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An excellent broad-spectrum (220-380 nm) UV photodetector, covering the UVA-UVC wavelength range, with an ultrahigh detectivity of ≈1015 cm Hz1/2 W-1 , is reported. It is based on a p-ß Ga2 O3 /n-GaN heterojunction, in which p-ß Ga2 O3 is synthesized by thermal oxidation of GaN and a heterostructure is constructed with the bottom n-GaN. XRD shows the oxide layer is (-201) preferred oriented ß-phase Ga2 O3 films. SIMS and XPS indicate that the residual N atoms as dopants remain in ß Ga2 O3 . XPS also demonstrates that the Fermi level is 0.2 eV lower than the central level of the band gap, indicating that the dominant carriers are holes and the ß Ga2 O3 is p-type conductive. Under a bias of -5 V, the photoresponsivity is 56 and 22 A W-1 for 255 and 360 nm, respectively. Correspondingly, the detectivities reach an ultrahigh value of 2.7 × 1015 cm Hz1/2 W-1 (255 nm) and 1.1 × 1015 cm Hz1/2 W-1 (360 nm). The high performance of this UV photodetector is attributed mainly to the continuous conduction band of the p-ß Ga2 O3 /n-GaN heterojunction without a potential energy barrier, which is more helpful for photogenerated electron transport from the space charge region to the n-type GaN layer.
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INTRODUCTION: Prostate smooth muscle contraction is promoted by receptor-induced activation of intracellular signaling pathways. The presumed involvement in etiology and medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) imparts a high clinical relevance to prostate smooth muscle contraction, which is contrasted by incomplete understanding at the molecular level. Involvement of protein kinase C (PKC) has been commonly assumed, but available studies were limited to nonhuman prostate smooth muscle or cell cultures. Here, we examined the effects of the PKC inhibitors Go6983 and GF109203x on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS), α1 -adrenergic agonists (noradrenaline, phenylephrine, methoxamine), thromboxane A2 analog U46619, endothelin-1, or calcium chloride in an organ bath. RESULTS: GF109203X (500 nM) and Go6983 (300 nM) reduced EFS-, noradrenaline-, phenylephrine-, methoxamine-, and U46619-induced contractions of human prostate tissues, with maximum inhibitions approaching up to 55%. Using concentrations of 3 µM, GF109203X and Go6983 inhibited EFS- and noradrenaline-induced contractions, with similar effect sizes as 500 and 300 nM, respectively. Endothelin-1-induced contractions were not inhibited by GF109203X, and to neglectable extent by Go6983. After depolarization in calcium-free solution, calcium chloride-induced concentration-dependent contractions, which were inhibited by GF109203X and Go6983. CONCLUSIONS: GF109203X and Go6983 inhibit neurogenic, α1 -adrenergic, and thromboxane A2 -induced smooth muscle contractions in the human prostate, suggesting a role of PKC for human prostate smooth muscle contraction. The inhibition may by be imparted by inhibition of calcium sensitivity.
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Indóis/farmacologia , Maleimidas/farmacologia , Hiperplasia Prostática , Proteína Quinase C , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/fisiopatologia , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/fisiopatologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.
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Curvaturas da Coluna Vertebral , Poluentes Químicos da Água , Animais , Ecossistema , Embrião não Mamífero/anormalidades , Desenvolvimento Embrionário/genética , Chumbo/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genéticaRESUMO
The presumed ADP ribosylation factor (ARF) 6 inhibitor NAV2729 inhibits human prostate smooth muscle contraction and proliferation of stromal cells, which are driving factors of voiding symptoms in benign prostatic hyperplasia (BPH). However, its specificity and a confirmed role of ARF6 for smooth muscle contraction are still pending. Here, we generated monoclonal ARF6 knockouts in human prostate stromal cells (WPMY-1), and characterized phenotypes of contractility, growth-related functions, and susceptibility to NAV2729 in knockout and control clones. ARF6 knockout was verified by Western blot. Knockout clones showed impaired contraction and actin organization, reduced proliferation and viability, and increased apoptosis and cell death. In ARF6-expressing control clones, NAV2729 (5 µM) strongly inhibited contraction (67% inhibition across all three control clones), actin organization (72%), proliferation (97%), and viability (up to 82%), and increased apoptosis (5-fold) and cell death (6-fold). In ARF6 knockouts, effects of NAV2729 (5 µM) were widely reduced, including lacking or minor effects on contractions (0% inhibition across all three knockout clones), actin (18%) and proliferation (13%), and lacking increases of apoptosis and cell death. Viability was reduced by NAV2729 with an IC50 of 3.3 µM across all three ARF6 control clones, but of 4.5-8.2 µM in ARF6 knockouts. In conclusion, ARF6 promotes prostate smooth muscle contraction and proliferation of stromal cells. Both are inhibited by NAV2729, which showed high specificity for ARF6 up to 5 µM and represents an attractive compound in the context of BPH. Considering the relevance of smooth muscle-based diseases, shared roles of ARF6 in other smooth muscle types merit further investigation. SIGNIFICANCE STATEMENT: By knockout of ARF6 in prostate stromal cells, this study demonstrates the involvement of ARF6 in promotion of prostate smooth muscle contraction and stromal growth, and defines concentration ranges for their ARF6-specific inhibition by NAV2729. Besides the context of benign prostatic hyperplasia and lower urinary tract symptoms, analog ARF6 functions in contraction and growth appear possible in other smooth muscle-rich organs, which merits further attention considering the high clinical relevance of smooth muscle-based diseases.
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Fatores de Ribosilação do ADP/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Clorobenzenos/farmacologia , Próstata/citologia , Próstata/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/deficiência , Fatores de Ribosilação do ADP/metabolismo , Apoptose/fisiologia , Linhagem Celular Transformada , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Técnicas de Silenciamento de Genes/métodos , Humanos , Masculino , Próstata/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
BACKGROUND: Medical treatment in benign prostatic hyperplasia targets prostate size to prevent disease progression, complications, and surgery, and prostate smooth muscle tone for rapid relief of lower urinary tract symptoms. Combination therapies are still required to target both at once. However, current medications are insufficient, due to an unfavorable balance between side effects and efficacy. The limited efficacy of α1 -blockers may be due to nonadrenergic mediators like endothelin-1 and thromboxane A2 (TXA2 ), which keep up prostate smooth muscle contraction even in the presence of α1 -blockers. Consequently, future options with higher efficacy need to target α1 -adrenergic and nonadrenergic contractions as well as stromal cell growth at once. Thalidomide has been approved as an oral medication for various diseases, including the treatment of prostate cancer. Therefore, we investigated the effect of thalidomide on cellular functions of prostate stromal cells and human prostate smooth muscle contraction. METHODS: Cytoskeletal organization was visualized by phalloidin staining, cell growth was assessed by 5-ethynyl-2'-deoxyuridine assay, cell viability by cell counting kit-8, and apoptosis and cell death by flow cytometry in cultured prostate stromal cells (WPMY-1). Contractions of human prostate tissues from radical prostatectomy were studied in an organ bath, where they were induced by the α1 -adrenoceptor agonists methoxamine, noradrenaline, phenylephrine, and the nonadrenergic agonists endothelin-1, TXA2 analog U46619, or electric field stimulation (EFS). RESULTS: Thalidomide significantly reduced the proliferation of WPMY-1 cells, which was time- and concentration-dependent (10-300 µM). In parallel, organization of actin filaments collapsed after treatment with thalidomide. Thalidomide (30-100 µM) inhibited noradrenaline-, phenylephrine-, and methoxamine-induced contractions, as well as nonadrenergic contractions induced by endothelin-1 and U46619, and neurogenic contractions induced by EFS. No reduction in viability and no increases in apoptosis or in cell death were observed in WPMY-1 cells. CONCLUSIONS: Thalidomide impairs the growth of human prostate stromal cells, without showing a decrease in cell viability. In parallel, thalidomide inhibits adrenergic, neurogenic, and nonadrenergic contractions. This may be explained by a breakdown of the actin cytoskeleton. In vivo, urodynamic effects of thalidomide appear possible and may even exceed those of α1 -blockers or combination therapies.
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Proliferação de Células/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Próstata/citologia , Células Estromais/efeitos dos fármacos , Talidomida/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sintomas do Trato Urinário Inferior , Masculino , Metoxamina/farmacologia , Norepinefrina/farmacologia , Células Estromais/citologiaRESUMO
CONTEXT: Inflammation and epithelial-mesenchymal transition (EMT) play important roles in the occurrence and development of benign prostatic hyperplasia (BPH); curcumin exerts anti-proliferative, anti-inflammatory, and anti-EMT effects. OBJECTIVE: To explore the anti-inflammatory and anti-EMT mechanisms of curcumin in BPH. MATERIALS AND METHODS: Ten-week-old male C57BL/6 mice were administered lipopolysaccharide (LPS, 100 µg/kg) in the prostate lobules to establish an inflammatory BPH model (LPS group), and curcumin (120 mg/kg) was administered into the abdominal cavity for 2 weeks (three times a week, curcumin-treated group). A group of healthy mice served as the control group. The expression of Toll-like receptor 4 (TLR4), bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), EMT markers, inflammatory cytokines, and transforming growth factor ß1 (TGF-ß1) was detected by PCR and western blotting. TGF-ß1 (0.1 ng/mL) and LPS (100 ng/mL) were used to induce EMT in benign prostatic hyperplasia epithelial cells (BPH-1). RESULTS: In vivo, curcumin reduced the size of the prostate, suppressed the expression of vimentin and TLR4, and increased the expression of E-cadherin and BAMBI in the LPS-induced BPH mouse model. Moreover, curcumin decreased the levels of IL-6 and TNF-α by 44.52 and 46.17%, respectively. In vitro, curcumin attenuated cell proliferation, suppressed the expression of vimentin and TLR4, and increased the expression of E-cadherin and BAMBI in BPH-1 cells. Furthermore, BAMBI knockdown reversed the expression of vimentin and E-cadherin induced by curcumin. DISCUSSION AND CONCLUSION: This study demonstrated that curcumin alleviated hyperplasia, EMT, and inflammation in vivo. Furthermore, curcumin suppressed EMT by targeting BAMBI via the TLR4/BAMBI/TGF-ß1 signalling pathway in vitro, demonstrating its potential utility in BPH treatment.
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Proteínas Morfogenéticas Ósseas/metabolismo , Curcumina/farmacologia , Proteínas de Membrana/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Animais , Caderinas/metabolismo , Linhagem Celular , Citocinas/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Próstata/efeitos dos fármacos , Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Vimentina/metabolismoRESUMO
Voiding symptoms in benign prostatic hyperplasia (BPH) are driven by prostate smooth muscle contraction and prostate growth. Smooth muscle contraction in the prostate and other organs critically depends on activation of the small monomeric GTPase RhoA and probably Rac1. A role of another GTPase, ADP-ribosylation factor 6 (ARF6), for smooth muscle contraction has been recently suggested by indirect evidence but remains to be proven for any organ. Here, we report effects of NAV2729, an inhibitor with assumed specificity for ARF6, in human prostate tissues and cultured prostate stromal cells (WPMY-1). NAV2729 (5 µm) inhibited neurogenic and α1-adrenergic contractions of human prostate tissues. Contractions induced by endothelin-1, by the thromboxane A2 agonist U46619, or by high molar KCl were not inhibited. Correlation analyses suggested up-regulation of prostatic ARF6 expression with increasing degree of BPH, as ARF6 expression increased with the content of prostate-specific antigen (PSA) of prostate tissues. NAV2729 inhibited ARF6 activity but not other GTPases (ARF1, RhoA, Rac1) in prostate tissues and in WPMY-1 cells. Proliferation of WPMY-1 cells was inhibited concentration-dependently by NAV2726, as reflected by decreased viability, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, and expression of Ki-67. Silencing of ARF6 expression mimicked effects of NAV2729 on viability and in the EdU assay. Effects of NAV2729 on viability and proliferation were attenuated in cells with silenced ARF6 expression. Our findings suggest that a NAV2729-sensitive mechanism promotes adrenergic contraction and stromal cell growth in the human prostate, which is probably ARF6-mediated. Similar actions in other organs and urodynamic effects of NAV2729 appear possible.
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Proliferação de Células/efeitos dos fármacos , Clorobenzenos/farmacologia , Contração Muscular/efeitos dos fármacos , Nitrocompostos/farmacologia , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/antagonistas & inibidores , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Humanos , Masculino , Músculo Liso/fisiologia , Nitrocompostos/química , Norepinefrina/farmacologia , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Pirazóis/química , Pirimidinonas/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.
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Integrina alfa2beta1/antagonistas & inibidores , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Dipeptídeos/farmacologia , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Piperazinas/farmacologia , Próstata/metabolismo , Próstata/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Tromboxano A2/metabolismo , Vasoconstritores/farmacologiaRESUMO
CONTEXT: Renal interstitial fibrosis (RIF) is characterized by the accumulation of inflammatory cytokines and epithelial-mesenchymal transition (EMT). Curcumin exerts antifibrogenic, anti-inflammatory and antiproliferative effects. OBJECTIVE: To explore the mechanisms underlying the effects of curcumin on RIF. MATERIALS AND METHODS: Eight-week-old male C57BL/6 mice were intragastrically administered curcumin (50 mg/kg/day) for 14 days after undergoing unilateral ureteral obstruction (UUO) operations. Renal function (blood urea nitrogen [BUN] and serum creatinine [Scr]) and inflammatory cytokine levels were tested using colorimetric assays and ELISA, respectively. EMT markers were evaluated through immunohistochemistry, western blotting and qPCR. Transforming growth factor beta 1 (TGF-ß1; 10 ng/mL) and lipopolysaccharides (LPS; 100 ng/mL) were used to stimulate EMT and an inflammatory response in human renal proximal tubular epithelial (HK-2) cells, respectively, for further investigation. RESULTS: In vivo, curcumin significantly improved the levels of BUN and Scr by 28.7% and 21.3%, respectively. Moreover, curcumin reduced the levels of IL-6, IL-1ß and TNF-α by 22.5%, 30.3% and 26.7%, respectively, and suppressed vimentin expression in UUO mice. In vitro, curcumin reduced the expression of vimentin and α-smooth muscle actin in TGF-ß1-induced HK-2 cells. In LPS-induced HK-2 cells, curcumin decreased the release of IL-6, IL-1ß and TNF-α by 43.4%, 38.1% and 28.3%, respectively. In addition, curcumin reduced the expression of TLR4, p-PI3K, p-AKT, p-NF- κB and p-IκBα in both LPS- and TGF-ß1-induced HK-2 cells. DISCUSSION AND CONCLUSIONS: Curcumin repressed EMT and the inflammatory response by inhibiting the TLR4/NF-κB and PI3K/AKT pathways, demonstrating its potential utility in RIF treatment.
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Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Nefropatias/tratamento farmacológico , Obstrução Ureteral/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Humanos , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like/metabolismo , Obstrução Ureteral/patologiaRESUMO
BACKGROUND: Inhibition of prostate smooth muscle contraction by α1 -adrenoceptor antagonists (α1 -blockers) is a first-line medical treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, efficacy of α1 -blockers is limited, as non-adrenergic mediators including endothelin-1 and thromboxane A2 (TXA2 ) increase prostate smooth muscle tension in parallel to α1 -adrenoceptors. This may maintain urethral obstruction despite therapy with α1 -blockers. Consequently, future treatment options with higher efficacy need to target α1 -adrenergic and non-adrenergic contractions simultaneouly. Recently, several compounds were reported to inhibit adrenergic or neurogenic prostate contractions, however, their effects on non-adrenergic contraction are unknown. Here, we examined effects of inhibitors for Rac-GTPase, Src family kinases (SFKs), and p21-activated kinases (PAKs) on non-adrenergic prostate contractions. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Viability of cultured stromal cells was assessed by CCK-8 assay. RESULTS: Inhibition of α1 -adrenergic contractions by Rac inhibitors EHT1864 (100 µM) and NSC23766 (100 µM), and SFK inhibitors AZM475721 (10 µM) and PP2 (10 µM) was confirmed by inhibition of methoxamine-induced contractions. No effects of the PAK inhibitors FRAX486 (30 µM) and IPA3 (300 µM) on α1 -adrenergic contraction were confirmed by absent effects on methoxamine-inuced contractions. EHT1864 caused inhibition of endothelin-1- and U46619-induced contractions. EHT1864 reduced the viability of stromal cells concentration- and time-dependently. EHT1864 attenuated KCl-induced contractions of prostate strips only slightly, so that toxic effects may not account alone for inhibition of agonist-induced contractions. NSC23766 inhibited U46619-induced contractions, but not endothelin-1-induced contractions. AZM475271 had no effects on endothelin-1- or U46619-induced contractions, while PP2 inhibited U46619- but not endothelin-1-induced contractions. FRAX486 caused inhibition of U46619-induced contractions. IPA3 inhibited U46619-, but not endothelin-1-induced contractions. CONCLUSIONS: Of all six inhibitors, EHT1864 seems to be most promising from a translational point of view, as it inhibited TXA2 - and endothelin-1-induced besides α1 -adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. In vivo, urodynamic effects of EHT1864 and possibly of FRAX486 may exceed those of α1 -blockers.
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Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Inibidores Enzimáticos/farmacologia , Contração Muscular/efeitos dos fármacos , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/metabolismo , Masculino , Músculo Liso/efeitos dos fármacos , Próstata/metabolismo , Próstata/cirurgia , Prostatectomia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/cirurgia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
In this paper, we report a sensitive lateral photovoltaic effect (LPE) in Fe3O4/3C-SiC Schottky junctions with a fast relaxation time at near-ultraviolet wavelengths. The rectifying behavior suggests that the large build-in electric field was formed in the Schottky junctions. This device has excellent position sensitivity as high as 67.8 mV mm-1 illuminated by a 405 nm laser. The optical relaxation time of the LPE is about 30 µs. The fast relaxation and high positional sensitivity of the LPE make the Fe3O4/3C-SiC junction a promising candidate for a wide range of ultraviolet/near-ultraviolet optoelectronic applications.
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PURPOSE: To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor. METHODS: Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and -20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT. RESULTS: VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT. CONCLUSION: VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.
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Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Vincristina/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Fenômenos Químicos/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Sinergismo Farmacológico , Feminino , Humanos , Lipossomos , Células MCF-7 , Camundongos , Camundongos Nus , Temperatura , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Vincristina/química , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Ferroelectric materials have aroused increasing interest in the field of self-powered ultraviolet (UV) photodetectors (PDs) for their switchable spontaneous polarization. However, the utilization of ferroelectric materials to modulate the built-in electric field and energy band at the junction interface has rarely been investigated. Herein, we design and fabricate self-powered solar-blind UV PDs based on a Ga2O3/ZnO:V heterojunction. The performance of the Ga2O3/ZnO:V PD is significantly enhanced through the reasonable coupling of ferroelectricity and piezoelectricity within the ZnO:V film. The device at 260 nm exhibits excellent photoelectric properties with high peak responsivity of 64.5 mA/W, a specific detectivity of 3.8 × 1010 Jones, and a rise/decay time of 1.9/45.2 µs, together with reproducibility and stability. Systematical energy band diagram analysis reveals that the excellent performance of Ga2O3/ZnO:V PD can be attributed to the driving forces arising from the addition of the depolarization field and piezoelectric field, which increases the intensity of built-in electric field and promotes the separation and transport of photogenerated carriers at the heterojunction interface. The findings of our research provide a novel avenue and valuable guidance for the design of high-performance self-powered photodetectors.
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Ultraviolet (UV) exposure causes damage to human skin and mucous membranes, resulting in oxidative stress, and can also lead to inflammation of human skin, skin aging, and even diseases such as squamous cell carcinoma and melanoma of the skin. The main means of protection against UV radiation is physical shielding and the use of sunscreen products. Carbon dots as a novel nanomaterial provide a new option for UV protection. In this article, we introduced sulfhydryl groups to synthesize l-cysteine-derived carbon dots (GLCDs) with UV resistance. GLCDs exhibit high-efficiency and excellent UV absorption, achieving 200-400 nm UV absorption (99% UVC, 97% UVB, and 86% UVA) at a low concentration of 0.5 mg/mL. Meanwhile, GLCDs can reduce apoptosis and UVB-induced oxidative damage, increase collagen type I gene expression, and inhibit skin aging in zebrafish. It also inhibits senescence caused by the senescence inducer 2,2'-azobis(2-methylpropionamidine) dihydrochloride and reduces oxidative damage. The above studies show that GLCDs possess efficient broad-spectrum UV absorption, antiphotoaging, and antiaging capabilities, which will have a broad application prospect in UV protection.
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Carbono , Cisteína , Estresse Oxidativo , Pontos Quânticos , Envelhecimento da Pele , Raios Ultravioleta , Peixe-Zebra , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Cisteína/química , Cisteína/farmacologia , Humanos , Animais , Carbono/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Pontos Quânticos/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/metabolismoRESUMO
Patched homolog 1 (PTCH1) is a known tumor suppressor that regulates the Hedgehog (Hh) pathway and has been implicated in tumorigenesis. The role of PTCH1 in colon carcinogenesis, however, is controversial. The aim of the present study was to investigate epigenetic modifications of PTCH1 in aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancer (CRC). Using laser-capture microdissection (LCM), a pure population of ACF epithelial cells was isolated and studied. The inherent protein expression levels of SHH, PTCH1, SMO and GLI1 were assessed by immunohistochemistry for 405 ACF, including 54 dysplastic ACF (d-ACF) and 351 non-dysplastic ACF (n-ACF). The mRNA levels and methylation status of PTCH1 were also determined in 54 d-ACF and 96 n-ACF. Our data showed that the expression of SHH, SMO and GLI1 was significantly up-regulated in d-ACF, compared to n-ACF. Also, the mRNA and protein levels of PTCH1 were lower in d-ACF than n-ACF. Using MSP or MS-HRM, PTCH1 methylation was present in 64.8% (35/54) or 63.3% (34/54), respectively, of d-ACF and 19.8% (19/96) or 22.9% (11/48), respectively, of n-ACF. PTCH1 methylation was more frequent in d-ACF than n-ACF (p < 0.001) and was associated with PTCH1 mRNA levels (r = 0.358, p < 0.01). There was a statistically significant correlation between PTCH1 methylation status and the prevalence of colorectal neoplasms. In conclusion, this study suggests that aberrant methylation of the PTCH1 promoter may be an early, initiating event of colon carcinogenesis.
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Focos de Criptas Aberrantes/genética , Neoplasias Colorretais/genética , Metilação de DNA , Regiões Promotoras Genéticas , Receptores de Superfície Celular/genética , Focos de Criptas Aberrantes/metabolismo , Focos de Criptas Aberrantes/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Proteínas Hedgehog/metabolismo , Humanos , Microdissecção e Captura a Laser , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Receptor Smoothened , Fatores de Transcrição/metabolismo , Transcrição Gênica , Adulto Jovem , Proteína GLI1 em Dedos de ZincoRESUMO
Background: Adrenocortical carcinoma (ACC) is a rare endocrine neoplasia with poor prognosis. Emerging evidence suggests that kinesin family member 11 (KIF11) protein is overexpressed in several tumors and associated with the onset and progression of certain types of cancer; however, its biological functions and mechanisms in ACC progression have not been studied yet. Therefore, this study evaluated the clinical significance and therapeutic potential of the KIF11 protein in ACC. Methods: The Cancer Genome Atlas (TCGA) database (n=79) and Genotype Tissue Expression (GTEx) database (n=128) were utilized to explore the expression of KIF11 in ACC and normal adrenal tissues. The TCGA datasets were then data mined and statistically analyzed. R survival analysis and univariate and multivariate Cox regression analyses were used to evaluate the effect of KIF11 expression on the survival rates, and a nomogram was used to predict its impact on prognosis. The clinical data from 30 ACC patients' from Xiangya Hospital were also analyzed. The effects of KIF11 on the proliferation and invasion of ACC NCI-H295R were further validated in vitro. Results: Analytical data from the TCGA and GTEx databases showed that KIF11 expression was upregulated in ACC tissues and associated with T (primary tumor), and M (metastasis) and stages of tumor progression. Increased KIF11 expression was significantly associated with shorter overall survival, disease-specific survival, and progression-free intervals. Clinical data from Xiangya Hospital illustrated that increased KIF11 had a significantly positive correlation with shorter overall survival, T and pathological stages, and tumor recurrence risk. Monastrol, a specific inhibitor of KIF11, was further confirmed to significantly inhibit the proliferation and invasion of ACC NCI-H295R cell in vitro. The nomogram demonstrated KIF11 was an excellent predictive biomarker in patients with ACC. Conclusions: The findings demonstrate that KIF11 could be a predictor of poor prognosis and thus possibly serve as a novel therapeutic target for ACC.
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Iron overloads osteoporosis mainly occurs to postmenopausal women and people requiring repeated blood transfusions. Iron overload increases the activity of osteoclasts and decreases the activity of osteoblasts, leading to the occurrence of osteoporosis. Conventional treatment options include calcium supplements and iron chelators. However, simple calcium supplementation is not effective, and it does not have a good therapeutic effect. Oxidative stress is one of the triggers for osteoporosis. Therefore, the study focuses on the antioxidant aspect of osteoporosis treatment. The present work revealed that antioxidant carboxymethyl chitosan-based carbon dots (AOCDs) can effectively treat iron overload osteoporosis. More interestingly, the functional modification of AOCDs by doping calcium gluconate (AOCDs:Ca) is superior to the use of any single component. AOCDs:Ca have the dual function of antioxidant and calcium supplement. AOCDs:Ca effectively improve the bioavailability of calcium and achieve ultra-low concentration calcium supplement for the treatment of iron-induced osteoporosis in zebrafish.
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Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-ß1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-ß1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.
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Nefropatias , MicroRNAs , RNA Longo não Codificante , Obstrução Ureteral , Animais , Humanos , Camundongos , Fibrose , Nefropatias/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/patologiaRESUMO
Background: Chyluria is a rare disease in which chylous is excreted in the urine. Currently, management of chyluria includes conservative treatments and surgical measures. This study aimed to report our experience in treating non-parasitic chyluria with retroperitoneal laparoscopic ligation of the renal lymphatic vessels. Methods: Data from 52 patients who underwent retroperitoneoscopic ligation of the renal lymphatic vessels for non-parasitic chyluria between December 2009 and May 2022 were reviewed. After general anesthesia, the patients were passively placed in the healthy lateral decubitus position and underwent three-port retroperitoneal laparoscopy. Detailed medical data, including demographic characteristics, intraoperative outcomes, postoperative data, and complications, were reviewed. Results: Fifty-two patients received surgery treatment at our institution. The mean disease course was 89.3 months. The mean age was 58.8 years, with females accounting for 57.7% (30/52); the majority of patients (33/52) had the laterality of chyluria on the left and 9 (17.3%) had a history of previous thoracic or abdominal surgery. Compared with the urine and blood data before the operation and on the first day after the operation, urinary protein, urinary tract infection, urinary red blood cells, hemoglobin, albumin, and serum total protein significantly improved 3 months after the operation. However, there were no significant differences in blood creatinine and blood urea nitrogen levels among the three groups. The mean surgery time was about 110.0 minutes, and the estimated total blood loss was 81.2 mL. The postoperative drainage volume was 229.9 mL. The average time to start a liquid diet and to be out of bed were 1.5 and 1.9 days, respectively. Transient postoperative gross hematuria occurred in eight patients, and complications occurred in five patients after surgery. The mean length of hospitalization was 6.6 days. The follow-up duration ranged from 3 to 152 months, and except for three patients who did not respond to treatment, the remaining patients had no recurrence and did not require reoperation. Conclusions: Our long-term follow-up results showed that renal pedicle lymphatic ligation via retroperitoneal laparoscopic surgery is an effective, safe, and reliable surgical option for patients with non-parasitic chyluria.
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We have achieved significantly improved device performance in solar-blind deep-ultraviolet photodetectors fabricated from ß-Ga2O3 thin films grown via metal-organic chemical vapor deposition (MOCVD) on p-Si(111) substrates by improving material quality through the use of an AlN buffer layer. High-structural-quality ß-Ga2O3 films with a (-201) preferred orientation are obtained after the introduction of the AlN buffer. Under 3 V bias, the dark current reaches a minimum of 45 fA, and the photo-to-dark current ratio (PDCR) reaches 8.5 × 105 in the photodetector with the metal-semiconductor-metal (MSM) structure. The peak responsivity and detectivity are 38.8 A/W and 2.27 × 1015 cm·Hz1/2/W, respectively, which are 16.5 and 230 times that without the buffer layer. Additionally, benefiting from the introduction of the AlN layer, the photodetection performance of the ß-Ga2O3/AlN/Si heterojunction is significantly improved. The PDCR, peak responsivity, and detectivity for the ß-Ga2O3/AlN/p-Si photodetector at 5 V bias are 2.7 × 103, 11.84 A/W, and 8.31 × 1013 cm·Hz1/2/W, respectively. The improved structural quality of ß-Ga2O3 is mainly attributed to the decreased in-plane lattice mismatch of 2.3% for ß-Ga2O3(-201)/AlN(002) compared to that of 20.83% for ß-Ga2O3(-201)/Si(111), as well as the elimination of the native amorphous SiOx surface layer on the Si substrate during the initial growth of oxide thin films.