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1.
Huan Jing Ke Xue ; 41(9): 4180-4196, 2020 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124300

RESUMO

In this study, 130 surface soil samples were collected at an industrial pollution site in Beijing and the contents of As, Be, Cd, Cu, Cr, Hg, Ni, Pb, Sb, Ti, Zn, and 16 PAHs were determined. The positive matrix factorization (PMF) model was used to analyze the sources of heavy metals and PAHs, and the contributions of these sources to carcinogenic risk and hazard index in the study area were calculated. The results showed that the contents of Cd, Cu, Pb, Hg, As, Zn, and Cr in the soil exceeded the background values in different degrees; Cd, Hg, Pb, Zn, and Cu exceeded the background values by>50%. Low molecular weight PAHs (two and three rings) and high molecular weight PAHs (four to six rings) accounted for 39.6% and 60.4% of the total content of 16 PAHs. The PAH content at 77% of the sampling points at the target site was more than 1000 µg ·kg-1, which suggests severe PAH pollution at the site. Heavy metals Be, Ti, As, and Ni mainly originated from natural sources. There are three major sources of 7 heavy metals and 16 PAHs at the site: coal combustion (Hg and ∑16PAHs), smelting (Cu, Cr, Pb, and Zn), and traffic (Sb and Cd). The contribution rates of these sources to the total average contents of seven heavy metals and sixteen PAHs at 130 sampling sites were 8.46% (coal combustion), 90.61% (smelting), and 0.94% (traffic). Human health risk assessment results showed that the carcinogenic risk of seven heavy metals and ∑16PAHs ranged from 4.17×10-6 to 39.38×10-4, and the hazard index ranged from 0 to 32.23. The maximum carcinogenic risk and hazard index values were calculated near the coking plant. Benzo[α]pyrene was the PAH that posed the highest carcinogenic risk and Zn was the heavy metal that had the highest hazard index value. The average carcinogenic risk of coal combustion was 2.16×10-4, accounting for 50.26% of the total average carcinogenic risk. The average hazard index of smelting was 0.834, accounting for 56.43% of the total average non-carcinogenic risk. These two pollution sources are responsible for the high levels of heavy metals and PAHs in the soil of the steel smelting sites that pose the most severe health risks. The results of this study can provide reference for soil remediation and process optimization at other heavily polluted industrial sites.


Assuntos
Metais Pesados , Poluentes do Solo , Pequim , China , Monitoramento Ambiental , Humanos , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise
2.
Korean J Intern Med ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32942841

RESUMO

Background/Aims: Accumulating evidence indicates that L-carnitine (LC) protects against multiorgan damage through its antioxidant properties and preservation of the mitochondria. Little information is available about the effects of LC on renal fibrosis. This study examined whether LC treatment would provide renoprotection in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Methods: Sprague-Dawley rats that underwent UUO were treated daily with LC for 7 or 14 days. The influence of LC on renal injury caused by UUO was evaluated by histopathology, and analysis of gene expression, oxidative stress, mitochondrial function, programmed cell death, and phosphatidylinositol 3-kinase (PI3K)/ AKT/forkhead box protein O 1a (FoxO1a) signaling. In addition, H2O2-exposed human kidney cells (HK-2) were treated with LC. Results: LC treatment inhibited expression of proinflammatory and profibrotic cytokines, and was followed by a significant attenuation of tubulointerstitial inflammation and fibrosis. The increased oxidative stress caused by UUO was associated with mitochondrial dysfunction and excessive apoptosis and autophagy via PI3K/AKT/FoxO1a-dependent signaling, and this was abrogated by administration of LC. In H2O2-exposed HK-2 cells, LC decreased intracellular production of reactive oxygen species, and suppressed expression of profibrotic cytokines and reduced the number of apoptotic cells. Conclusions: LC protects against the progression of tubulointerstitial fibrosis in an obstructed kidney.

3.
Cardiovasc Diabetol ; 19(1): 120, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746821

RESUMO

BACKGROUND: Growth differentiation factor-15 (GDF-15) is a marker of inflammation, oxidative stress and it is associated with adverse prognosis in cardiovascular disease. The aim of the present cohort study is to investigate the prognostic value of GDF-15 in patients with coronary artery disease (CAD) during long-term follow up. METHODS: A total of 3641 consecutive patients with CAD were prospectively enrolled into the study and followed up for major adverse cardiovascular events (MACEs) and all-cause death up to 5.3-7.6 years. Plasma GDF-15 was measured and clinical data and long-term events were registered. The patients were subsequently divided into three groups by the levels of GDF-15 and the prognostic value of GDF-15 level with MACEs and all-cause death was evaluated. RESULTS: After a median follow-up at 6.4 years later, 775 patients (event rate of 21%) had developed MACEs and 275 patients died (event rate of 7.55%). Kaplan-Meier analysis indicated that the patients with GDF-15 > 1800 ng/L were significantly associated with an increased risk of MACEs and all-cause death. Cox regression analysis indicated that GDF-15 > 1800 ng/L were independently associated with the composite of MACEs (HR 1.74; 95% CI 1.44-2.02; P < 0.001) and all-cause death (HR 2.04; 95% CI 1.57-2.61; P < 0.001). For MACEs, GDF-15 significantly improved the C-statistic (area under the curve, 0.583 [95% CI 0.559-0.606] to 0.628 [0.605-0.651]; P < 0.001), net reclassification index (0.578; P = 0.031), and integrated discrimination index (0.021; P = 0.027). For all-cause death, GDF-15 significantly improved the C-statistic (0.728 [95% CI 0.694-0.761] to 0.817 [0.781-0.846]; P < 0.001), net reclassification index (0.629; P = 0.001), and integrated discrimination index (0.035; P = 0.002). CONCLUSIONS: In the setting of CAD, GDF-15 is associated with long-term MACEs and all-cause death, and provides incremental prognostic value beyond traditional risks factors.

4.
Cryobiology ; 96: 99-105, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32738264

RESUMO

Cryopreservation of ovarian tissues (OTs) has become the most effective way to preserve the fertility of female cancer patients. However, cryopreservation of OTs is still relatively at an experimental stage. The aim of study is to examine the effect of melatonin (MTL) on cryopreserved-thawed OTs. Fragments of OTs were cryopreserved in medium containing different concentrations (0 mM, 0.001 mM, 0.01 mM, 0.1 mM and 1 mM) of MLT. The endogenous enzymes (GSH-PX, GSH, SOD, CAT and T-AOC), MDA and ROS levels were all evaluated after cryopreservation. Our results showed that the 0.1 mM of MLT significantly improved the survival and diameter of follicles (P < 0.001). Meanwhile, the antioxidant enzymes activities (including GSH-PX, GSH, SOD, CAT and T-AOC) were enhanced and MDA content were significantly decreased in 0.1 mM of MLT group compared to other groups (P < 0.001). Additionally, compared to the control group, MTL of 0.1 mM resulted in a significantly lower ROS level. In conclusion, MLT protects the quality of cryopreserved OTs by decreasing oxidative stress level and the optimal concentration is 0.1 mM.

5.
Acta Pharmacol Sin ; 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555441

RESUMO

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

6.
Chin Med J (Engl) ; 133(10): 1211-1220, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433053

RESUMO

BACKGROUND: Pancreatic cancer (PC) is a highly deadly malignancy with few effective therapies. We aimed to unmask the role that long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) plays in PC cells by targeting far upstream element binding protein 1 (FUBP1) via microRNA-26a-5p (miR-26a-5p). METHODS: SNHG6 expression was predicted by bioinformatics, followed by verification via reverse transcription quantitative polymerase chain reaction. Then, the interactions among SNHG6, miR-26a-5p, and FUBP1 were detected through online software analysis, dual luciferase reporter assay and RNA pull-down. After that, cells were treated with different small interfering RNAs and/or mimic to determine the interactions among SNHG6, miR-26a-5p, and FUBP1 and their roles in PC cells. Finally, the role of SNHG6 in tumor growth in vivo was evaluated by measuring the growth and weight of transplanted tumors in nude mice. A t-test, one-way and two-way analysis of variance were used for data analysis. RESULTS: Compared with that in normal tissues, SNHG6 was highly expressed in PC tissues (1.00 ±â€Š0.05 vs. 1.56 ±â€Š0.06, t = 16.03, P < 0.001). Compared with that in human pancreatic duct epithelial cells (HPDE6-C7), SNHG6 showed the highest expression in PANC-1 cells (1.00 ±â€Š0.06 vs. 3.87 ±â€Š0.13, t = 34.72, P < 0.001) and the lowest expression in human pancreatic cancer cells (MIAPaCa-2) (1.00 ±â€Š0.06 vs. 1.41 ±â€Š0.07, t = 7.70, P = 0.0015). Compared with the levels in the si-negative control group, SNHG6 (0.97 ±â€Š0.05 vs. 0.21 ±â€Š0.06, t = 16.85, P < 0.001), N-cadherin (0.74 ±â€Š0.05 vs. 0.41 ±â€Š0.04, t = 8.93, P < 0.001), Vimentin (0.55 ±â€Š0.04 vs. 0.25 ±â€Š0.03, t = 10.39, P < 0.001), and ß-catenin (0.62 ±â€Š0.05 vs. 0.32 ±â€Š0.03, t = 8.91, P < 0.001) were decreased, while E-cadherin (0.65 ±â€Š0.06 vs. 1.36 ±â€Š0.07, t = 13.34, P < 0.001) was increased after SNHG6 knockdown or miR-26a-5p overexpression, accompanied by inhibited cell proliferation, migration, and invasion. SNHG6 overexpression exerted the opposite effects. SNHG6 upregulated FUBP1 expression by sponging miR-26a-5p. Silencing SNHG6 blocked the growth of PC in vivo. CONCLUSION: Silencing SNHG6 might ameliorate PC through inhibition of FUBP1 by sponging miR-26a-5p, thus providing further supporting evidence for its use in PC treatment.

7.
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.

8.
J Dairy Sci ; 103(6): 4895-4906, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32229112

RESUMO

The objective of this study was to evaluate the protection conferred by lactoferrin, α-lactalbumin, and ß-lactoglobulin in cerebral ischemia reperfusion (I/R) injury. Rat pheochromocytoma (PC12) cells were used to construct an oxygen and glucose deprivation model in vitro, and ICR mice underwent carotid artery "ligation-relaxation" to construct a cerebral I/R injury model in vivo. The levels of toll-like receptor 4 (TLR4) and downstream factors including nuclear factor-κB, tumor necrosis factor-α, and IL-1ß were measured. Metabonomics detection and data mining were conducted to identify the specific metabolic sponsor of the 3 proteins. The results showed that lactoferrin, α-lactalbumin, and ß-lactoglobulin protected neurons from cerebral I/R injury by increasing the level of bopindolol and subsequently inhibiting the TLR4-related pathway to different degrees; ß-lactoglobulin had the strongest activity of the 3 proteins. In summary, this study is the first to investigate and compare the protective effects of lactoferrin, α-lactalbumin, and ß-lactoglobulin in a cerebral stroke model. The results implicate TLR4 as a novel target of the 3 bioactive proteins to prevent cerebral I/R injury.


Assuntos
Lactalbumina/uso terapêutico , Lactoferrina/uso terapêutico , Lactoglobulinas/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Glucose/metabolismo , Interleucina-1beta/metabolismo , Lactalbumina/metabolismo , Lactoferrina/metabolismo , Lactoglobulinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Oxigênio/metabolismo , Células PC12 , Ratos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Cryobiology ; 95: 1-8, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32001217

RESUMO

Melatonin is a ubiquitous indoleamine hormone synthesized primarily by the pineal gland. Diverse biological actions of melatonin involve quite complex mechanisms via its membrane receptors. More recently, studies have focused on the role of melatonin in male fertility preservation and male reproductive system. The protective effects of melatonin on immature testicular tissue freshness and activity maintenance and the preservation of sperm and spermatogonial stem cells (SSCs) have attracted considerable attention in recent years. Furthermore, since melatonin has strong antioxidant and anti-apoptotic properties, researchers have examined its potential role in male reproductive system. In this article, recent progress regarding melatonin's effects on male fertility preservation and its potential role is reviewed.

10.
World J Clin Cases ; 8(2): 370-376, 2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-32047787

RESUMO

BACKGROUND: Central nervous system (CNS) metastases are a catastrophic complication of non-small cell lung cancer (NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging. CASE SUMMARY: We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor (EGFR). A standard dosage of icotinib (125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib (1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects. CONCLUSION: This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

11.
Acta Pharmacol Sin ; 41(1): 110-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31515527

RESUMO

In addition to the well-known cardiotonic effects, cardiac glycosides (CGs) produce potent anticancer effects with various molecular mechanisms. We previously show that ouabain induces autophagic cell death in human lung cancer cells by regulating AMPK-mediated mTOR and Src-mediated ERK1/2 signaling pathways. However, whether and how AMPK and Src signaling interacts in ouabain-treated cancer cells remains unclear. Given the pivotal role of AMPK in metabolism, whether ouabain affects cancer cell metabolism remains elusive. In this study we showed that treatment with ouabain (25 nM) caused simultaneous activation of AMPK and Src signaling pathways in human lung cancer A549 cells and human breast cancer MCF7 cells. Cotreatment with AMPK inhibitor compound C or siRNA greatly abrogates ouabain-induced Src activation, whereas cotreatment with Src inhibitor PP2 has little effect on ouabain-induced AMPK activity, suggesting that AMPK served as an upstream regulator of the Src signaling pathway. On the other hand, ouabain treatment greatly depletes ATP production in A549 and MCF7 cells, and supplement of ATP (100 µM) blocked ouabain-induced AMPK activation. We further demonstrated that ouabain greatly inhibited the mitochondrial oxidative phosphorylation (OXPHOS) in the cancer cells, and exerted differential metabolic effects on glycolysis depending on cancer cell type. Taken together, this study reveals that the altered cancer cell metabolism caused by ouabain may contribute to AMPK activation, as well as its cytotoxicity towards cancer cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cardiotônicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Ouabaína/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinases da Família src/antagonistas & inibidores
12.
J Altern Complement Med ; 26(1): 58-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31580705

RESUMO

Objectives: Large sample and high-quality evidence to evaluate the preliminary safety of the mobilizations and massage for cervical vertigo are not yet available. Thus, the present study aimed to investigate the comparative effectiveness and preliminary safety of Shi-style cervical mobilizations (SCM) compared with traditional massage (TM) in cervical vertigo patients. Design: A prospective, multicenter, open-label, randomized, controlled clinical trial with a 1:1 allocation ratio. Settings: Five academic medical centers. Subjects: A total of 360 adult patients with a diagnosis of cervical vertigo. Interventions: The patients were randomly allocated to either an SCM (n = 180) or TM (n = 180) group. The patients were treated during six sessions over 2 weeks. The primary outcome was the Dizziness Handicap Inventory (DHI) total scale score, and secondary outcomes included the DHI subscales, Chinese version of the Short-Form 36 Health Survey (CSF-36), and adverse events (AEs). Outcomes were assessed in the short term at 2 weeks, 1 month, and 3 months, and in the intermediate term at 6 months after randomization. Results: Significant changes were observed from the baseline in the DHI total scale and subscales at 2 weeks and 1, 3, and 6 months in both groups (all p < 0.05). However, the differences between the two groups were not significant (all p > 0.05). Furthermore, we noted significant changes from the baseline in SF-36 scores at 2 weeks in both groups (all p < 0.05), whereas CSF-36 scores were not significantly higher in the SCM group (all p > 0.05) compared with the TM group. No serious AEs were reported in either of the two groups. Conclusions: No differences in outcomes were detected between the SCM and TM groups in terms of treatment of cervicogenic dizziness. Efficacy trials are required to determine whether the improvement observed for each treatment was causally related to the interventions.


Assuntos
Massagem , Manipulações Musculoesqueléticas , Vertigem/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pescoço/fisiopatologia , Vertigem/fisiopatologia
13.
J Dairy Sci ; 103(2): 1151-1163, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837800

RESUMO

This study aimed to investigate the modulation activity of heated and nonheated lactoferrins in an inflammatory pathway in anoxia and reoxygenation cell and cerebral ischemic reperfusion mouse models. Rat pheochromocytoma 12 (PC-12) cells were subjected to oxygen and glucose deprivation in vitro to construct an anoxia and reoxygenation cell model, and Institute for Cancer Research (ICR) mice were given carotid artery "ligation-relaxation" in vivo to construct a cerebral ischemic reperfusion mouse model. The protein levels of toll-like receptor 4 (TLR-4) and downstream inflammatory proteins including nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and IL-1ß were detected. Meanwhile, metabonomic detection of overall metabolites of PC-12 cells was performed to screen out the specific changed metabolite affected by lactoferrin at the condition of anoxia and reoxygenation. The results showed that lactoferrin could inhibit the TLR-4-related pathway triggered by anoxia and reoxygenation and ischemic reperfusion. A total of 41 significantly changed metabolites were identified by metabonomic analysis, and glutathione was seen as a metabolite of interest in suppressing TLR-4-related pathway in anoxia and reoxygenation cell models. However, heated lactoferrin lost the ability of attenuating the TLR-4-related pathway. The loss of modulation activity of heated lactoferrin might be due to its protein aggregation, which was evidenced by larger average particle diameter than the unheated lactoferrin. This study is the first to investigate the effect of heat treatment on the modulation activity of lactoferrin in the TLR-4-related pathway in anoxia and reoxygenation cell and cerebral ischemic reperfusion mouse models, and indicate that lactoferrin may serve as a dietary intervention for cerebral ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Hipóxia Celular , Hipóxia-Isquemia Encefálica/metabolismo , Lactoferrina/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Isquemia Encefálica/prevenção & controle , Modelos Animais de Doenças , Glucose/farmacologia , Lactoferrina/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Oxigênio/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Temperatura , Fator de Necrose Tumoral alfa/metabolismo
14.
BMC Infect Dis ; 19(1): 595, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288749

RESUMO

BACKGROUND: Noroviruses (NVs) are an important cause of acute gastroenteritis (AGE) worldwide. There are limited data on the prevalence and molecular characterization of NVs in children in Hohhot, China. METHODS: Between January 2012 and December 2017, 1863 stool samples were collected at Maternal and Child Health Hospital in Hohhot. All samples were screened for NVs by real-time reverse transcription polymerase chain reaction (real-time RT-PCR). RESULTS: NVs were detected in 24.15% of these inpatient cases, ranging from 12.78 to 32.92% in different years. NV was detected throughout the year, with a peak in winter. Based on sequence analysis of the partial VP1 gene, the 306 identified NV strains were divided into six genotypes: GII.3 (71.24%), GII.4 (23.53%), and GII.2, GII.5, GII.6, and GII.13 (total 5.23%). Based on further sequence analysis of the RNA-dependent RNA polymerase (RdRp), GII.P12/GII.3, GII.Pe/GII.4, and GII.P4/GII.4 were identified as predominant genotypes, accounting for 92.6% of genotyped strains. The median age of the children with NV infection was 8.0 (range 0-59) months. However, children infected with GII.3 were younger (median 7.0 months) than GII.4-positive patients (median 10.0 months). CONCLUSION: NV contributed greatly to AGE among hospitalized children in Hohhot in China. Continuous surveillance is important for understanding the local prevalence and characterization of NV.


Assuntos
Infecções por Caliciviridae/diagnóstico , Gastroenterite/diagnóstico , Norovirus/genética , Doença Aguda , Infecções por Caliciviridae/epidemiologia , Criança Hospitalizada , Pré-Escolar , China/epidemiologia , Fezes/virologia , Feminino , Gastroenterite/epidemiologia , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Norovirus/classificação , Norovirus/isolamento & purificação , Filogenia , Prevalência , RNA Viral/isolamento & purificação , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estações do Ano
15.
Exp Mol Med ; 51(2): 1-10, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770784

RESUMO

Mesangial cell proliferation has been identified as a major factor contributing to glomerulosclerosis, which is a typical symptom of diabetic nephropathy (DN). Lysophosphatidic acid (LPA) levels are increased in the glomerulus of the kidney in diabetic mice. LPA is a critical regulator that induces mesangial cell proliferation; however, its effect and molecular mechanisms remain unknown. The proportion of α-SMA+/PCNA+ cells was increased in the kidney cortex of db/db mice compared with control mice. Treatment with LPA concomitantly increased the proliferation of mouse mesangial cells (SV40 MES13) and the expression of cyclin D1 and CDK4. On the other hand, the expression of p27Kip1 was decreased. The expression of Krüppel-like factor 5 (KLF5) was upregulated in the kidney cortex of db/db mice and LPA-treated SV40 MES13 cells. RNAi-mediated silencing of KLF5 reversed these effects and inhibited the proliferation of LPA-treated cells. Mitogen-activated protein kinases (MAPKs) were activated, and the expression of early growth response 1 (Egr1) was subsequently increased in LPA-treated SV40 MES13 cells and the kidney cortex of db/db mice. Moreover, LPA significantly increased the activity of the Ras-related C3 botulinum toxin substrate (Rac1) GTPase in SV40 MES13 cells, and the dominant-negative form of Rac1 partially inhibited the phosphorylation of p38 and upregulation of Egr1 and KLF5 induced by LPA. LPA-induced hyperproliferation was attenuated by the inhibition of Rac1 activity. Based on these results, the Rac1/MAPK/KLF5 signaling pathway was one of the mechanisms by which LPA induced mesangial cell proliferation in DN models.


Assuntos
Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Lisofosfolipídeos/farmacologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Biomarcadores , Proliferação de Células , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Expressão Gênica , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos
16.
J Agric Food Chem ; 67(1): 140-147, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30418775

RESUMO

To investigate the effect of heat treatment on the antitumor activity of lactoferrin in colon cancer cells and colon tumors, the HT-29 (human intestinal epithelial tumor cell) cell line was exposed to lactoferrin and various heat treatments. The impacts on cell proliferation, invasion, and migration were observed in vitro, and nude mice bearing HT29 tumors were administered lactoferrin and underwent various heat treatments in vivo. In the HT29 cell proliferation test using transwell and scratch analyses, lactoferrin (20 mg/mL) without or with heat treatment (50 and 70 °C) significantly inhibited cell proliferation, migration, and invasion (compared with the control, p < 0.05), while lactoferrin with heat treatment (100 °C) did not affect these parameters. In vivo, HT29 tumor weight was significantly reduced in the lactoferrin (without heat treatment and with 50 and 70 °C treatment) groups (1.59 ± 0.20, 1.67 ± 0.25, and 2.41 ± 0.42 g, compared with the control, p < 0.05), and there was no significant difference between the control (3.73 ± 0.33 g) and the 100 °C treatment group (3.58 ± 0.29 g). Moreover, 100 °C heat treatment reduced inhibition of the VEGFR2/VEGFA/PI3K/Akt/Erk1/2 angiogenesis pathway by lactoferrin. In summary, HT29 tumors were effectively suppressed by lactoferrin via inhibition of VEGFR2/VEGFA/PI3K/Akt/Erk1/2 pathway, and heat treatment affected the antitumor activity of lactoferrin in a temperature-dependent manner.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Lactoferrina/administração & dosagem , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Células HT29 , Temperatura Alta , Humanos , Lactoferrina/química , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Toxicol Lett ; 291: 101-111, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29458171

RESUMO

AIM: Furosine is one of the Maillard reaction products (MRPs) and is found in a variety of heat-processed food. Yet its toxicity is still unclear. The present study was designed to assess furosine toxicity in cell models and in CD-1 mice, respectively. METHODS: In vitro, the effects of furosine on the cell viability, cell cycle and apoptosis (Hek293, HepG2, SK-N-SH and Caco2) were detected and evaluated, sensitive cell lines and proper dosage of furosine for further animal experiment were determined, and the mechanisms of toxicity were explored. In vivo, the acute toxicity studieswere performed, organ index, hematology parameters, functions of liver/kidney and pathological changes were detected and the target organs were uncovered. RESULTS: Hek293 cells and HepG2 cells were themost sensitive to furosine with respect to cytotoxicity and apoptosis. Furosine inhibited mice weight gain, and affected the functions of liver and kidney. CONCLUSIONS: Furosine posed toxic effects on mice liver and kidney, suggested thatthey were the target organs for furosine toxicity. This study for the first time provides evidence that high dosages of furosine pose adverse biological effects on the health of animals through induction of cell apoptosis and activation of inflammatory necrosis response.


Assuntos
Lisina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Contagem de Células Sanguíneas , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Testes de Função Renal , Testes de Função Hepática , Lisina/toxicidade , Masculino , Camundongos , Necrose , Ganho de Peso/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 28(4): 700-706, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395973

RESUMO

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC50 = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC50 = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d-15f and oxadiazole compounds 24a-24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC50 = 0.14 µM and 0.05 µM vs. 8.98 µM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo.


Assuntos
Antineoplásicos/farmacologia , Dasatinibe/análogos & derivados , Dasatinibe/farmacologia , Leucemia/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dasatinibe/síntese química , Dasatinibe/toxicidade , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Oxidiazóis/toxicidade , Triazóis/síntese química , Triazóis/farmacologia , Triazóis/toxicidade
19.
Bioorg Med Chem Lett ; 28(4): 737-741, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395981

RESUMO

Isothiocyanates 7a and 7b have poor stability and aqueous solubility. To address these problems, prodrugs 8a and 8b were synthesized. Prodrugs 8a and 8b were stable in HEPES buffer at pH 4.4, but released the active compounds 7a and 7b in HEPES buffer at pH 7.4 and in mouse plasma, respectively. Compound 8a and especially compound 8b showed anti-inflammatory effects. Compound 8b demonstrated significant efficacy in animal models of traumatic inflammation, acute inflammation and rheumatoid arthritis. Compound 8b also did not cause appreciable toxicity in mice after 5 weeks at a daily dose of 200 mg/kg.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Isotiocianatos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Peso Corporal/efeitos dos fármacos , Meia-Vida , Isotiocianatos/síntese química , Isotiocianatos/farmacocinética , Isotiocianatos/toxicidade , Camundongos , Neutrófilos/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Ratos Sprague-Dawley , Ratos Wistar , Peixe-Zebra
20.
J Agric Food Chem ; 65(48): 10464-10472, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29112400

RESUMO

To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3 ± 16.7 mg/mL and 101 ± 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 ± 6.7 mg) and the lactoferrin/5-Fu group (14.5 ± 5.1 mg), compared with the control one (39.3 ± 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2-PI3K/Akt-Erk1/2 pathway.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Lactoferrina/administração & dosagem , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/fisiopatologia , Modelos Animais de Doenças , Células HT29 , Humanos , Lactoferrina/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/fisiopatologia , Ensaios Antitumorais Modelo de Xenoenxerto
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