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1.
Int J Mol Sci ; 26(2)2025 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-39859201

RESUMO

Alzheimer's disease (AD) remains a leading cause of cognitive decline and mortality worldwide, characterized by neurodegeneration, synaptic deficiencies, and neuroinflammation. Despite advancements in early detection, diagnosis, and treatment, AD presents substantial challenges due to its complex pathology, heterogeneity, and the limited efficacy of current therapies. Consequently, there is a pressing need for novel therapeutic agents to target the multifaceted aspects of AD pathology, enhance current treatments, and minimize adverse effects. AdipoRon, an adiponectin receptor agonist, has garnered interest for its potential neuroprotective effects, including reducing neuroinflammation, improving mitochondrial function, and mitigating tau hyperphosphorylation. This review aimed to evaluate the effects of AdipoRon-based adiponectin replacement therapy against AD, using a comprehensive approach grounded in the PICO framework-Population, Intervention, Comparison, and Outcomes. A total of six studies were reviewed, including in vitro and in vivo investigations examining AdipoRon's impact on various AD models. These studies involved different cell lines and transgenic mouse models, assessing various outcomes such as cognitive function, neuroinflammation, tau phosphorylation, synaptic deficiencies, and relevant molecular pathways. By synthesizing data from these studies, our review thoroughly explains AdipoRon's neuroprotective effects, mechanisms of action, and potential as a therapeutic agent for AD. This analysis aims to highlight the current state of knowledge, identify gaps in the research, and suggest directions for future studies and clinical applications.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Animais , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Adiponectina/metabolismo , Adiponectina/uso terapêutico , Proteínas tau/metabolismo , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/agonistas , Indenos/uso terapêutico , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Modelos Animais de Doenças
2.
Nanomedicine (Lond) ; 20(1): 9-22, 2025 01.
Artigo em Inglês | MEDLINE | ID: mdl-39469848

RESUMO

Aim: In this study, PLGA nanoparticles (PNPs) emulsified in Pluronic F127 (F127)/Lecithin (LEC) were designed to load Itacitinib (ITA), a selective JAK1 inhibitor, for targeting human monocytes.Materials & methods: The physicochemical characteristics of empty and ITA-loaded F127/LEC PNPs were analyzed. The binding and internalization of NPs in leukocytes were evaluated. The effect of NPs on monocyte activation and JAK1 inhibition was assessed.Results: F127/LEC PNPs were selectively bound and internalized by monocytes, sparing other leukocytes. ITA-F127/LEC PNPs significantly dampened monocyte activation. They also inhibited the monocyte's ability to promote T-cell proliferation and inhibited proinflammatory cytokine production.Conclusion: ITA-loaded F127/LEC PNPs showed potential for monocyte-targeted therapy, offering new avenues for disease treatment.


[Box: see text].


Assuntos
Portadores de Fármacos , Monócitos , Nanopartículas , Poloxâmero , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Humanos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nanopartículas/química , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Portadores de Fármacos/química , Proliferação de Células/efeitos dos fármacos , Janus Quinase 1/metabolismo , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/uso terapêutico , Citocinas/metabolismo
3.
Adv Rheumatol ; 64(1): 85, 2024 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-39538350

RESUMO

BACKGROUND: Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice. METHODS: CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey's or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05. RESULTS: Tofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn't modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels. CONCLUSION: Tofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss.


Assuntos
Artrite Experimental , Camundongos Endogâmicos DBA , Músculo Esquelético , Miogenina , Piperidinas , Pirimidinas , Animais , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Artrite Experimental/tratamento farmacológico , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Miogenina/metabolismo , Pirróis/uso terapêutico , Pirróis/farmacologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia
4.
J Biochem Mol Toxicol ; 38(11): e70040, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39503200

RESUMO

Obesity is a risk factor for the development of noncommunicable diseases that impair the quality of life. Orlistat is one of the most widely used drugs in the management of obesity due to its accessibility and low cost. However, cases of hepatotoxicity have been reported due to the consumption of this drug. On the other hand, piperine is an alkaloid found in black pepper that has demonstrated antiobesity, antihyperlipidemic, antioxidant, prebiotic, and hepatoprotective effects. The aim of this study was to evaluate the protective effect of piperine on the toxicity of orlistat in liver tissue. Obese male rats were administered piperine (30 mg/kg), orlistat (60 mg/kg), and the orlistat-piperine combination (30 mg/kg + 60 mg/kg) daily for 6 weeks. It was observed that the orlistat-piperine treatment resulted in greater weight loss, decreased biochemical markers (lipid profile, liver enzymes, pancreatic lipase activity), and histopathological analysis showed decreased hepatic steatosis and reduction of duodenal inflammation. Transcriptomic analysis revealed that the administration of piperine with orlistat increased the expression of genes related to the beta-oxidation of fatty acids, carbohydrate metabolism, detoxification of xenobiotics, and response to oxidative stress. Therefore, the results suggest that the administration of orlistat-piperine activates signaling pathways that confer a hepatoprotective effect, reducing the toxic impact of this drug.


Assuntos
Alcaloides , Benzodioxóis , Fígado , Obesidade , Orlistate , Piperidinas , Alcamidas Poli-Insaturadas , Ratos Wistar , Animais , Alcamidas Poli-Insaturadas/farmacologia , Benzodioxóis/farmacologia , Piperidinas/farmacologia , Alcaloides/farmacologia , Masculino , Orlistate/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fármacos Antiobesidade/farmacologia , Perfilação da Expressão Gênica , Transcriptoma/efeitos dos fármacos
5.
Genes Chromosomes Cancer ; 63(11): e70012, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39565115

RESUMO

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that can locally recur and potentially metastasize. Approximately 50% of IMTs harbor rearrangements in the gene encoding anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase that can be therapeutically targeted with tyrosine kinase inhibitors (TKIs). With successful application of TKI in ALK-positive nonsmall cell carcinoma (NSCLC), ALK inhibitors are often first-line treatments for patients with unresectable or metastatic IMTs. Although acquired resistance to these agents may develop, resistance mechanisms are sparsely reported for IMTs. Here we report a case of a 71 year-old man with metastatic pulmonary IMT harboring a DCTN1::ALK fusion that progressed during alectinib TKI treatment. Whole exome sequencing of an enlarging metastatic lesion in right 4th rib revealed a novel p.V1180L mutation in the ALK tyrosine kinase domain as the mechanism of acquired resistance. To our knowledge, this is the first report of acquired p. V1180L mutation in IMTs treated with TKIs. In cases of ALK-positive IMTs that progress on TKI therapy, targeted sequencing for acquired ALK mutations may inform clinical decisions to adopt second-line therapeutic strategies.


Assuntos
Quinase do Linfoma Anaplásico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Humanos , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Idoso , Piperidinas/uso terapêutico , Mutação , Neoplasias de Tecido Muscular/genética , Neoplasias de Tecido Muscular/tratamento farmacológico , Neoplasias de Tecido Muscular/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carbazóis/uso terapêutico
6.
Einstein (Sao Paulo) ; 22: eAO0821, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39504090

RESUMO

OBJECTIVE: Tofacitinib, an oral Janus kinase inhibitor, has been tested against a placebo in 289 patients with COVID-19 pneumonia. We analyzed the data from the tofacitinib- and placebo-treated patient cohorts to evaluate the laboratory profiles between baseline and day 7. METHODS: We performed post hoc analyses on the following laboratory tests over time during the first 7 days after randomization: hemoglobin, leukocytes, neutrophils, lymphocytes, platelets, alanine aminotransferase, and aspartate aminotransferase. RESULTS: Through the first 7 days after randomization, the levels of hemoglobin, white blood cells, neutrophils, and platelet counts were not significantly different between patients treated with tofacitinib or a placebo (all p>0.05). Non-significant differences were observed in aspartate aminotransferase levels over time between treatment groups, whereas alanine aminotransferase levels (U/L) were higher among tofacitinib-treated patients compared to placebo-treated patients (mean ratio, 1.30 [95% confidence interval (95%CI) = 1.14-1.48; p<0.01)]. CONCLUSION: In patients with COVID-19 pneumonia, the use of tofacitinib compared to placebo did not result in clinically meaningful changes in blood counts or liver enzymes over the first 7 days after randomization. REGISTRY OF CLINICAL TRIALS: NCT04469114.


In a post hoc analysis of the study of tofacitinib in hospitalized patients with COVID-19 pneumonia (STOP-COVID) trial, Guimaraes et al. evaluated the laboratory safety profile of tofacitinib use during the first 7 days of treatment in patients hospitalized with COVID-19 pneumonia compared with placebo. No clinically meaningful changes were observed in the value of white blood cells, lymphocytes, neutrophils, platelets, hemoglobin, or liver enzymes.


■Tofacitinib use did not result in meaningful changes in hematological parameters. ■Tofacitinib use did not lead to clinically meaningful changes in liver enzymes.


Assuntos
Aspartato Aminotransferases , Tratamento Farmacológico da COVID-19 , Piperidinas , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Piperidinas/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Aspartato Aminotransferases/sangue , COVID-19/sangue , Alanina Transaminase/sangue , Idoso , Hospitalização , SARS-CoV-2 , Adulto , Resultado do Tratamento , Método Duplo-Cego , Inibidores de Proteínas Quinases/uso terapêutico
7.
J Org Chem ; 89(21): 15808-15821, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39437173

RESUMO

Despite the enormous importance of chromone and flavonoid piperidine alkaloids, a general method for their synthesis has not been described. Accordingly, from simple tetrahydro-3-pyridinemethanols (A) and phenol derivatives (B), a synthetic approach to chromone and flavonoid piperidine alkaloids is presented. The access to a novel chromone and flavonoid alkaloid precursors 4-(2-hydroxyphenyl)-3-methylenepiperidines (C) is achieved in only two steps: Mitsunobu reaction followed by an intramolecular C-H phenolization via an aromatic Claisen rearrangement of the respective Mitsunobu adducts (D). Consequently, the simultaneous installation of the functionalized phenol group and the exo-methylene group within the piperidine skeleton, permits, not only the easy construction of the chromone or flavonoid cores but also the simultaneous installation of the hydroxyl group with the required cis-orientation. Additionally, the synthetic utility of this novel approach is showcased in the formal synthesis of flavopiridol, rohitukine, and their N-Moc analogues.


Assuntos
Alcaloides , Cromonas , Flavonoides , Piperidinas , Piperidinas/química , Piperidinas/síntese química , Cromonas/química , Cromonas/síntese química , Alcaloides/química , Alcaloides/síntese química , Flavonoides/química , Flavonoides/síntese química , Estrutura Molecular
8.
Braz J Med Biol Res ; 57: e13278, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39383379

RESUMO

Despite the widespread use of R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL), the therapeutic efficacy for this disease remains suboptimal, primarily due to the heterogeneity of refractory and/or relapsed diseases. To address this challenge, optimization of DLBCL treatment regimens has focused on the strategy of combining an additional drug "X" with R-CHOP to enhance efficacy. However, the failure of R-CHOP combined with the BTK inhibitor ibrutinib in treating ABC-type DLBCL patients has raised significant concerns regarding ibrutinib resistance. While some studies suggest that venetoclax may synergize with ibrutinib to kill ibrutinib-resistant cells, the underlying mechanisms remain unclear. Our study aimed to validate the enhanced tumor-suppressive effect of combining ibrutinib with venetoclax against ibrutinib-resistant cells and elucidate its potential mechanisms. Our experimental results demonstrated that ibrutinib-resistant cells exhibited significant cytotoxicity to the combination therapy of ibrutinib and venetoclax, inducing cell apoptosis through activation of the mitochondrial pathway and inhibition of aerobic respiration. Furthermore, we validated the inhibitory effect of this combination therapy on tumor growth in in vivo models. Therefore, our study proposes that the combination therapy of ibrutinib and venetoclax is a promising treatment strategy that can be applied in clinical practice for ABC-type DLBCL, offering a new solution to overcome the urgent challenge of ibrutinib resistance.


Assuntos
Adenina , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Linfoma Difuso de Grandes Células B , Piperidinas , Pirazóis , Pirimidinas , Sulfonamidas , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Sulfonamidas/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Humanos , Piperidinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirazóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
9.
J Psychopharmacol ; 38(12): 1170-1183, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39262284

RESUMO

BACKGROUND: Blackcurrant (Ribes nigrum L.) is a berry rich in anthocyanins, bioactive compounds known for their antioxidant and neuroprotective properties that benefit human health. AIMS: This study aimed to investigate the effects of blackcurrant and its association with Donepezil on memory impairment, cholinergic neurotransmission, and antioxidant systems in a mouse model of amnesia induced by chronic administration of Scopolamine. METHODS: Adult male Swiss mice were given saline, blackcurrant (50 mg/kg, orally), and/or Donepezil (5 mg/kg, orally) and/or Scopolamine (1 mg/kg, intraperitoneally). RESULTS: Behavioral tests revealed that blackcurrant and/or Donepezil prevented the learning and memory deficits induced by Scopolamine. In the cerebral cortex and hippocampus, blackcurrant and/or Donepezil treatments prevented the increase in acetylcholinesterase and butyrylcholinesterase activities induced by Scopolamine. Scopolamine also disrupted the glutathione redox system and increased levels of reactive species; nevertheless, blackcurrant and/or Donepezil treatments were able to prevent oxidative stress. Furthermore, these treatments prevented the increase in gene expression and protein density of acetylcholinesterase and the decrease in gene expression of the choline acetyltransferase enzyme induced by Scopolamine. CONCLUSIONS: Findings suggest that blackcurrant and Donepezil, either alone or in combination, have anti-amnesic effects by modulating cholinergic system enzymes and improving the redox profile. Therefore, blackcurrant could be used as a natural supplement for the prevention and treatment of memory impairment in neurodegenerative diseases.


Assuntos
Acetilcolinesterase , Antioxidantes , Donepezila , Transtornos da Memória , Estresse Oxidativo , Extratos Vegetais , Ribes , Escopolamina , Animais , Masculino , Camundongos , Donepezila/farmacologia , Ribes/química , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Transtornos da Memória/metabolismo , Acetilcolinesterase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Modelos Animais de Doenças , Piperidinas/farmacologia , Indanos/farmacologia , Butirilcolinesterase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Glutationa/metabolismo , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Amnésia/metabolismo , Amnésia/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
10.
Ocul Immunol Inflamm ; 32(8): 1882-1887, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39316714

RESUMO

PURPOSE: To report two cases of ibrutinib-related uveitis and review the literature to date. METHODS: We report two cases of ibrutinib-related uveitis using CARE guidelines and review the cases reported in the literature. RESULTS: Case 1) A 55-year-old female with recurrent primary central nervous system lymphoma presented with bilateral decreased visual acuity, photophobia, and floaters that started one month after initiating oral treatment with ibrutinib. Chronic non-granulomatous bilateral anterior-intermediate uveitis with macular edema was identified. Secondary causes were ruled out, and a presumptive diagnosis of ibrutinib-related uveitis was made. Case 2) A 57-year-old female with Waldenström macroglobulinemia who was treated with ibrutinib for two years presented with bilateral blurred vision, photophobia, red eyes, and floaters. A diagnosis of non-granulomatous, noninfectious panuveitis with bilateral cystoid macular edema was made. Secondary causes were ruled out, and ibrutinib toxicity was the most likely cause. CONCLUSION: Ibrutinib-related uveitis is a novel and under-diagnosed clinical entity. The most frequent clinical presentation in the literature is bilateral, non-granulomatous, anterior, and intermediate uveitis. Macular edema is a frequent complication. Uveitis usually requires topical treatment and the suspension of ibrutinib. Switching to second-generation Bruton tyrosine kinase inhibitors is proposed as a potential therapeutic alternative.


Assuntos
Adenina , Piperidinas , Humanos , Feminino , Adenina/análogos & derivados , Adenina/efeitos adversos , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Tomografia de Coerência Óptica , Acuidade Visual , Inibidores de Proteínas Quinases/efeitos adversos , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/diagnóstico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Edema Macular/induzido quimicamente , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Angiofluoresceinografia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnóstico
11.
Rev Bras Parasitol Vet ; 33(3): e001824, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39292065

RESUMO

Toxoplasma gondii is a coccidian protozoan of zoonotic importance that causes toxoplasmosis. Although the current treatments for toxoplasmosis may be associated with adverse effects and limited efficacy for different biological forms of the parasite, evidence suggests that alkaloid molecules such as harmaline and piperine exhibit antiparasitic effects against protozoa parasites. This investigation aimed to evaluate the in vitro effect of harmaline and piperine against T. gondii tachyzoites in infected Vero cell cultures. After 24 hours of host cell infection, the cultures were treated with harmaline or piperine (0.49 to 15.63 µg/mL). Negative and positive controls were RPMI/DMSO (0.1%) and sulfadiazine (200 µg/mL). Harmaline significantly reduced parasite multiplication by 20% compared to the negative control, while piperine decreased between 55.56% and 88.89% in a dose-dependent manner. According to an intracellular parasite proportion scale, it was observed that the Vero cells with low or moderate parasitic proliferation were more prevalent after the alkaloid treatment. The study demonstrated that the alkaloids had antiparasitic effects on T. gondii, with piperine being the most effective. Additional studies must be carried out to clarify other aspects of the action of the alkaloids on parasites.


Assuntos
Alcaloides , Benzodioxóis , Harmalina , Piperidinas , Alcamidas Poli-Insaturadas , Toxoplasma , Benzodioxóis/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/farmacologia , Toxoplasma/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Chlorocebus aethiops , Células Vero , Harmalina/farmacologia , Testes de Sensibilidade Parasitária
12.
Sci Rep ; 14(1): 19906, 2024 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-39191849

RESUMO

Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.


Assuntos
Adenina , Tecido Adiposo , Proliferação de Células , Sobrevivência Celular , Células-Tronco Mesenquimais , Piperidinas , Pirazóis , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Piperidinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Pirazóis/farmacologia , Fenótipo , Pirimidinas/farmacologia , Anti-Inflamatórios/farmacologia , Células Cultivadas
13.
J Neuroimmunol ; 394: 578427, 2024 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-39116522

RESUMO

The hypothalamus receives serotonergic projections from the raphe nucleus in a sex-specific manner. During systemic inflammation, hypothalamic levels of serotonin (5-hydroxytryptamine [5-HT]) decrease in male rats. The present study evaluated the involvement of endothelin-1 (ET-1) in the febrile response, hypolocomotion, and changes in hypothalamic 5-HT levels during systemic inflammation in male and female rats. An intraperitoneal injection of lipopolysaccharide (LPS) induced a febrile response and hypolocomotion in both male and female rats. However, although LPS reduced hypothalamic levels of 5-HT and its metabolite 5-hydroxyindol acetic acid (5-HIAA) in male rats, it increased these levels in female rats. An intracerebroventricular injection of the endothelin-B receptor antagonist BQ788 significantly reduced LPS-induced fever and hypolocomotion and changes in hypothalamic 5-HT and 5-HIAA levels in both male and female rats. The i.c.v. administration of ET-1 induced a significant fever and hypolocomotion, but reduced the hypothalamic levels of 5-HT and 5-HIAA in both males and females. These results suggest an important sexual dimorphism during systemic inflammation regarding the release of 5-HT in the hypothalamus. Moreover, ET-1 arises as an important mediator involved in the changes in hypothalamic 5-HT levels in both male and female rats.


Assuntos
Endotelina-1 , Hipotálamo , Inflamação , Piperidinas , Ratos Wistar , Serotonina , Caracteres Sexuais , Animais , Masculino , Feminino , Endotelina-1/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Ratos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Serotonina/metabolismo , Piperidinas/farmacologia , Lipopolissacarídeos/toxicidade , Oligopeptídeos/farmacologia , Ácido Hidroxi-Indolacético/metabolismo , Antagonistas dos Receptores de Endotelina/farmacologia , Febre/metabolismo , Febre/induzido quimicamente
14.
PLoS Pathog ; 20(8): e1011812, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39173086

RESUMO

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers - an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-ß and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-ß and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction - an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis.


Assuntos
Granuloma , Cirrose Hepática , Prostaglandina D2 , Receptores Imunológicos , Receptores de Prostaglandina , Schistosoma mansoni , Esquistossomose mansoni , Animais , Prostaglandina D2/metabolismo , Esquistossomose mansoni/metabolismo , Esquistossomose mansoni/patologia , Esquistossomose mansoni/parasitologia , Camundongos , Receptores de Prostaglandina/metabolismo , Cirrose Hepática/parasitologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Granuloma/parasitologia , Granuloma/metabolismo , Granuloma/patologia , Receptores Imunológicos/metabolismo , Fígado/parasitologia , Fígado/metabolismo , Fígado/patologia , Masculino , Feminino , Carbazóis , Piperidinas , Sulfonamidas
15.
Ann Hematol ; 103(11): 4613-4620, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39153144

RESUMO

Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. The purpose of this study is to compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with the first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from a collaborative multinational network. We used data from the network (TriNetX), which encompasses more than 100 healthcare organizations worldwide. We queried the database for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past ten years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. We compared 2,107 patients in each group. Atrial fibrillation or flutter occurred in 150 (7.1%) patients with acalabrutinib and 310 (14.7%) patients with ibrutinib during the 3-year follow-up (hazard ratio, 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred in 342 (16.3%) patients in the acalabrutinib group and 584 (27.7%) patients in the ibrutinib group (hazard ratio 0.81, 95% CI 0.66-0.98). Sepsis was diagnosed in 136 (6.5%) patients in the acalabrutinib group versus 239 (11.3%) patients in the ibrutinib group (hazard ratio 0.77, 95 CI 0.60-0.98). The two groups had no significant differences concerning the other adverse events. In a large retrospective cohort using real-world data from electronic medical registers, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower risks of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis.


Assuntos
Adenina , Tirosina Quinase da Agamaglobulinemia , Benzamidas , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Pirazinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Adenina/análogos & derivados , Adenina/efeitos adversos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirazinas/administração & dosagem , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/uso terapêutico , Benzamidas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Idoso de 80 Anos ou mais , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Retrospectivos , Adulto
16.
Braz J Med Biol Res ; 57: e13429, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39082579

RESUMO

The chemical structure of piperidine has a unique ability to combine with other molecular fragments. This fact makes it possible to actively use it as an effective basis for the creation of new drug-like substances. Thus, the aim of the current investigation was to study the acute toxicity, local anesthetic potency, and antiarrhythmic activity of the two new synthesized piperidine derivatives under laboratory codes LAS-286 and LAS-294 (local anesthetic substances). The Bulbring & Wajda animal model and method of determining the nociception threshold during electrical stimulation was used to investigate the action of the substance during infiltration anesthesia. An antiarrhythmic activity was observed by the aconitine-induced rat arrhythmia model. Additionally, these compounds were studied in relation to molecular docking to delineate the structure-activity relationships. The tested piperidine derivatives had a low toxicity in the subcutaneous and intravenous administration routes. The experimental results showed a higher prolonged and pronounced local anesthetic activity for LAS-286 at a 0.5% concentration, compared to the reference preparations. The low dosage of 0.1 mg/kg of LAS-294 demonstrated a pronounced preventive antiarrhythmic effect in 90% of cases on the development of mixed arrhythmia, caused by aconitine. The results of molecular docking confirmed a higher binding affinity of the tested piperidines with the Nav1.4 and Nav1.5 macromolecules. The results of the present study are very promising, because these piperidines have shown a high biological activity, which can suggest a potential therapeutic application in the future.


Assuntos
Anestésicos Locais , Antiarrítmicos , Simulação de Acoplamento Molecular , Piperidinas , Animais , Antiarrítmicos/farmacologia , Anestésicos Locais/farmacologia , Piperidinas/farmacologia , Piperidinas/química , Ratos , Masculino , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Relação Estrutura-Atividade , Ratos Wistar , Modelos Animais de Doenças
17.
Future Med Chem ; 16(15): 1537-1550, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-38949866

RESUMO

Aim: This study aimed to enhance the aqueous dissolution of SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340).Materials & Methods: A complex with p-sulfonic calix[6]arene (Host) and SRPIN340 (Guest) was prepared, studied via 1H nuclear magnetic resonance (NMR) and theoretical calculations and biologically evaluated on cancer cell lines.Results & conclusion: The 1:1 host (H)/guest (G) complex significantly enhanced the aqueous dissolution of SRPIN340, achieving 64.8% water solubility as determined by 1H NMR quantification analysis. The H/G complex reduced cell viability by 75% for HL60, ∼50% for Nalm6 and Jurkat, and ∼30% for B16F10 cells. It exhibited greater cytotoxicity than free SRPIN340 against Jurkat and B16F10 cells. Theoretical studies indicated hydrogen bond stabilization of the complex, suggesting broader applicability of SRPIN340 across diverse biological systems.


[Box: see text].


Assuntos
Antineoplásicos , Calixarenos , Sobrevivência Celular , Calixarenos/química , Calixarenos/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Camundongos , Espectroscopia de Ressonância Magnética , Animais , Ácidos Sulfônicos/química , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Linhagem Celular Tumoral , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia
18.
Phytochem Anal ; 35(7): 1688-1694, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38925584

RESUMO

INTRODUCTION: 2,6-Disubstituted piperidin-3-ols are an important group of piperidine alkaloids found in species such as Senna spectabilis, whose main constituents include cassine and spectaline, compounds with relevant pharmacological activity. The analysis of these compounds is challenging due to the complexity of plant extracts and the absence of chromophores capable of absorbing ultraviolet (UV) radiation. OBJECTIVE: This paper presents a new analytical method to separate and quantify the non-UV-absorbing alkaloids present in ethanol extracts from S. spectabilis flowers using capillary zone electrophoresis (CZE) with indirect UV detection. METHODOLOGY: The optimized CZE method employs a background electrolyte containing 60 mM histidine (His), 15 mM α-cyclodextrin, 20% acetonitrile (ACN), and pH-adjusted to 4.7 with acetic acid (AcOH). RESULTS: The limit of detection (LOD) values was 10.2 and 13.9 mg L-1 for cassine and spectaline, respectively. For both analytes, the precision data were better than 2% of relative standard deviation (RSD) for migration times and peak areas. To evaluate the applicability of the developed method, ethanolic extracts from S. spectabilis flowers were prepared and analyzed. CONCLUSIONS: Thereby, the method proved to be efficient and complementary to conventional techniques, offering a cost-effective alternative in the quantification of the non-UV-absorbing piperidine alkaloids present in plant extracts.


Assuntos
Eletroforese Capilar , Etanol , Extratos Vegetais , Senna , Eletroforese Capilar/métodos , Extratos Vegetais/química , Extratos Vegetais/análise , Senna/química , Etanol/química , Alcaloides/análise , Limite de Detecção , Espectrofotometria Ultravioleta/métodos , Flores/química , Piperidinas/análise , Piperidinas/química
19.
J Clin Rheumatol ; 30(5): 208-216, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38880956

RESUMO

BACKGROUND/OBJECTIVE: To assess safety/efficacy of tofacitinib and tumor necrosis factor inhibitors (TNFi) in patients from Latin America (LATAM) in ORAL Surveillance. METHODS: In ORAL Surveillance, 4362 patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily or TNFi. This post hoc analysis stratified patients by geographical location (LATAM, n = 1202; non-LATAM, n = 3160). Incidence rates (IRs; patients with first event/100 patient-years) and hazard ratios for adverse events of special interest were reported. Efficacy outcomes included Clinical Disease Activity Index and American College of Rheumatology 20/50/70 responses. RESULTS: Risk factors associated with cardiovascular disease and malignancies were less prevalent in the LATAM cohort compared with the non-LATAM cohort. IRs for patients receiving tofacitinib (combined doses) versus TNFi were 0.54 versus 0.28 (LATAM) and 1.14 versus 0.92 (non-LATAM) for major adverse cardiovascular events; 0.58 versus 0.27 (LATAM) and 1.33 versus 0.95 (non-LATAM) for malignancies excluding nonmelanoma skin cancer; and 0.69 versus 0.35 (LATAM) and 0.63 versus 0.33 (non-LATAM) for all-cause death. IRs for nonmelanoma skin cancer and venous thromboembolism were also numerically higher with tofacitinib versus TNFi and in the non-LATAM cohort versus LATAM. Efficacy was similar across treatment groups within each cohort. CONCLUSIONS: Adverse events of special interest were generally less frequent in LATAM versus non-LATAM patients, reflecting differences in baseline characteristics, and higher with tofacitinib versus TNFi in both cohorts, consistent with the overall findings of ORAL Surveillance. Our findings emphasize the importance of assessing individual risk factors to guide benefit/risk assessment and treatment decisions. CLINICAL TRIAL REGISTRATION NUMBER: NCT02092467.


Assuntos
Artrite Reumatoide , Doenças Cardiovasculares , Neoplasias , Piperidinas , Pirimidinas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antirreumáticos/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Incidência , América Latina/epidemiologia , Neoplasias/epidemiologia , Neoplasias/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Inibidores do Fator de Necrose Tumoral/administração & dosagem
20.
Int J Mol Sci ; 25(11)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38891950

RESUMO

Piperine, an active plant alkaloid from black pepper (Piper nigrum), has several pharmacological effects, namely antioxidant, anti-inflammatory and immunomodulatory effects, which involve inhibiting molecular events associated with various stages of cancer development. The aim of this study was to investigate the molecular mechanisms of action of piperine in relation to its potential anticancer effect on head and neck cancer cells. Parameters related to neoplastic potential and cytokine, protein and gene expression were investigated in head and neck cancer cell lines (HEp-2 and SCC-25) treated with piperine. The results of the tests indicated that piperine modified morphology and inhibited viability and the formation of cell colonies. Piperine promoted genotoxicity by triggering apoptosis and cell cycle arrest in the G2/M and S phases. A decrease in cell migration was also observed, and there was decreased expression of MMP2/9 genes. Piperine also reduced the expression of inflammatory molecules (PTGS2 and PTGER4), regulated the secretion of cytokines (IFN-γ and IL-8) and modulated the expression of ERK and p38. These results suggest that piperine exerts anticancer effects on tumor cells by regulating signaling pathways associated with head and neck cancer.


Assuntos
Alcaloides , Apoptose , Benzodioxóis , Neoplasias de Cabeça e Pescoço , Inflamação , Piperidinas , Alcamidas Poli-Insaturadas , Transdução de Sinais , Alcamidas Poli-Insaturadas/farmacologia , Benzodioxóis/farmacologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Alcaloides/farmacologia , Humanos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/genética , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Citocinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos
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