RESUMEN
Considering the possible interaction between mesenchymal stem cells (MSCs) and PI3Kγ-associated drugs, we evaluated the efficacy and action mechanism of MSCs in the treatment of colitis in PI3Kγ-/- mice. Trinitro-benzene-sulfonic acid enema was used to create a colitis model, and MSCs were transplanted through the caudal vein to treat colitis in wild-type and PI3Kγ-/- mice. We sequenced microbial 16S rRNA genes in the colonic mucosa of PI3Kγ-/- and wild-type mice and quantified colonic IgA, IL-2, IL-10, IL-17A, occludin, and serum IgA. MSC transplantation led to a more serious reduction in the weight of trinitro-benzene-sulfonic acid-administered PI3Kγ-/- mice than that in wild-type mice. The disease activity index, pathological scoring, number of taxa in the colon, Berger-Parker index, I-index, proportion of Proteobacteria, and IgA level in the blood were higher in PI3Kγ-/- mice than in wild-type mice after MSC transplantation. The occludin and IL-10 levels in the colon tissues decreased before and after MSC transplantation in PI3Kγ-/- mice, whereas they were increased in wild-type mice The IL-17 level decreased in both wild-type and PI3Kγ-/- mice, with knockout mice showing a greater decrease. Therefore, MSC transplantation in PI3Kγ-/- mice led to increased numbers of exogenous pathogenic microorganisms and enhanced colitis that was difficult to relieve.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Colitis , Trasplante de Células Madre Mesenquimatosas , Animales , Benceno , Colitis/inducido químicamente , Citocinas , Modelos Animales de Enfermedad , Inmunoglobulina A , Inflamación , Interleucina-10/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ocludina , ARN Ribosómico 16S , Ácido TrinitrobencenosulfónicoRESUMEN
Jian-pi-yang-zheng Decoction (JPYZ) is a traditional Chinese medicine that is used for the treatment of advanced gastric cancer, and it shows good efficacy in patients. A previous study indicated that JPYZ inhibited the progression of gastric cancer via the regulation of tumor-associated macrophages (TAMs), but the underlying molecular target of JPYZ regulation of TAMs has not been determined. The present study used modified-JPYZ (mJPYZ) to extend our investigation of gastric cancer. Our results showed that mJPYZ inhibited gastric cancer progression in vivo and in vitro. We found that mJPYZ decreased the activity of PI3-kinase γ (PI3Kγ) in TAMs, reduced the anti-inflammatory factor IL-10 and increased the expression of pro-inflammatory cytokines, such as TNF-α and IL-1ß, which ultimately promoted the conversion of TAMs from M2 to M1. Our findings also indicated that mJPYZ inhibited the growth and metastasis of gastric cancer by alleviating the unfavorable differentiation of TAMs via the PI3Kγ signaling cascades. In conclusion, the present findings indicated that mJPYZ inhibited gastric cancer cell EMT via PI3Kγ-dependent TAM reprogramming, which eventually suppressed gastric cancer growth and metastasis. Our study provides an underlying mechanism of a Chinese medicine in the treatment of gastric cancer via PI3Kγ in macrophages.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Medicamentos Herbarios Chinos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Macrófagos Asociados a Tumores/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Técnicas de Cocultivo , Citocinas/metabolismo , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Metástasis de la Neoplasia , Fenotipo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Células THP-1 , Microambiente Tumoral , Macrófagos Asociados a Tumores/enzimología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patologíaRESUMEN
INTRODUCTION: Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III 'DUO' trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab. AREAS COVERED: This review provides analysis of the mechanism of action of duvelisib and includes the rationale for the use of double inhibition. The authors also give their clinical experience with duvelisib. Overall, despite the high efficacy of the drug, some concern remains on duvelisib-related adverse events leading to treatment interruption in a significant proportion of patients. EXPERT OPINION: Considering the unmet need of salvage therapies in patients failing BTK and/or Bcl2 inhibitors, treatment with duvelisib represents a new valid option in the CLL therapeutic armamentarium. Therefore, the correct management of adverse events with early treatment suspension, dose reductions and prompt supportive treatment could help to manage treatment, thus improving patient outcome. Finally, the association of duvelisib with other targeted therapies, such as ibrutinib or venetoclax, could allow clinicians to capitalize on the synergistic activity of these agents.