Isoproterenol induces MD2 activation by ß-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.

Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating ß-adrenergic receptors (ß-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-ß-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg-1·d-1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 µM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via ß1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via ß2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana.

The organic extract of Periplaneta americana L. (Dictyoptera; Blattidae) has been traditionally used in southwestern China as an alternative medicine against disorders such as hepatitis, trauma, gastric ulcers, burns, and heart disease. The present study describes bioassay-guided purification and chemotherapeutic evaluation of the 60% ethanolic fraction of P americana organic extracts (PAE60). The most effective cytotoxic fraction was determined by way of repeated in vitro screenings against 12 distinct cultured human carcinoma cell lines: Eca 109, BGC823, HO8910, LS174T, CNE, HeLa, K562, PC-3, A549, BEL 7404, HL-60, and KB, followed by in vivo antitumor assays of the lead fraction (PAE60). The complexity of enriched active fraction was qualitatively evaluated using thin layer chromatography. Reconstituted PAE60 was effective at inhibiting HL-60, KB, CNE, and BGC823 cell growth with IC(50) values <20 µg mL-(1). PAE60 reduced tumor growth in S180-bearing immunocompetent mice by 72.62% after 10 days following oral doses of 500 mg kg d-(1) compared with 78.75% inhibition following 40 mg kg d-(1) of cyclophosphamide (CTX). Thymus and spleen indices of S180-bearing mice treated with PAE60 were significantly greater (P < .05) than CTX treatment groups, suggesting potential immunomodulation of antitumor host defenses by PAE60. Antiviral activity was also investigated and PAE60 inhibited herpes simplex type-2 replication (IC(50) = 4.11 ± 0.64 µg mL-(1)) with a selectivity index (CC(50) to IC(50) ratio) of 64.84 in Vero cells but was less effective on type-1 virus (IC(50) of 25.6 ± 3.16 µg mL-(1)). These results support future clinical trials on P. americana as an alternative or complementary medicinal agent.