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1.
Mol Pharm ; 19(2): 720-727, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34936367

RESUMO

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of 18F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and 18F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, 18F-PEG3-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and 18F-PEG2-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved 68Ga-PSMA-11, the newly developed 18F-PEG3-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, 18F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents 18F-PEG2-VS-PSMAi and 18F-PEG3-VS-PSMAi warrant further evaluation in prostate cancer patients.


Assuntos
Próstata , Neoplasias da Próstata , Animais , Antígenos de Superfície , Linhagem Celular Tumoral , Radioisótopos de Flúor/farmacocinética , Isótopos de Gálio , Radioisótopos de Gálio , Glutamato Carboxipeptidase II , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/farmacocinética , Sulfonas
2.
J Cancer Res Ther ; 18(2): 516-524, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35645123

RESUMO

Objectives: The real-world intracranial efficacy data of ceritinib at a dose of 450 mg quaque die (QD) are currently unavailable. Therefore, we evaluated the intracranial efficacy of ceritinib (450 mg QD) in anaplastic lymphoma kinase (ALK)-rearrangement NSCLC patients in China. Materials and Methods: In total, 57 ALK-rearrangement NSCLC patients with brain metastases (BM) were enrolled retrospectively in this real-world study. Of these, 53 patients experienced progression at baseline during or after prior crizotinib administration, and 24 patients received prior brain radiotherapy. Patients received ceritinib (450 mg QD) treatment. Intracranial efficacy [objective response rate (ORR) and disease control rate (DCR)] was evaluated according to the Response Assessment in Neuro-Oncology (RANO) standard; progression-free survival (PFS) and adverse events (AEs) data were obtained through follow-ups. Results: The intracranial ORR and DCR of ceritinib were 73.7% and 93.0%, respectively. The median intracranial PFS in patients reaching the endpoint was 8.75 months, whereas the median intracranial PFS in all patients was not reached and predicted to be not evaluable (NE) (95% CI: 12.9-NE). The estimated 12-month event-free probability (EFP) of intracranial lesions was 68.1%. A subgroup analysis revealed that the estimated 12-month EFP of intracranial lesions was relatively higher in patients with prior brain radiotherapy (93.8% vs. 47.1%, P = 0.0006). Conclusion: Ceritinib administered at 450 mg QD to ALK-rearrangement NSCLC patients with BM in China exhibited superior ORR and DCR, as well as PFS and event free probability. The estimated 12-month EFP for intracranial lesions improved in patients with prior brain radiotherapy.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Aberrações Cromossômicas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pirimidinas , Estudos Retrospectivos , Sulfonas
3.
Front Endocrinol (Lausanne) ; 13: 892213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685208

RESUMO

Bisphenol A (BPA), a plasticizer and endocrine disruptor, has been substituted by bisphenol S (BPS), a structural analogue that had already shown adverse effects on granulosa cell steroidogenesis. The objective of this study was to assess the effect of chronic exposure to BPS, a possible endocrine disruptor, on steroid hormones in the ovary, oviduct and plasma using the ewe as a model. Given the interaction between steroidogenesis and the metabolic status, the BPS effect was tested according to two diet groups. Eighty adult ewes were allotted to restricted (R) and well-fed (WF) groups, that were further subdivided into two subgroups. Ewes were exposed to 50 µg BPS/kg/day in their diet (R50 and WF50 groups) or were unexposed controls (R0 and WF0 groups). After at least 3 months of BPS exposure, preovulatory follicular fluid, oviduct fluid and plasma were collected and steroid hormones were analyzed by gas chromatography coupled with tandem mass spectrometry (GC-MS/MS). A deleterious effect of restricted diet on the volume of oviduct fluid and numbers of pre-ovulatory follicles was observed. Exposure to BPS impaired estradiol concentrations in both follicular and oviduct fluids of well-fed ewes and progesterone, estradiol and estrone concentrations in plasma of restricted ewes. In addition, a significant interaction between metabolic status and BPS exposure was observed for seven steroids, including estradiol. In conclusion, BPS acts in ewes as an endocrine disruptor with differential actions according to metabolic status.


Assuntos
Disruptores Endócrinos , Animais , Disruptores Endócrinos/toxicidade , Estradiol , Feminino , Humanos , Oviductos/metabolismo , Fenóis , Progesterona/metabolismo , Ovinos , Sulfonas , Espectrometria de Massas em Tandem
4.
Front Cell Infect Microbiol ; 12: 868338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35651751

RESUMO

Biofilm-associated implant infections represent a major challenge for healthcare systems around the world due to high patient burden and enormous costs incurred. Enterococcus faecalis (E. faecalis) is the most prevalent enterococcal species identified in biofilm-associated infections. The steadily growing areas of application of implants demand a solution for the control of bacterial infections. Therefore, the development of modified anti-microbial implant materials and the testing of the behavior of different relevant bacterial strains towards them display an indispensable task. Recently, we demonstrated an anti-microbial effect of zwitterionic modified silicone rubber (LSR) against Staphylococcus aureus. The aim of this study was to evaluate bacterial colonization and biofilm formation of another clinically relevant strain, E. faecalis, on this material in comparison to two of the most commonly used thermoplastic polyurethanes (TPUs) and other modified LSR surfaces. By generating growth curves, crystal violet, and fluorescence staining, as well as analyzing the expression of biofilm-associated genes, we demonstrated no anti-microbial activity of the investigated materials against E. faecalis. These results point to the fact that anti-microbial effects of novel implant materials do not always apply across the board to all bacterial strains.


Assuntos
Aderência Bacteriana , Enterococcus faecalis , Bactérias , Biofilmes , Humanos , Polímeros , Sulfonas/metabolismo
5.
Med Oncol ; 39(8): 113, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666314

RESUMO

Aromatase Inhibitors (AIs) are recommended for the adjuvant treatment of hormone receptor positive breast cancer in both high-risk pre-menopausal and post-menopausal population; arthralgia is the main cause of discontinuation of therapy and affects up to 25% of population on AI treatment. The objective of the study was to prospectively evaluate OPERA® (GAMFARMA srl, Milan, Italy), a new dietary supplement where α-Lipoic acid, Boswellia serrata, Methylsulfonylmethane and Bromelain are combined in a single hard-gelatin capsule to be taken once a day. Fifty-three patients with arthralgia (NCI-CTCAE v4.0 grade ≥ 1) occurring during AI therapy were enrolled. All patients received OPERA® from enrollment (T0) up to sixth months (T3). Patients' AI-related arthralgia was evaluated every two months with VAS Scale, PRAI questionnaire, and CTCAE scale. Primary endpoint was the number of patients with symptom resolution (G0) at T3 if compared to T0, according to CTCAE and VAS scale. Secondary endpoints were decrease in arthralgia intensity measured with PRAI score at T3 compared to baseline, safety of OPERA® and rate of AI interruption. Treatment with OPERA® supplement was overall well tolerated; no relevant toxicities related to OPERA® intake were reported. Seven subjects (13.2%) were not included in the final analysis because of consent withdrawal. 46 participants were eligible for final analysis. According to CTCAE scale, 10 out of 46 patients reported symptoms resolution at 6-month follow-up from the time of enrollment T0 (p = 0.0009). According to VAS score, 5 patients reported complete resolution of symptoms at T3 if compared to baseline starting situation T0 (p = 0.0222). Analysis of PRAI score showed a significant reduction in arthralgia-related pain perceived (p = 0.0001). OPERA® was able to reduce the intensity of arthralgia related to AI therapy. Randomized, double-blind studies are warranted to confirm the effectiveness of this dietary supplement.


Assuntos
Boswellia , Neoplasias da Mama , Inibidores da Aromatase/efeitos adversos , Artralgia/induzido quimicamente , Artralgia/diagnóstico , Artralgia/tratamento farmacológico , Neoplasias da Mama/diagnóstico , Bromelaínas/uso terapêutico , Suplementos Nutricionais , Dimetil Sulfóxido , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Estudos Prospectivos , Sulfonas
6.
J Med Food ; 25(6): 607-617, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35708633

RESUMO

The objective of this study was to identify alterations in lipids and polyunsaturated fatty acid (PUFA) metabolism in both the streptozotocin (STZ)-induced type 1 diabetic (T1D) mouse and the mutant db/db type 2 diabetic (T2D) mouse to establish a biological signature for the evaluation of natural products with purported lipid-altering activity. Eight-week-old male C57BL/6J mice were randomized to nondiabetic group or STZ-induced diabetic groups (n = 10/group). STZ-induced diabetic mice and 6-week-old male db/db mice (n = 10/group) were randomized to the following groups: (1) diabetic control, no treatment, (2) methylsulfonylmethane (MSM) treatment, (3) sesame seed oil (SSO) treatment, and (4) MSM+SSO combination treatment. Clinical parameters measured included weights, blood glucose, serum lipid panels, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of free fatty acids in serum, liver, brain, and eyes. Blood glucose significantly decreased after 4 weeks of MSM treatment in T1D mice. Serum PUFA levels were significantly reduced in T2D mice compared with control mice. In contrast, treatment with SSO reversed this effect in T2D mice, exhibiting serum PUFA levels comparable to control mice. Serum triglycerides were significantly increased in both diabetic models compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in T1D receiving MSM+SSO and all T2D treatment groups. A corresponding significant decrease in non-HDL cholesterol was seen in T2D mice in all treatment groups. MSM+SSO treatment's effects on HDL and non-HDL cholesterol and PUFA metabolism could lead to improved clinical outcomes in diabetics by improving the lipid profile.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Dislipidemias , Sesamum , Animais , Glicemia/metabolismo , Colesterol , Cromatografia Líquida , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dimetil Sulfóxido , Dislipidemias/tratamento farmacológico , Ácidos Graxos Insaturados/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Óleo de Gergelim/uso terapêutico , Sesamum/metabolismo , Estreptozocina , Sulfonas , Espectrometria de Massas em Tandem , Triglicerídeos
7.
Water Sci Technol ; 85(11): 3196-3207, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35704405

RESUMO

Fluorine is one of the essential trace elements for human life activities, but excessive intake of fluoride poses a great risk to people's health. In this paper, a series of mixed matrix membrane (MMM)-based polysulfone for removing fluoride were prepared by phase inversion, and their properties, adsorption capacity, adsorption isotherms, adsorption kinetics of fluoride ions, and mechanism were all investigated. The results confirmed that the MMM contained a large number of hydroxyl and aluminum functional groups due to resin being added. The MMM exhibited the best fluorine ion adsorption capacity of 2.502 mg/g at a pH of 6 with the initial concentration of 6 mg/L. As well, adsorption kinetics of fluorine ion on MMM followed the pseudo-second-order model, while the adsorption behavior of fluorine ion on MMM was well simulated by the Langmuir isotherm model. The adsorption capacity of MMM remained stable after six cycles and the regeneration efficiency was still above 80%, resulting in a long-term stability adequate for fluorine ion removal. Complexation and ion exchange played a key role in the fluorine ion adsorption of MMM. These results indicated the MMM as novel type of absorbent had an excellent capacity for removing fluoride.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Adsorção , Fluoretos , Flúor , Humanos , Concentração de Íons de Hidrogênio , Cinética , Polímeros , Sulfonas , Poluentes Químicos da Água/química , Purificação da Água/métodos
8.
BMC Cancer ; 22(1): 627, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35672711

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) constitutes 10-20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801. METHODS: RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies. RESULTS: Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1 and TAGLN (validated by RT-qPCR) and upregulation of GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4 and RNASEK-C17orf49 when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation. CONCLUSION: JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Indolizinas , Kisspeptinas/genética , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Depuradores Classe A/genética , Sulfonas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
9.
Wei Sheng Yan Jiu ; 51(3): 483-489, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35718915

RESUMO

OBJECTIVE: A method for the rapid determination of dichlorvos, trichlorfon, fenthion, fenthion-sulfone, fenthion-sulfoxide, fenthion-oxon, fenthion-oxon-sulfone, fenthion-oxon-sulfoxide, phoxim, propetamphos, malathion, diazinon and coumaphos 13 common organophosphorus pesticides and their metabolites poison residues in milk of cows and sheep by ultra-high-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) with passing type solid phase extraction(SPE) purification was developed. METHODS: After centrifugation at 4 ℃, the milk was purified by passing type SPE with acetonitrile precipitating protein and determined by UPLC-MS/MS in electrospray positive ion mode(ESI+) and multi-reaction monitoring scanning(MRM), external standard method for quantitative analysis with matrix matching standard curve. RESULTS: The recoveries of 13 target compounds were between 81.5% and 107.5% and relative standard deviation was between 1.24% and 6.23% at three spiked levels of 5, 10, 20 µg/L. The detection limits of 13 target compounds were between 0.015 and 0.15 µg/L, and the quantitative limits were between 0.05 and 0.50 µg/L. No organophosphorus pesticide residues were detected in 20 samples of cows and sheep milk. CONCLUSION: The method has the advantages of good linear independence, low detection limit, high precision and accuracy, and can be used for daily monitoring of milk and related products.


Assuntos
Resíduos de Praguicidas , Praguicidas , Animais , Bovinos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Feminino , Fention/análise , Leite/química , Compostos Organofosforados , Resíduos de Praguicidas/análise , Praguicidas/análise , Ovinos , Extração em Fase Sólida , Sulfonas/análise , Sulfóxidos/análise , Espectrometria de Massas em Tandem/métodos
10.
Front Immunol ; 13: 903834, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720309

RESUMO

Interstitial cystitis (IC)/bladder pain syndrome (BPS), hereafter referred together as IC, is a clinical syndrome characterized by sterile inflammation in the bladder. While the etiology and pathophysiology of IC remain unclear, it may involve autoimmunity in light of the significant role played by the NLRP3 inflammasome. However, the effect of NLRP3 inhibitors including dapansutrile (Dap) on IC had not been explored previously. Here, we investigated the effect of Dap in the cyclophosphamide (CYP)-induced experimental mouse model of IC, which results in functional and histological alterations confined to the urinary bladder (UB) comparable to that of clinical IC. CYP-induced mice treated with Dap exhibited improved UB pathology and reductions in inflammation scores and the frequency and the number of mast cells and neutrophils, relative to mice that received CYP alone. Dap- and CYP-treated mice also exhibited infiltration of T cells in the spleen and iliac lymph nodes (ILNs) and a concurrent significant decrease (p<0.01) in CXCR3+CD8+ T cells in the UB, induction of systemic and mucosal dendritic cells (DCs), and reduced levels of systemic proinflammatory cytokines, as compared to CYP alone. We also observed decreases in the expression of several signaling pathways regulators, including interleukin-1 beta (IL-1ß), NLRP3, caspase-1, nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS) in the UB of CYP- and Dap-treated mice, relative to those receiving CYP alone. Taken together, these results suggest that Dap suppresses IC through the reduction of CXCR3+T cells, mast cells, and neutrophils in the UB and induces DCs as a protective measure. The present study identifies the mechanisms underlying the amelioration of IC by the NLRP3 inhibitor Dap and may provide an avenue for a potential therapeutic agent for the treatment of IC.


Assuntos
Cistite Intersticial , Animais , Linfócitos T CD8-Positivos/metabolismo , Ciclofosfamida/efeitos adversos , Cistite Intersticial/induzido quimicamente , Cistite Intersticial/tratamento farmacológico , Cistite Intersticial/metabolismo , Inflamassomos/uso terapêutico , Inflamação , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitrilas , Sulfonas
11.
Biochem Biophys Res Commun ; 617(Pt 1): 30-35, 2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-35671608

RESUMO

The accumulation of senescent cells in aged tissues has been implicated in a variety of age-related diseases, including cancer and neurodegenerative disorders. Recent studies have demonstrated a link between age-associated increase of senescent glial cells in the brain and the pathogenesis of Alzheimer's disease (AD). However, there is a lack of in vitro cellular models of senescent human microglia, which significantly limits our approaches to study AD pathogenesis. Here, we show for the first time that ionizing radiation (IR) dose-dependently induces premature senescence in HMC3 human microglial cells. Senescence-associated ß-galactosidase activity, a well-characterized marker of cellular senescence, was substantially increased in irradiated HMC3 cells compared with control cells. Furthermore, we found that phosphorylated p53 levels and p21 expression levels were markedly higher in IR-induced senescent microglia than in control cells. Senescent human microglia exhibited the senescence-associated secretory phenotype (SASP), as evidenced by the increased secretion of pro-inflammatory cytokine interleukin-6 (IL-6). Treatment with an NF-κB inhibitor, BAY 11-7082, inhibits the secretion of IL-6 by senescent HMC3 cells. Collectively, our studies have established an in vitro cellular model of human microglial senescence and suggest that the NF-κB pathway may play a critical role in regulating the SASP of senescent HMC3 cells.


Assuntos
Interleucina-6 , Microglia , Idoso , Senescência Celular/fisiologia , Humanos , Interleucina-6/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo , Nitrilas , Sulfonas
12.
PLoS One ; 17(6): e0268503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35709251

RESUMO

BACKGROUND: Hyperuricemia has a suspected relationship with hypertension, metabolic syndrome, kidney disease, and cardiovascular disease. Endocrine disruptors may affect uric acid metabolism; however, few epidemiologic studies have been performed in children regarding newly developed bisphenol A (BPA) substitutes. We evaluated the associations between BPA, bisphenol S (BPS), and bisphenol F (BPF) exposure and serum uric acid concentrations in 6-year-old Korean children. METHODS: From the Environment and Development of Children cohort study, six-year-old children (N = 489; 251 boys) who underwent an examination during 2015-2017 were included. Anthropometry, questionnaires, and biological samples were evaluated. BPA, BPS, and BPF levels were measured from spot urine samples, and log-transformed or categorized into groups for analysis. We constructed linear regression models adjusting for age, sex, urinary creatinine levels, body mass index z-scores, and estimated glomerular filtration rates. RESULTS: Mean serum uric level was 4.2 mg dL-1 (0.8 SD) without sex-differences. Among the three bisphenols, higher BPS exposure was associated with increased serum uric acid concentrations (P-value for trend = 0.002). When BPS levels were categorized into three groups (non-detection < 0.02 µg L-1 vs. medium BPS; 0.02-0.05 µg L-1 vs. high BPS ≥ 0.05 µg L-1), the high BPS group showed higher serum uric acid concentrations (by 0.26 mg dL-1, P = 0.003) than the non-detection group after adjusting for covariates, which was significant in boys but not girls. DISCUSSIONS: Urinary BPS levels was positively associated with serum uric acid concentrations in 6-year-old children, and the association was more pronounced in boys. Considering the increasing use of BPS and concerning effect of hyperuricemia on health outcomes, their positive relationship should be investigated further.


Assuntos
Hiperuricemia , Ácido Úrico , Compostos Benzidrílicos/urina , Criança , Estudos de Coortes , Humanos , Masculino , Fenóis , Sulfonas
13.
Molecules ; 27(11)2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35684538

RESUMO

This study highlights the value of nonisothermal kinetic methods in selecting temperature conditions for the isothermal preparation of microporous polymeric materials. A dicyanate ester is synthesized and the kinetics of its polymerization in diphenyl sulfone are studied by calorimetry under nonisothermal conditions. The kinetics are analyzed by a model-based approach, using the Kamal model, as well as by a model-free approach, using an advanced isoconversional method. Both approaches correctly predict the time to completion of polymerization at a given temperature. The material prepared independently at the predicted temperature is characterized by electron microscopy and CO2 adsorption measurements and is confirmed to possess a microporous structure with a multimodal distribution of micropores with two major maxima at ~0.5 and 0.8 nm.


Assuntos
Compostos de Bifenilo , Sulfonas , Cinética , Polimerização
14.
Environ Toxicol Pharmacol ; 93: 103883, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35550874

RESUMO

The global use of bisphenol S (BPS) has now been significantly increased for commensurate utilization as a substitute for BPA for its regulatory concerns. Though, previous reports indicated that BPS been also appeared as a toxic congener comparable to BPA. In the present study, we determined nephrotoxicity condition induced due to BPS exposure. Results indicated that BPS significantly promoted histopathological disturbance in the kidney, and altered the levels of biomarkers of kidney damage in serum and urine samples of Wistar rats. It is also indicated that BPS altered the expression of kidney damage biomarkers associated with glomerular and tubular injury. Additionally, we determined the perturbation of kidney metabolites in the underlying pathophysiological response of kidney injury due to BPS exposure. Gas chromatography-mass spectrometry based untargeted metabolomics exhibited 20 significantly perturbed metabolites. Moreover, metabolic pathway analysis revealed significant disturbance in the TCA cycle and pyruvate metabolism pathways.


Assuntos
Nefropatias , Metabolômica , Animais , Compostos Benzidrílicos/toxicidade , Biomarcadores/urina , Cromatografia Gasosa-Espectrometria de Massas , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Metabolômica/métodos , Fenóis , Ratos , Ratos Wistar , Sulfonas
15.
Mater Sci Eng C Mater Biol Appl ; 135: 112659, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35577688

RESUMO

Blood purification therapy is widely used in patients with renal insufficiency and severe infections, where membrane-associated thrombosis is a side effect. How to improve the hemocompatibility of dialysis membranes and reduce thrombosis is a focus of current research, in which platelets play a key role. However, few dialysis membranes that directly inhibit platelets have been developed to date. In this study, a polyethersulfone (PES) membrane was modified with ticagrelor, a platelet P2Y12 receptor inhibitor, and detailed characterization was performed. The ticagrelor modified PES membrane (TMPES) showed good hydrophilicity and anti-protein adsorption and significantly inhibited platelet adhesion, aggregation, and activation, which demonstrated good antithrombotic properties. In addition, the membrane had excellent red blood cell (RBC) compatibility, anticoagulant, and antiinflammatory effects, which demonstrated superior biosafety in cell and animal experiments. Therefore, the TMPES dialysis membrane could have potential in clinical applications.


Assuntos
Membranas Artificiais , Trombose , Animais , Plaquetas/metabolismo , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Polímeros , Diálise Renal , Sulfonas , Trombose/tratamento farmacológico , Ticagrelor
16.
Chem Commun (Camb) ; 58(47): 6765-6768, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35612002

RESUMO

A new type of organocatalyzed 1,3-thiosulfonylation has been developed to straightforwardly access highly functionalized vinyl sulfones, which features mild conditions, atom- and step-economy, practicability, conciseness, and environmental friendliness. Moreover, these valuable products can be transformed to vinyl sulfides via a base-promoted isomerization. The versatile route can efficiently and rapidly introduce SCD3 groups with excellent levels of deuterium content (>99% D) by utilizing our newly developed SCD3 reagents. Gram-scale operations and further transformations are smoothly carried out, providing promising applications for drug discovery.


Assuntos
Alcadienos , Sulfetos , Sulfonas
17.
Anal Chem ; 94(22): 7928-7935, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35613044

RESUMO

Sulfonate esters, a class of potentially mutagenic drug impurities, are strictly regulated in pharmaceuticals. On the other hand, sulfite esters and sulfones, analogs of sulfonate esters, have limited safety concerns. However, previously developed analytical methods for sulfonate ester identification cannot be used to differentiate sulfonate esters from the isomeric sulfite esters and sulfones. A tandem mass spectrometric method is introduced here for the differentiation of these compounds. Diisopropoxymethylborane (DIMB) reacts with protonated sulfonate esters, sulfite esters, and sulfones (and many other compounds) in the gas phase to form the product ion [M + H + DIMB - CH3CH(OH)CH3]+. Upon collision-activated dissociation (CAD), these product ions generate diagnostic fragment ions that enable the differentiation of sulfonate esters, sulfite esters, and sulfones from each other. For example, SO2 elimination enabled the unambiguous identification of sulfite esters. On the other hand, elimination of CH3B═O followed by elimination of (CH3)2C═O was only observed for sulfonate esters. Neither type of diagnostic fragment ions was detected for the products of sulfones. However, the product ions formed for sulfones with an additional hydroxyl substituent underwent the elimination of another CH3CH(OH)CH3 molecule, which enabled their identification. Finally, ion-molecule reactions of DIMB with various other functionalities were also examined. Some of them yielded the product ions [M + H + DIMB - CH3CH(OH)CH3]+ but none of these product ions underwent the diagnostic CAD reactions discussed above. Quantum chemical calculations were employed to explore the mechanisms of the reactions. The limits of detection for the diagnostic ion-molecule reaction product ions in high-performance liquid chromatography (HPLC)/mass spectrometry (MS2) experiments were found to range from 0.075 to 1.25 nmol.


Assuntos
Ésteres , Espectrometria de Massas em Tandem , Íons/química , Sulfitos , Sulfonas , Espectrometria de Massas em Tandem/métodos
18.
Life Sci ; 301: 120619, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561750

RESUMO

AIMS: In biology and medicine, hypoxia refers to reduced oxygen tension or oxygen starvation resulting from various environmental or pathological conditions. Prolonged hypoxia may lead to an imbalance in protein production and a loss of muscle mass in animals. The physiological response to hypoxia includes oxidative stress-induced activation of complex cell-signaling networks such as hypoxia-inducible factor (HIF), phosphoinositide 3-kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK-STAT). Methylsulfonylmethane (MSM) is a natural sulfur compound that regulates HIF-1α expression and provides cytoprotection from oxidative stress. In this study, we explored the anti-hypoxic activity and cytoprotective effect of MSM in cobalt chloride (CoCl2)-induced hypoxic C2C12 mouse myoblast culture. MATERIALS AND METHODS: We used western blotting, real time PCR, flow cytometry for molecular signaling studies and we also used MTT assay and ChIP assay along with comet assay for cellular processes. KEY FINDINGS: MSM prevented the CoCl2 induced cytotoxicity. Molecular markers of hypoxia, induced by CoCl2, were normalized or reduced by MSM, which also inhibited the effect of CoCl2-induced JAK2/STAT5b/Cyclin D1 and PI3K/AKT signaling. CoCl2-induced oxidative stress results in activation of the NRF2/HO-1-mediated cell survival pathway and inhibition of DNA repair, both of which were prevented by MSM. SIGNIFICANCE: We suggest MSM can be considered as a candidate drug for reducing the effects of hypoxia in both animals and humans.


Assuntos
Cloretos , Fosfatidilinositol 3-Quinases , Animais , Hipóxia Celular , Cloretos/farmacologia , Cobalto/metabolismo , Dimetil Sulfóxido , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Mioblastos/metabolismo , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Sulfonas
19.
J Org Chem ; 87(10): 6812-6823, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35509227

RESUMO

We report a cascaded oxidative sulfonylation of N-propargylamine via a three-component coupling reaction using DABCO·(SO2)2 (DABSO). 3-Arylsulfonylquinolines were obtained by mixing diazonium tetrafluoroborate, N-propargylamine, and DABSO under argon atmosphere in dichloroethane (DCE) for 1 h. In a radical pathway, DABSO was utilized as the sulfone source and an oxidant in this radical-mediated cascaded reaction.


Assuntos
Pargilina , Propilaminas , Estresse Oxidativo , Pargilina/análogos & derivados , Sulfonas
20.
Org Biomol Chem ; 20(21): 4369-4375, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35575463

RESUMO

A base-promoted direct deaminative olefination of organoammonium salts was developed. Only mediated by KOtBu, a series of benzyl and cinnamyl ammonium salts reacted smoothly with sulfones, producing the valuable stilbenes and related 1,3-diene derivatives in good to high yields with good functional group tolerance and excellent E-selectivity. With this developed method, biologically active resveratrol and DMU-212 were also successfully prepared, which further demonstrates the practicality of this reaction.


Assuntos
Estilbenos , Sulfonas , Polienos , Sais
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