RESUMO
BACKGROUND: In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D. RESEARCH DESIGN AND METHODS: Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018-20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer's safety database (21 December 2018-31 December 2021), including patient background characteristics. RESULTS: During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors. CONCLUSIONS: In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.
Assuntos
Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/epidemiologia , Hipoglicemiantes/efeitos adversos , Farmacovigilância , Japão , Fatores de Risco , Insulina/efeitos adversosRESUMO
Previously, we have revealed that the miR-130 family (miR-130b, miR-301a, and miR-301b) functions as an oncomiR in bladder cancer. The pharmacological inhibition of the miR-130 family molecules by the seed-targeting strategy with an 8-mer tiny locked nucleic acid (LNA) inhibits the growth, migration, and invasion of bladder cancer cells by repressing stress fiber formation. Here, we searched for a functionally advanced target sequence with LNA for the miR-130 family with low cytotoxicity and found LNA #9 (A(L)^i^i^A(L)^T(L)^T(L)^G(L)^5(L)^A(L)^5(L)^T(L)^G) as a candidate LNA. LNA #9 inhibited cell growth in vitro and in an in vivo orthotopic bladder cancer model. Proteome-wide tyrosine phosphorylation analysis suggested that the miR-130 family upregulates a wide range of receptor tyrosine kinases (RTKs) signaling via the expression of phosphorylated Src (pSrcTyr416). SILAC-based proteome analysis and a luciferase assay identified protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is implicated as a negative regulator of multiple signaling pathways downstream of RTKs as a target gene of the miR-130 family. The miR-130-targeted LNA increased and decreased PTPN1 and pSrcTyr416 expressions, respectively. PTPN1 knockdown led to increased tumor properties (cell growth, invasion, and migration) and increased pSrcTyr416 expression in bladder cancer cells, suggesting that the miR-130 family upregulates multiple RTK signaling by targeting PTPN1 and subsequent Src activation in bladder cancer. Thus, our newly designed miR-130 family targeting LNA could be a promising nucleic acid therapeutic agent for bladder cancer.
Assuntos
Antineoplásicos/uso terapêutico , MicroRNAs/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Oligonucleotídeos/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , RNA Neoplásico/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Camundongos , MicroRNAs/genética , RNA Neoplásico/genética , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/genética , Proteínas Recombinantes/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b. Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.
