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1.
Environ Toxicol ; 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36715143

RESUMO

Di-n-pentyl phthalate (DPeP) is an endocrine-disrupting phthalate plasticizer. The objective of this study was to investigate the effect of DPeP on adrenocortical function in adult male rats following in utero exposure. DPeP (0, 10, 50, 100, and 500 mg/kg/day) was administered by gavage to pregnant Sprague-Dawley rats from gestational day 14 to 21. The morphology and function of the adrenal cortex in 56-day-old male offspring were studied. DPeP at 100 and 500 mg/kg/day significantly reduced serum aldosterone levels and at 500 mg/kg/day markedly reduced corticosterone and adrenocorticotropic hormone levels. DPeP at 10-500 mg/kg markedly reduced the thickness of zona glomerulosa without affecting the thickness of zona fasciculata. DPeP significantly downregulated the expression of Agtr1a, Mc2r, Scarb1, Cyp11a1, Hsd3b1, Cyp21, Cyp11b1, Cyp11b2, Nr5a1, Nr4a2, and Bcl2 genes as well as their proteins. DPeP at 500 mg/kg/day significantly increased phosphorylated AMPK, while DPeP at 100 mg/kg/day and higher doses reduced phosphorylated AKT1 and total SIRT1 level. DPeP at 100 and 500 µM markedly induced reactive oxygen species and apoptosis in H295R cells after 24 h of culture. In conclusion, in utero exposure to DPeP disrupts adrenocortical function of the adult male offspring by (1) increasing AMPK phosphorylation and decreasing AKT1 phosphorylation and SIRT1 levels, (2) reducing adrenocorticotropic hormone levels, and (3) possibly inducing oxidative stress and apoptosis.

2.
Toxicol Appl Pharmacol ; 456: 116262, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198370

RESUMO

Testicular dysgenesis syndrome in male neonates manifests as cryptorchidism and hypospadias, which can be mimicked by in utero phthalate exposure. However, the underlying phthalate mediated mechanism and therapeutic effects of taxifolin remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundantly used phthalate and can induce testicular dysgenesis syndrome in male rats. To explore the mechanism of DEHP mediated effects and develop a therapeutic drug, the natural phytomedicine taxifolin was used. Pregnant Sprague-Dawley female rats were daily gavaged with 750 mg/kg/d DEHP or 10 or 20 mg/kg/d taxifolin alone or in combination from gestational day 14 to 21, and male pup's fetal Leydig cell function, testicular MDA, and antioxidants were examined. DEHP significantly reduced serum testosterone levels of male pups, down-regulated the expression of SCARB1, CYP11A1, HSD3B1, HSD17B3, and INSL3, reduced the cell size of fetal Leydig cells, decreased the levels of antioxidant and related signals (SOD2 and CAT, SIRT1, and PGC1α), induced abnormal aggregation of fetal Leydig cells, and stimulated formation of multinucleated gonocytes and MDA levels. Taxifolin alone (10 and 20 mg/kg/d) did not affect these parameters. However, taxifolin significantly rescued DEHP-induced alterations. DEHP exposure in utero can induce testicular dysgenesis syndrome by altering the oxidative balance and SIRT1/PGC1α levels, and taxifolin is an ideal phytomedicine to prevent phthalate induced testicular dysgenesis syndrome.


Assuntos
Dietilexilftalato , Doenças Testiculares , Gravidez , Humanos , Ratos , Masculino , Feminino , Animais , Dietilexilftalato/toxicidade , Animais Recém-Nascidos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Testosterona/metabolismo , Sirtuína 1/metabolismo , Ratos Sprague-Dawley , Células Intersticiais do Testículo , Testículo , Doenças Testiculares/induzido quimicamente , Doenças Testiculares/prevenção & controle , Doenças Testiculares/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo
3.
Front Cell Neurosci ; 16: 911973, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35928572

RESUMO

Objective: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease with high incidence, disability, and mortality. Casein kinase 2 (CK2) is a serine/threonine kinase with hundreds of identified substrates and plays an important role in many diseases. This study aimed to explore whether CK2 plays protective roles in ICH-induced neuronal apoptosis, inflammation, and oxidative stress through regulation NR2B phosphorylation. Methods: CK2 expression level of brain tissues taken from ICH patients was determined by immunoblotting. Neurons from embryonic rat and astrocytes from newborn rats were cultured and treated by Hemoglobin chloride (Hemin). The proliferation of astrocytes, the apoptosis and oxidative stress of neurons and the inflammatory factors of astrocytes were detected. CK2 expression was determined in ICH model rats. The effects of CK2 overexpression plasmid (pc-CK2) on neurobehavioral defects and brain water content in ICH rats were observed. Results: CK2 expression in ICH patients was down-regulated. Overexpression of CK2 promoted the astrocyte proliferation, inhibited neuronal apoptosis, and reduced astrocyte-mediated inflammation. N-methyl-D-aspartate receptor 2B (NR2B) reversed the effects of pc-CK2 on neurons and astrocytes. CK2 phosphorylated NR2B at the S1480 site, down-regulated the expression of NR2B and interfered with the interaction between NR2B and postsynaptic density protein 95 (PSD95). In vivo experiments showed that the expression of CK2 decreased and the expression of NR2B increased in ICH rats. Furthermore, pc-CK2 attenuated neurobehavioral defects, brain water content and neuronal damage in ICH rats. Conclusion: CK2 phosphorylated NR2B, down-regulated the expression of NR2B, interfered with the interaction between NR2B and PSD95, alleviated inflammatory reactions, inhibited neuronal apoptosis and oxidative stress after ICH. CK2 and NR2B may be new potential therapeutic targets for the treatment of ICH. However, the limitation of this study is that we only investigated the regulation of NR2B by CK2.

4.
Toxicol Lett ; 366: 58-71, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35810996

RESUMO

Dimethylbisphenol A (DMBPA) is a novel alternative to bisphenol A. Whether short-term exposure to DMBPA affects Leydig cell regeneration remains unknown. The Leydig cell regeneration model was generated by intraperitoneal injection of 75 mg/kg ethane dimethane sulfonate (EDS) to adult male Sprague-Dawley rats. Leydig cell regeneration began on day 14 after EDS. Rats were gavaged with 0, 10, 50, or 200 mg/kg DMBPA from days 14-28 post-EDS, and Leydig cell regeneration was assessed on days 28 and 56 post-EDS. DMBPA significantly reduced serum testosterone levels on days 28 and 56 at 10 mg/kg and higher doses and sperm count in the caudal epididymis on day 56 at 200 mg/kg, without affecting estradiol, luteinizing hormone, and follicle-stimulating hormone. DMBPA had no effect on Leydig cell number but significantly down-regulated Scarb1 expression at ≥ 10 mg/kg on day 28, Cyp17a1 expression on day 28 at 200 mg/kg and on day 56 at ≥ 10 mg/kg. DMBPA markedly upregulated Srd5a1 expression at doses of 50 and 200 mg/kg on day 56 after EDS. DMBPA significantly down-regulated the expression of Sod1 and Nr3c4 at a dose of 200 mg/kg on day 28. Further semi-quantitative immunohistochemistry showed that DMBPA reduced NR3C4 levels in Leydig and Sertoli cells at 50 and 200 mg/kg. In vitro DMBPA treatment of immature Leydig cells for 24 h showed that it significantly reduced testosterone production at 10 and 50 µM, and further mechanistic studies showed that an NR3C4 agonist 7α-methyl-19-nortestosterone significantly reversed DMBPA-mediated suppression on testosterone output, but the estrogen receptor antagonist ICI 182,780 and G-coupled estrogen receptor 1 agonist G15 had no effect. In conclusion, DMBPA delays Leydig cell regeneration after short-term exposure during early Leydig cell regeneration via NR3C4 antagonism.


Assuntos
Compostos Benzidrílicos/farmacologia , Células Intersticiais do Testículo , Fenóis/farmacologia , Receptores Androgênicos , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Sêmen , Testículo , Testosterona
5.
Food Chem Toxicol ; 167: 113268, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35803362

RESUMO

Bisphenol F (BPF) is a new analog of bisphenol A (BPA). BPA has deleterious effects on the male reproductive system, but the effect of BPF has not been studied in detail. In this study we focus on the effect of BPF on Leydig cell maturation. Male Sprague-Dawley rats were gavaged with 0, 1, 10, or 100 mg/kg BPF from postnatal days 35-56. BPF significantly reduced serum testosterone levels and sperm count in cauda epididymis at dose ≥1 mg/kg. It significantly down-regulated the expression of steroidogenic enzymes, while increasing FSHR and SOX9 levels at 10 and 100 mg/kg. Further studies showed that BPF reduced NR3C4 expression in Leydig and Sertoli cells without affecting its levels in peritubular myoid cells. BPF markedly increased GPER1 in Leydig cells at 100 mg/kg, and it significantly reduced SIRT1 and PGC1α levels in the testes at 100 mg/kg. BPF significantly inhibited testosterone production by immature Leydig cells at 50 µM after 24 h of treatment, which was completely reversed by NR3C4 agonist 7α-methyl-19-nortestosterone and partially reversed by GPER1 antagonist G15 not by ESR1 antagonist ICI 182,780. In conclusion, BPF negatively affects Leydig cell maturation in pubertal male rats through NR3C4 antagonism and GPER1 agonism.


Assuntos
Células Intersticiais do Testículo , Receptores Androgênicos , Animais , Compostos Benzidrílicos/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/farmacologia , Masculino , Fenóis , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Receptores Acoplados a Proteínas G , Sêmen/metabolismo , Testosterona/metabolismo
6.
Angew Chem Int Ed Engl ; 61(37): e202208460, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-35841180

RESUMO

Dynamic patterns based on luminescent materials play an essential role in the digital age. However, it is still challenging to develop highly emissive photofluorochromic materials with dynamic behaviors to store information with multiple characteristics. Here, we report a series of dihydroazulene-based compounds which show typical aggregation-induced emission (AIE) effect. Moreover, the photo-switching ability of the dihydroazulene units, undergoing light-induced ring-opening, enables photofluorochromic properties. The photofluorochromism also shows quantitively described responses to time and temperature via a reverse ring-closing process. Ultimately, a rewritable 4D information system, embedded with a quick response code, dot matrix with microstructures, color matrix of fluorescence, and time/temperature-dependent intensity change, is established with dynamic patterns. This work not only develops a dynamic AIE skeleton with photofluorochromic properties but also provides a new strategy for information encryption and cybernetics.

7.
Cell Mol Biol Lett ; 27(1): 47, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705912

RESUMO

BACKGROUND: Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling diseases. Recently, it has been discovered that tRNA-derived small RNAs (tsRNAs), a new type of noncoding RNAs, are related to the proliferation and migration of VSMCs. tsRNAs regulate target gene expression through miRNA-like functions. This study aims to explore the potential of tsRNAs in human aortic smooth muscle cell (HASMC) proliferation. METHODS: High-throughput sequencing was performed to analyze the tsRNA expression profile of proliferative and quiescent HASMCs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the sequence results and subcellular distribution of AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076. Based on the microRNA-like functions of tsRNAs, we predicted target promoters and mRNAs and constructed tsRNA-promoter and tsRNA-mRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the function of target genes. EdU incorporation assay, Western blot, and dual-luciferase reporter gene assay were utilized to detect the effects of tsRNAs on HASMC proliferation. RESULTS: Compared with quiescent HASMCs, there were 1838 differentially expressed tsRNAs in proliferative HASMCs, including 887 with increased expression (fold change > 2, p < 0.05) and 951 with decreased expression (fold change < ½, p < 0.05). AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076 were increased in proliferative HASMCs and were mainly located in the nucleus. Bioinformatics analysis suggested that the four tsRNAs involved a variety of GO terms and pathways related to VSMC proliferation. AS-tDR-000067 promoted HASMC proliferation by suppressing p53 transcription in a promoter-targeted manner. AS-tDR-000076 accelerated HASMC proliferation by attenuating mitofusin 2 (MFN2) levels in a 3'-untranslated region (UTR)-targeted manner. CONCLUSIONS: During HASMC proliferation, the expression levels of many tsRNAs are altered. AS-tDR-000067 and AS-tDR-000076 act as new factors promoting VSMC proliferation.


Assuntos
MicroRNAs , Miócitos de Músculo Liso , Regiões 3' não Traduzidas , Aorta/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , RNA de Transferência/farmacologia
8.
Cell Death Dis ; 13(5): 477, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35589691

RESUMO

Circular RNA (circRNA) is a type of non-coding RNA that is widely expressed in mammals. It is highly conserved and abundantly expressed in the brain. Here, we report the regulatory role of circRNA derived from the pantothenate kinase 1 (Pank1) gene (circ-Pank1) in Parkinson's disease (PD). Circ-Pank1 is highly expressed in the substantia nigra (SN) of PD model mice treated with rotenone and in the MN9D cell model of dopaminergic neurons. The circ-Pank1 knockdown ameliorated dopaminergic neuron damage and locomotor dysfunction after the treatment with rotenone. We found that circ-Pank1 could adsorb miR-7a-5p and upregulate the expression of α-synuclein (α-syn), which is a molecular hallmark closely related to PD. The inhibition of miR-7a-5p reversed the circ-Pank1 knockdown-induced amelioration of dopaminergic neuron injury. In conclusion, circ-Pank1 is overexpressed in PD and enhances the locomotor dysfunction via the miR-7a-5p/α-syn signaling axis. We revealed the functional role of circRNAs in the progression of PD and provided a potential target for noncoding RNAs in delaying the progression of PD.


Assuntos
MicroRNAs , Doença de Parkinson , Animais , Proliferação de Células , Neurônios Dopaminérgicos/metabolismo , Mamíferos/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , RNA Circular/genética , Rotenona , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
9.
Toxicol Appl Pharmacol ; 447: 116069, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35605789

RESUMO

Bisphenol AF (BPAF) is one of the primary alternatives of bisphenol A. It has been ubiquitously detected in the environment and is an emerging endocrine disrupting compound. However, the effects of BPAF exposure on fetal Leydig cells and germ cells and the underlying mechanisms remain largely unknown. To this end, pregnant Sprague-Dawley rats were exposed to 10, 50, and 200 mg/kg/d BPAF by gavage from gestational days 14 to 21. The neonatal rats were sacrificed on day 1 at birth. The results showed that serum testosterone levels were significantly decreased at 50 and 200 mg/kg/d, the expression of Scarb1, Star, Cyp17a1, Hsd17b3, and Dhh and their proteins were markedly down-regulated at 50 and 100 mg/kg/d. BPAF exposure also significantly increased the incidence of multinucleated gonocytes at 200 mg/kg/d. We further detected significant increase of testicular malondialdehyde levels and reduction of antioxidants, including SOD1, SOD2, and CAT at 50 and/or 200 mg/kg/d. Furthermore, BPAF markedly reduced the levels of SIRT1 and PGC1α at 200 mg/kg/d while significantly increased AMPK phosphorylation in the testes at 50 and 200 mg/kg/d. In conclusion, our results provide novel in vivo data that BPAF can induce fetal Leydig cell dysfunction by interfering with steroidogenic networks and induce the formation of multinucleated gonocytes after suppressing the antioxidant defense system and reducing SIRT1 and PGC1α signals and increasing the phosphorylation of AMPK, which highlights the potential health risk of environmental exposure to BPAF in inducing male reproductive tract malformation.


Assuntos
Células Intersticiais do Testículo , Sirtuína 1 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Feminino , Fluorcarbonetos , Células Germinativas/metabolismo , Masculino , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenóis , Gravidez , Ratos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Testículo , Testosterona
10.
Ecotoxicol Environ Saf ; 232: 113282, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35131586

RESUMO

Methyl tert-butyl ether (MTBE) is a widely used gasoline additive. It is considered an endocrine-disrupting chemical. Whether MTBE affects the development of Leydig cells in late puberty of males and its underlying mechanism remains unclear. Twenty-four male Sprague-Dawley rats (35 days old) were randomly allocated into four groups and were orally given MTBE (0, 300, 600, and 1200 mg/kg/day) from postnatal day (PND) 35-56. MTBE markedly reduced serum testosterone levels at 300 mg/kg and higher doses without altering the serum levels of luteinizing hormone and follicle-stimulating hormone. It mainly inhibited cell proliferation, induced mitochondrial autophagy and apoptosis, and indirectly stimulated Sertoli cells to secrete anti-Müllerian hormones, thereby significantly reducing the number of Leydig cells at 1200 mg/kg. MTBE also markedly down-regulated the expression of mature Leydig cell biomarker Cyp11a1 and Hsd3b1 and their proteins, while up-regulating the expression of immature Leydig cell biomarker Akr1c14 and its protein at 600 mg/kg and higher. MTBE significantly down-regulated the expression of cell cycle gene Ccnd1, antioxidant gene Gpx1, and anti-apoptotic gene Bcl2, while increasing pro-apoptotic gene Bax level at 1200 mg/kg. In vitro study further confirmed that MTBE can inhibit testosterone synthesis by inducing reactive oxygen species (ROS) generation, mitophagy, and apoptosis at 200 and 300 mM. In conclusion, exposure to MTBE compromises the development of Leydig cells in late puberty in male rats.


Assuntos
Células Intersticiais do Testículo , Testosterona , Animais , Apoptose , Células Intersticiais do Testículo/metabolismo , Masculino , Éteres Metílicos , Mitofagia , Ratos , Ratos Sprague-Dawley
11.
Microb Ecol ; 83(2): 393-407, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33893533

RESUMO

Ecological processes (e.g., nutrient cycling) in riparian zones are often affected by land-use type and flooding. The extent to which land-use types and flooding conditions affect soil microorganisms and their ecological functions in riparian zones is not well known. By using high-throughput sequencing and quantitative PCR (q-PCR), we tested the effects of three land-use types (i.e., forest, wetland, and grassland) and two flooding conditions (i.e., landward locations and waterward locations within the land-use types) on soil microbial communities and microbial functional genes in the riparian zones of a reservoir. Land-use type but not flooding significantly affected soil microbial community composition at the phylum level, while both land-use type and flooding significantly affected the orders Nitrosotaleales and Nitrososphaerales. Alpha diversity was higher in the wetland and forest regardless of flooding conditions. Functional gene abundance differed among the three land-use types. Archaeal amoA (AOA) and nirS genes were more abundant in the wetland than in the grassland or forest. Bacterial amoA (AOB), nirK, nirS, and nosZ genes were more abundant in the waterward location than in the landward location but only in the wetland. Soil pH, moisture, and concentrations of soil organic matter and total soil nitrogen were significantly associated with the composition of archaeal and bacterial communities as well as with their gene abundance. This study revealed that soil microorganisms putatively involved in nitrogen cycling in riparian zones were more affected by land-use type than flooding.


Assuntos
Microbiota , Solo , Archaea/genética , Microbiota/genética , Ciclo do Nitrogênio , Solo/química , Microbiologia do Solo
12.
Nutr Res ; 93: 79-86, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34428718

RESUMO

Natural (RRR-) α-tocopherol (αT) is more bioactive than synthetic (all racemic, all rac-) αT, but not enough is known about the tissue kinetics of the 2 αT sources. We examined the time-course bioaccumulation of natural versus synthetic αT in tissues of young, marginally vitamin E-deficient mice using 13C-RRR-αT or 13C-all rac-αT tracers. In experiment 1, 3-week old male wild-type mice were fed a vitamin E-deficient diet for 0, 1, 2, or 3 weeks (n = 5/time point). Tissue αT levels were analyzed by HPLC-PDA. Feeding a vitamin E-deficient diet for up to 3 weeks decreased total αT concentrations in all analyzed tissues except the brain, which maintained its αT level. In experiment 2, a 2-week αT-depletion period was followed by administration of a single oral dose of 0.5 mg of 13C-RRR-αT or 13C-all rac-αT. At 12 hr, 1, 2, and 4 days post-dose, serum and multiple tissues were collected (n = 3/time point). αT was quantified by HPLC-PDA, and 13C-αT enrichment was determined by LC-MS. Both sources of 13C-αT reached maximum serum levels at 12 hr post-dose. 13C-RRR-αT levels were significantly higher than 13C-all rac-αT in serum at 1 d post-dose, and in heart, lungs, and kidney at 2d post-dose. In brain, 13C-RRR-αT concentrations were significantly higher than 13C-all rac-αT at 2 and 4 d post-dose. At 4 d post-dose, 13C-αT levels were similar between the 2 sources in examined tissues except for brain and adipose tissue where 13C-RRR-αT was higher. In conclusion, αT bioaccumulation over time varied substantially depending on αT source and tissue type.


Assuntos
Tocoferóis , alfa-Tocoferol , Animais , Dieta , Masculino , Camundongos , Distribuição Tecidual , Vitamina E
13.
J Am Chem Soc ; 143(25): 9468-9477, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34152134

RESUMO

Solid-state molecular motions (SSMM) play a critical role in adjusting behaviors and properties of materials. However, research on SSMM, especially for multicomponent systems, suffers from various problems and is rarely explored. Herein, through collaboration with cocrystal engineering, visualization and manipulation of SSMM in two-component systems, namely, FSBO ((E)-2-(4-fluorostyryl)benzo[d]oxazole)/TCB (1,2,4,5-tetracyanobenzene) and PVBO ((E)-2-(2-(pyridin-4-yl)vinyl)benzo[d]oxazole)/TCB, were realized. The obtained yellow-emissive F/T (FSBO/TCB) cocrystal displayed turn-on fluorescence, and the green-emissive P/T (PVBO/TCB) cocrystal presented redder emission, both of which exhibited an aggregation-induced emission property. At varied pressure and temperature, the grinding mixtures of FSBO/TCB and PVBO/TCB displayed different molecular motions that were readily observed through the fluorescence signal. Notably, even without grinding, FSBO and TCB molecules could move over for 4 mm in a 1D tube. The unique emission changes induced by SSMM were applied in information storage and dynamic anticounterfeiting. This work not only visualized and manipulated SSMM but offered more insights for multicomponent study in aggregate science.

14.
Acta Biomater ; 126: 119-131, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33684536

RESUMO

Tissue engineering method provides a promising solution for meniscus repair and regeneration. However, the inflammatory environment that persists after meniscus injury in the knee joint impedes meniscus tissue regeneration. The purpose of this study was to investigate the applicability of silk/graphene oxide (GO)-based meniscus scaffold modified with tannic acid (TA)/Sr2+ coating for the elimination of inflammatory cytokines and reactive oxygen species (ROS) under osteoarthritis (OA) environment along with cartilage protection by using a rat model. The self-assembled coating composed of a series of TA-Sr2+ complex concentrations was formed by a facile, rapid, and efficient method on the scaffold. The phenolic hydroxyl groups on the coating endowed the meniscus scaffold with excellent anti-inflammatory and ROS scavenging capacities. We also found that the coating could promote cell migration in a mock wound model and could increase extracellular matrix secretion in vitro. Moreover, the coating components at a certain concentration played an effective role in delaying OA and providing cartilage protection in the rat model. The expression of inflammation cytokines (e.g., IL-6, IL-8, and MMPs) in rat knee tissue was significantly downregulated, and cartilage degeneration and OA damage were also inhibited according to tissue staining results and the OARSI (Osteoarthritis Research Society International) scoring system. Combining these performances, we suggest that this silk/GO-based scaffold modified with TA/Sr2+ coating could have broader application prospects by virtue of its effective and user-friendly properties. STATEMENT OF SIGNIFICANCE: The biological properties of the meniscus play a role in activating and regulating the metabolic and inflammatory responses that influence the homeostasis of joint health and ultimately lead to knee osteoarthritis (OA). The inflammation condition of the knee joint may exacerbate the degeneration of meniscus and cartilage. The present study aimed to develop a functional coating composed of tannic acid/Sr2+ complex on a silk/graphene oxide-based meniscus scaffold and to endow the scaffold with anti-inflammatory and ROS elimination capacities during the meniscus regeneration process to protect cartilage and delay OA development. The in vitro cytocompatibility study and the in vivo rat OA model study revealed that the coating was effective in promoting cell migration, facilitating ECM secretion, inhibiting inflammation, and delaying OA development.


Assuntos
Cartilagem Articular , Menisco , Osteoartrite , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Cartilagem , Grafite , Osteoartrite/tratamento farmacológico , Ratos , Seda , Taninos/farmacologia
15.
Angew Chem Int Ed Engl ; 60(13): 7148-7154, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33300645

RESUMO

Herein we report a linear ionic molecule that assembles into a supramolecular nano-tunnel structure through synergy of trident-type ionic interactions and π-π stacking interactions. The nano-tunnel crystal exhibits anisotropic guest adsorption behavior. The material shows good thermal stability and undergoes multi-stage single-crystal-to-single-crystal phase transformations to a nonporous structure on heating. The material exhibits a remarkable chemical stability under both acidic and basic conditions, which is rarely observed in supramolecular organic frameworks and is often related to structures with designed hydrogen-bonding interactions. Because of the high polarity of the tunnels, this molecular crystal also shows a large CO2 -adsorption capacity while excluding other gases at ambient temperature, leading to high CO2 /CH4 selectivity. Aggregation-induced emission of the molecules gives the bulk crystals vapochromic properties.

16.
Acta Biomater ; 116: 223-245, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32889111

RESUMO

Biomedical device-associated infections (BAI) and osteosynthesis are two main complications following the orthopedic implant surgery, especially while infecting bacteria form a mature biofilm, which can protect the organisms from the host immune system and antibiotic therapy. Comparing with the single antibiotics therapeutic method, the combination of silver nanoparticles (AgNPs) and conventional antibiotics exert a high level of antibacterial activity. Nevertheless, one major issue that extremely restricts the potential application of AgNP/antiviotics is the uncontrolled release. Moreover, the lack of osteogenic ability may cause the osteosynthesis. Thus, herein we fabricated a structure-controlled drug-loaded silk fibroin (SF) coating that can achieve the size and release control of AgNPs and high efficient osteogenesis. Three comparative SF-based coatings were fabricated: α-structured coating (α-helices 32.7%,), m-structured coating (ß-sheets 28.3%) and ß-structured coating (ß-sheets 41%). Owning to the high content of α-helices structure and small AgNPs (20 nm), α-structured coating displayed better protein adsorption and hydrophilicity, as well as pH-dependent and long-lasting antibacterial performance. In vitro studies demonstrated that α coating showed biocompatibility (cellular attachment, spreading and proliferation), high ALP expression, collagen secretion and calcium mineralization. Moreover, after one month subcutaneous implantation in vivo, α-structured coating elicited minimal, comparable inflammatory response. Additionally, in a rabbit femoral defect model, α-structured coating displayed a significant improvement on the generation of new-born bone and bonding between the new bone and the tissue, implying a rapid and durable osteointegration. Expectedly, this optimized structure-controlled SF-based coating can be an alternative and prospective solution for the current challenges in orthopedics. STATEMENT OF SIGNIFICANCE: In this study, an AgNPs/Gentamycin-loaded structured-controlled silk fibroin coatings were constructed on Ti implant's surface to guarantee the success of implantation even in the face of bacterial infection. In comparison, the α-structured coating had the lowest content of ß-sheets structure (19.0%) and the smallest particle size of AgNPs (~ 20 nm), and owned pH-responsive characteristic due to reversible α-helices structural. Thanks to pH-responsive release of Ag+, the α-structure coating could effectively inhibit adhesive bacteria and kill planktonic bacteria by releasing a large amount of reactive oxygen radicals. Through in vitro biological results (cell proliferation, differentiation and osteogenic gene expression) and in vivo rabbit femur implantation results, the α-structure coating had good biocompatible and osteogenic properties.


Assuntos
Fibroínas , Nanopartículas Metálicas , Ortopedia , Animais , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Fibroínas/farmacologia , Osteogênese , Estudos Prospectivos , Coelhos , Prata/farmacologia
17.
Acta Biomater ; 115: 220-234, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777292

RESUMO

Polyetheretherketone has been widely used for bone defect repair, whereas failures may happen due to implant loosening and infection. Thus, PEEK implant with multi-function (osteogenesis, angiogenesis, and bacteria-killing) is essential to solve this problem. Herein, copper oxide microspheres (µCuO) decorated with silver nanoparticles (nAg) were constructed on porous PEEK surface via silk fibroin. In vitro studies highlighted the pH controlled release ability of this coating. It liberated a high dose of Cu2+ and Ag+ at low pH environment (pH 5.0), leading to 99.99% killing of planktonic bacteria and complete eradication of sessile bacteria, avoiding biofilm formation. Under physiological environment (pH 7.4), a lower amount of leaked metal ions induced promoted ALP production, collagen secretion, and calcium deposition, as well as NO production, which indicated potentiated osteogenesis and angiogenesis. In vivo results displayed the highest new bone volume around, and the appearance of new bone inside porous structure of, PEEK implant with this coating in rabbit tibia, signified the abilities of this coating to promote bone regeneration and osseointegration. Our study established solid support for implants with this coating to be a successful bone defect repair solution. STATEMENT OF SIGNIFICANCE: In this study, CuO/Ag micro/nano particles were incorporated into the porous surface of PEEK through polydopamine and silk fibroin layers. The design of this coating conferred pH-controlled release behavior to Cu2+ and Ag+. High dose of metal ions were released at pH 5.0, which presented synergistic antibacterial ability and killed 99.99% of planktonic bacteria. Low concentration of metal ions were controlled by this coating at physiological environment, which potentiated osteodifferentiation of Ad-MSC in vitro and led to complete integration of implant with bone tissue in vivo.


Assuntos
Fibroínas , Nanopartículas Metálicas , Animais , Antibacterianos/farmacologia , Benzofenonas , Cobre , Fibroínas/farmacologia , Concentração de Íons de Hidrogênio , Cetonas/farmacologia , Osteogênese , Polietilenoglicóis , Polímeros , Coelhos , Prata/farmacologia
18.
Acta Biomater ; 113: 196-209, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561472

RESUMO

Considering the intrinsic poor self-healing capacity of meniscus, tissue engineering has become a new direction for the treatment of meniscus lesions. However, disturbed by mechanical stability and biocompatibility, most meniscus implants fail to relieve symptoms and prevent the development of osteoarthritis. The goal of this study was to develop a potential meniscal substitute for clinical application. Here, silk fibroin with good mechanical performance and biocompatibility, and strontium ion acting as bioactive factor, were incorporated with Ɛ-Polycaprolactone to fabricate a meniscus scaffold (SP-Sr). By the wet-electrospun method, the 3D SP-Sr provided suitable pore size (100-200 µm) and enough mechanical support (61.6 ± 2.9 MPa for tensile modulus and 0.11 ± 0.03 MPa for compressive modulus). Moreover, after addition of Sr2+, the SP-Sr seeded by rabbit adipose tissue-derived stromal cells (rADSCs) showed the highest secretion with 2.61- and 2.98-fold increase in collagen and aggrecan, respectively, compared with SF/PCL group. And the extracellular matrix related genes expression in SP-Sr also showed upregulation results. Particularly, the expression of the collagen II gene, which played a crucial role in the formation of meniscal inner avascular region, showed a 9-fold increase in SP-Sr compared with pure PCL group. Furthermore, the MRI results of SP-Sr implanted in rabbits with total meniscectomy for 6 months demonstrated effective prevention of meniscus extrusion and relieving joint space narrowing compared with meniscectomy group. And the effects of cartilage protection and delaying osteoarthritis development were confirmed by Pathological examination. Especially, after 6-month implantation, the neo-menisci showed similar structural constituent and mechanical performance. STATEMENT OF SIGNIFICANCE: Meniscus regeneration faces great challenge due to the meniscus having limited healing potential owing to its anisotropic structure, its hypocellularity and hypovascularity. The present tissue engineering solutions have failed to maintain the biological function for meniscus reconstruction in vivo because of fragile and poor biocompatible materials, leading to long-term joint degeneration. The goal of this study was to develop a meniscal substitute potential for clinical application. Here, silk fibroin and strontium were incorporated with Ɛ-Polycaprolactone by wet-electrospinning method to fabricate a meniscus scaffold (SP-Sr). The 6-month implantation results revealed that SP-Sr scaffold was effective in preventing meniscus extrusion, cartilage protection and delaying osteoarthritis development, and the regenerated menisci showed similar structural constituent and mechanical performance.


Assuntos
Fibroínas , Menisco , Engenharia Tecidual , Animais , Coelhos , Regeneração , Tecidos Suporte
19.
Angew Chem Int Ed Engl ; 59(24): 9470-9477, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-31557385

RESUMO

Pathogen infections and cancer are two major human health problems. Herein, we report the synthesis of an organic salt photosensitizer (PS), called 4TPA-BQ, by a one-step reaction. 4TPA-BQ presents aggregation-induced emission features. Owing to the aggregation-induced reactive oxygen species generated and a sufficiently small ΔEST , 4TPA-BQ shows a satisfactorily high 1 O2 generation efficiency of 97.8 %. In vitro and in vivo experiments confirmed that 4TPA-BQ exhibited potent photodynamic antibacterial performance against ampicillin-resistant Escherichia coli with good biocompatibility in a short time (15 minutes). When the incubation duration persisted long enough (12 hours), cancer cells were ablated efficiently, leaving normal cells essentially unaffected. This is the first reported time-dependent fluorescence-guided photodynamic therapy in one individual PS, which achieves ordered and multiple targeting simply by varying the external conditions. 4TPA-BQ reveals new design principles for the implementation of efficient PSs in clinical applications.


Assuntos
Técnicas de Ablação , Terapia de Alvo Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Animais , Células COS , Chlorocebus aethiops , Escherichia coli/efeitos dos fármacos , Escherichia coli/efeitos da radiação , Humanos
20.
Chem Sci ; 12(2): 709-717, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34163804

RESUMO

Developing versatile synthetic methodologies with merits of simplicity, efficiency, and environment friendliness for five-membered heterocycles is of incredible importance to pharmaceutical and material science, as well as a huge challenge to synthetic chemistry. Herein, an unexpected regioselective photoreaction to construct a fused five-membered azaheterocycle with an aggregation-induced emission (AIE) characteristic is developed under mild conditions. The formation of the five-membered ring is both thermodynamically and kinetically favored, as justified by theoretical calculation and experimental evidence. Markedly, a light-driven amplification strategy is proposed and applied in selective mitochondria-targeted cancer cell recognition and fluorescent photopattern fabrication with improved resolution. The work not only delivers the first report on efficiently generating a fused five-membered azaheterocyclic AIE luminogen under mild conditions via photoreaction, but also offers deep insight into the essence of the photosynthesis of fused five-membered azaheterocyclic compounds.

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