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1.
Appl Opt ; 60(30): 9347-9351, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34807070

RESUMO

At various temperatures, ranging from 25°C to 50°C, we characterized two types of photodetectors based on surface-state absorption in silicon: (1) contactless integrated photonic probes (CLIPPs) and (2) normal-incidence photoconductors. Both types of photodetectors exhibited temperature-dependent AC admittance without illumination. With illumination at telecommunication wavelengths near 1550 nm, in the temperature range we measured, the photoresponse of CLIPPs, i.e., the variance of admittance due to illumination, was relatively insensitive to temperature changes; in comparison, the temperature dependence of the photoresponse of normal-incidence photoconductors was more pronounced-their responsivity increased as temperature raised.

2.
Hypertension ; 78(4): 1027-1038, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34495675

RESUMO

[Figure: see text].

3.
Am J Physiol Renal Physiol ; 320(6): F1025-F1027, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938241
4.
Physiol Rep ; 9(11): e14881, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34057312

RESUMO

INTRODUCTION: (Pro)renin receptor has emerged as a new member of the renin-angiotensin system implicated in the pathogenesis of chronic kidney disease (CKD). Herein we report characterization of the therapeutic potential of (pro)renin receptor (PRR) antagonist PRO20 in 5/6 nephrectomy (5/6Nx) rats. METHODS: Male Wistar rats underwent 5/6Nx followed by treatment with vehicle or received daily injections of a PRR inhibitor PRO20 (700 µg/kg) via the 3 s.c. Sham group served as a control. RESULTS: As compared with the sham control, the 5/6Nx rats exhibited significant increases in proteinuria, glomerulosclerosis, tubular injury, and interstitial inflammation in the remnant kidneys. Treatment with PRO20 significantly attenuated these abnormalities, as evidenced by reduced expression of fibronectin, α-SMA, collagen 1, TGF-ß1, IL-6, IL-8, IL-1ß, MCP-1 and increased expression of E-cadherin. Increased urinary/renal levels of renin activity, angiotensinogen (AGT), and Angiotensin II (Ang II) by 5/6Nx, which were all ameliorated by PRO20. Renal PRR, the secreted proteolytic fragment of PRR (sPRR) in renal and urinary, were all elevated in 5/6Nx rats. Moreover, our results revealed that renal Wnt3A and ß-catenin expression were upregulated during 5/6Nx, which were all attenuated by PRO20. CONCLUSIONS: Overall we conclude that in vivo antagonism of PRR with PRO20 will improve 5/6Nx-induced CKD mainly through inhibition of intrarenal RAS and Wnt/ß-catenin signaling pathway.

6.
Appl Opt ; 60(13): 3591-3595, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33983288

RESUMO

We demonstrate the generation of a type of square-shaped pulse in a passively mode-locked erbium-doped fiber laser based on the nonlinear optical loop mirror technique. Through adjusting the pump power and polarization state, square-shaped pulses are generated. Furthermore, we investigate the pulse profile in relation to the optical spectrum. By filtering out short-wavelength spectrum components gradually, pulse shaping is achieved, and the top of the square-shaped pulse becomes flat. Subsequently, by filtering out long-wavelength spectrum components, a type of h-shaped pulse is obtained and the formation reason is also investigated.

7.
J Am Soc Nephrol ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952630

RESUMO

BACKGROUND: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients. METHODS: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray. RESULTS: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%. CONCLUSIONS: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.

8.
Front Physiol ; 12: 642274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868005

RESUMO

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear ß-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or ß-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.

9.
Ann Palliat Med ; 10(3): 3105-3114, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33752428

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD. METHODS: This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR). RESULTS: Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts. CONCLUSIONS: Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.


Assuntos
Remoção de Componentes Sanguíneos , Neuromielite Óptica , Neurite Óptica , Humanos , Neuromielite Óptica/terapia , Neurite Óptica/terapia , Estudos Retrospectivos
10.
Clin Sci (Lond) ; 135(6): 793-810, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33625485

RESUMO

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.


Assuntos
Hipertensão/fisiopatologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Dieta Hiperlipídica/efeitos adversos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio , Losartan/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade , Sistema Renina-Angiotensina/efeitos dos fármacos
11.
Hypertension ; 77(2): 405-416, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33280408

RESUMO

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/genética , Pró-Proteína Convertases/antagonistas & inibidores , Pirrolidinas/farmacologia , Receptores de Superfície Celular/genética , Animais , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Camundongos , Receptores de Superfície Celular/metabolismo , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Serina Endopeptidases
12.
Lab Chip ; 20(22): 4235-4245, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33057530

RESUMO

Raman activated cell sorting has emerged as a label-free technology that can link phenotypic function with genotypic properties of cells. However, its broad implementation is limited by challenges associated with throughput and the complexity of biological systems. Here, we describe a three-dimensional hydrodynamic focusing microfluidic system for a fully automated, continuous Raman activated cell sorting (3D-RACS). The system consists of a 3D printed detection chamber (1 mm3) that is integrated with a PDMS based sorting unit, optical sensors and an in-line collection module. It has the ability to precisely position cells in the detection chamber for Raman measurements, effectively eliminating spectroscopic interference from the device materials. This enables the sorting of a range of cell sizes (from 1 µm bacteria to 10's µm mammalian cells) with stable operation over >8 hours and high throughput. As a proof-of-concept demonstration, Raman-activated sorting of mixtures of Chlorella vulgaris and E. coli has demonstrated a purity level of 92.0% at a throughput of 310 cells per min. The platform employed in this demonstration features a simple "Raman window" detection system, enabling it to be built on a standard, inverted microscope. Together with its facile and robust operation, it provides a versatile tool for function-based flow cytometry and sorting applications in the fields of microbiology, biotechnology, life science and diagnostics.


Assuntos
Chlorella vulgaris , Microfluídica , Animais , Escherichia coli/genética , Análise de Célula Única , Análise Espectral Raman
13.
Am J Physiol Renal Physiol ; 319(5): F930-F940, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865014

RESUMO

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 µg·kg-1·day-1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.


Assuntos
Nefropatias/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/metabolismo , Angiotensina II/toxicidade , Animais , Anti-Hipertensivos/farmacologia , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/metabolismo , Peróxido de Hidrogênio/metabolismo , Nefropatias/metabolismo , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Substâncias Protetoras/farmacologia , Renina/efeitos dos fármacos , Renina/farmacologia
14.
Am J Physiol Renal Physiol ; 319(5): F941-F953, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865015

RESUMO

Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease. The soluble form of (pro)renin receptor (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, can be detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in the regulation of the fibrotic response in a cultured human renal proximal tubular cell line (HK-2 cells) in the setting of transforming growth factor (TGF)-ß or sPRR-His treatment. The TGF-ß-induced fibrotic response of HK-2 cells was indicated by upregulation of fibronectin (FN) expression; meanwhile, TGF-ß could also induce the generation of sPRR, due to enhanced cleavage of full-length PRR. To explore the role of sPRR in the fibrotic response of HK-2 cells, we blocked the production of sPRR with a the S1P inhibitor PF429242 and found that PF429242 remarkably suppressed TGF-ß-induced sPRR generation and FN expression in HK-2 cells. Administration of sPRR-His restored the PF429242-attenuated FN expression in HK-2 cells, indicating that sPRR could promote the TGF-ß-induced fibrotic response. Furthermore, sPRR-His alone also increased the abundance of FN in HK-2 cells. These data suggested that sPRR was sufficient and necessary for the TGF-ß-induced fibrotic response of HK-2 cells. Mechanistically, sPRR activated the AKT and ß-catenin pathway in HK-2 cells, and blockade of the AKT or ß-catenin pathway significantly abrogated sPRR-induced FN and Snail expression. Taking together, sPRR promoted the fibrotic response of HK-2 cells by activating Akt/ß-catenin/Snail signaling, and it may serve as a potential therapeutic target in renal fibrosis.


Assuntos
Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Humanos , Rim/metabolismo , Receptores de Superfície Celular/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
15.
Am J Physiol Renal Physiol ; 319(4): F647-F653, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799674

RESUMO

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.


Assuntos
Pressão Sanguínea , Ciclo-Oxigenase 2/metabolismo , Acetato de Desoxicorticosterona , Hipertensão/enzimologia , Rim/enzimologia , Receptores de Superfície Celular/metabolismo , Cloreto de Sódio na Dieta , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/enzimologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Proteinúria/induzido quimicamente , Proteinúria/enzimologia , Proteinúria/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais
16.
Sensors (Basel) ; 20(14)2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660043

RESUMO

Ultrafast linear frequency modulated continuous-wave (FMCW) lasers are a special category of CW lasers. The linear FMCW laser is the light source for many sensing applications, especially for light detection and ranging (LiDAR). However, systems for the generation of high quality linear FMCW light are limited and diverse in terms of technical approaches and mechanisms. Due to a lack of characterization methods for linear FMCW lasers, it is difficult to compare and judge the generation systems in the same category. We propose a novel scheme for measuring the mapping relationship between instantaneous frequency and time of a FMCW laser based on a modified coherent optical spectrum analyzer (COSA) and digital signal processing (DSP) method. Our method has the potential to measure the instantaneous frequency of a FMCW laser at an unlimited sweep rate. In this paper, we demonstrate how to use this new method to precisely measure a FMCW laser at a large fast sweep rate of 5000 THz/s by both simulation and experiments. We find experimentally that the uncertainty of this method is less than 100 kHz and can be improved further if a frequency feedback servo system is introduced to stabilize the local CW laser.

17.
Drug Des Devel Ther ; 14: 2413-2422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606608

RESUMO

Purpose: Acute myeloid leukemia (AML) is a complex malignancy characterized by the clonal expansion of immature myeloid precursors. The standard treatment for newly diagnosed AML is chemotherapy consisting of cytosine arabinoside (Ara-C) and anthracyclines with disappointing clinical outcomes and severe adverse effects, such as symptomatic bradycardia, neurotoxicity. Thus, it is promising to treat AML through combination drug therapy to reduce the adverse effects of chemotherapeutics. In our recent published PNAS paper, we reported that NK-1R antagonists, both Aprepitant and SR140333, induce apoptosis of myeloid leukemia cells by inducing oxidative stress through mitochondrial calcium overload. We, therefore, tested the hypothesis of the combination Ara-C with NK-1R antagonist could enhance the efficacy of Ara-C. Methods: MTT assay was employed to detect the cell proliferation. Flow cytometry was applied to detect the cell cycle and necrosis. PI uptake and LDH release assay were used to detect the disintegration of the plasma membrane. Xenograft model was constructed to explore the effect of combination Ara-C with Aprepitant in vivo. Results: Our results showed that Aprepitant sensitizes HL60 cells to the cytotoxic effects of Ara-C more than 5-fold by enhancing G0/G1 cell cycle arrest and necrosis in vitro. Furthermore, Nec-1, a specific inhibitor of necroptosis, could recover the cell proliferative viability significantly. Attractively, once every 2-days regimen of Ara-C (5 mg/kg) and Aprepitant (10 mg/kg) via in situ injection dramatically reduced the tumor volume from 2175.0 ± 341.9 mm3 in the vehicle group to 828.4 ± 232.4 mm3 in the combination group without obvious toxicity in human myeloid leukemia xenograft mice. Conclusion: Taken together, reduced dose of Ara-C combination with moderate Aprepitant provides more effective therapeutical methods for AML treatment in vitro and in vivo with the elimination of the toxicity of Ara-C, which may pay new avenue for the usage of the routine chemotherapy drug Ara-C with low dose to enhance efficacy and reduce toxicity in clinical practice.


Assuntos
Antineoplásicos/farmacologia , Aprepitanto/farmacologia , Citarabina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citarabina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia
18.
J Clin Apher ; 35(3): 206-216, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32240559

RESUMO

INTRODUCTION: Neuromyelitis optica (NMO) is an autoimmune disease with a high rate of blindness and positive for the detection of aquaporin-4 antibody (AQP4) in most patients. NMO acute attacks are managed by high-doses of intravenous methylprednisolone followed by oral taper, and if symptoms fail to resolve, therapeutic plasma exchange (TPE) is added. TPE can remove pathological antibodies and inflammatory factors leading to clinical improvement. METHODS: A total of 40 TPE fluid collections from the first to fifth TPE treatments were obtained from eight patients. Exosomes were isolated by ultracentrifugation. Mass spectrometry analyses were used to compare protein change in TPE fluid collection exosomes after the first to the fifth TPE treatments in these patients. RESULTS: We detected 647 exosome proteins through data-independent acquisition analysis. It was found that some unknown functional antibody fragments and complement pathway proteins decreased after TPE treatment. The results revealed a significant involvement of the following two key pathways: the primary immunodeficiency and systemic lupus erythematosus that may be associated with NMO pathophysiology and TPE treatment efficacy (P < .05). A series of complement proteins may contribute to NMO; in addition, the following proteins increased with plasma exchange: complement factor H-related protein 5, bridging integrator 2, neuroplastin, pigment epithelium-derived factor, ficolin-1, extracellular matrix protein 1, and fatty acid-binding protein 5. CONCLUSION: Our study may provide a new perspective on the pathogenesis and treatment efficacy of NMO.


Assuntos
Aquaporina 4/imunologia , Exossomos/patologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/terapia , Troca Plasmática/efeitos adversos , Adulto , Autoanticorpos/imunologia , Biologia Computacional , Feminino , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Plasmaferese/efeitos adversos , Doenças da Imunodeficiência Primária/imunologia , Ultracentrifugação
19.
JCI Insight ; 5(7)2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32271168

RESUMO

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.


Assuntos
Adipócitos/metabolismo , Gorduras na Dieta/efeitos adversos , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Adipócitos/patologia , Animais , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Masculino , Síndrome Metabólica/induzido quimicamente , Camundongos , Obesidade/induzido quimicamente , Obesidade/genética , PPAR gama/genética , Receptores de Superfície Celular/genética
20.
Am J Physiol Renal Physiol ; 318(5): F1122-F1135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174138

RESUMO

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na+ and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). Apelin was also found in the medullary CDs as assessed by immunofluorescence. In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of full-length PRR (fPRR), soluble PRR (sPRR), and prorenin/renin protein expression as assessed by immunoblotting and medium sPRR and prorenin/renin levels by ELISA, all of which were reversed by 8-bromoadenosine 3',5'-cyclic monophosphate. Conversely, deletion of PRR in the CD or nephron in mice elevated Apela and Apln mRNA levels as well as urinary ELA and apelin excretion, supporting the antagonistic relationship between the two systems. Administration of exogenous ELA-32 infusion (1.5 mg·kg-1·day-1, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure, systolic blood pressure, diastolic blood pressure, and albuminuria, accompanied with a reduction of urinary sPRR, angiotensin II, and prorenin/renin excretion. HS upregulated renal medullary protein expression of fPRR, sPRR, prorenin, and renin in Dahl SS rats, all of which were significantly blunted by exogenous ELA-32 infusion. Additionally, HS-induced upregulation of inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-17A, IFN-γ, VCAM-1, ICAM-1, and MCP-1), fibrosis markers (TGF-ß1, FN, Col1A1, PAI-1, and TIMP-1), and kidney injury markers (NGAL, Kim-1, albuminuria, and urinary NGAL excretion) were markedly blocked by exogenous ELA infusion. Together, these results support the antagonistic interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.


Assuntos
Pressão Sanguínea , Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Hormônios Peptídicos/metabolismo , Sistema Renina-Angiotensina , Animais , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Nefropatias/prevenção & controle , Masculino , Camundongos Knockout , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/genética , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Ratos Endogâmicos Dahl , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais
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