RESUMO
BACKGROUND: Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity. METHODS: SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines. RESULTS: We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1. CONCLUSION: In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future.
Assuntos
Manganês , Neuroblastoma , Humanos , Masculino , Ratos , Animais , Manganês/toxicidade , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ferro/metabolismo , Proteína X Associada a bcl-2/metabolismo , Ratos Sprague-Dawley , Estresse Oxidativo , Apoptose , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD(P)H Desidrogenase (Quinona)/farmacologiaRESUMO
Heavy metal(loid)s contamination prevails in the water-soil-plant system around non-ferrous metal mining areas. The present study aimed to evaluate the heavy metal(loid)s contamination in Nandan Pb-Zn mining area (Guangxi, China). A total of 36 river water samples, 75 paired paddy soil and rice samples, and 128 paired upland soil and plant samples were collected from this area. The concentrations of arsenic (As), lead (Pb), and cadmium (Cd) in these samples were measured. Results showed that the average water quality indexes (WQIs) at the 12 sampling sites along the main river ranged from 41 to 5008, indicating the water qualities decreasing from "Excellent" to "Undrinkable". The WQIs nearby tailings or industrial park were significantly higher than those at the other sites. 34.0% and 64.5% of soil samples exceeded the risk screening values for As and Cd. The Pb and Cd concentrations in all rice samples exceeded the Chinese food safety limits by 18.7% and 82.7%, respectively. Leafy vegetables had a higher concentration of As, Pb, and Cd than other vegetables, exceeding the maximum permissible limits by 14.1%, 61.2%, and 40.0%, respectively. The biological accumulation coefficient (BAC) of Cd was the highest in rice and lettuce leaves. The hazard quotients (HQs) of As and Cd, indicating non-carcinogenic risks, were 4.15 and 1.76 in adult males, and 3.40 and 1.45 in adult females, all higher than the permitted level (1.0). The carcinogenic probabilities of As and Cd from rice and leafy vegetables consumption were all higher than 1 × 10-4. We conclude that metal(loid)s contamination of the water-soil-plant system has posed great non-carcinogenic and carcinogenic risks to the local population.
Assuntos
Arsênio , Metais Pesados , Poluentes do Solo , Humanos , Adulto , Cádmio/análise , Arsênio/análise , Chumbo , Solo , Poluentes do Solo/análise , China , Metais Pesados/análise , Verduras , Mineração , Medição de Risco , Monitoramento AmbientalRESUMO
Lead is one of the heavy metals that is toxic and widely distributed in the environment, and children are more sensitive to the toxic effects of lead because the blood-brain barrier and immune system are not yet well developed. The objective of the study was to investigate the clinical characteristics of lead poisoning in children aged 0â¼6 years in a hospital in Guangxi, and to provide scientific basis for the prevention and treatment of lead poisoning. We collected and analyzed the clinical data of 32 children with lead poisoning admitted to a hospital in Guangxi from 2010 to 2018. The results showed that most of the 32 cases presented with hyperactivity, irritability, poor appetite, abdominal pain, diarrhea, or constipation. The hemoglobin (HGB), mean corpusular volume (MCV), mean corpuscular hemoglobin (MCH), and hematocrit (HCT) of the lead-poisoned children were all decreased to different degrees and were below normal acceptable levels. Urinary ß2-microglobulin was increased. Blood lead levels (BLL) decreased significantly after intravenous injection of the lead chelator, calcium disodium edetate (CaNa2-EDTA). In addition, HGB returned to normal levels, while MCV, MCH, and HCT increased but remained below normal levels. Urinary ß2-microglobulin was reduced to normal levels. Therefore, in this cohort of children, the high-risk factors for lead poisoning are mainly Chinese medicines, such as baby powder. In conclusion, lead poisoning caused neurological damage and behavioral changes in children and decreased erythrocyte parameters, leading to digestive symptoms and renal impairment, which can be attenuated by CaNa2-EDTA treatment.
Assuntos
Intoxicação por Chumbo , Chumbo , Criança , Lactente , Humanos , Chumbo/toxicidade , China/epidemiologia , Ácido Edético , Intoxicação por Chumbo/epidemiologia , Intoxicação por Chumbo/etiologia , Hematócrito , HemoglobinasRESUMO
Lead (Pb) is considered to be a major environmental pollutant and occupational health hazard worldwide which may lead to neuroinflammation. However, an effective treatment for Pb-induced neuroinflammation remains elusive. The aim of this study was to investigate the mechanisms of Pb-induced neuroinflammation, and the therapeutic effect of sodium para-aminosalicylic acid (PAS-Na, a non-steroidal anti-inflammatory drug) in rat cerebral cortex. The results indicated that Pb exposure induced pathological damage in cerebral cortex, accompanied by increased levels of inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). Moreover, Pb decreased the expression of silencing information regulator 2 related enzyme 1 (SIRT1) and brain-derived neurotrophic factor (BDNF), and increased the levels of high mobile group box 1 (HMGB1) expression and p65 nuclear factor-κB (NF-κB) phosphorylation. PAS-Na treatment ameliorated Pb-induced histopathological changes in rat cerebral cortex. Moreover, PAS-Na reduced the Pb-induced increase of TNF-α and IL-1ß levels concomitant with a significant increase in SIRT1 and BDNF levels, and a decrease in HMGB1 and the phosphorylation of p65 NF-κB expression. Thus, PAS-Na may exert anti-inflammatory effects by mediating the SIRT1/HMGB1/NF-κB pathway and BDNF expression. In conclusion, in this novel study PAS-Na was shown to possess an anti-inflammatory effect on cortical neuroinflammation, establishing its efficacy as a potential treatment for Pb exposures.
Assuntos
Ácido Aminossalicílico , Proteína HMGB1 , Ratos , Animais , NF-kappa B/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína HMGB1/metabolismo , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Sódio , Sirtuína 1/metabolismo , Chumbo/toxicidade , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Anti-InflamatóriosRESUMO
Lead (Pb) is a corrosion-resistant, heavy, non-ferrous metal. Several metal chelators have been used for the treatment of Pb poisoning. However, the efficacy of sodium para-aminosalicylic acid (PAS-Na) in enhancing Pb excretion has yet to be fully characterized. Healthy male mice (90) were divided into six groups, the normal control group was intraperitoneally (i.p.) injected with saline and the remaining group of mice i.p. 120 mg/kg Pb acetate. Four hour later, mice were subcutaneously (back) injected (s.c.) with (80, 160, 240 mg/kg) PAS-Na or 240 mg/kg edetate calcium disodium (CaNa2EDTA) or an equivalent amount of saline, once per day for 6 days. After 24-h urine sample collections, the animals were anesthetized with 5% chloral hydrate and sacrificed in batches on the 2nd, 4th, or 6th day. Levels of Pb [including manganese (Mn) and copper (Cu)] in the urine, whole blood, and brain tissues were analyzed by graphite furnace atomic absorption spectrometry. The results showed that Pb exposure increased its levels in urine and blood, and PAS-Na treatment may afford antagonistic effect on Pb poisoning, suggesting that PAS-Na is a potentially effective treatment to promote excretion of Pb.
Assuntos
Ácido Aminossalicílico , Ratos , Masculino , Camundongos , Animais , Ácido Aminossalicílico/uso terapêutico , Ácido Aminossalicílico/farmacologia , Ratos Sprague-Dawley , Chumbo/toxicidade , Sódio , Quelantes/farmacologia , Quelantes/uso terapêuticoRESUMO
The antiknock additive methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese(Mn) compound. Mn neurotoxicity caused by occupational Mn exposure (mostly inorganic MnCl2) is associated with motor and cognitive disturbances, referred to as Manganism. However, the impact of environmentally relevant Mn exposure on MMT-induced Manganism is poorly understood. In this investigation, we studied the effects of MMT on motor function and brain structure, and compared its effects with those of inorganic MnCl2. After adaptive feeding for 7 days, male and female Sprague-Dawley (SD) rats in the MMT-treated groups and positive control group were treated for 8 weeks with MMT (1, 2 and 4 mg/kg/i.g.) or MnCl2·4H2O (200 mg/kg/i.g.). Mn content in blood, liver, spleen and distinct brain regions was determined by inductively coupled plasma-mass spectrometer (ICP-MS). We found that MMT and MnCl2 exposure led to slower body-weight-gain in female rats, impaired motor and balance function and spatial learning and memory both in male and female rats. HE staining showed that MMT and MnCl2 led to altered structure of the substantia nigra pars compacta (SNpc), and Nissl staining corroborated MMT's propensity to damage the SNpc both in male and female rat. In addition, Immunostaining of the SNpc showed decreased TH-positive neurons in MMT- and MnCl2-treated rats, concomitant with Iba1 activation in microglia. Moreover, no statistically significant difference was noted between the rats in the H-MMT and MnCl2 groups. In summary, these findings suggest that MMT and MnCl2 exposure cause ultrastructural changes in the SNpc neurons culminating in altered motor behavior and cognition, suggesting that altered SNpc structure and function may underline the motor and cognitive deficits inherent to Manganism, and accounting for MMT and MnCl2's manifestations of atypical parkinsonism.
Assuntos
Intoxicação por Manganês , Manganês , Animais , Cloretos , Feminino , Masculino , Manganês/toxicidade , Compostos de Manganês , Ratos , Ratos Sprague-Dawley , Substância NegraRESUMO
Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inï¬ammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efï¬cacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP3R) expression and enhanced intracellular calcium [Ca2+]i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP3R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP3R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP3R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning.
Assuntos
Ácido Aminossalicílico , Ácido Aminossalicílico/farmacologia , Animais , Apoptose , Hipocampo , Chumbo/toxicidade , Ratos , Transdução de Sinais , SódioRESUMO
Although there have been many studies identifying clinical and pathologic factors that may predict central lymph node metastases (CLNM) in papillary thyroid microcarcinoma (PTMC) patients without clinically cervical lymph node metastasis (cN0), the results were inconsistent. And whether prophylactic central lymph node dissection (pCLND) should be performed in cN0 PTMC remains controversial. The EMBASE, PubMed, MEDLINE and the Cochrane Library were searched until Oct 2015 to identify relevant studies. Primary outcomes were clinical and pathologic factors for CLNM. Secondary outcomes included CLNM rate, surgical complications of hypocalcaemia and recurrent laryngeal nerve(RLN) injury and neck recurrences. Statistical analysis was performed using Stata 12.0. Fourteen eligible studies enrolling 4573 patients were included in this meta-analysis. The overall incidence of CLNM was 33 % (95 % CI 29-37). An elevated risk of CLNM was significantly associated with male gender (OR 2.33, 95 % CI 1.71-3.17), age <45 years (OR 1.27, 95 % CI 1.08-1.48), tumor size >5 mm (OR 2.16, 95 % CI 1.87-2.50), multifocality (OR 1.73, 95 % CI 1.45-2.05), extrathyroidal extension (OR 1.99, 95 % CI 1.66-2.37) and lymphovascular invasion (OR 3.87, 95 % CI 1.64-9.10), but not with thyroid bilaterality (OR 1.41, 95 % CI 0.89-2.22) and chronic lymphocytic thyroiditis (OR 0.98, 95 % CI 0.66-1.47). The pooled frequency of permanent hypocalcaemia, permanent RLN injury and neck recurrences was 1.1, 0.5 and 2.8 %, respectively. cN0 PTMC patients have a considerable CLNM rate and have a low pooled incident of surgical complications and neck recurrences with pCLND. Six unfavorable clinical and pathologic factors, which were significantly associated with CLNM, were identified. These findings may help guide the application of pCLND or subsequent treatment in cN0 PTMC.
Assuntos
Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , Carcinoma Papilar/cirurgia , Humanos , Hipocalcemia/etiologia , Incidência , Metástase Linfática , Esvaziamento Cervical , Recidiva Local de Neoplasia , Complicações Pós-Operatórias , Traumatismos do Nervo Laríngeo Recorrente/etiologia , Fatores de Risco , Fatores Sexuais , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
BACKGROUND: Cadmium is a widespread environmental and occupational pollutant that accumulates in human body with a biological half-life exceeding 10 years. Cadmium exposure has been demonstrated to increase rates of cardiovascular diseases. Whether occupational cadmium exposure is associated with the increase in the prevalence of dyslipidemia and hence contributes to the risk of cardiovascular diseases is still equivocal. To test the hypothesis that exposure to cadmium is related to the prevalence of dyslipidemia, we examined the associations between blood cadmium concentration and the prevalence of dyslipidemia in workers occupationally exposed to cadmium in China. METHODS: A cross-sectional survey on demographic data, blood cadmium level and lipid profile in cadmium exposed workers from seven cadmium smelting factories in central and southwestern China was conducted. We measured blood cadmium concentration and lipid components of 1489 cadmium exposed workers. The prevalence of dyslipidemia was compared across blood cadmium quartiles. Associations between the blood cadmium concentrations and the prevalence of dyslipidemia were assessed using confounder adjusted linear and logistic regressions. RESULTS: The blood cadmium concentration was 3.61±0.84µg/L ( mean ±SD). The prevalence of dyslipidemia in this occupational population was 66.3%. Mean blood cadmium concentration of workers with dyslipedemia was significantly higher than that of workers without dyslipidemia (p <0.01). The prevalence of dyslipidemia increased dose-dependently with elevations in blood cadmium concentrations (p for trend <0.001). Elevated levels of blood cadmium were associated with BMI, education attainment, income, smoking status and duration of exposure (all p <0.01). Furthermore, the profile of blood lipid was obviously changed in this occupational population. The prevalence of high TC, high TG, Low HDL-C and high LDL-C rose with increases in blood cadmium levels dose-dependently (p for trend <0.001). The odds ratios (95% confidence interval) for dyslipidemia across the increasing blood cadmium quartiles were 1.21(1.16-1.55), 1.56(1.11-1.87), 1.79(1.26-2.25) respectively (referencing to 1.00; p for trend <0.001), after multivariate adjustment for BMI, education attainment, income, lifestyle factors and duration of exposure, the association between blood cadmium concentrations and the prevalence of dyslipidemia remained unchanged (all p for trend <0.001). CONCLUSION: Elevated blood cadmium concentration is associated with prevalence of dyslipidemia. Cadmium exposure could alter lipid metabolism in humans. It is imperative to control cadmium exposure of occupational population in cadmium related industries and reduce adverse health effects.
Assuntos
Cádmio/sangue , Dislipidemias/sangue , Dislipidemias/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Adulto , Feminino , Humanos , Lipídeos/sangue , Masculino , Análise Multivariada , Razão de Chances , PrevalênciaRESUMO
Essential metals play critical roles in maintaining human health as they participate in various physiological activities. Nonetheless, both excessive accumulation and deficiency of these metals may result in neurotoxicity secondary to neuroinflammation and the activation of microglia and astrocytes. Activation of these cells can promote the release of pro-inflammatory cytokines. It is well known that neuroinflammation plays a critical role in metal-induced neurotoxicity as well as the development of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Initially seen as a defense mechanism, persistent inflammatory responses are now considered harmful. Astrocytes and microglia are key regulators of neuroinflammation in the central nervous system, and their excessive activation may induce sustained neuroinflammation. Therefore, in this review, we aim to emphasize the important role and molecular mechanisms underlying metal-induced neurotoxicity. Our objective is to raise the awareness on metal-induced neuroinflammation in neurological disorders. However, it is not only just neuroinflammation that different metals could induce; they can also cause harm to the nervous system through oxidative stress, apoptosis, and autophagy, to name a few. The primary pathophysiological mechanism by which these metals induce neurological disorders remains to be determined. In addition, given the various pathways through which individuals are exposed to metals, it is necessary to also consider the effects of co-exposure to multiple metals on neurological disorders.
Assuntos
Inflamação , Metais , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Metais/efeitos adversos , Metais/toxicidade , Animais , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso/induzido quimicamente , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologiaRESUMO
Manganese (Mn) is a heavy metal that occurs widely in nature and has a vital physiological role in growth and development. However, excessive exposure to Mn can cause neurological damage, especially cognitive dysfunction, such as learning disability and memory loss. Numerous studies on the mechanisms of Mn-induced nervous system damage found that this metal targets a variety of metabolic pathways, for example, endoplasmic reticulum stress, apoptosis, neuroinflammation, cellular signaling pathway changes, and neurotransmitter metabolism interference. This article reviews the latest research progress on multiple signaling pathways related to Mn-induced neurological dysfunction.
Assuntos
Manganês , Transdução de Sinais , Humanos , Manganês/efeitos adversos , Manganês/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/metabolismo , Apoptose/efeitos dos fármacosRESUMO
We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.
Assuntos
Ácido Aminossalicílico , Manganês , Sinapses , Animais , Ratos , Células PC12 , Sinapses/efeitos dos fármacos , Masculino , Ácido Aminossalicílico/farmacologia , Manganês/toxicidade , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/metabolismo , Ratos Sprague-Dawley , Ferro/metabolismo , Fármacos Neuroprotetores/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Modelos Animais de DoençasRESUMO
Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa2-EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application.
Assuntos
Ácido Aminossalicílico , Intoxicação por Chumbo , Intoxicação por Manganês , Humanos , Animais , Ácido Aminossalicílico/uso terapêutico , Intoxicação por Manganês/tratamento farmacológico , Intoxicação por Chumbo/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Manganês/toxicidadeRESUMO
The aim of study was to address the effects of manganese and iron, alone and in combination, on apoptosis of BV2 microglia cells, and to determine if combined exposure to these metals augments their individual toxicity. We used a murine microglial BV2 cell line. Cell cytotoxicity was analyzed by propidium iodide (PI) exclusion assay. Cell ROS production was analyzed by 2', 7'-dichlorofluorescin diacetate (DCFH-DA) probe staining. Pro-inflammatory cytokine production was monitored by ELISA. Cell apoptosis was analyzed by PE Annexin V/7-AAD staining. Mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting to analyze the effect of manganese, iron alone, or their combined exposure on the activation of caspase9, P53, Bax, and Bcl2 apoptosis signaling pathways. Caspase3 activity was determined using a Colorimetric. Manganese, iron, and their combined exposure for 24 h induced the activation of BV2 microglia cells and increased ROS production and the expression of the inflammatory cytokines, IL-1ß and TNF-α. And we also found that the apoptosis rate increased, mitochondrial membrane potential decreased, apoptosis-related proteins caspase9, P53, Bax, and Bcl2 expression increased, and caspase3 activity increased. Furthermore, we found that combined manganese-iron cytotoxicity was lower than that induced by manganese exposure alone. Manganese, iron alone, or their combination exposure can induce apoptosis in glial cells. Iron can reduce the toxicity of manganese, and there is an antagonistic effect between manganese and iron.
Assuntos
Ferro , Manganês , Camundongos , Animais , Manganês/toxicidade , Manganês/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ferro/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Proteínas Reguladoras de Apoptose/metabolismoRESUMO
ETHNOPHARMACOLOGY RELEVANCE: Rohdea pachynema F.T.Wang & Tang (R. pachynema), is a traditional folk medicine used for the treatment of stomach pain, stomach ulcers, bruises, and skin infections in China. Some of the diseases may relate to microbial infections in traditional applications. However few reports on its antimicrobial properties and bioactive components. AIM OF THE STUDY: To identify its bioactive constituents against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo, and its mechanism. MATERIALS AND METHODS: The anti-MRSA ingredient 6α-O-[ß-D-xylopyranosyl-(1 â 3)-ß-D-quinovopyranosyl]-(25S)-5α-spirostan-3ß-ol (XQS) was obtained from R. pachynema by phytochemical isolation. Subsequently, XQS underwent screening using the broth microdilution method and growth inhibition curves to assess its antibacterial activity. The mechanism of XQS was evaluated by multigeneration induction, biofilm resistance assay, scanning electron microscopy, transmission electron microscopy, and metabolomics. Additionally, a mouse skin infection model was established in vivo. RESULTS: 26 compounds were identified from the R. pachynema, in which anti-MRSA spirostane saponin (XQS) was reported for the first time with a minimum inhibitory concentration (MIC) of 8 µg/mL. XQS might bind to peptidoglycan (PGN) of the cell wall, phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) of the cell membrane, then destroying the cell wall and the cell membrane, resulting in reduced membrane fluidity and membrane depolarization. Furthermore, XQS affected MRSA lipid metabolism, amino acid metabolism, and ABC transporters by metabolomics analysis, which targeted cell walls and membranes causing less susceptibility to drug resistance. Furthermore, XQS (8 mg/kg) recovered skin wounds in mice infected by MRSA effectively, superior to vancomycin (8 mg/kg). CONCLUSIONS: XQS showed anti-MRSA bioactivity in vitro and in vivo, and its mechanism association with cell walls and membranes was reported for the first, which supported the traditional uses of R. pachynema and explained its sensitivity to MRSA.
Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Saponinas , Animais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Camundongos , Saponinas/farmacologia , Saponinas/isolamento & purificação , Espirostanos/farmacologia , Espirostanos/isolamento & purificação , Biofilmes/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Feminino , Peixes , MasculinoRESUMO
Plants that grow in extreme environments represent unique sources of stress-resistance genes and mechanisms. Ammopiptanthus mongolicus (Leguminosae) is a xerophytic evergreen broadleaf shrub native to semi-arid and desert regions; however, its drought-tolerance mechanisms remain poorly understood. Here, we report the assembly of a reference-grade genome for A. mongolicus, describe its evolutionary history within the legume family, and examine its drought-tolerance mechanisms. The assembled genome is 843.07 Mb in length, with 98.7% of the sequences successfully anchored to the nine chromosomes of A. mongolicus. The genome is predicted to contain 47 611 protein-coding genes, and 70.71% of the genome is composed of repetitive sequences; these are dominated by transposable elements, particularly long-terminal-repeat retrotransposons. Evolutionary analyses revealed two whole-genome duplication (WGD) events at 130 and 58 million years ago (mya) that are shared by the genus Ammopiptanthus and other legumes, but no species-specific WGDs were found within this genus. Ancestral genome reconstruction revealed that the A. mongolicus genome has undergone fewer rearrangements than other genomes in the legume family, confirming its status as a "relict plant". Transcriptomic analyses demonstrated that genes involved in cuticular wax biosynthesis and transport are highly expressed, both under normal conditions and in response to polyethylene glycol-induced dehydration. Significant induction of genes related to ethylene biosynthesis and signaling was also observed in leaves under dehydration stress, suggesting that enhanced ethylene response and formation of thick waxy cuticles are two major mechanisms of drought tolerance in A. mongolicus. Ectopic expression of AmERF2, an ethylene response factor unique to A. mongolicus, can markedly increase the drought tolerance of transgenic Arabidopsis thaliana plants, demonstrating the potential for application of A. mongolicus genes in crop improvement.
Assuntos
Secas , Fabaceae , Genoma de Planta , Fabaceae/genética , Fabaceae/fisiologia , Estresse Fisiológico/genética , Evolução Molecular , Regulação da Expressão Gênica de Plantas , FilogeniaRESUMO
The involvement of ethylene response factor (ERF) transcription factor (TF) in the transcriptional regulation of ethylene biosynthesis genes during fruit ripening remains largely unclear. In this study, 15 ERF genes, designated as MaERF1-MaERF15, were isolated and characterized from banana fruit. These MaERFs were classified into seven of the 12 known ERF families. Subcellular localization showed that MaERF proteins of five different subfamilies preferentially localized to the nucleus. The 15 MaERF genes displayed differential expression patterns and levels in peel and pulp of banana fruit, in association with four different ripening treatments caused by natural, ethylene-induced, 1-methylcyclopropene (1-MCP)-delayed, and combined 1-MCP and ethylene treatments. MaERF9 was upregulated while MaERF11 was downregulated in peel and pulp of banana fruit during ripening or after treatment with ethylene. Furthermore, yeast-one hybrid (Y1H) and transient expression assays showed that the potential repressor MaERF11 bound to MaACS1 and MaACO1 promoters to suppress their activities and that MaERF9 activated MaACO1 promoter activity. Interestingly, protein-protein interaction analysis revealed that MaERF9 and -11 physically interacted with MaACO1. Taken together, these results suggest that MaERFs are involved in banana fruit ripening via transcriptional regulation of or interaction with ethylene biosynthesis genes.
Assuntos
Etilenos/biossíntese , Frutas/fisiologia , Genes de Plantas/fisiologia , Musa/fisiologia , Reguladores de Crescimento de Plantas/biossíntese , Sequência de Aminoácidos , Etilenos/metabolismo , Frutas/genética , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Dados de Sequência Molecular , Musa/genética , Musa/crescimento & desenvolvimento , Musa/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Alinhamento de Sequência , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Transcriptoma , Técnicas do Sistema de Duplo-HíbridoRESUMO
This retrospective observational study aims to investigate the patient-controlled intravenous analgesia (PCIA) of dexmedetomidine (DEX) with nalbuphine (NAL) versus sufentanil (SUF) for post-cesarean delivery management. A total of 300 women were evaluated who underwent cesarean section surgery with combined spinal-epidural anesthesia. After surgery, all patients were connected to a patient-controlled analgesia pump. The PCIA protocol was programmed with 0.11 µg/kg/h DEX in combination with 0.03 µg/kg/h SUF in Group I (n = 150) or 0.11 µg/kg/h DEX in combination with 0.03 mg/kg/h NAL in Group II (n = 150). There was no significant difference in incision pain and sedation level between the two groups within 48 h after the surgery assessed by visual analog scale (VAS) and Ramsay sedation scale, respectively. However, at 2, 6, 12, and 24 h after surgery, visceral pain at rest and at mobilization was alleviated in the Group II as compared with the Group I with lower VAS scores. Moreover, fewer adverse reactions were found in the Group II when compared with Group I, including postpartum respiratory depression, nausea/vomiting, urinary retention, and cardiovascular events. Overall, there was an increased patient satisfaction in the Group II as compared with the Group I. Based on the results of this study, it seems that adding NAL to PCIA with DEX, as compared to SUF with DEX, have an effect on reducing the intensity of visceral pain after cesarean section with less adverse reactions and higher patient satisfaction.
Assuntos
Analgésicos não Narcóticos , Dexmedetomidina , Nalbufina , Dor Visceral , Humanos , Feminino , Gravidez , Sufentanil/uso terapêutico , Sufentanil/efeitos adversos , Nalbufina/uso terapêutico , Dexmedetomidina/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Cesárea/efeitos adversos , Dor Visceral/induzido quimicamente , Dor Visceral/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Analgesia Controlada pelo Paciente/métodos , Administração IntravenosaRESUMO
Lead (Pb) is a developmental neurotoxin that can disrupt brain development and damage the brain regions responsible for executive function, behavioral regulation and fine motor control. Sodium para-aminosalicylic acid (PAS-Na) is a non-steroidal anti-inflammatory drug that can cross the blood-brain barrier. The purpose of this study was to examine the effects of juvenile rat Pb exposure on behavioral changes and brain inflammation, and the efficacy of PAS-Na in ameliorating these effects. The results showed that Pb exposure during the juvenile period (from weaning to adult period) delayed rats' growth development and impaired their motor learning. Pb exposure not only increased Pb concentrations in several brain regions (including hippocampus, striatum and substantia nigra), but also disrupted metal-homeostasis in the brain, as higher levels of iron (Fe) and calcium (Ca) were observed in the substantia nigra. Moreover, Pb activated the MAPK pathway and increased levels of inflammatory factors such as IL-1ß, TNF-α and IL-6 in the hippocampus, striatum and substantia nigra. Furthermore, Pb increased the levels of alpha-synuclein (α-syn) in these brain sites. PAS-Na improved the motor deficits and brain inflammation in the Pb-exposed rats. Moreover, the elevated Pb, Fe and Ca concentrations in the brain were significantly reduced by PAS-Na, which contains amino, carboxyl and hydroxyl functional groups, suggesting that it may act as a chelator of brain metals. In addition, PAS-Na inhibited the Pb-induced MAPK pathway activation and α-syn accumulation in the same brain regions. Taken together, our novel study suggest that PAS-Na shows efficacy in improving the Pb-induced behavioral changes in rats by inhibiting MAPK-dependent inflammatory pathways and reducing α-syn accumulation.
Assuntos
Ácido Aminossalicílico , Encefalite , Ratos , Animais , Ácido Aminossalicílico/farmacologia , Ácido Aminossalicílico/uso terapêutico , alfa-Sinucleína , Chumbo/toxicidade , Doenças Neuroinflamatórias , Sódio , Encéfalo , Encefalite/induzido quimicamente , Encefalite/tratamento farmacológico , Sistema de Sinalização das MAP QuinasesRESUMO
Lead (Pb) is a common heavy metal contaminant in the environment, and it may perturb autophagy and cause neurodegeneration. Although sodium para-aminosalicylic (PAS-Na) has been shown to protect the brain from lead-induced toxicity, the mechanisms associated with its efficacy have yet to be fully understood. In this study, we evaluated the efficacy of PAS-Na in attenuating the neurotoxic effects of lead, as well as the specific mechanisms that mediate such protection. Lead exposure resulted in weight loss and injury to the liver and kidney, and PAS-Na had a protective effect against this damage. Both short-term and subchronic lead exposure impaired learning ability, and this effect was reversed by PAS-Na intervention. Lead exposure also perturbed autophagic processes through the modulation of autophagy-related factors. Short-term lead exposure downregulated LC3 and beclin1 and upregulated the expression of p62; subchronic lead exposure upregulated the expression of LC3, beclin1, and P62. It follows that PAS-Na had an antagonistic effect on the activation of the above autophagy-related factors. Overall, our novel findings suggest that PAS-Na can protect the rat cortex from lead-induced toxicity by regulating autophagic processes. (1) Short-term lead exposure inhibits autophagy, whereas subchronic lead exposure promotes autophagy. (2) PAS-NA ameliorated the abnormal process of lead-induced autophagy, which had a protective effect on the cerebral cortex.