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1.
Braz J Biol ; 83: e242942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468508

RESUMO

Thimerosal is an organomercurial compound, which is used in the preparation of intramuscular immunoglobulin, antivenoms, tattoo inks, skin test antigens, nasal products, ophthalmic drops, and vaccines as a preservative. In most of animal species and humans, the kidney is one of the main sites for mercurial compounds deposition and target organs for toxicity. So, the current research was intended to assess the thimerosal induced nephrotoxicity in male rats. Twenty-four adult male albino rats were categorized into four groups. The first group was a control group. Rats of Group-II, Group-III, and Group-IV were administered with 0.5µg/kg, 10µg/kg, and 50µg/kg of thimerosal once a day, respectively. Thimerosal administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), glutathione (GSH), and protein content while increased the thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) levels dose-dependently. Blood urea nitrogen (BUN), creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, urinary albumin and creatinine clearance was reduced dose-dependently in thimerosal treated groups. The results demonstrated that thimerosal significantly increased the inflammation indicators including nuclear factor kappaB (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities, DNA and histopathological damages dose-dependently. So, the present findings ascertained that thimerosal exerted nephrotoxicity in male albino rats.


Assuntos
Estresse Oxidativo , Timerosal , Animais , Peróxido de Hidrogênio/metabolismo , Rim , Masculino , Ratos , Superóxido Dismutase/metabolismo , Timerosal/metabolismo , Timerosal/toxicidade
2.
Biochem Biophys Res Commun ; 562: 105-111, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34049203

RESUMO

Sperm head-to-head agglutination is a well-known known phenomenon in mammalian and non-mammalian species. Although several factors have been reported to induce sperm agglutination, information on the trigger and process of sperm detachment from the agglutination is scarce. Since hyperactivated motility is involved in bovine sperm detachment from the oviduct, we focused on caffeine, a well-known hyperactivation inducer, and aimed to determine the role of caffeine in sperm detachment from agglutination. Agglutination rate of bovine sperm was significantly decreased upon incubation with caffeine following pre-incubation without caffeine. Additionally, we observed that bovine sperm were detached from agglutination only when the medium contained caffeine. The detached sperm showed more asymmetrical flagellar beating compared to the undetached motile sperm, regardless of whether before or after the detachment. Intriguingly, some sperm that detached from agglutination re-agglutinated with different sperm agglutination. These findings indicated caffeine as a trigger for sperm detachment from the agglutination in bull. Furthermore, another well-known hyperactivation inducer, thimerosal, also significantly reduced the sperm agglutination rate. Overall, the study demonstrated the complete process of sperm detachment from sperm head-to-head agglutination and proposed that hyperactivated motility facilitates sperm detachment from another sperm. These findings would provide a better understanding of sperm physiology and fertilization process in mammals.


Assuntos
Cafeína/farmacologia , Aglutinação Espermática/efeitos dos fármacos , Cabeça do Espermatozoide/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Animais , Bovinos , Masculino , Progesterona/farmacologia , Timerosal/farmacologia
3.
J Pharm Sci ; 110(3): 1054-1066, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33278412

RESUMO

In a companion paper, a two-step developability assessment is presented to rapidly evaluate low-cost formulations (multi-dose, aluminum-adjuvanted) for new subunit vaccine candidates. As a case study, a non-replicating rotavirus (NRRV) recombinant protein antigen P[4] was found to be destabilized by the vaccine preservative thimerosal, and this effect was mitigated by modification of the free cysteine (C173S). In this work, the mechanism(s) of thimerosal-P[4] protein interactions, along with subsequent effects on the P[4] protein's structural integrity, are determined. Reversible complexation of ethylmercury, a thimerosal degradation byproduct, with the single cysteine residue of P[4] protein is demonstrated by intact protein mass analysis and biophysical studies. A working mechanism involving a reversible S-Hg coordinate bond is presented based on the literature. This reaction increased the local backbone flexibility of P[4] within the helical region surrounding the cysteine residue and then caused more global destabilization, both as detected by HX-MS. These effects correlate with changes in antibody-P[4] binding parameters and alterations in P[4] conformational stability due to C173S modification. Epitope mapping by HX-MS demonstrated involvement of the same cysteine-containing helical region of P[4] in antibody-antigen binding. Future formulation challenges to develop low-cost, multi-dose formulations for new recombinant protein vaccine candidates are discussed.


Assuntos
Rotavirus , Timerosal , Antígenos Virais , Conservantes Farmacêuticos , Vacinas de Subunidades
4.
Talanta ; 221: 121545, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33076104

RESUMO

CdTe quantum dots (CdTe QD) have been produced at different times of synthesis (1, 2, and 4 h) using thiols as capping agents: mercaptopropionic acid (MPA), mercaptosuccinic acid (MSA) and N-acetyl-l-cysteine (NAC) using water as a solvent. The produced CdTe QD were characterized by UV-vis and photoluminescence (PL) spectroscopy and showed a relationship among reflux time, size, and spectroscopic properties. CdTe QD were shown to interact with thimerosal (TM), an organic mercury compound, and the PL intensity was effectively quenched, characterizing an ON-OFF process. However, the NAC capped CdTe (CdTe-NAC) at 1 h presented the best sensitivity for TM determination. Under optimized conditions, a linear range from 0.1 to 1.0 µg mL-1 (0.25-2.5 µM) and a LOD of 26.6 µg L-1 (66.7 nM) were achieved. The influence of different mercuric species [Hg(II), methylmercury, ethylmercury, and phenylmercury], along with thiosalicylic acid (TSA), and other ionic species on the sensitivity of the method and the interaction mechanism between TM and CdTe-NAC have been discussed. The method was successfully applied for direct quantification of TM in vaccines, and the results were validated by cold vapor atomic fluorescence spectroscopy (CV AFS). Finally, the proposed method proved to be fast, sensitive, and simple for suitable use in vaccine quality control.


Assuntos
Compostos de Cádmio , Pontos Quânticos , Vacinas , Corantes Fluorescentes , Compostos de Sulfidrila , Telúrio , Timerosal
5.
7.
Environ Res ; 188: 109734, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544722

RESUMO

Aluminum and mercury are environmentally ubiquitous. Individually they are both neurotoxic elements with shared neuro-pathogenic pathways: oxidative stress, altered neurotransmission, and disruption of the neuroendocrine and immune systems. In the infant, Al and Hg differ in type of exposure, absorption, distribution (brain access), and metabolism. In environmentally associated exposure (breast milk and infant formulas) their co-occurrences fluctuate randomly, but in Thimerosal-containing vaccines (TCVs) they occur combined in a proprietary ratio; in these cases, low-doses of Thimerosal-ethylmercury (EtHg) and adjuvant-Al present the most widespread binary mixture in less developed countries. Although experimental studies at low doses of the binary Hg and Al mixture are rare, when studied individually they have been shown to affect neurological outcomes negatively. In invitro systems, comparative neurotoxicity between Al and Hg varies in relation to the measured parameters but seems less for Al than for Hg. While neurotoxicity of environmental Hg (mainly fish methyl-Hg, MeHg) is associated with neurobehavioral outcomes in children, environmental Al is not associated, except in certain clinical conditions. Therefore, the issues of their neurotoxic effects (singly or combined) are discussed. In the infant (up to six months) the organic-Hg and Al body burdens from a full TCV schedule are estimated to reach levels higher than that originating from breastfeeding or from high aluminum soy-based formulas. Despite worldwide exposure to both Al and Hg (inorganic Hg, MeHg, and Thimerosal/EtHg), our knowledge on this combined exposure is insufficient to predict their combined neurotoxic effects (and with other co-occurring neurotoxicants).


Assuntos
Mercúrio , Compostos de Metilmercúrio , Vacinas , Alumínio/toxicidade , Animais , Carga Corporal (Radioterapia) , Criança , Feminino , Humanos , Lactente , Mercúrio/toxicidade , Leite Humano , Síndromes Neurotóxicas/epidemiologia , Timerosal/toxicidade
8.
mSphere ; 5(3)2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404512

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS coronavirus 2, or SARS-CoV-2) is the cause of the respiratory infection known as COVID-19. From an immunopathological standpoint, coronaviruses such as SARS-CoV-2 induce increased levels of a variety of T-helper 1 (Th1) and inflammatory cytokines and chemokines, including interleukin-1 (IL-1), IL-6, CCL2 protein, and CXCL10 protein. In the absence of proven antiviral agents or an effective vaccine, substances with immunomodulatory activity may be able to inhibit inflammatory and Th1 cytokines and/or yield an anti-inflammatory and/or Th2 immune response to counteract COVID-19 symptoms and severity. This report briefly describes the following four unconventional but commercially accessible immunomodulatory agents that can be employed in clinical trials to evaluate their effectiveness at alleviating disease symptoms and severity: low-dose oral interferon alpha, microdose DNA, low-dose thimerosal, and phytocannabinoids.


Assuntos
Canabinoides/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , DNA/uso terapêutico , Imunomodulação , Interferon-alfa/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Timerosal/uso terapêutico , Betacoronavirus , COVID-19 , Citocinas/imunologia , Humanos , Pandemias , Compostos Fitoquímicos/uso terapêutico , SARS-CoV-2
10.
Talanta ; 215: 120938, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32312472

RESUMO

Thiomersal is an organomercury derivative that degrades producing thiosalicylic acid, dithiobenzoic acid and ethylmercury. It is widely used in topical pharmaceutical preparations and as preservative in vaccines and cosmetics. In this work, an electro-analytical method for thiomersal was developed using graphene quantum dots (GQDs) as a surface modifier of a glassy carbon electrode. The method rely on using square-wave voltammetry and exploring the synergistic effect between GQDs, visible radiation and the applied potential in producing very intense Hg oxidation peak during the anodic scan. A linear voltammetric response was obtained for the analyte in the concentration range from 3.0 µmol L-1 (1.2 µg mL-1) to 32 µmol L-1 (12 µg mL-1), with a detection limit of 0.9 µmol L-1 (0.34 µg mL-1). The proposed method was successfully applied for thiomersal determination in influenza vaccine.


Assuntos
Carbono/química , Técnicas Eletroquímicas , Vacinas contra Influenza/química , Pontos Quânticos/química , Timerosal/análise , Eletrodos , Tamanho da Partícula , Processos Fotoquímicos , Propriedades de Superfície
11.
Int J Biol Macromol ; 154: 661-671, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198046

RESUMO

Thimerosal (TH), an organomercurial compound, is used as a preservative in vaccines and cosmetics. Its interaction with human hemoglobin (Hb) was investigated under physiological conditions using biophysical and biological assays, aiming to evaluate hazardous effects. TH interacts spontaneously with Hb (stoichiometry 2:1, ligand-protein), preferably by electrostatic forces, with a binding constant of 1.41 × 106 M-1. Spectroscopic data allows to proposing that TH induces structural changes in Hg, through ethylmercury transfer to human Hb-Cys93 residues, forming thiosalicylic acid, which, in turn, interacts with the positive side of the amino acid in the Hb-HgEt adduct chain. As a consequence, inhibition of Hb-O2 binding capacity up to 72% (human Hb), and 50% (human erythrocytes), was verified. Dose-dependent induction of TH forming advanced glycation end products (AGE) and protein aggregates (amyloids) was additionally observed. Finally, these results highlight the toxic potential of the use of TH in biological systems, with a consequent risk to human health.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hemoglobinas/metabolismo , Oxigênio/metabolismo , Conservantes Farmacêuticos/toxicidade , Timerosal/toxicidade , Humanos
12.
Vaccine ; 38(9): 2216-2220, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32014269

RESUMO

BACKGROUND: The discussion on the safety of thimerosal-containing vaccines (TCVs) and their impact on child development it́s very relevant. METHODS: This is a cohort study with mother-child dyads who received prenatal care in the Unified Health System. The domains of motor, cognitive and language development were evaluated in children between 24 and 36 months of age. Data on vaccination were obtained through the child's immunization record. A linear regression analysis was carried out considering possible confounders. RESULTS: In bivariate analyses, motor and language development were associated with TCVs (p < 0.05). However, in the multivariate analysis, this association was not maintained (p > 0.05). These results indicate that the use of TCVs is not associated with child development. The importance of this study is summarized in transmitting relevant information regarding public health, based on reliable data.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Conservantes Farmacêuticos , Timerosal , Vacinas , Brasil , Pré-Escolar , Estudos de Coortes , Humanos , Conservantes Farmacêuticos/efeitos adversos , Timerosal/efeitos adversos , Vacinação , Vacinas/efeitos adversos
13.
PLoS One ; 15(1): e0217192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945067

RESUMO

BACKGROUND: Dermatological services in Laos, South East Asia are limited to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population. OBJECTIVES: The aim of this study was to document positive patch tests in medical students without evidence of contact dermatitis in Laos. PATIENTS/MATERIALS/METHODS: One hundred and fifty medical students were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4. RESULTS: Thirty-eight students (25.3%) had a positive reaction to at least one allergen, accounting for 52 reactions in total. The proportion of the students with positive patch test reading was significantly higher in the female [33/96 (34%)] than in the male [5/54 (9%)], p<0.001. The most common allergens were: nickel (10%), gold (6.6%), thiomersal (6.6%), cobalt dichloride (2%) and p-tert-Butylphenol formaldehyde resin (2%). Balsam of Peru (0.66%), black rubber mix (0.66%), Cl+Me-Isothiazolinone (0.66%), fragrance mix 1 (0.66%), quinolone mix (0.66%), methyldibromo glutaronitrile (0.66%), mercapto mix (0.66%), epoxy resin (0.66%), paraben mix (0.66%), thiuram (0.66%) and wool alcohols (0.66%) accounted for all of the other positive reactions. CONCLUSION: This study represents the first documented patch test results in Lao medical students and in the adult Lao population. The results of this study will inform any future research into contact allergy in Laos and give an insight into the background level of contact sensitivity in this population.


Assuntos
Alérgenos/efeitos adversos , Dermatite Alérgica de Contato/diagnóstico , Testes do Emplastro , 2-Naftilamina/efeitos adversos , 2-Naftilamina/análogos & derivados , Adolescente , Adulto , Alérgenos/imunologia , Bálsamos/efeitos adversos , Cobalto/efeitos adversos , Dermatite Alérgica de Contato/imunologia , Dermatite Alérgica de Contato/patologia , Resinas Epóxi/efeitos adversos , Feminino , Ouro/efeitos adversos , Humanos , Laos , Masculino , Pessoa de Meia-Idade , Níquel/efeitos adversos , Fenilenodiaminas/efeitos adversos , Resinas Sintéticas/efeitos adversos , Estudantes de Medicina , Timerosal/efeitos adversos
15.
Environ Toxicol Pharmacol ; 74: 103312, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31841767

RESUMO

Scientific research can provide us with factual, repeatable, measurable, and determinable results. As such, scientific research can provide information that can be used in the decision-making process in the care of patients and in public policy. Although it has been suggested that ethylmercury (C2H5Hg+)-containing compounds do not cross the blood-brain barrier (BBB), this review examines the literature that addresses the question as to whether ethylmercury-containing compounds cross the BBB. The review will begin with cellular studies that provide evidence for the passive and active transport of mercury species across the BBB. Then, animal and clinical studies will be presented that specifically examine whether mercury accumulates in the brain after exposure to ethylmercury-containing compounds or Thimerosal (an ethylmercury-containing compound used as a preservative in vaccines and other drugs that metabolizes or degrades to ethylmercury-containing compounds and thiosalicylate). The results indicate that ethylmercury-containing compounds are actively transported across membranes by the L (leucine-preferring)-amino acid transport (LAT) system, the same as methylmercury-containing compounds. Further, 22 studies from 1971 to 2019 show that exposure to ethylmercury-containing compounds (intravenously, intraperitoneally, topically, subcutaneously, intramuscularly, or intranasally administered) results in accumulation of mercury in the brain. In total, these studies indicate that ethylmercury-containing compounds and Thimerosal readily cross the BBB, convert, for the most part, to highly toxic inorganic mercury-containing compounds, which significantly and persistently bind to tissues in the brain, even in the absence of concurrent detectable blood mercury levels.


Assuntos
Barreira Hematoencefálica/química , Compostos de Etilmercúrio/farmacocinética , Timerosal/farmacocinética , Animais , Transporte Biológico Ativo , Química Encefálica , Humanos
16.
J Chem Neuroanat ; 103: 101727, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31740419

RESUMO

Thimerosal (THIM) is a common preservative used in many pharmaceutical drugs, vaccines, cosmetics and many other products. Today, it was somewhat clear that Thimerosal (THIM) is a neurotoxicant preservative. We aimed to use of a suitable agent for preventing of THIM side effects on brain. Therefore, in this research, the protective effects of Alpha Lipoic Acid (ALA), against THIM-induced brain cell loss, changes in neuroimmune cell and enzymatically contents were examined. Male Wistar rats (n = 60) were randomly distributed into five groups: 1- THIM group; this group received THIM at dose of 300 µg /kg on 7, 9, 11, 15 days after birth 2- ALA group; received ALA (20 mg/kg) in the same order. 3- THIM & ALA group; this group received ALA in the same dose, 30 min before THIM administration.4& 5; Saline and ALA vehicle groups were also included. At 56th postnatal day, samples of the prefrontal cortex were collected and prepared for stereological, immune-histochemical, and enzymatic evaluations. The result showed that ALA, prevents the adverse effects of THIM on brain cell loss, abnormal changes in neuroimmune cells (p < 0.05), prefrontal cortex volume (p < 0.05), and the glutathione content of prefrontal cortex (p < 0.05). In conclusion, neonatal exposure to THIM can induce abnormal alterations in neuroimmune cells and brain cell density as well as prefrontal cortex volume & glutathione content, and ALA can ameliorate these abnormalities.


Assuntos
Morte Celular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Conservantes Farmacêuticos/farmacologia , Timerosal/farmacologia , Ácido Tióctico/farmacologia , Animais , Masculino , Tamanho do Órgão/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Ratos , Ratos Wistar
17.
J Pharm Sci ; 109(1): 476-487, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589875

RESUMO

A nonreplicating rotavirus vaccine (NRRV) containing 3 recombinant fusion proteins adsorbed to aluminum adjuvant (Alhydrogel [AH]) is currently in clinical trials. The compatibility and stability of monovalent NRRV antigen with key components of a multidose vaccine formulation were examined using physicochemical and immunochemical methods. The extent and strength of antigen-adjuvant binding were diminished by increasing phosphate concentration, and acceptable levels were identified along with alternate buffering agents. Addition of the preservative thimerosal destabilized AH-adsorbed P2-VP8-P[8] as measured by differential scanning calorimetry. Over 3 months at 4°C, AH-adsorbed P2-VP8-P[8] was stable, whereas at 25°C and 37°C, instability was observed which was greatly accelerated by thimerosal addition. Loss of antibody binding (enzyme-linked immunosorbent assay) correlated with loss of structural integrity (differential scanning calorimetry, fluorescence spectroscopy) with concomitant nonnative disulfide bond formation (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and Asn deamidation (liquid chromatography -mass spectrometry peptide mapping). An alternative preservative (2-phenoxyethanol) showed similar antigen destabilization. Due to limited availability, only key assays were performed with monovalent P2-VP8-P[4] and P2-VP8-P[6] AH-adsorbed antigens, and varying levels of preservative incompatibility were observed. In summary, monovalent AH-adsorbed NRRV antigens stored at 4°C showed good stability without preservatives; however, future formulation development efforts are required to prepare a stable, preservative-containing, multidose NRRV formulation.


Assuntos
Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Antígenos Virais/química , Conservantes Farmacêuticos/química , Vacinas contra Rotavirus/química , Timerosal/química , Proteínas Virais/química , Antígenos Virais/genética , Tampões (Química) , Composição de Medicamentos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Conformação Proteica , Estabilidade Proteica , Vacinas contra Rotavirus/genética , Temperatura , Vacinas de Subunidades/química , Vacinas Sintéticas/química , Proteínas Virais/genética
18.
J Dermatol Sci ; 95(3): 99-106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31558225

RESUMO

BACKGROUND: Thimerosal has been used as a preservative in many products which may cause contact dermatitis. It is the second most common allergen in positive patch test reactions, though being a clinical irrelevant allergen. Thimerosal-induced contact dermatitis is generally considered to be a delayed-type hypersensitivity reaction, but it is difficult to explain the fact that most patients develop an allergic reaction upon first encounter with thimerosal. Recent studies have demonstrated the association between Mas-related G protein coupled receptor X2 (MRGPRX2) and pseudo-allergic reactions which occur at the first contact with stimulation. This suggests the possibility that thimerosal may cause contact dermatitis via MRGPRX2 mediated mechanism. OBJECTIVES: To investigate the role of Mas-related G-protein coupled receptor B2 (MrgprB2)/MRGPRX2 in contact dermatitis induced by thimerosal. METHODS: Thimerosal induced pseudo-allergic reactions via MrgprB2/ MRGPRX2 were investigated using a novel skin pseudo-allergic reaction mouse model, footpad swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. RESULTS: Thimerosal induced contact dermatitis in dorsal skin and footpad swelling in wild-type mice, but had no significant effect in MrgprB2-knockout mice. Thimerosal-induced dermatitis is characterized by infiltration of inflammatory cells and elevation of serum histamine and inflammatory cytokines, rather than elevation of serum IgE level. Thimerosal increased the intracellular Ca2+ concentration in HEK293 cells overexpressing MrgprB2/MRGPRX2. Downregulation of MRGPRX2 resulted in the reduced degranulation of LAD2 human mast cells. CONCLUSIONS: MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis.


Assuntos
Dermatite de Contato/etiologia , Hipersensibilidade Tardia/etiologia , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Conservantes Farmacêuticos/toxicidade , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Timerosal/efeitos adversos , Administração Cutânea , Animais , Degranulação Celular/efeitos dos fármacos , Dermatite de Contato/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Hipersensibilidade Tardia/patologia , Masculino , Mastócitos/patologia , Camundongos , Camundongos Knockout , Conservantes Farmacêuticos/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Timerosal/administração & dosagem
19.
Eur J Pharm Biopharm ; 141: 221-231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154067

RESUMO

Thimerosal has been widely used as a preservative in human vaccines for decades. Thimerosal, a thiol capping agent with ethyl mercury being the active degradant, could have impacts on the vaccine potency due to potential thiol modification. The effects on the antigenicity and immunogenicity of human papillomavirus (HPV) virus-like particles (VLPs) in the presence of thimerosal was studied. In general, reduced binding activity was observed between HPV antigens and monoclonal antibodies (mAbs) upon thimerosal treatment, accompanied by reduced protein conformational stability. The immunogenicity of a pentavalent vaccine formulation (HPV6, HPV11, HPV16, HPV18 and hepatitis E virus) with or without thimerosal was studied in mice. The functional antibody titres, as well as the binding titres, were determined, showing a substantial decrease for vaccine formulations containing thimerosal for HPV16/18. Similarly, epitope-specific competition assays using specific and functional mAbs as tracers also showed a significant reduction in immunogenicity for HPV16/18 in the presence of thimerosal. Structural alterations in the capsid protein for HPV18 were observed with cryo-electron microscopy and 3-dimensional reconstruction in the comparative structural analysis. The results should alert scientists in formulation development field on the choice for vaccine preservatives, in particular for thiol-containing antigens.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos Virais/imunologia , Papillomaviridae/imunologia , Timerosal/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Proteínas do Capsídeo/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Vacinação/métodos
20.
Biol Reprod ; 101(2): 338-346, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201423

RESUMO

Mammalian oocytes are stored in the ovary for prolonged periods, and arrested in meiotic prophase. During this period, their plasma membranes are constantly being recycled by endocytosis and exocytosis. However, the function of this membrane turnover is unknown. Here, we investigated the requirement for exocytosis in the maintenance of meiotic arrest. Using Trim-away, a newly developed method for rapidly and specifically depleting proteins in oocytes, we have identified the SNARE protein, SNAP23, to be required for meiotic arrest. Degradation of SNAP23 causes premature meiotic resumption in follicle-enclosed oocytes. The reduction in SNAP23 is associated with loss of gap junction communication between the oocyte and surrounding follicle cells. Reduction of SNAP23 protein also inhibits regulated exocytosis in response to a Ca2+ stimulus (cortical granule exocytosis), as measured by lectin staining and cleavage of ZP2. Our results show an essential role for SNAP23 in two key processes that occur in mouse oocytes and eggs.


Assuntos
Exocitose/fisiologia , Oócitos/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Animais , Cálcio/metabolismo , Técnicas de Cultura de Células , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Meiose/fisiologia , Camundongos , Oócitos/efeitos dos fármacos , Folículo Ovariano , Conservantes Farmacêuticos , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Proteína 25 Associada a Sinaptossoma/genética , Proteína 25 Associada a Sinaptossoma/metabolismo , Timerosal/farmacologia
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