors for PD. The following clinical symptoms could be used to identify patients with PD with appendicitis-like lesions: first motor symptoms were bradykinesia/rigidity, onset of motor symptoms in the central axis or left limb, prodromal constipation, high ratio of Unified Parkinson's Disease Rating Scale Part III score to symptom duration, low Montreal Cognitive Assessment score, and high Epworth Sleepiness Scale score. The seven patients with PD who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation. CONCLUSIONS: These results indicate an association between chronic appendicitis-like lesions and PD, and suggest that α-Syn accumulation in the diseased appendix occurs in PD. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Apêndice , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Apendicectomia , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , alfa-Sinucleína
19.
Cells ; 10(4)2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920690

RESUMO

Citrus tristeza virus is a member of the genus Closterovirus in the family Closteroviridae. The p23 of citrus tristeza virus (CTV) is a multifunctional protein and RNA silencing suppressor. In this study, we identified a p23 interacting partner, FK506-binding protein (FKBP) 17-2, from Citrus aurantifolia (CaFKBP17-2), a susceptible host, and Nicotiana benthamiana (NbFKBP17-2), an experimental host for CTV. The interaction of p23 with CaFKBP17-2 and NbFKBP17-2 were individually confirmed by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Subcellular localization tests showed that the viral p23 translocated FKBP17-2 from chloroplasts to the plasmodesmata of epidermal cells of N. benthamiana leaves. The knocked-down expression level of NbFKBP17-2 mRNA resulted in a decreased CTV titer in N. benthamiana plants. Further, BiFC and Y2H assays showed that NbFKBP17-2 also interacted with the coat protein (CP) of CTV, and the complexes of CP/NbFKBP17-2 rapidly moved in the cytoplasm. Moreover, p23 guided the CP/NbFKBP17-2 complexes to move along the cell wall. To the best of our knowledge, this is the first report of viral proteins interacting with FKBP17-2 encoded by plants. Our results provide insights for further revealing the mechanism of the CTV CP protein movement.

20.
J Pharm Pharmacol ; 73(9): 1230-1239, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-33909081

RESUMO

OBJECTIVES: Xanthohumol (XAN) is a unique component of Humulus lupulus L. and is known for its diverse biological activities. In this study, we investigated whether Xanthohumol could ameliorate memory impairment of APP/PS1 mice, and explored its potential mechanism of action. METHODS: APP/PS1 mice were used for in vivo test and were treated with N-acetylcysteine and Xanthohumol for 2 months. Learning and memory levels were evaluated by the Morris water maze. Inflammatory and oxidative markers in serum and hippocampus and the deposition of Aß in the hippocampus were determined. Moreover, the expression of autophagy and apoptosis proteins was also evaluated by western blot. KEY FINDINGS: Xanthohumol significantly reduced the latency and increased the residence time of mice in the target quadrant. Additionally, Xanthohumol increased superoxide dismutase level and reduced Interleukin-6 and Interleukin-1ß levels both in serum and hippocampus. Xanthohumol also significantly reduced Aß deposition in the hippocampus and activated autophagy and anti-apoptotic signals. CONCLUSIONS: Xanthohumol effectively ameliorates memory impairment of APP/PS1 mice by activating mTOR/LC3 and Bax/Bcl-2 signalling pathways, which provides new insight into the neuroprotective effects of Xanthohumol.

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