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1.
Anticancer Res ; 41(9): 4443-4446, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475067

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued. PATIENTS AND METHODS: Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed. RESULTS: A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p<0.0001). The eGFR decreased with the duration of ADT treatment. At 12 months, renal function had started to recover in group 1, while it had continued to decrease in group 2. CONCLUSION: Discontinuation of ADT tended to result in improvements in renal function. Furthermore, this study indicated that renal dysfunction caused by 6 months of ADT is transient. Normalization of the serum testosterone level seen after the discontinuation of ADT may be associated with improvements in renal function. Thus, intermittent ADT may be a useful treatment for PCa, as it would help to preserve renal function.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiopatologia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Humanos , Japão , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Testosterona/sangue , Fatores de Tempo , Suspensão de Tratamento
2.
BMC Nephrol ; 22(1): 297, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465289

RESUMO

BACKGROUND: Kidney disease and renal failure are associated with hospital deaths in patients with COVID - 19. We aimed to test if contrast enhancement affects short-term renal function in hospitalized COVID - 19 patients. METHODS: Plasma creatinine (P-creatinine) was measured on the day of computed tomography (CT) and 24 h, 48 h, and 4-10 days after CT. Contrast-enhanced (n = 142) and unenhanced (n = 24) groups were subdivided, based on estimated glomerular filtration rates (eGFR), > 60 and ≤ 60 ml/min/1.73 m2. Contrast-induced acute renal failure (CI-AKI) was defined as ≥27 µmol/L increase or a > 50% rise in P-creatinine from CT or initiation of renal replacement therapy during follow-up. Patients with renal replacement therapy were studied separately. We evaluated factors associated with a > 50% rise in P-creatinine at 48 h and at 4-10 days after contrast-enhanced CT. RESULTS: Median P-creatinine at 24-48 h and days 4-10 post-CT in patients with eGFR> 60 and eGFR≥30-60 in contrast-enhanced and unenhanced groups did not differ from basal values. CI-AKI was observed at 48 h and at 4-10 days post contrast administration in 24 and 36% (n = 5/14) of patients with eGFR≥30-60. Corresponding figures in the eGFR> 60 contrast-enhanced CT group were 5 and 5% respectively, (p < 0.037 and p < 0.001, Pearson χ2 test). In the former group, four of the five patients died within 30 days. Odds ratio analysis showed that an eGFR≥30-60 and 30-day mortality were associated with CK-AKI both at 48 h and 4-10 days after contrast-enhanced CT. CONCLUSION: Patients with COVID - 19 and eGFR≥30-60 had a high frequency of CK-AKI at 48 h and at 4-10 days after contrast administration, which was associated with increased 30-day mortality. For patients with eGFR≥30-60, we recommend strict indications are practiced for contrast-enhanced CT. Contrast-enhanced CT had a modest effect in patients with eGFR> 60.


Assuntos
Injúria Renal Aguda/induzido quimicamente , COVID-19/complicações , Meios de Contraste/efeitos adversos , Creatinina/sangue , Iodo/efeitos adversos , Rim/efeitos dos fármacos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Idoso , COVID-19/sangue , COVID-19/mortalidade , COVID-19/fisiopatologia , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Regressão , Terapia de Substituição Renal , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X
3.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445068

RESUMO

In this paper, we assess the nephroprotective effects of thyrotropin and follitropin during ischaemia. The studies were performed in vitro in a model of isolated porcine kidneys stored in Biolasol (FZNP, Biochefa, Sosnowiec, Poland) and modified Biolasol (TSH: 1 µg/L; FSH 1 µg/L). We used the static cold storage method. The study was carried out based on 30 kidneys. The kidneys were placed in 500 mL of preservation solution chilled to 4 °C. The samples for biochemical tests were collected during the first kidney perfusion (after 2 h of storage) and during the second perfusion (after 48 h of storage). The results of ALT, AST, and LDH activities confirm the effectiveness of Biolasol + p-TSH in maintaining the structural integrity of renal cell membranes. Significantly reduced biochemical parameters of kidney function, i.e., creatinine and protein concentrations were also observed after 48 h storage. The protective effect of Biasol + p-TSH is most pronounced after 2 h of storage, suggesting a mild course of damage thereafter. A mild deterioration of renal function was observed after 48 h. The results of our analyses did not show any protective effect of Biolasol + p-FSH on the kidneys during ischaemia.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Rim/fisiologia , Soluções para Preservação de Órgãos/metabolismo , Preservação de Órgãos/métodos , Tireotropina/metabolismo , Animais , Temperatura Baixa , Rim/efeitos dos fármacos , Suínos
4.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445625

RESUMO

Arthropod antimicrobial peptides (AMPs) offer a promising source of new leads to address the declining number of novel antibiotics and the increasing prevalence of multidrug-resistant bacterial pathogens. AMPs with potent activity against Gram-negative bacteria and distinct modes of action have been identified in insects and scorpions, allowing the discovery of AMP combinations with additive and/or synergistic effects. Here, we tested the synergistic activity of two AMPs, from the dung beetle Copris tripartitus (CopA3) and the scorpion Heterometrus petersii (Hp1090), against two strains of Escherichia coli. We also tested the antibacterial activity of two hybrid peptides generated by joining CopA3 and Hp1090 with linkers comprising two (InSco2) or six (InSco6) glycine residues. We found that CopA3 and Hp1090 acted synergistically against both bacterial strains, and the hybrid peptide InSco2 showed more potent bactericidal activity than the parental AMPs or InSco6. Molecular dynamics simulations revealed that the short linker stabilizes an N-terminal 310-helix in the hybrid peptide InSco2. This secondary structure forms from a coil region that interacts with phosphatidylethanolamine in the membrane bilayer model. The highest concentration of the hybrid peptides used in this study was associated with stronger hemolytic activity than equivalent concentrations of the parental AMPs. As observed for CopA3, the increasing concentration of InSco2 was also cytotoxic to BHK-21 cells. We conclude that AMP hybrids linked by glycine spacers display potent antibacterial activity and that the cytotoxic activity can be modulated by adjusting the nature of the linker peptide, thus offering a strategy to produce hybrid peptides as safe replacements or adjuncts for conventional antibiotic therapy.


Assuntos
Antibacterianos/farmacologia , Artrópodes/química , Bactérias/efeitos dos fármacos , Glicina/química , Hemólise/efeitos dos fármacos , Rim/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Animais , Antibacterianos/química , Apoptose , Células Cultivadas , Cricetinae , Camundongos , Proteínas Citotóxicas Formadoras de Poros/química
5.
Molecules ; 26(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34443393

RESUMO

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.


Assuntos
Injúria Renal Aguda/patologia , Citoproteção/efeitos dos fármacos , Frutas/química , Gentamicinas/efeitos adversos , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ziziphus/química , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Ratos , Ratos Wistar
6.
Medicine (Baltimore) ; 100(30): e26431, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397684

RESUMO

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished. METHODS: We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions. RESULTS: Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61-0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40-0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47-0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37-0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD. CONCLUSIONS: This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Diabetes Mellitus Tipo 2/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Coração/fisiopatologia , Humanos , Rim/fisiopatologia , Metanálise em Rede , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do Tratamento
7.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361023

RESUMO

Aging is an unavoidable part of life. The more aged we become, the more susceptible we become to various complications and damages to the vital organs, including the kidneys. The existing drugs for kidney diseases are mostly of synthetic origins; thus, natural compounds with minimal side-effects have attracted growing interest from the scientific community and pharmaceutical companies. A literature search was carried out to collect published research information on the effects of resveratrol on kidney aging. Recently, resveratrol has emerged as a potential anti-aging agent. This versatile polyphenol exerts its anti-aging effects by intervening in various pathologies and multi-signaling systems, including sirtuin type 1, AMP-activated protein kinase, and nuclear factor-κB. Researchers are trying to figure out the detailed mechanisms and possible resveratrol-mediated interventions in divergent pathways at the molecular level. This review highlights (i) the causative factors implicated in kidney aging and the therapeutic aspects of resveratrol, and (ii) the effectiveness of resveratrol in delaying the aging process of the kidney while minimizing all possible side effects.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Rim/efeitos dos fármacos , Resveratrol/farmacologia , Envelhecimento/metabolismo , Animais , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Sirtuína 1/metabolismo
8.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445781

RESUMO

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-ß signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Benzoquinonas/farmacologia , Rim/efeitos dos fármacos , Nigella sativa/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos
9.
Chem Biol Interact ; 347: 109605, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34333021

RESUMO

Cell injury is a necessary and critical event during CaOx kidney stone formation. Sirt1 exerts a number of pleiotropic effects, protecting against renal cell injury. This study aims to explore the relationship between Sirt1 and CaOx kidney stone formation and the underlying mechanism. Sirt1 expression in renal tissues or HK-2 cells was detected by Western blot, immunohistochemistry and immunofluorescence. Apoptosis in renal tissues was examined by TUNEL staining. Renal pathological changes and the crystals deposition were detected by hematoxylin-eosin and Von Kossa staining. Crystal-cell adhesion and cell injury in HK-2 cells were assessed by atomic absorption spectrometry and flow cytometry, respectively. Sirt1 expression in nephrolithiasis patients was downregulated and the level of apoptosis was increased. Further study found that Sirt1 expression was decreased in both in vivo and in vitro models. Interestingly, the levels of cell injury were elevated in vivo and in vitro models. Suppressing Sirt1 expression promoted COM-induced crystal-cell adhesion and exacerbated cell injury. In contrast, increasing the expression of Sirt1 by lentivirus transfection in vitro and resveratrol administration in vivo, alleviated crystal deposition and cell damage. Our findings suggest that Sirt1 could inhibit kidney stone formation, at least in part, through attenuating CaOx -induced cell injury.


Assuntos
Oxalato de Cálcio/efeitos adversos , Cálculos Renais/metabolismo , Sirtuína 1/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Oxalato de Cálcio/química , Oxalato de Cálcio/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular , Cristalização , Feminino , Inativação Gênica , Glioxilatos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Cálculos Renais/induzido quimicamente , Cálculos Renais/tratamento farmacológico , Cálculos Renais/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Necrose/induzido quimicamente , Necrose/metabolismo , Resveratrol/uso terapêutico , Sirtuína 1/genética
10.
Chem Biol Interact ; 347: 109614, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34364835

RESUMO

Ochratoxin A (OTA), an important fungal metabolite in foods and feeds has been shown to induce oxidative stress and cellular injuries to human and animal subjects. This study was designed to investigate the mode of action of a biological modifier Trichosporon mycotoxinivorans (TM), against OTA-mediated oxidative stress and tissue toxicity on broiler chickens. The birds were offered diets supplemented with OTA (0.15 and 0.3 mg/kg feed) and/or TM (0.5, 1.0 g/kg) for 42 days of age, and blood and tissue samples were collected to examine the oxidative stress, biochemical and histopathological parameters. Dietary OTA at all the tested levels induced the hepatic and renal tissue injury as indicated by significant decreased total antioxidant capacity in these organs along with significant decreased (p ≤ 0.05) serum concentrations of total proteins and albumin. The serum concentrations of alanine aminotransferase (ALT) and urea were significantly increased, and these observations were further supported by degenerative changes and increased relative weights of liver and kidneys. The dietary supplementation of TM at both tested levels relieved the detrimental impact of 0.15 and 0.3 mg OTA/kg on the studied parameters. The results of the study demonstrated that dietary TM significantly protects broiler chickens by reducing OTA-induced oxidative damage and tissue injury.


Assuntos
Basidiomycota/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/dietoterapia , Suplementos Nutricionais/microbiologia , Nefropatias/dietoterapia , Micotoxinas/toxicidade , Ocratoxinas/toxicidade , Animais , Aspergillus ochraceus , Galinhas , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Micotoxinas/metabolismo , Ocratoxinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
11.
Chem Biol Interact ; 347: 109619, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34364837

RESUMO

Owing to the ineffectiveness of the currently used therapies against melanoma, there has been a shift in focus toward alternative therapies involving the use of natural compounds. This study assessed the anticancer effects of oleanolic acid (OA) and its ability to induce apoptosis in A375SM and A375P melanoma cells in vivo. Compared to the control group, viability of A375P and A375SM cells decreased following OA treatment. In OA-treated A375SM and A375P cells, 4',6-diamidino-2-phenylindole staining showed an increase in the apoptotic body, and flow cytometry revealed increased number of apoptotic cells compared to that in the control group. OA-treated A375SM cells exhibited an increased expression of the apoptotic proteins, cleaved poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma (Bcl)-2-associated X protein (Bax) as well as decreased expression of the antiapoptotic protein Bcl-2 compared to that in the control group. In OA-treated A375P cells, expression patterns of cleaved PARP and Bcl-2 were similar to those in OA-treated A375SM cells; however, no difference was reported in the expression of Bax compared to that in the control group. Additionally, OA-treated melanoma cells showed decreased expression of phospho-nuclear factor-κB (p-NF-κB), phospho-inhibitor of nuclear factor-κBα (p-IκBα), and phospho-IκB kinase αß than that in the control group. Moreover, immunohistochemistry showed a comparatively decreased level of p-NF-κB in the OA-treated group than that in the control group. Xenograft analysis confirmed the in vivo anticancer effects of OA against A375SM cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed an increased number of TUNEL-positive cells in the OA-treated group compared to that in the control group. In conclusion, the study results suggest that OA induces apoptosis of A375SM and A375P cells in vitro and apoptosis of A375SM cells in vivo. Furthermore, the in vitro and in vivo anticancer effects were mediated by the NF-κB pathway.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácido Oleanólico/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Subunidade p50 de NF-kappa B/metabolismo , Neoplasias/metabolismo , Ácido Oleanólico/farmacologia , Ácido Oleanólico/toxicidade , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Commun ; 12(1): 4662, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341345

RESUMO

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Compostos Orgânicos/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Knockout , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Podócitos/citologia , Interferência de RNA , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células THP-1
13.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360657

RESUMO

Although some metallic nanoparticles (NPs) are commonly used in the food processing plants as nanomaterials for food packaging, or as coatings on the food handling equipment, little is known about antimicrobial properties of palladium (PdNPs) and platinum (PtNPs) nanoparticles and their potential use in the food industry. In this study, common food-borne pathogens Salmonella enterica Infantis, Escherichia coli, Listeria monocytogenes and Staphylococcus aureus were tested. Both NPs reduced viable cells with the log10 CFU reduction of 0.3-2.4 (PdNPs) and 0.8-2.0 (PtNPs), average inhibitory rates of 55.2-99% for PdNPs and of 83.8-99% for PtNPs. However, both NPs seemed to be less effective for biofilm formation and its reduction. The most effective concentrations were evaluated to be 22.25-44.5 mg/L for PdNPs and 50.5-101 mg/L for PtNPs. Furthermore, the interactions of tested NPs with bacterial cell were visualized by transmission electron microscopy (TEM). TEM visualization confirmed that NPs entered bacteria and caused direct damage of the cell walls, which resulted in bacterial disruption. The in vitro cytotoxicity of individual NPs was determined in primary human renal tubular epithelial cells (HRTECs), human keratinocytes (HaCat), human dermal fibroblasts (HDFs), human epithelial kidney cells (HEK 293), and primary human coronary artery endothelial cells (HCAECs). Due to their antimicrobial properties on bacterial cells and no acute cytotoxicity, both types of NPs could potentially fight food-borne pathogens.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Doenças Transmitidas por Alimentos/prevenção & controle , Nanopartículas Metálicas/administração & dosagem , Paládio/química , Platina/química , Antibacterianos/química , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Microbiologia de Alimentos , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Nanopartículas Metálicas/química
14.
Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299391

RESUMO

In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1-6) as well as one new metabolite (7), which were characterized by analysis of NMR, IR, UV, and ESI-HRMS data. The new compound 7 exhibited potent activity against the clinically relevant intracellular forms of T. cruzi (amastigotes), with an IC50 value of 4.3 µM and no observed mammalian cytotoxicity in fibroblasts (CC50 > 200 µM). Based on the results obtained and our previous antitrypanosomal data of 50 natural and semi-synthetic related neolignans, 2D and 3D molecular modeling techniques were employed to help the design of new neolignan-based compounds with higher activity. The results obtained from the models were important to understand the main structural features related to the biological response of the neolignans and to aid in the design of new neolignan-based compounds with better biological activity. Therefore, the results acquired from phytochemical, biological, and in silico studies showed that the integration of experimental and computational techniques consists of a powerful tool for the discovery of new prototypes for development of new drugs to treat CD.


Assuntos
Produtos Biológicos/farmacologia , Doença de Chagas/tratamento farmacológico , Simulação por Computador , Descoberta de Drogas , Lauraceae/química , Lignanas/farmacologia , Tripanossomicidas/farmacologia , Animais , Fibroblastos/efeitos dos fármacos , Rim/efeitos dos fármacos , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Compostos Fitoquímicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/efeitos dos fármacos
15.
Int J Biol Macromol ; 185: 434-440, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197848

RESUMO

This study investigated the interacting mechanism of CdTe quantum dots (QDs) with typical plasma protein transferrin (TF) as well as the impact of the formation of QDs-TF complex on the structure of TF and the cytotoxicity of mouse primary kidney cells. Dialysis experiments and cell viability assays revealed that the formation of QDs-TF complex reduced the contents of Cd released from CdTe QDs and thus counteracted the cytotoxicity of CdTe QDs. The assay of isothermal titration calorimetry found that CdTe QDs complexed with TF majorly through hydrophobic interaction. Multi-spectroscopic measurements showed that CdTe QDs caused the loosening of polypeptide chain, the changes of secondary and tertiary structures as well as the attenuated aggregation of TF molecule. Moreover, these structural and conformational changes were attributed to the nano-effects of CdTe QDs rather than the released Cd. This study is of great significance for fully evaluating the biocompatibility of Cd-QDs and comprehensively understanding the mechanism of Cd-QDs toxicity at the molecular and cellular level.


Assuntos
Compostos de Cádmio/toxicidade , Rim/citologia , Telúrio/toxicidade , Transferrina/química , Transferrina/metabolismo , Animais , Compostos de Cádmio/química , Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Rim/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Cultura Primária de Células , Estrutura Secundária de Proteína , Pontos Quânticos/química , Telúrio/química
16.
Medicine (Baltimore) ; 100(27): e26510, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232183

RESUMO

BACKGROUND: Aristolochic acid nephropathy (AAN) is a type of drug-induced nephropathy that may result in acute kidney injury and is associated with a potentially progressive course of kidney fibrosis and upper tract urothelial carcinoma. Aristolochic acids (AAs) are a group of toxins commonly present in plants of the genera Aristolochia and Asarum, which are found worldwide. AAN still occurs in Asian and Balkan regions. The progressive lesions and mutational events initiated by AAs are irreversible, and no effective therapeutic regimen for AAN has been established. Furthermore, more people are at risk of this disease due to casual exposure to AAs. This study performed a scientometric analysis of global research literature focusing on AAN. METHODS: The Web of Science database was searched to identify all publications pertaining to "aristolochic acid nephropathy" or "Balkan endemic nephropathy" using these terms as key words to search the literature from 1971 to 2019. The collected data included the document type, author, journal, publication year, citation reports, and country of publication, and were analyzed using the VOSviewer software. RESULTS: A total of 1251 records were initially obtained. Publication types, including "meeting abstract," "letter," "editorial material," and "proceedings paper" were excluded, which left 1083 publications comprising 923 articles and 160 reviews. English was the predominant language of the publications. China had the most number of articles published with 217 (20.0%), followed by the USA with 186 articles (17.2%), and Germany with 138 articles (12.7%). Kidney International, Food and Chemical Toxicology, and Toxins were the 3 most active journals in publishing articles related to AAN. The total number of citations received by all publications was 39,970, with an average of 36.91 citations per article (range: 0-1769). The literature mainly focused on apoptosis, oxidative stress, and inflammation in AAN. CONCLUSION: This study indicated that AAN is a significant topic in nephrology research, as shown by the large number of publications. The literature has mainly focused on the mechanisms of AA-induced nephropathy.


Assuntos
Ácidos Aristolóquicos/efeitos adversos , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Publicações Periódicas como Assunto , Humanos , Estudos Retrospectivos
17.
Medicine (Baltimore) ; 100(27): e26606, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232214

RESUMO

RATIONALE: Momordica charantia is often used to treat type 2 diabetes mellitus in Korea. Drug-induced acute interstitial nephritis (AIN) accounts for 60% to 70% of AIN cases. However, only 1 case of AIN associated with ingesting M charantia has been reported in the English literature. We report an extremely rare case of AIN that occurred after a patient ingested a pure M charantia extract over 7 months. PATIENT CONCERNS: A 60-year-old Korean woman was admitted to our hospital for a renal biopsy. Her renal function had decreased gradually over the last 9 months without symptoms or signs. DIAGNOSIS: Her blood urea nitrogen and serum creatinine levels were 29.7 mg/dL (range: 8.0-20.0 mg/dL) and 1.45 mg/dL (range: 0.51-0.95 mg/dL) on admission. Renal histology indicated AIN; there was immune cell infiltration into the interstitium, tubulitis, and epithelial casts, although the glomeruli were largely intact. INTERVENTIONS: M charantia was discontinued and prednisolone was prescribed. OUTCOMES: The value of serum creatinine has almost been restored to the baseline level after 3 months. CONCLUSION: s: This is the first case report of AIN associated with the ingestion of a pure M charantia extract. Recognition of the possible adverse effects of these agents by physicians is very important for early diagnosis and appropriate management.


Assuntos
Momordica charantia/efeitos adversos , Nefrite Intersticial/induzido quimicamente , Biópsia , Ingestão de Alimentos , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Extratos Vegetais/efeitos adversos , Ultrassonografia
18.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208557

RESUMO

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 µM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 µM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 µM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 µM). Ondansetron (0.5-20 µM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 µM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 µM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.


Assuntos
Antieméticos/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Transportador 2 de Cátion Orgânico/biossíntese , Animais , Antieméticos/química , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Cães , Expressão Gênica , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Estrutura Molecular , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/genética , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia
19.
Biomed Pharmacother ; 139: 111386, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243594

RESUMO

Renal interstitial fibrosis (RIF) is a common pathological response in a broad range of prevalent chronic kidney diseases and ultimately leads to renal failure and death. Although RIF causes a high morbi-mortality worldwide, effective therapeutic drugs are urgently needed. Myofibroblasts are identified as the main effector during the process of RIF. Multiple types of cells, including fibroblasts, epithelial cells, endothelial cells, macrophages and pericytes, contribute to renal myofibroblasts origin, and lots of mediators, including signaling pathways (Transforming growth factor-ß1, mammalian target of rapamycin and reactive oxygen species) and epigenetic modifications (Histone acetylation, microRNA and long non-coding RNA) are participated in renal myofibroblasts activation during renal fibrogenesis, suggesting that these mediators may be the promising targets for treating RIF. In addition, many small molecules show profound therapeutic effects on RIF by suppressing the origin and activation of renal myofibroblasts. Taken together, the review focuses on the mechanisms of the origin and activation of renal myofibroblasts in RIF and the small molecules against them improving RIF, which will provide a new insight for RIF therapy.


Assuntos
Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fibroblastos/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos
20.
Biomed Pharmacother ; 139: 111660, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243628

RESUMO

The current study investigates the biochemical and histopathological effects of taxifolin on acrylamide-induced kidney damage. A 50 mg/kg dose of taxifolin was administered via oral gavage to the taxifolin + acrylamide (TACR) group (n-6) consisting of male albino Wistar rats. The same volume of distilled water used as solvent was orally administered to the acrylamide (ACR) (n-6) and healthy (HG) (n-6) groups. One hour after the administration of taxifolin and distilled water, a 20 mg/kg dose of acrylamide was orally administered to the TACR and ACR groups. This procedure was repeated once a day for 30 days. In the acrylamide group, malondialdehyde (MDA), tumour necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) levels were found to be high, total glutathione (tGSH) levels were found to be low, and there was severe interstitial haemorrhage; additionally, tubular necrosis, tubular atrophy, leucocyte infiltration, and glomerular structures with expanded Bowman's space were observed. In the taxifolin group, where the increase of MDA, IL-1ß, and TNF-α and the decrease of tGSH associated with acrylamide have been prevented, any histopathological finding other than mild necrosis and atrophic tubules was not found. This suggests that Taxifolin would prevent kidney tissue from acrylamide-induced damage would be effective in treating acrylamide-induced nephrotoxicity, inhibiting the increase of MDA, IL-1ß and TNF-α, and decreasing tGSH associated with acrylamide.


Assuntos
Acrilamida/farmacologia , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Substâncias Protetoras/farmacologia , Quercetina/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/farmacologia , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
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