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1.
Korean J Intern Med ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33430574

RESUMO

Background/Aims: Coenzyme Q10 (CoQ10), is a promising antioxidant; however, low bioavailability owing to lipid-solubility is a limiting factor. We developed water-soluble CoQ10 (CoQ10-W) and compared its effects with conventional lipid-soluble CoQ10 (CoQ10-L) in an experimental model of chronic tacrolimus (Tac) nephropathy. Methods: CoQ10-W was developed from a glycyrrhizic-carnitine mixed layer CoQ10 micelle based on acyltransferases. Chronic nephropathy was induced in rats with 28-day Tac treatment; they were concomitantly treated with CoQ10-L or CoQ10-W. CoQ10 level in plasma and kidney were measured using liquid chromatography-mass spectrometry. CoQ10-W and CoQ10-L effects on Tac-induced nephropathy were assessed in terms of renal function, histopathology, oxidative stress, and apoptotic cell death. Their effects on cell viability and reactive oxygen species (ROS) production were assessed in cultured proximal tubular cells, human kidney 2 (HK-2) cells. Results: The plasma CoQ10 level was significantly higher in the CoQ10-W group than in the CoQ10-L group. Tac treatment caused renal dysfunction, typical pathologic lesions, and oxidative stress markers. Serum creatinine was restored in the Tac + CoQ10-L or CoQ10-W groups compared with that in the Tac group. CoQ10-W administration reduced oxidative stress and apoptosis markers. Mitochondrial ultrastructure assessment revealed that the addition of CoQ10-L or CoQ10-W with Tac increased mitochondrial size and number than Tac treatment alone. In vitro investigations revealed that both CoQ10-L and CoQ10-W improved cell viability and reduced ROS production in the Tac-induced HK-2 cell injury. Conclusions: CoQ10-W has a better therapeutic effect in Tac-induced renal injury than conventional CoQ10-L, possibly associated with improved CoQ10 bioavailability.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33238597

RESUMO

We measured the health resource agglomeration capacities of 31 Chinese provinces (or municipalities) in 2004-2018 based on the entropy weight method. Using a modified spatial gravity model, we constructed and analyzed the spatial correlation network of these health resource agglomeration capacities and their influencing factors through social network analysis. We found that: (i) China's health resource agglomeration capacity had a gradual strengthening trend, with capacity weakening from east to west (strongest in the eastern region, second strongest in the central region, and weakest in the western region). (ii) The spatial network of such capacities became more densely connected, and the network density and level (efficiency) showed an upward (downward) trend. (iii) In terms of centrality, the high-ranking provinces (or municipalities) were Beijing, Shanghai, Jiangsu, Zhejiang, Guangdong, Shandong, Hunan, Hubei, Fujian, Anhui, Jiangxi, and Tianjin, while the low-ranking were Tibet, Qinghai, Gansu, Ningxia, Inner Mongolia, Heilongjiang, Yunnan, Guizhou, Xinjiang, Hainan, Shaanxi, and Shanxi. (iv) Block 1 (eight provinces or municipalities), including Beijing, Tianjin, and Hebei, had a "net spillover" effect in the spatial network of health resource agglomeration capacities; Block 2, (seven provinces or municipalities), including Shanghai, Jiangsu, and Zhejiang, had a "bidirectional spillover" effect in the spatial network; Block 3 (seven provinces or municipalities), including Anhui, Hubei, and Hunan, had a "mediator" effect in the network; and Block 4, (nine provinces or municipalities), including Sichuan, Guizhou, and Tibet, had a "net beneficial" effect in the network. (v) The economic development, urbanization wage, and financial health expenditure levels, and population size had significant positive correlations with the spatial network of health resource agglomeration capacities. Policy recommendations to enhance the radiating role of health resources in core provinces (or municipalities), rationally allocate health resources, and transform ideas to support public health resource services were provided.

4.
Environ Pollut ; : 115867, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33160734

RESUMO

Litterfall mercury (Hg) deposition is the dominant source of soil Hg in forests. Identifying reduction processes and tracking the fate of legacy Hg on forest floor are challenging tasks. Interplays between isotopes of carbon (C) and nitrogen (N) may shed some lights on Hg biogeochemical processes because their biogeochemical cycling closely links with organic matters. Isotope measurements at the evergreen broadleaf forest floor at Mt. Ailao (Mountain Ailao) display that δ202Hg and Δ199Hg both significantly correlate with δ13C and δ15N in soil profiles. Data analysis results show that microbial reduction is the dominant process for the distinct δ202Hg shift (up to ∼1.0‰) between Oi and 0-10 cm surface mineral soil, and dark abiotic organic matter reduction is the main cause for the Δ199Hg shift (∼-0.18‰). Higher N in foliage leads to greater Hg concentration, and Hg0 re-emission via microbial reduction on forest floor is likely linked to N release and immobilization on forest floor. We thus suggest that the enhanced N deposition in global forest ecosystems can potentially influence Hg uptake by vegetation and litter Hg sequestration on forest floor.

5.
Spectrochim Acta A Mol Biomol Spectrosc ; 240: 118563, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32554262

RESUMO

Iron disulfide (FeS2) quantum dots have potential applications in various fields such as photocatalysis, lithium-ion batteries and bioimaging. At present, there is no report on the fluorescent characteristics of FeS2 quantum dots (FeS2 QDs). In this work, a synthesis of multiple-color emission FeS2 QDs by changing the temperature, time and raw ratio has been reported. The blue, green, yellow and red emission FeS2 QDs can be obtained, respectively. They were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and transmission electron microscope (TEM). On this basis, a novel molecular imprinting ratiometric fluorescence sensor (MIR sensor) had been constructed, in which the blue-emission FeS2 QDs (b-FeS2 QDs) was used as a fluorescent responsive signal material and the yellow-emission FeS2 QDs (y-FeS2 QDs) was served as a reference signal material. And this MIR sensor was applied for highly selective and sensitive detection of ACO in traditional Chinese medicine (TCM). Under the optimum conditions, the MIR sensor exhibited an excellent linear relationship between the fluorescence intensity ratio (I443/I590) and the concentration of ACO in the range of 0.05-5.0 µM with a detection limit of 24 nM. Furthermore, the established method was successfully utilized to the detection of ACO in TCM Fuzi Lizhong Pills with satisfactory results. It provided a reference for the application of the FeS2 QDs with multiple color emission and the detection of the hazardous alkaloids.

6.
Anal Chim Acta ; 1124: 113-120, 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32534663

RESUMO

Calcium fluoride (CaF2) quantum dots have many applications in various fields. But there is no report on fluorescent characteristics of CaF2 quantum dots (CaF2 QDs). Here, a synthesis of multiple-color emission CaF2 QDs by changing the temperature, time and raw ratio is reported, by which the CaF2 QDs with purple, blue, green, and yellow emission can be obtained, respectively. They were characterized by X-ray diffraction (XRD) and transmission electron microscope (TEM). On this basis, a novel molecular imprinting ratiometric fluorescence sensor (MIR sensor) had been constructed based on the prepared CaF2 QDs and CdTe QDs, in which the yellow emission CaF2 QDs was used as a responsive signal material and the red emission CdTe QDs was served as a reference signal material. And the ß-CD and methylacrylic acid (MAA) as bifunctional monomers were used for constructing the specific molecularly imprinted polymers (MIPs) in MIR sensor. This MIR sensor was applied for highly selective and excellent sensitive detection of 5-hydroxymethylfurfural (HMF). Under optimum conditions, it exhibited an excellent linear relationship between the fluorescence intensity ratio (I599/I625) and the concentration of HMF in the range of 0.1-6.0 µg/mL with a detection limit of 0.043 µg/mL. Finally, the established HMF-MIR sensor was successfully utilized to detect HMF in honey with satisfactory results. This work provided a reference for the application of the CaF2 QDs and the detection of the furfural substances.

7.
J Ginseng Res ; 44(3): 399-404, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32372861

RESUMO

Korean ginseng (Panax ginseng) is associated with a variety of therapeutic effects, including antioxidative, anti-inflammatory, vasorelaxative, antiallergic, antidiabetic, and anticancer effects. Accordingly, the use of ginseng has reached an all-time high among members of the general public. However, the safety and efficacy of ginseng in transplant recipients receiving immunosuppressant drugs have still not been elucidated. Transplantation is the most challenging and complex of surgical procedures and may require causation for the use of ginseng. In this regard, we have previously examined the safety, immunological benefits, and protective mechanisms of ginseng with respect to calcineurin inhibitor-based immunosuppression, which is the most widely used regimen in organ transplantation. Using an experimental model of calcineurin inhibitor-induced organ injury, we found that ginseng does not affect drug levels in the peripheral blood and tissue, favorably regulates immune response, and protects against calcineurin inhibitor-induced nephrotoxicity and pancreatic islet injury. On the basis of our experimental studies and a review of the related literature, we propose that ginseng may provide benefits in organ transplant recipients administered calcineurin inhibitors. Through the present review, we aimed to briefly discuss our current understanding of the therapeutic benefits of ginseng related to transplant patient survival.

8.
Acta Pharmacol Sin ; 41(12): 1597-1608, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32300244

RESUMO

Tissue kallikrein has protective function against various types of injury. In this study, we investigated whether exogenous pancreatic kininogenase (PK) conferred renoprotection in a rat model of unilateral ureteral obstruction (UUO) and H2O2-treated HK-2 cells in vitro. SD rats were subjected to UUO surgery, then PK (7.2 U/g per day, ip) was administered for 7 or 14 days. After the treatment, rats were euthanized; the obstructed kidneys were harvested for further examination. We found that PK administration significantly attenuated interstitial inflammation and fibrosis, and downregulated the expression of proinflammatory (MCP-1, TLR-2, and OPN) and profibrotic (TGF-ß1 and CTGF) cytokines in obstructed kidney. UUO-induced oxidative stress, closely associated with excessive apoptotic cell death and autophagy via PI3K/AKT/FoxO1a signaling, which were abolished by PK administration. We further showed that PK administration increased the expression of bradykinin receptors 1 and 2 (B1R and B2R) mRNA and the production of NO and cAMP in kidney tissues. Coadministration with either B1R antagonist (des-Arg9-[Leu8]-bradykinin) or B2R antagonist (icatibant) abrogated the renoprotective effects of PK, and reduced the levels of NO and cAMP in obstructed kidney. In H2O2-treated HK-2 cells, addition of PK (6 pg/mL) significantly decreased ROS production, regulated the expression of oxidant and antioxidant enzymes, suppressed the expression of TGF-ß1 and MCP-1, and inhibited cell apoptosis. Our data demonstrate that PK treatment protects against the progression of renal fibrosis in obstructed kidneys.

9.
Korean J Intern Med ; 35(6): 1443-1456, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32279476

RESUMO

BACKGROUND/AIMS: Coenzyme Q10 (CoQ10) has antioxidant effects and is commercially available and marketed extensively. However, due to its low bioavailability, its effects are still controversial. We developed a water-soluble CoQ10-based micelle formulation (CoQ10-W) and tested it in an experimental model of tacrolimus (TAC)-induced diabetes mellitus (DM). METHODS: We developed CoQ10-W from a glycyrrhizic-carnitine mixed layer CoQ10 micelle preparation based on acyltransferases. TAC-induced DM rats were treated with either lipid-soluble CoQ10 (CoQ10-L) or CoQ10-W for 4 weeks. Their plasma and pancreatic CoQ10 concentrations were measured using liquid chromatography- tandem mass spectrometry. The therapeutic efficacies of CoQ10-W and CoQ10-L on TAC-induced DM were compared using functional and morphological parameters and their effects on cell viability and reactive oxygen species (ROS) production were also evaluated in cultured rat insulinoma cells. RESULTS: The plasma CoQ10 level was significantly increased in the CoQ10-W group compared to that in the CoQ10-L group. Intraperitoneal glucose tolerance tests and glucose-stimulated insulin secretion revealed that CoQ10-W controlled hyperglycemia and restored insulin secretion significantly better than CoQ10-L. The TAC-mediated decrease in pancreatic islet size was significantly attenuated by CoQ10-W but not by CoQ10-L. TAC-induced oxidative stress and apoptosis were significantly more reduced by CoQ10-W than CoQ10-L. Electron microscopy revealed that CoQ10-W restored TAC-induced attenuation in the number of insulin granules and the average mitochondrial area, unlike CoQ10-L. In vitro studies showed that CoQ10-L and CoQ10-W both improved cell viability and reduced ROS production in TAC-treated islet cells to a similar extent. CONCLUSION: CoQ10-W has better therapeutic efficacy than CoQ10-L in TAC-induced DM.

10.
Korean J Intern Med ; 35(2): 400-407, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31739654

RESUMO

BACKGROUND/AIMS: It is undetermined if herbal medicines (HM) containing aristolochic acid (AA)-containing have similar nephrotoxicity to AA itself. METHODS: We administered HM containing a high concentration of AA for 5 days (short-term study) or a low concentration of AA for 30 days (long-term study) to C57BL/6 mice; for comparison, same dose of AA compound was used as controls. RESULTS: The nephrotoxicity in the HM- and AA-treated mice was compared in terms of renal function, histopathology, oxidative stress, apoptotic cell death, and mitochondrial damage. Short-term HM treatment resulted in acute kidney injury (marked renal dysfunction, acute tubular necrosis, and neutrophil gelatinase-associated lipocalin [NGAL] expression) in which the severity of renal dysfunction and histopathology was comparable with that induced by the administration of AA alone. Long-term HM treatment resulted in features of chronic kidney disease (CKD, mild renal dysfunction and tubular atrophy and dilatation). No significant differences in these parameters were observed between the HM- and AA-treated mice. HM-induced oxidative stress (8-hydroxy-2'-deoxyguanosine and manganese- dependent superoxide dismutase expression) and apoptotic cell death (terminal deoxynucleotidyl transferase dUTP nick end labelling [TUNEL]-positive cells and active caspase-3 expression) were similar in HM- and AA-treated mice in the short-term and long-term studies. Mitochondrial injury, evaluated by electron microscopy, was also similar in HM- and AA-treated mice in the short-term and long-term studies. CONCLUSION: The nephrotoxic potential of HM containing AA was similar to that of AA itself.

11.
Oxid Med Cell Longev ; 2019: 1825018, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772699

RESUMO

Calcineurin inhibitors (CNIs) are the most popular immunosuppressants in organ transplantation, but nephrotoxicity is a major concern. The common mechanism underlying chronic CNI nephropathy is oxidative stress, and the process of chronic CNI nephropathy is similar to that of aging. Current studies provide evidence that antiaging Klotho protein plays an important role in protecting against oxidative stress, and its signaling is a target for preventing oxidative stress-induced aging process. In this review, we focus on the association between Klotho and oxidative stress and the protective mechanism of action of Klotho against oxidative stress in chronic CNI nephropathy. In addition, we discuss the delivery strategy for Klotho in CNI-induced nephropathy.


Assuntos
Inibidores de Calcineurina/efeitos adversos , Glucuronidase/efeitos adversos , Falência Renal Crônica/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
12.
Artigo em Inglês | MEDLINE | ID: mdl-31757034

RESUMO

This paper estimated and evaluated the spatial-temporal evolution of the concentration of healthcare resources (HCRs), in 31 provinces in China between 2004 and 2017, by using the entropy method. The spatial Durbin model (SDM) was used to further analyze the mechanisms behind the spatial driving forces at the national and regional levels. The findings revealed that: (i) The concentration of HCRs differed significantly among eastern, central, and western regions. The eastern, followed by the central region, had the highest concentration. Going east to west, the concentration of HCRs in the first echelon decreased, while it increased in the second and third echelons; (ii) places with higher concentrations clustered, while those with lower concentrations agglomerated; and (iii) economic development, population size, and urbanization promoted concentration. Education facilitated HCR concentration in the eastern and central regions, income stimulated HCR concentration in the eastern and western regions, and fiscal expenditure on healthcare promoted HCR concentration in the eastern region. Economic development inhibited HCR concentration in neighboring regions, population size restrained HCR concentration in neighboring areas in the western region, urbanization and income curbed HCR concentration in neighboring areas in the eastern and western regions, and fiscal expenditure on healthcare hindered HCR concentration in neighboring areas in the eastern region. Policy recommendations were proposed toward optimizing allocation of healthcare resources, increasing support for healthcare and education, and accelerating urbanization.


Assuntos
Recursos em Saúde/estatística & dados numéricos , Análise Espaço-Temporal , China , Países em Desenvolvimento , Desenvolvimento Econômico , Escolaridade , Política de Saúde , Humanos , Renda , Modelos Teóricos , Saúde da População Rural , Saúde da População Urbana , Urbanização
13.
Phys Rev E ; 100(1-1): 013306, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31499901

RESUMO

Melting in the presence of electrohydrodynamic (EHD) flow driven by the Coulomb force in dielectric phase change material is numerically studied. A model is developed for the EHD flow in the solid-liquid phase change process. The fully coupled equations including mechanical equations, electrical equations, energy equations, and the continuity equations in the solid-liquid interface are solved using a unified lattice Boltzmann model (LBM). Firstly, the numerical model is validated by several cases in the hydrostatic state, and all LBM results are found to be highly consistent with analytical solutions. Besides, our LBM code is able to reproduce the step changes in the distribution of charge density and electric field due to the discontinuous distribution of physical properties at the interface. Then, a systematical investigation is conducted on various nondimensional parameters, including electric Rayleigh number T, Prandtl number Pr, and Stefan number St. Results are presented for the transient evolutions of temperature, fluid flow, charge density fields, and liquid fraction. Four flow stages in the melting process together with three kinds of flow instabilities are observed. It is found that the electric field has significant influence on the melting, especially at high T and Pr and low St. Over the tested cases, a maximum melting time saving of around 50% is found.

14.
Aging (Albany NY) ; 11(15): 5548-5569, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400753

RESUMO

The antioxidant function of Klotho is well-documented as a regulatory factor implicated in countering the aging process. This study investigated whether ginseng upregulates Klotho and its antiaging signaling in a setting of calcineurin inhibitor-induced oxidative stress. Although tacrolimus treatment reduced Klotho level in the serum and kidney, ginseng treatment was found to reverse the levels. Tacrolimus-induced oxidative stress was reduced by ginseng treatment, with functional and histological improvements. Effect of ginseng on Klotho-induced manganese superoxide dismutase signaling pathway during tacrolimus treatment in mice revealed that ginseng suppressed phosphatidylinositol 3-kinase/serine-threonine kinase Akt-mediated phosphorylation of forkhead box protein O3a and promoted the binding of forkhead box protein O3a to manganese superoxide dismutase promoter. In the mitochondria, ginseng reduced mitochondrial reactive oxygen species production, mitochondrial membrane potential, and oxygen consumption rate, whereas blocking phosphatidylinositol 3-kinase activity with LY294002 enhanced them. These findings together suggested that ginseng attenuated tacrolimus-induced oxidative stress via signaling between Klotho and the phosphatidylinositol 3-kinase/serine-threonine kinase Akt/forkhead box protein O3a-related antioxidant pathway.


Assuntos
Proteína Forkhead Box O3/metabolismo , Glucuronidase/metabolismo , Panax , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Superóxido Dismutase/metabolismo , Tacrolimo/efeitos adversos , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Antioxidantes/metabolismo , Inibidores de Calcineurina/efeitos adversos , Linhagem Celular , Modelos Animais de Doenças , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fitoterapia , Insuficiência Renal Crônica/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética
15.
FASEB J ; 33(11): 12288-12298, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31431058

RESUMO

The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ10 reduced the production of Tac-induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ10 decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ10 treatment. The effect of the CoQ10 in vitro study was observed in an experimental model of chronic Tac-induced nephropathy. CoQ10 attenuated Tac-induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ10 increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ10 improves Tac-induced mitochondrial dysfunction in kidney. Supplementary CoQ10 treatment may be a promising approach to reduce Tac-induced nephrotoxicity.-Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.


Assuntos
Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Tacrolimo/toxicidade , Ubiquinona/análogos & derivados , Apoptose/efeitos dos fármacos , Células Cultivadas , Humanos , Rim/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologia
16.
FASEB J ; 33(10): 10889-10901, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31266358

RESUMO

Synthetic biologic drugs are highly successful for induction therapy in transplantation, but the development of novel biologics is limited because of the high cost of synthesis and purification. In this study, we developed a novel strategy for the production of synthetic protein drugs in vivo by the host itself. We utilized minicircle (MC) technology, which can robustly express a target molecule and secrete it from cells, as an indirect method to produce a protein of interest in vivo. We designed an MC vector containing the sequences of basiliximab (anti-CD25 mAb) and IL-10. We verified the substantial production of the anti-CD25/IL-10 protein from the MC in vitro and in vivo. The therapeutic effect of MC-derived anti-CD25/IL-10 was evaluated in a skin allograft mouse model by single intravenous infusion. Mice treated with the MC encoding anti-CD25/IL-10 exhibited prolonged skin allograft survival times accompanied by improved histologic changes and immunologic regulation. These findings indicate that the anti-CD25/IL-10 protein drug obtained by MC technology is functionally active and relevant for reducing allograft rejection. This self-reproducible strategy for synthetic protein drugs using MCs is a promising tool for transplantation.-Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Host cell in vivo production of the synthetic drug anti-CD25/IL-10 using minicircle vector.


Assuntos
Vetores Genéticos/genética , Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Plasmídeos/genética , Animais , Vetores Genéticos/metabolismo , Rejeição de Enxerto/tratamento farmacológico , Células HEK293 , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Injeções Intravenosas , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos/metabolismo , Transplante de Pele/efeitos adversos , Medicamentos Sintéticos/administração & dosagem , Medicamentos Sintéticos/uso terapêutico
17.
BMC Nephrol ; 20(1): 221, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200653

RESUMO

BACKGROUND: Cilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protective effects of CL against chronic TAC-induced nephropathy. METHODS: Chronic nephropathy was induced by administering TAC (1.5 mg/kg/ day, subcutaneous injection) to rats on a low-salt diet for 4 weeks. CL (75 or 150 mg/kg/day, intraperitoneal injection) was concomitantly treated with TAC. Human proximal tubular cells were exposed to TAC (50 µg/mL) with or without CL (250 µg/mL). We investigated the effects of CL on TAC-induced injury in terms of renal function, tubulointerstitial fibrosis, and inflammation. The effects of CL on oxidative stress and apoptosis were evaluated in both in vivo and in vitro models of TAC nephrotoxicity. RESULTS: CL treatment improved TAC-induced renal dysfunction and decreased renal interstitial fibrosis (reduced expression of e-cadherin and TGFß-1) and interstitial inflammation (decreased infiltration of ED-1-positive and osteopontin-positive cells). Compared to TAC treatment alone, CL co-treatment reduced oxidative stress (serum 8-OHdG level and immunoreactivity of 8-OHdG and 4-HHE in renal tissue) and increased renal expression of anti-oxidant enzyme, manganese superoxide dismutase. CL treatment decreased apoptotic cell death (decreased TUNEL-positive cells and reduced expression of active caspase-3) in TAC-treated kidney. In vitro CL treatment prevented tubular cell death from TAC treatment and decreased number of annexin V-positive cells were observed in cilastatin-cotreated cells. CONCLUSION: CL has protective effects against chronic TAC-induced nephrotoxicity owing to its anti-oxidative and anti-apoptotic properties.


Assuntos
Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Apoptose/efeitos dos fármacos , Cilastatina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Tacrolimo/toxicidade , Lesão Renal Aguda/induzido quimicamente , Animais , Apoptose/fisiologia , Cilastatina/farmacologia , Humanos , Imunossupressores/toxicidade , Masculino , Estresse Oxidativo/fisiologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
18.
Neurotox Res ; 36(2): 396-410, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201731

RESUMO

The neurotoxicity of immunosuppressive agents and diabetes mellitus are known risk factors of neurological complications in kidney transplant recipients. The aim of the present study was to investigate the influence of tacrolimus on brain-derived neurotrophic factor (BDNF), the critical protein for maintenance of neuronal functions, in the hippocampus in a diabetic condition. A diabetic rat model was established by a single streptozotocin injection (60 mg/kg). Control and diabetic rats then received daily tacrolimus (1.5 mg/kg per day) injections for 6 weeks. BDNF expression in the hippocampus was examined in the dentate gyrus (DG) and CA3 region using immunohistochemistry. There was a significant decrease of BDNF expression in the DG and CA3 region in tacrolimus-treated and diabetic rats compared with that of the control group injected with vehicle only. However, there was no difference in BDNF expression between the two experimental groups. Tacrolimus treatment in diabetic rats further decreased the BDNF expression level in the DG and CA3 region. Interestingly, mossy fiber sprouting, demonstrated by prominent punctate immunolabeling of BDNF with synaptoporin, was observed in the diabetic group treated with tacrolimus, which localized at the stratum oriens of the CA3 region. These data suggest that tacrolimus treatment or a diabetic condition decreases BDNF expression in the hippocampus, and that tacrolimus treatment in the diabetic condition further injures the CA3 region of the hippocampus. In addition to BDNF expression, decreased locomotor activity and evident depressive behavior were observed in tacrolimus-treated diabetic rats. Moreover, there were significant decreases of the mRNA levels of γ-aminobutyric acid and serotonin receptors in the diabetic hippocampus with tacrolimus treatment. This finding suggests that tacrolimus treatment may cause further psychiatric and neurological complications for patients with diabetes, and should thus be used with caution.


Assuntos
Depressão/induzido quimicamente , Depressão/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipocampo/metabolismo , Imunossupressores/toxicidade , Tacrolimo/toxicidade , Animais , Fator Neurotrófico Derivado do Encéfalo , Depressão/patologia , Diabetes Mellitus Experimental/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Ratos , Ratos Sprague-Dawley
19.
Sci Rep ; 9(1): 7995, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142763

RESUMO

We previously reported that oxidative stress induced by long-term tacrolimus treatment impairs mitochondrial function in pancreatic beta cells. In this study, we aimed to investigate the therapeutic potential of coenzyme Q10, which is known to be a powerful antioxidant, in mitochondrial dysfunction in tacrolimus-induced diabetic rats. In a rat model of tacrolimus-induced diabetes mellitus, coenzyme Q10 treatment improved pancreatic beta cell function. The administration of coenzyme Q10 improved insulin immunoreactivity within islets, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that coenzyme Q10 treatment increased the size, number, and volume of mitochondria, as well as the number of insulin granules compared with that induced by tacrolimus treatment alone. An in vitro study using a pancreatic beta cell line showed that tacrolimus treatment increased apoptosis and the production of mitochondrial reactive oxygen species, while cotreatment with coenzyme Q10 effectively attenuated these alterations. At the subcellular level, tacrolimus-induced impairment of mitochondrial respiration was significantly improved by coenzyme Q10, as evidenced by the increased mitochondrial oxygen consumption and ATP production. Our data indicate that coenzyme Q10 plays an important role in reducing tacrolimus-induced oxidative stress and protects the mitochondria in pancreatic beta cells. These findings suggest that supplementation with coenzyme Q10 has beneficial effects in tacrolimus-induced diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Tacrolimo/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/genética , Ubiquinona/farmacologia
20.
Am J Nephrol ; 49(5): 413-424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30982029

RESUMO

BACKGROUND: Klotho treatment is a promising approach against kidney injury, but its clinical application is still undetermined. We developed a novel strategy to allow self-production of Klotho protein, using minicircle (MC) technology, and evaluated its feasibility in therapeutic Klotho delivery. METHODS: We engineered MC vectors to carry cassette sequences of Klotho and verified the self-production of Klotho protein from in HEK293T cells. We evaluated the location and persistence of delivered MC in vivo, and the duration of Klotho protein production from MCs by serial measurement of Klotho protein in blood. We subsequently evaluated the therapeutic potential of Klotho-encoding MCs in experimental model of renal injury. RESULTS: We confirmed the production of Klotho from MC by its significant availability in cells transfected with the MC, as well as in its conditioned medium, compared to that in cells transfected with parent vector. MCs were delivered in vivo by hydrodynamic injection via tail vein. After a single injection of MCs, red fluorescence protein was detected until 30 days in liver, and Klotho protein was maintained until 10 days in the blood, suggesting the production of Klotho protein from MCs via protein synthesis machinery in liver. Therapeutic effect of MC was confirmed by functional and histological improvement seen in mouse model of acute ischemia-reperfusion injury and unilateral ureteral obstruction. CONCLUSION: Together, these findings implied that self-generated Klotho protein, using MC technology, is functionally active and relevant as a therapeutic approach in renal injury.


Assuntos
Lesão Renal Aguda/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Glucuronidase/genética , Plasmídeos/administração & dosagem , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Estudos de Viabilidade , Vetores Genéticos/genética , Glucuronidase/administração & dosagem , Células HEK293 , Humanos , Microscopia Intravital , Rim/irrigação sanguínea , Rim/patologia , Masculino , Camundongos , Microscopia de Fluorescência , Plasmídeos/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Transfecção
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