RESUMO
The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.
Assuntos
Antineoplásicos , Apoptose , Neoplasias da Mama , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Tiossemicarbazonas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Feminino , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Platina/química , Platina/farmacologia , Autofagia/efeitos dos fármacosRESUMO
A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties of dystonia can impact people of all ages, leading to severe impairment and a decreased standard of living. The discovery of genes causing variations of single or mixed dystonia has improved our understanding of the disease's etiology. Genetic dystonias are linked to several genes, including pathogenic variations of VPS16, TOR1A, THAP1, GNAL, and ANO3. Diagnosis of dystonia is primarily based on clinical symptoms, which can be challenging due to overlapping symptoms with other neurological conditions, such as Parkinson's disease. This review aims to summarize recent advances in the genetic origins and management of focal dystonia.
Assuntos
Distonia , Distúrbios Distônicos , Doença de Parkinson , Humanos , Distonia/diagnóstico , Distonia/genética , Distonia/terapia , Movimento , Chaperonas Moleculares/genética , Proteínas de Ligação a DNA , Proteínas Reguladoras de Apoptose , AnoctaminasRESUMO
Despite the success of combination antiretroviral therapy, people living with human immunodeficiency virus (HIV) still have an increased risk of Epstein-Barr virus (EBV)-associated B cell malignancies. In the HIV setting, B cell physiology is altered by coexistence with HIV-infected cells and the chronic action of secreted viral proteins, for example, HIV-1 Tat that, once released, efficiently penetrates noninfected cells. We modeled the chronic action of HIV-1 Tat on B cells by ectopically expressing Tat or TatC22G mutant in two lymphoblastoid B cell lines. The RNA-sequencing analysis revealed that Tat deregulated the expression of hundreds of genes in B cells, including the downregulation of a subset of major histocompatibility complex (MHC) class II-related genes. Tat-induced downregulation of HLA-DRB1 and HLA-DRB5 genes led to a decrease in HLA-DR surface expression; this effect was reproduced by coculturing B cells with Tat-expressing T cells. Chronic Tat presence decreased the NF-á´B pathway activity in B cells; this downregulated NF-á´B-dependent transcriptional targets, including MHC class II genes. Notably, HLA-DRB1 and surface HLA-DR expression was also decreased in B cells from people with HIV. Tat-induced HLA-DR downregulation in B cells impaired EBV-specific CD4+ T cell response, which contributed to the escape from immune surveillance and could eventually promote B cell lymphomagenesis in people with HIV.