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1.
Nature ; 617(7962): 717-723, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37225883

RESUMO

Flexible solar cells have a lot of market potential for application in photovoltaics integrated into buildings and wearable electronics because they are lightweight, shockproof and self-powered. Silicon solar cells have been successfully used in large power plants. However, despite the efforts made for more than 50 years, there has been no notable progress in the development of flexible silicon solar cells because of their rigidity1-4. Here we provide a strategy for fabricating large-scale, foldable silicon wafers and manufacturing flexible solar cells. A textured crystalline silicon wafer always starts to crack at the sharp channels between surface pyramids in the marginal region of the wafer. This fact enabled us to improve the flexibility of silicon wafers by blunting the pyramidal structure in the marginal regions. This edge-blunting technique enables commercial production of large-scale (>240 cm2), high-efficiency (>24%) silicon solar cells that can be rolled similarly to a sheet of paper. The cells retain 100% of their power conversion efficiency after 1,000 side-to-side bending cycles. After being assembled into large (>10,000 cm2) flexible modules, these cells retain 99.62% of their power after thermal cycling between -70 °C and 85 °C for 120 h. Furthermore, they retain 96.03% of their power after 20 min of exposure to air flow when attached to a soft gasbag, which models wind blowing during a violent storm.

2.
Int J Mol Sci ; 25(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38397109

RESUMO

Insecticide resistance has long been a problem in crop pest control. Bactericera gobica is a major pest on the well-known medicinal plants Lycium barbarum L. Investigating insecticide resistance mechanisms of B. gobica will help to identify pesticide reduction strategies to control the pest. Gene expression normalization by RT-qPCR requires the selection and validation of appropriate reference genes (RGs). Here, 15 candidate RGs were selected from transcriptome data of B. gobica. Their expression stability was evaluated with five algorithms (Delta Ct, GeNorm, Normfinder, BestKeeper and RefFinder) for sample types differing in response to five insecticide stresses and in four other experimental conditions. Our results indicated that the RGs RPL10 + RPS15 for Imidacloprid and Abamectin; RPL10 + AK for Thiamethoxam; RPL32 + RPL10 for λ-cyhalothrin; RPL10 + RPL8 for Matrine; and EF2 + RPL32 under different insecticide stresses were the most suitable RGs for RT-qPCR normalization. EF1α + RPL8, EF1α + ß-actin, ß-actin + EF2 and ß-actin + RPS15 were the optimal combination of RGs under odor stimulation, temperature, developmental stages and both sexes, respectively. Overall, EF2 and RPL8 were the two most stable RGs in all conditions, while α-TUB and RPL32 were the least stable RGs. The corresponding suitable RGs and one unstable RG were used to normalize a target cytochrome P450 CYP6a1 gene between adult and nymph stages and under imidacloprid stress. The results of CYP6a1 expression were consistent with transcriptome data. This study is the first research on the most stable RG selection in B. gobica nymphs exposed to different insecticides, which will contribute to further research on insecticide resistance mechanisms in B. gobica.


Assuntos
Perfilação da Expressão Gênica , Inseticidas , Neonicotinoides , Nitrocompostos , Masculino , Feminino , Humanos , Perfilação da Expressão Gênica/métodos , Inseticidas/farmacologia , Actinas , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transcriptoma , Padrões de Referência
3.
J Environ Manage ; 351: 119690, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38048707

RESUMO

Understanding the dynamics between public disaster assistance, disaster damages, and social vulnerability at county-level is crucial for designing effective disaster mitigation strategies. This study utilized the Local Bivariate Moran Index (LBMI) and geographically weighted regression (GWR) models to examine spatial patterns and relationships between disaster damages, social vulnerability, and public disaster assistance in contiguous US counties from 2001 to 2021. LBMI results reveal that public disaster assistance has predominantly been directed towards post-disaster recovery efforts, with a particular focus on coastal communities affected by major declared disasters. However, the distributions of public assistance and individual housing assistance, which are the two primary sources of public disaster assistance, do not adequately cover physically and socially vulnerable communities. The distribution of pre-disaster risk mitigation also falls short of sufficiently covering vulnerable communities. Results further indicate the complex interactions between different categories of natural disasters and public assistances. The GWR model results demonstrate spatial variations in predicting each category of public disaster assistance. These findings indicate the need to address disparities in accessing public disaster assistance in the US, and advocate for more equitable disaster mitigation strategies.


Assuntos
Desastres , Vulnerabilidade Social , Habitação , Assistência Pública
4.
Opt Express ; 31(2): 2112-2119, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36785232

RESUMO

Coherent perfect absorption-lasing (CPAL) and collimation have been intensively studied for normal and small angle wave incidence. Here, we report a two-dimensional non-Hermitian photonic crystal for broad-angle CPAL and super-collimation. The synergy of a nonsymmorphic glide symmetry of the lattice, gain-loss modulation and an optimization of unit cell induces a parity-time phase transition in the band structure along the Brillouin zone boundary. The transition points, i.e., the exceptional points, form a slab-like contour, with nearly zero dispersion in both real and imaginary parts of the band structure. Such dispersionless band structure significantly enhances the range of incident angle for CPAL and collimation.

5.
Opt Lett ; 48(20): 5407-5410, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37831879

RESUMO

Zero-index materials have emerged as a topic of significant scientific interest in recent years. In this Letter, we investigate the electromagnetic properties of epsilon-near-zero (ENZ) gratings composed of materials with near-zero effective permittivity. Our study reveals that ENZ gratings exhibit a unique polarization selectivity that is opposite to that observed in perfect conductor gratings. Furthermore, we demonstrate that hybrid gratings combining perfect conductors and ENZ materials can block omnidirectional electromagnetic waves of any polarization. In addition, we propose a practical design of the ENZ and hybrid gratings based on dielectric ENZ MMs, exhibiting excellent polarization selectivity and blocking effect. Our research presents a promising approach for the flexible manipulation of polarizations using ENZ gratings.

6.
Int J Mol Sci ; 24(9)2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37175675

RESUMO

The medicinal plant Cistanche deserticola Ma (Orobanchaceae) is a holoparasitic angiosperm that takes life-essential materials from Haloxylon ammodendron (C. A. Mey.) Bunge (Amaranthaceae) roots. Although many experiments have been conducted to improve the quality of C. deserticola, little attention has been paid to the host's influence on metabolite accumulation. In this study, transcriptomic and metabolomic analyses were performed to unveil the host's role in C. deserticola's metabolite accumulation, especially of phenylethanoid glycosides (PhGs). The results indicate that parasitism by C. deserticola causes significant changes in H. ammodendron roots in relation to metabolites and genes linked to phenylalanine metabolism, tryptophan metabolism and phenylpropanoid biosynthesis pathways, which provide precursors for PhGs. Correlation analysis of genes and metabolites further confirms that C. deserticola's parasitism affects PhG biosynthesis in H. ammodendron roots. Then we found specific upregulation of glycosyltransferases in haustoria which connect the parasites and hosts. It was shown that C. deserticola absorbs PhG precursors from the host and that glycosylation takes place in the haustorium. We mainly discuss how the host resists C. deserticola parasitism and how this medicinal parasite exploits its unfavorable position and takes advantage of host-derived metabolites. Our study highlights that the status of the host plant affects not only the production but also the quality of Cistanches Herba, which provides a practical direction for medicinal plant cultivation.


Assuntos
Cistanche , Plantas Medicinais , Cistanche/genética , Cistanche/metabolismo , Perfilação da Expressão Gênica , Glicosídeos/metabolismo , Transcriptoma , Plantas Medicinais/genética , Metaboloma
7.
Int J Mol Sci ; 24(12)2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37372986

RESUMO

Galls have become the best model for exploring plant-gall inducer relationships, with most studies focusing on gall-inducing insects but few on gall mites. The gall mite Aceria pallida is a major pest of wolfberry, usually inducing galls on its leaves. For a better understanding of gall mite growth and development, the dynamics of the morphological and molecular characteristics and phytohormones of galls induced by A. pallida were studied by histological observation, transcriptomics and metabolomics. The galls developed from cell elongation of the epidermis and cell hyperplasia of mesophylls. The galls grew quickly, within 9 days, and the mite population increased rapidly within 18 days. The genes involved in chlorophyll biosynthesis, photosynthesis and phytohormone synthesis were significantly downregulated in galled tissues, but the genes associated with mitochondrial energy metabolism, transmembrane transport, carbohydrates and amino acid synthesis were distinctly upregulated. The levels of carbohydrates, amino acids and their derivatives, and indole-3-acetic acid (IAA) and cytokinins (CKs), were markedly enhanced in galled tissues. Interestingly, much higher contents of IAA and CKs were detected in gall mites than in plant tissues. These results suggest that galls act as nutrient sinks and favor increased accumulation of nutrients for mites, and that gall mites may contribute IAA and CKs during gall formation.


Assuntos
Lycium , Ácaros , Animais , Lycium/genética , Ácaros/metabolismo , Transcriptoma , Reguladores de Crescimento de Plantas/metabolismo , Citocininas , Metaboloma , Tumores de Planta/genética , Folhas de Planta/metabolismo
8.
Exp Appl Acarol ; 91(3): 381-403, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37882995

RESUMO

Phoresy is one of the most distinctive relationships between mites and insects, and the off-host interaction between phoretic mites and their carriers is the most critical factor sustaining the phoretic association. As phoretic associations commonly occur in temporary habitats, little is known about off-host interactions between phoronts and carriers. However, an off-host interaction has been reported, in which the plant-mediated competition between a phoretic gall mite, Aceria pallida, and its psyllid vector, Bactericera gobica, after detachment decreases leaf abscission caused by B. gobica and then directly facilitates their phoretic association. In this obligate phoresy, A. pallida seasonally attaches to B. gobica for overwinter survival and they share the same host plant, Lycium barbarum, during the growing season. It is unknown how the host plant responds to these two herbivores and what plant metabolites are involved in their interspecific interaction. Here, effects of A. pallida and B. gobica on the host plant's transcriptome and metabolome, and on enzymes involved in plant defence, at various infestation stages were studied by inoculating A. pallida and B. gobica either separately or simultaneously on leaves of L. barbarum. Our results showed that (a) A. pallida significantly promoted primary and secondary metabolite accumulation, (b) B. gobica markedly inhibited primary and secondary metabolite accumulation and had little influence on defence enzyme activity, and (c) under simultaneous A. pallida and B. gobica infestation, an intermediate response was predicted. These findings indicate that A. pallida and B. gobica have different effects on host plants, A. pallida inhibits B. gobica mainly by increasing the secondary metabolism of L. barbarum, whereas B. gobica inhibits A. pallida mainly by decreasing the primary metabolism of L. barbarum. In conjunction with our previous research, we speculate that this trade-off in host plant metabolite response between A. pallida and B. gobica after detachment promotes a stable phoretic association.


Assuntos
Hemípteros , Ácaros , Animais , Ácaros/fisiologia
9.
Pak J Med Sci ; 39(1): 248-252, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36694744

RESUMO

Objective: To evaluate the clinical efficacy and immune function of Daratumumab combined with chemotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Methods: Eighty patients with RRMM treated in Xingtai People's Hospital from January, 2020 to December, 2021 were randomly divided into two groups. Patients in the study group were treated with Daratumumab combined with PAD regimen, while patients in the control group were provided with PAD regimen alone. Further comparison was performed on the therapeutic effects, adverse drug reactions, the levels of T lymphocyte subsets CD3+, CD4+, CD8+ and CD4+/CD8+, the positive expression rate of CD38 and the expression level of Notch-1 on the membrane of plasma cells between the two groups. Results: The overall response rate in the study group (67.50%) was significantly better than that in the control group (45.00%). There was no significant difference in the incidence of adverse reactions between the two groups. After treatment, the reviewed levels of CD3+, CD4+ and CD4+/CD8+ were obviously higher in the study group than those in the control group, while the positive expression rate of CD38 and the expression level of Notch one on the membrane of plasma cells were both lower than those in the control group (p<0.05). Conclusion: Daratumumab combined with a PAD regimen is a safe and effective approach that has a definite curative effect on patients with RRMM, which can improve immune function significantly and result in no significant increase in adverse reactions.

10.
Zhongguo Zhong Yao Za Zhi ; 48(10): 2630-2638, 2023 May.
Artigo em Zh | MEDLINE | ID: mdl-37282924

RESUMO

Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-ß(TGF-ß)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-ß/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-ß/Smad signaling pathway. This study clarified the mechanism of TGF-ß/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-ß/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Medicina Tradicional Chinesa , Rim/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Transição Epitelial-Mesenquimal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética
11.
Int J Mol Sci ; 24(1)2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36613890

RESUMO

Goji fruit fly, Neoceratitis asiatica, is a major pest on the well-known medicinal plant Lycium barbarum. Dissecting molecular mechanisms of infestation and host selection of N. asiatica will contribute to the determination of best management practices for pest fly control. Gene expression normalization by Real-time quantitative PCR (qPCR) requires the selection and validation of appropriate reference genes (RGs). Hence, 15 candidate RGs were selected from transcriptome data of N. asiatica. Their expression stability was evaluated with five algorithms (∆Ct, Normfinder, GeNorm, BestKeeper, and RefFinder) for sample types differing in the developmental stage, sex, tissue type, and in response to five different abiotic stresses. Our results indicated that the RGs ß-Actin + GST for sex, RPL32 + EF1α for tissue type, RPS13+ EF1α for developmental stages along with odor stimulation, color induction, and starvation-refeeding stresses, EF1α + GAPDH under insecticide stress, RPS13 + RPS18 under temperature stress, respectively, were selected as the most suitable RGs for qPCR normalization. Overall, RPS18 and EF1α were the two most stable RGs in all conditions, while RPS15 and EF1ß were the least stable RGs. The corresponding suitable RGs and one unstable RG were used to normalize a target odorant-binding protein OBP56a gene in male and female antennae, different tissues, and under odor stimulation. The results of OBP56a expression were consistent with transcriptome data. Our study is the first research on the most stable RGs selection in N. asiatica, which will facilitate further studies on the mechanisms of host selection and insecticide resistance in N. asiatica.


Assuntos
Tephritidae , Transcriptoma , Animais , Algoritmos , Perfilação da Expressão Gênica/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de Referência , Estresse Fisiológico/genética , Tephritidae/genética
12.
J Environ Manage ; 304: 114230, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34883437

RESUMO

This study conducts a life cycle environmental and economic quantification comparison of urban runoff source control facilities (URSCFs) through construction and operation stages in two urban functional regions (i.e., residential area and campus). From the environmental perspective, URSCFs construction in residential area has both higher environmental impacts and benefits than that in campus. The operation stage of URSCFs can observe significant benefit for both residential area and campus. We then develop a set of monetized method to make a comprehensive benefit evaluation (i.e., environmental, economic, and social benefit) of URSCFs. Overall, the two areas have payback time less than thirteen years for their investment which is acceptable when compared with the assumed total service period (30 years). Specifically, the payback time of campus is 5.62 years and residential area is 12.44 years. This implies that the campus has great potential to achieve high cost-benefit ratio and thus the Sponge City construction in campus can implement URSCFs with less engineering and material consumption due to its more spacious site than residential area with high building density. For both residential area and campus, permeable pavement has the highest environmental impact and economic cost because of the concrete consumption. Thus, we recommend that it should be cautious of the construction of concrete permeable pavement and find environmentally and economically alternatives in future URSCFs projects.


Assuntos
Meio Ambiente , Poluição Ambiental/prevenção & controle , Cidades , Análise Custo-Benefício , Poluição Ambiental/economia
13.
J Environ Manage ; 304: 114241, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34906811

RESUMO

Urban runoff source control facilities (URSCFs) are important parts of Sponge City (SC) by controlling urban flooding, restoring eco-balance, and enhancing city resilience. To evaluate the performance of URSCF, one needs to summarize and analyze the past SC construction and operation data. Previous studies however are predominately engineering practice studies. There lacks localized reference datasets to quantitatively evaluate the performance and guide public policy development for SC. Therefore, it is imperative to develop a database, which would summarize data obtained through the already completed pilot sponge cities, and provide a reference for future URSCFs planning and construction. This study makes a zero to one breakthrough by establishing a SC database using New Orleans method. Then statistical results of facility type, size, and costs information for 30 pilot sponge cities have been summarized and analyzed. The URSCFs type distribution statistical results show that bioretention, permeable pavement, detention cell, grassed swale and constructed wetland are the top five most constructed facilities in China. The cost statistical results display that the range of facility cost collected is usually larger than the range given by the reference value, which may attribute to the variation in material cost, labor cost and design parameters in different cities. To check the similarities and differences of URSCFs parameters between China and the US. A configuration parameters comparison of URSCFs has been conducted. Bioretention is taken as an exampl. Comparison results show that factors such as climate type, geographical environment, and socio-economic conditions will affect the configuration parameters of URSCFs. The groundwater depth and designed rainfall intensity are mainly influenced by local climate and geographical conditions. Surface area is influenced by local socio-economic conditions. The thickness of the covering layer and drainage layer are not affected by geographic location. The service area ratio, water storage depth and planting soil layer thickness are significantly different between China and the US.


Assuntos
Poluição Ambiental/prevenção & controle , Chuva , Movimentos da Água , China , Cidades , Inundações , Estados Unidos
14.
Int Nurs Rev ; 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36409288

RESUMO

The development of advanced practice nursing has evolved globally over the past decades and has become an important component in the contemporary healthcare system. The term 'advanced practice nurse' is used to refer to nurses practising at a higher level than traditional nurses and is defined as a registered nurse who has acquired the expert knowledge base, complex decision-making skills and clinical competencies for expanded practice. In 2003, Singapore embarked on the development of advanced practice nurses as an initiative to improve the nursing professional image, retain excellent clinical nurses and fill the gaps in the provision of healthcare services for the ageing population. This paper documents Singapore's journey of advanced practice nursing development and shares our unique learning experience in the aspects of education, certification, registration and scope of practice.

15.
Opt Express ; 29(5): 6810-6823, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33726193

RESUMO

In this paper, a novel approach to modelling intracavity second harmonic generation (SHG) in periodically poled MgO-doped lithium niobate (PPLN) is presented and verified against experimental results. This approach involves combining the coupled nonlinear wave equations with a rate equation model for a diode-pumped solid-state Nd:YVO4 laser, taking into account both the depletion of the fundamental wave due to the energy conversion from the fundamental wave to the SHG wave and the reduction of the fundamental wave within a laser cavity due to the loss as a result of the SHG nonlinear process. It was shown that the theoretical simulation matched the experimental results well, while also providing physical insight into the importance of the fundamental wave depletion in the intracavity SHG nonlinear processes. The resulting model is computationally simple and has the potential to generalize to the other nonlinear processes such as three-wave mixing and optical parametric oscillation.

16.
Opt Express ; 29(12): 18070-18080, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34154074

RESUMO

Symmetry usually plays a key role in the formation of the Dirac cone in the band structure of triangular or hexagonal systems. In this work, we demonstrate a systematic method to create Dirac cones of accidental degeneracy in general photonic crystals without symmetry. With this method, a band gap can be closed gradually through a series of modification to the unit structure based on the eigenfields of the band edges, and consequently a Dirac point is formed with Dirac conical dispersions in its vicinity. The validity of this approach is demonstrated by three examples. We further show that the Dirac cones of accidental degeneracy have the same properties as the symmetry-induced Dirac cones, such as finite group velocity and pseudo-diffusive transmission. Our finding opens a route for the engineering of accidental degeneracy in general photonic crystals beyond the scope of high-symmetry ones.

17.
Phys Rev Lett ; 127(12): 123902, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34597082

RESUMO

Electromagnetic void space is a medium, while geometrically occupying a finite volume of space, optically equivalent to an infinitesimal point, in which electromagnetic waves do not experience any phase accumulation. Here, we report the first realization of three-dimensional (3D) electromagnetic void space by an all-dielectric photonic crystal possessing vanishing permittivity and permeability simultaneously. The 3D electromagnetic void space offers distinctive functionalities inaccessible to its 2D or acoustic counterparts because of the fundamental changes in topology, which comes from the ascension of dimensionality as well as the transverse nature of electromagnetic waves. In particular, we demonstrate, both theoretically and experimentally, that the transmission through such a 3D void space is unaffected by its inner boundaries, but highly sensitive to the outer boundaries. This enables many applications such as the impurity "antidoping" effect, outer-boundary-controlled switching, and 3D perfect wave steering. Our work paves a road toward 3D exotic optics of an optically infinitesimal point.

18.
Cardiovasc Drugs Ther ; 35(1): 73-85, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32918657

RESUMO

PURPOSE: To determine the mediation of spermine on energy metabolism disorder and diabetic cardiomyopathy (DCM) development as well as the underlying mechanisms. METHODS: An in vitro model of DCM was established by incubating primary cultured neonatal rat cardiomyocytes with high glucose (HG). Spermine content was assessed by RP-HPLC. The protein levels were detected by western blot. Mitochondrial functions were analyzed using the respiratory chain complex assay kit and immunofluorescence staining. RESULTS: The endogenous content of spermine was decreased in the HG group, and the protein levels of ornithine decarboxylase, respiratory chain complex (I-V), mitochondrial fusion-related protein (Mfn1, Mfn2), Cx43, N-cadherin, CaSR, and ß-catenin (in cytomembrane) were also down-regulated by HG. In contrast, the protein levels of spermine-N1-acetyltransferase, gp78, Fis1, Drp1, and ß-catenin were up-regulated by HG. Meanwhile, we observed that HG increased ubiquitination levels of Mfn1, Mfn2, and Cx43, decreased membrane potential (ΔΨm), and the opening of mitochondrial permeability transport pore (mPTP) followed by intracellular ATP leakage. The supplement of spermine or siRNA-mediated knockdown of gp78 significantly alleviated the detrimental effects of HG, while downregulation of CaSR aggravated the development of DCM. We further confirmed that the lower level of spermine by HG activates the gp78-ubiquitin-proteasome pathway via downregulation of CaSR protein level, which in turn damages mitochondrial gap junction intercellular communication and leads to reduced ATP level. CONCLUSION: The protective role of spermine on energy metabolism disorder is based on higher CaSR protein level and lower gp78 activation, pointing to the possibility that spermine can be a target for the prevention and treatment of DCM.


Assuntos
Cardiomiopatias Diabéticas/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Espermina/farmacologia , Animais , Técnicas de Cultura de Células , Glucose/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Wistar , Receptores de Detecção de Cálcio/biossíntese , Ubiquitina/metabolismo
19.
Bioorg Chem ; 112: 104968, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34000704

RESUMO

Ibrutinib, a potent irreversible Bruton's tyrosine kinase (BTK) inhibitor, was approved by the FDA for treating mantle cell lymphoma (MCL). Although ibrutinib exhibited excellent antitumor activity, it was associated with certain adverse reactions, with off-target effects against EGFR, Itk and Src family kinases. Our studies yielded a novel series of substituted benzyl pyrrolopyrimidine derivatives capable of potent inhibition of BTK. Compared with ibrutinib, compound 15c exhibited potent BTK inhibitory activity and enhanced antiproliferative activity, a 12-24-fold increase, against MCL cell lines, with IC50 values lower than 1 µM. Low micromolar doses of 15c inhibited the BCR signaling pathway and strongly induced the apoptosis of Z138 cells. Ibrutinib and 15c induced autophagy in a dose-dependent manner in Z138 cells. Moreover, compound 15c induced the production of reactive oxygen species (ROS), which may be a reason for its potent antiproliferative activity. Importantly, compound 15c showed greater BTK selectivity than ibrutinib, indicating a potentially safer treatment of MCL.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenho de Fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma de Célula do Manto/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
20.
Exp Cell Res ; 388(2): 111849, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954110

RESUMO

Diabetic nephropathy (DN) is a major microvascular complication of diabetes that can lead to end-stage renal disease. Podocytes constitute the last barrier of glomerular filtration, whose damage are the direct cause of proteinuria. Dopamine receptors are involved in the regulation of diabetes-induced glomerular hyperfiltration, and only dopamine 1 receptor (D1R) can be amplified in cultured mouse podocytes. However, the exact effect of D1R on diabetic podocytes remains unclear. This study aims to investigate the protective role of D1R activation on diabetic podocytes injury in vivo and vitro as well as its potential mechanism. We observed D1R protective effect respectively in streptozotocin (STZ)-induced type 1 diabetes (T1D) mice as well as mouse podocytes (MPC5) cultured in high glucose (HG, 40 mM) medium. It showed that D1R and podocyte-associated proteins (Podocin, CD2AP and Nephrin) expression were significantly decreased both in the T1D mice (fed for 8 and 12 weeks) and HG-cultured MPC5 cells, while the NOX-5 expression increased. In T1D mice, the levels of 24-h urine protein, serum creatinine and urinary 8-OHdG were increased in a time-dependent manner, at the same time, hematoxylin-eosin (HE) staining and electron microscope observed the kidney lesion and podocytes injury. In vitro, HG induced podocytes oxidative stress and apoptosis, which could be inhibited by SKF38393 (a D1R agonist) and N-acetyl-l-cysteine (NAC, a reactive oxygen species scavenger). Furthermore, there was a decreasing Podocin expression and a significant increasing NOX-5 expression in podocytes transfected with D1R-small interfering RNA (siRNA). More importantly, the expression of phospho-CREB (the PKA downstream transcription factor) was decreased and phospho-p38 MAPK was increased in HG-induced podocytes, which can respectively be activated or blocked by SKF38393, 8-Bromo-CAMP (a PKA activator), NAC, and SB20380 (a p38 MAPK inhibitor). In conclusion, D1R activation can protect diabetic podocytes from apoptosis and oxidative damage, in part through the PKA/NOX-5/p38 MAPK pathway.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 5/metabolismo , Podócitos/metabolismo , Receptores de Dopamina D1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Proteínas Quinases Dependentes de AMP Cíclico/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 5/genética , Podócitos/patologia , Substâncias Protetoras , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/genética , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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