RESUMO
Objective: Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globally. A better understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,ß-unsaturated aldehyde, is a common dietary and environmental pollutant. Design: The role of acrolein and the potential protective action of acrolein scavengers in DN were investigated using high-fat diet/ streptozotocin-induced DN mice and in vitro DN cellular models. Methods: Acrolein-protein conjugates (Acr-PCs) in kidney tissues were examined using immunohistochemistry. Renin-angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an established Acr-PC ELISA system. Results: We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathways, increasing inflammatory cytokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD patients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function. Conclusions: These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN.
Assuntos
Carnosina , Diabetes Mellitus , Nefropatias Diabéticas , Poluentes Ambientais , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Acroleína/metabolismo , Acroleína/farmacologia , Acroleína/uso terapêutico , Animais , Carnosina/metabolismo , Carnosina/farmacologia , Carnosina/uso terapêutico , Citocinas , Diabetes Mellitus/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Poluentes Ambientais/metabolismo , Poluentes Ambientais/farmacologia , Poluentes Ambientais/uso terapêutico , Células HEK293 , Humanos , Hidralazina/metabolismo , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Rim/metabolismo , Camundongos , Estreptozocina/metabolismo , Estreptozocina/farmacologia , Estreptozocina/uso terapêuticoRESUMO
Arsenic is a well-known environmental pollutant due to its toxicity, which can do harm to animals and human. Curcumin is a polyphenolic compound derived from turmeric, commonly accepted to have antioxidant properties. However, whether curcumin can ameliorate the damage caused by arsenic trioxide (ATO) in duck skeletal muscle remains largely unknown. Therefore, the present study aims to investigate the potential molecular mechanism of curcumin against ATO-induced skeletal muscle injury. The results showed that treating with curcumin could attenuate body weight loss induced by ATO and reduced arsenic content accumulation in the skeletal muscle of duck. Curcumin was also able to alleviated the oxidative stress triggered by ATO, which was manifested by the increase of T-AOC and SOD, and MDA decrease. Moreover, we observed that curcumin could ease mitochondrial damage and vacuolate degeneration of nucleus. Our further investigation found that ATO disrupted normal mitochondrial fission/fusion (Drp1, OPA1, Mfn1/2) and restrained mitochondrial biogenesis (PGC-1α, Nrf1/2, TFAM), while curcumin could promote mitochondrial fusion and activated PGC-1α pathway. Furthermore, curcumin was found that it could not only reduce the mRNA and protein levels of mitophagy (PINK1, Parkin, LC3, p62) and pro-apoptotic genes (p53, Bax, Caspase-3, Cytc), but also increased the levels of anti-apoptotic genes (Bcl-2). In conclusion, curcumin was able to alleviate ATO-induced skeletal muscle damage by improving mitophagy and preserving mitochondrial function, which can serve as a novel strategy to take precautions against ATO toxicity.
Assuntos
Arsênio/toxicidade , Curcumina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biologia Computacional , Patos , Poluentes Ambientais/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
Previously we demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed experimental autoimmune encephalomyelitis (EAE), a model to study multiple sclerosis (MS), through induction of regulatory T cells (Tregs) and suppression of effector T cell function in the spleen. Since B cells and specifically regulatory B cells (Bregs) have been shown to be so critical in the pathology associated with EAE and MS, we wanted to determine whether TCDD could also induce Bregs. We specifically hypothesized that a Fas ligand (FasL)+ Breg population would be induced by TCDD in EAE thereby triggering apoptosis in Fas-expressing effector T cells as one mechanism to account for inhibition of T cell function by TCDD. TCDD (0.1-2.5 µg/kg/day administered orally for 12 days) modestly increased the percentage of FasL + B cells in the spleen and spinal cord in TCDD-treated EAE mice. However, we did not detect significant increases in percentages of FasL + B cells using TCDD in vitro in mouse splenocytes or human peripheral blood mononuclear cells (PBMCs). Part of the modest effect by TCDD was likely related to the localized expression of FasL; for instance, in the spleen, FasL was more highly expressed by IgMhiIgDlo marginal zone (MZ) B cells, but IgMloIgDhi follicular (FO) B cells were more responsive to TCDD. Consistent with our observation of modest upregulation of FasL, we also observed modest changes in mitochondrial membrane potential in T cells co-cultured with isolated total B cells or IgM-depleted (i.e., FO-enriched) B cells from TCDD-treated EAE mice. These data suggest that while small microenvironments of apoptosis might be occurring in T cells in response to TCDD-treated B cells, it is not a major mechanism by which T cell function is compromised by TCDD in EAE. TCDD did robustly suppress IgG production systemically and in spleen and spinal cord B cells at end stage disease. Thus, these studies show that TCDD's primary effect on B cells in EAE is compromised IgG production but not FasL + Breg induction.
Assuntos
Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Proteína Ligante Fas/biossíntese , Imunoglobulina G/metabolismo , Dibenzodioxinas Policloradas/uso terapêutico , Animais , Linfócitos B/efeitos dos fármacos , Células Cultivadas , Poluentes Ambientais/farmacologia , Poluentes Ambientais/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Dibenzodioxinas Policloradas/farmacologiaRESUMO
In this review, we present the environmental perspectives of the viruses and antiviral drugs related to SARS-CoV-2. The present review paper discusses occurrence, fate, transport, susceptibility, and inactivation mechanisms of viruses in the environment as well as environmental occurrence and fate of antiviral drugs, and prospects (prevalence and occurrence) of antiviral drug resistance (both antiviral drug resistant viruses and antiviral resistance in the human). During winter, the number of viral disease cases and environmental occurrence of antiviral drug surge due to various biotic and abiotic factors such as transmission pathways, human behaviour, susceptibility, and immunity as well as cold climatic conditions. Adsorption and persistence critically determine the fate and transport of viruses in the environment. Inactivation and disinfection of virus include UV, alcohol, and other chemical-base methods but the susceptibility of virus against these methods varies. Wastewater treatment plants (WWTPs) are major reserviors of antiviral drugs and their metabolites and transformation products. Ecotoxicity of antiviral drug residues against aquatic organisms have been reported, however more threatening is the development of antiviral resistance, both in humans and in wild animal reservoirs. In particular, emergence of antiviral drug-resistant viruses via exposure of wild animals to high loads of antiviral residues during the current pandemic needs further evaluation.
Assuntos
Antivirais , Farmacorresistência Viral/efeitos dos fármacos , Microbiologia Ambiental , Poluentes Ambientais , SARS-CoV-2 , Inativação de Vírus , Adsorção , Animais , Antivirais/química , Antivirais/uso terapêutico , Antivirais/toxicidade , Organismos Aquáticos/efeitos dos fármacos , COVID-19/epidemiologia , COVID-19/etiologia , Ecotoxicologia , Poluentes Ambientais/química , Poluentes Ambientais/uso terapêutico , Poluentes Ambientais/toxicidade , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Estações do Ano , Inativação de Vírus/efeitos dos fármacos , Inativação de Vírus/efeitos da radiação , Purificação da Água , Tratamento Farmacológico da COVID-19RESUMO
Metal oxide affinity chromatography (MOAC) is one of the most commonly used techniques for selective isolation phosphoproteins and phosphopeptides. This technique is capable of capturing the phosphorylated biomolecules through the affinity of the phosphoryl group for metal oxides/hydroxides. Fly-ash (FA), a by-product of coal-combustion power plants, is primarily composed of oxides of silicon and metals, among which iron and titanium. A number of studies have demonstrated the potential of these metal oxides for phosphoprotein and phosphopeptide enrichment. FA is annually produced over hundred million tons worldwide and generally considered as hazardous waste. It is thus of great importance to enhance its utilization. Here we present the first demonstration of the utility of FA as a low-cost MOAC material for the enrichment of phosphoproteins. With an FA-microcolumn, phosphoproteins can be successfully sequestered from other proteins. FA-microcolumns are shown to be simple, cheap and selective devices for phosphoprotein enrichment from a small volume of mixtures.
Assuntos
Cinza de Carvão/uso terapêutico , Poluentes Ambientais/uso terapêutico , Fosfoproteínas/química , Adsorção , Cinza de Carvão/farmacologia , Poluentes Ambientais/farmacologia , Fosfoproteínas/metabolismoRESUMO
Chemotherapy treatment of cancer patients has shifted from inpatient to outpatient administration. Thus, family members are potentially exposed to cytotoxic drug residues from patients' excretions inside their homes. The study's aim was to evaluate the surface contamination and the potential uptake of antineoplastic drug residues by family members at home of chemotherapy patients. Overall, 265 wipe samples from 13 homes were taken at two times after chemotherapy from different surfaces (toilet, bathroom, kitchen). 62 urine samples were collected from patients and family members on three days. Samples were analyzed for cyclophosphamide, 5-fluorouracil (urine: FBAL) and platinum (as marker for cis-, carbo- and oxaliplatin). Substantial contamination was found on every surface type (PT: 0.02-42.5pg/cm2, 5-FU: ND-98.3pg/cm2, CP: ND-283.3pg/cm2) with highest concentrations on toilet and bathroom surfaces. While patients' urinary drug concentrations often were elevated for more than 48h after administration, no drug residues were detectable in the family members' urine. This study provided an insight in the exposure situation against antineoplastic drug residues at home of chemotherapy patients. As contamination could be found on various surfaces adequate hygienic and protective measures are necessary to minimize the exposure risk for cohabitants.
Assuntos
Antineoplásicos/análise , Poluentes Ambientais/análise , Habitação , Adulto , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/urina , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Ciclofosfamida/análise , Ciclofosfamida/uso terapêutico , Ciclofosfamida/urina , Monitoramento Ambiental , Poluentes Ambientais/uso terapêutico , Poluentes Ambientais/urina , Família , Feminino , Fluoruracila/análise , Fluoruracila/uso terapêutico , Fluoruracila/urina , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/urina , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Platina/análise , Platina/urinaRESUMO
This paper assesses how medicine adopted the threshold dose-response to evaluate health effects of drugs and chemicals throughout the 20th century to the present. Homeopathy first adopted the biphasic dose-response, making it an explanatory principle. Medicine used its influence to discredit the biphasic dose-response model to harm homeopathy and to promote its alternative, the threshold dose-response. However, it failed to validate the capacity of its model to make accurate predictions in the low-dose zone. Recent attempts to validate the threshold dose-response indicate that it poorly predicts responses below the threshold. The long marginalized biphasic/hormetic dose-response model made accurate predictions in these validation studies. The failure to accept the possibility of the hormetic-biphasic dose-response during toxicology's dose-response concept formative period, while adopting the threshold model, and later the linear no-threshold model for carcinogens, led toxicology to adopt a hazard assessment process that involved testing only a few very high doses. This created the framework that toxicology was a discipline that only studied harmful responses, ignoring the possibility of benefit at low doses by the induction of adaptive mechanisms. Toxicology needs to assess the entire dose-response continuum, incorporating both harmful and beneficial effects into the risk assessment process.
Assuntos
Ecotoxicologia/métodos , Poluentes Ambientais/toxicidade , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Relação Dose-Resposta a Droga , Ecotoxicologia/história , Poluentes Ambientais/farmacologia , Poluentes Ambientais/uso terapêutico , Previsões , História do Século XX , Homeopatia/história , Homeopatia/métodos , Hormese , Humanos , Projetos de Pesquisa , Risco , Medição de Risco/métodosRESUMO
Antibiotics are among the most successful drugs used for human therapy. However, since they can challenge microbial populations, they must be considered as important pollutants as well. Besides being used for human therapy, antibiotics are extensively used for animal farming and for agricultural purposes. Residues from human environments and from farms may contain antibiotics and antibiotic resistance genes that can contaminate natural environments. The clearest consequence of antibiotic release in natural environments is the selection of resistant bacteria. The same resistance genes found at clinical settings are currently disseminated among pristine ecosystems without any record of antibiotic contamination. Nevertheless, the effect of antibiotics on the biosphere is wider than this and can impact the structure and activity of environmental microbiota. Along the article, we review the impact that pollution by antibiotics or by antibiotic resistance genes may have for both human health and for the evolution of environmental microbial populations.
Assuntos
Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Bactérias/genética , Resistência Microbiana a Medicamentos , Poluentes Ambientais/toxicidade , Poluição Ambiental , Antibacterianos/análise , Antibacterianos/uso terapêutico , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana , Tratamento Farmacológico , Ecossistema , Poluentes Ambientais/análise , Poluentes Ambientais/uso terapêutico , HumanosAssuntos
Cádmio/toxicidade , Poluentes Ambientais/uso terapêutico , Hipertensão/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Hipertensão/fisiopatologia , Calicreínas/urina , Masculino , Ratos , Ratos Wistar , Verapamil/farmacologiaRESUMO
Chlorinated aromatic contaminants are active in carcinogenic processes within the skin and may have the potential to modulate ultraviolet radiation (UV)-induced skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans) during the irradiation phase of photocarcinogenesis was associated with significant (P < or = 0.001) reductions in papilloma incidence and squamous cell carcinoma multiplicity at irradiated skin sites. This protective effect was associated with significantly (P < 0.0001) reduced chronic epidermal thickening in UV and contaminant-exposed mice compared with mice exposed to UV only. Contaminant exposure was also associated with increased UV absorbance of skin methanol extracts implying a sunscreen-like effect.
Assuntos
Carcinoma de Células Escamosas/prevenção & controle , Poluentes Ambientais/uso terapêutico , Neoplasias Induzidas por Radiação/prevenção & controle , Papiloma/prevenção & controle , Dibenzodioxinas Policloradas/análogos & derivados , Neoplasias Cutâneas/prevenção & controle , Poluentes do Solo/uso terapêutico , Animais , Benzofuranos/uso terapêutico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Dibenzofuranos Policlorados , Feminino , Metanol/metabolismo , Camundongos , Camundongos Pelados , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Papiloma/etiologia , Papiloma/patologia , Bifenilos Policlorados/uso terapêutico , Dibenzodioxinas Policloradas/uso terapêutico , Pele/efeitos da radiação , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Raios UltravioletaRESUMO
There is no effective treatment for patients with pulmonary hypertension because of the lack of a selective pulmonary vasodilator. Recently, nitric oxide (NO) has been found to be the endothelium-derived factor that produces relaxation of the vascular smooth muscle. This discovery has led to the experimental use of inhaled NO as the first selective pulmonary vasodilator. This review summarizes the development of NO inhalation for pulmonary hypertension, including the essential aspects of basic research, which identified NO as a potent endogenous vasodilator. The use of inhaled NO in animal studies of experimental pulmonary hypertension, as well as in the clinical experience so far reported in newborns, children, and adults are summarized. It is concluded that inhaled NO remains experimental and that controlled clinical trials and further studies on potential toxicity are needed before this new therapy can be accepted for routine clinical use.