Targeting of adipose tissue macrophages by bee venom phospholipase A2 attenuates high-fat diet-induced obesity.

BACKGROUND/OBJECTIVES: Adipose tissue macrophages (ATMs) exist in either the M1 or M2 form. The anti-inflammatory M2 ATMs accumulate in lean individuals, whereas the pro-inflammatory M1 ATMs accumulate in obese individuals. Bee venom phospholipase A2 (bvPLA2), a major component in honeybee (Apis mellifera) venom, exerts potent anti-inflammatory effects via interactions with regulatory T cells (Treg) and macrophages. This study investigated the effects of bvPLA2 on a high-fat diet (HFD)-induced obesity in mice. SUBJECTS/METHODS: For in vivo experiments, male C57BL/6, CD206-deficient, and Treg-depleted mice models were fed either a normal diet 41.86 kJ (ND, 10 kcal% fat) or high-fat diet 251.16 kJ (HFD, 60 kcal% fat). Each group was i.p. injected with PBS or bvPLA2 (0.5 mg/kg) every 3 days for 11 weeks. Body weight and food intake were measured weekly. Histological changes in the white adipose tissue (WAT), liver, and kidney as well as the immune phenotypes of the WAT were examined. Immune cells, cytokines, and lipid profiles were also evaluated. The direct effects of bvPLA2 on 3T3-L1 pre-adipocytes and bone marrow-derived macrophages were measured in vitro. RESULTS: bvPLA2 markedly decreased bodyweight in HFD-fed mice. bvPLA2 treatment also decreased lipid accumulation in the liver and reduced kidney inflammation in the mice. It was confirmed that bvPLA2 exerted immunomodulatory effects through the CD206 receptor. In addition, bvPLA2 decreased M1 ATM and alleviated the M1/M2 imbalance in vivo. However, bvPLA2 did not directly inhibit adipogenesis in the 3T3-L1 adipose cells in vitro. CONCLUSIONS: bvPLA2 is a potential therapeutic strategy for the management of obesity by regulating adipose tissue macrophage homeostasis.

Evaluation of the Efficacy and Safety of the Herbal Formula PM014 in a Cisplatin- and Paclitaxel-Treated Tumor-Bearing Mouse Model.

PM014 (HL301) is a standardized herbal mixture derived from a traditional Korean medicine, Chung-Sang-Bo-Ha-Tang. Previously, we reported that PM014 treatment significantly suppressed pulmonary fibrosis, one of the frequent adverse effects of anticancer therapy in lung cancer. Before the clinical application of PM014 in anticancer therapy, the safety and efficacy of PM014 in combination with conventional anticancer drugs should be addressed to determine whether PM014 can be used in lung cancer. Lewis lung cancer-bearing mice were injected with 10 mg/kg of cisplatin or paclitaxel on day 5. Starting on day 7, the mice were administered 200 mg/kg PM014 every 2 days. On day 15, all mice were assessed by biochemical and histological analyses. PM014 did not block the antitumor activity of cisplatin and paclitaxel. Coadministration of PM014 and antitumor agents did not elevate the aspartate transaminase/alanine transaminase ratio or the blood urea nitrogen/creatinine ratio. Histopathological analysis also showed that PM014 did not induce hepatic or renal injury. Moreover, PM014 had no apparent inhibitory effects on drug metabolizing enzymes, indicating that PM014 did not alter the pharmacokinetics of chemotherapeutic drugs. Overall, these data show the safety and compatibility of combination therapy of PM014 and chemotherapies for the treatment of lung cancer.

Magnolol Attenuates Cisplatin-Induced Muscle Wasting by M2c Macrophage Activation.

Cancer chemotherapy induces sarcopenia, which is a rapid loss of muscle mass that directly restricts daily activities and leads to poor quality of life and increased mortality. Although hormone-related therapies have been used to improve appetite and nutritional status, current treatments are considered palliative. Thus, the protection of skeletal muscle loss without adverse effects is essential to allow the maintenance of chemotherapy in cancer patients. Magnolol from Magnolia officinalis has several pharmacological effects including anti-cancer and anti-inflammatory activities, but the protection from muscle atrophy is not well-understood. In the present study, we investigated the effects of magnolol on muscle wasting and macrophage subtypes in a cisplatin-induced sarcopenia mouse model. We showed that magnolol significantly attenuated the body weight and the muscle loss induced by cisplatin injection. The diameter of the tibialis anterior muscle was markedly increased after magnolol treatment in cisplatin-treated mice. Importantly, magnolol increased macrophage infiltration into skeletal muscle while not affecting proliferation of macrophages. Magnolol attenuated the imbalance of M1/M2c macrophages by increasing CD206+CD163+ M2c tissue reparative macrophages. Further, magnolol increased insulin-like growth factor (IGF)-1 expression. This effect was also observed in bone marrow-derived macrophages upon magnolol treatment. Taken together, magnolol may be a promising chemoprotective agent for the prevention of muscle atrophy through the upregulating M2c macrophages, which are a major source of IGF-1.

Targeting of M2-like tumor-associated macrophages with a melittin-based pro-apoptotic peptide.

BACKGROUND: Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating immune cells. Macrophages are broadly categorized as M1 or M2 types, and TAMs have been shown to express an M2-like phenotype. TAMs promote tumor progression and contribute to resistance to chemotherapies. Therefore, M2-like TAMs are potential targets for the cancer immunotherapy. In this study, we targeted M2-like TAMs using a hybrid peptide, MEL-dKLA, composed of melittin (MEL), which binds preferentially to M2-like TAMs, and the pro-apoptotic peptide d (KLAKLAK)2 (dKLA), which induces mitochondrial death after cell membrane penetration. METHODS: The M1 or M2-differentiated RAW264.7 cells were used for mitochondrial colocalization and apoptosis test in vitro. For in vivo study, the murine Lewis lung carcinoma cells were inoculated subcutaneously in the right flank of mouse. The dKLA, MEL and MEL-dKLA peptides were intraperitoneally injected at 175 nmol/kg every 3 days. Flow cytometry analysis of tumor-associated macrophages and immunofluorescence staining were performed to investigate the immunotherapeutic effects of MEL-dKLA. RESULTS: We showed that MEL-dKLA induced selective cell death of M2 macrophages in vitro, whereas MEL did not disrupt the mitochondrial membrane. We also showed that MEL-dKLA selectively targeted M2-like TAMs without affecting other leukocytes, such as T cells and dendritic cells, in vivo. These features resulted in lower tumor growth rates, tumor weights, and angiogenesis in vivo. Importantly, although both MEL and MEL-dKLA reduced numbers of CD206+ M2-like TAMs in tumors, only MEL-dKLA induced apoptosis in CD206+ M2-like TAMs, and MEL did not induce cell death. CONCLUSION: Taken together, our study demonstrated that MEL-dKLA could be used to target M2-like TAMs as a promising cancer therapeutic agent.

Impacts of Combined Cooling, Heating and Power Systems, and Rainwater Harvesting on Water Demand, Carbon Dioxide, and NOx Emissions for Atlanta.

The purpose of this study is to explore the potential water, CO2 and NOx emission, and cost savings that the deployment of decentralized water and energy technologies within two urban growth scenarios can achieve. We assess the effectiveness of urban growth, technological, and political strategies to reduce these burdens in the 13-county Atlanta metropolitan region. The urban growth between 2005 and 2030 was modeled for a business as usual (BAU) scenario and a more compact growth (MCG) scenario. We considered combined cooling, heating and power (CCHP) systems using microturbines for our decentralized energy technology and rooftop rainwater harvesting and low flow fixtures for the decentralized water technologies. Decentralized water and energy technologies had more of an impact in reducing the CO2 and NOx emissions and water withdrawal and consumption than an MCG growth scenario (which does not consider energy for transit). Decentralized energy can reduce the CO2 and NOx emissions by 8% and 63%, respectively. Decentralized energy and water technologies can reduce the water withdrawal and consumption in the MCG scenario by 49% and 50% respectively. Installing CCHP systems on both the existing and new building stocks with a net metering policy could reduce the CO2, NOx, and water consumption by 50%, 90%, and 75% respectively.

Use of impact fees to incentivize low-impact development and promote compact growth.

Low-impact development (LID) is an innovative stormwater management strategy that restores the predevelopment hydrology to prevent increased stormwater runoff from land development. Integrating LID into residential subdivisions and increasing population density by building more compact living spaces (e.g., apartment homes) can result in a more sustainable city by reducing stormwater runoff, saving infrastructural cost, increasing the number of affordable homes, and supporting public transportation. We develop an agent-based model (ABM) that describes the interactions between several decision-makers (i.e., local government, a developer, and homebuyers) and fiscal drivers (e.g., property taxes, impact fees). The model simulates the development of nine square miles of greenfield land. A more sustainable development (MSD) scenario introduces an impact fee that developers must pay if they choose not to use LID to build houses or apartment homes. Model simulations show homeowners selecting apartment homes 60% or 35% of the time after 30 years of development in MSD or business as usual (BAU) scenarios, respectively. The increased adoption of apartment homes results from the lower cost of using LID and improved quality of life for apartment homes relative to single-family homes. The MSD scenario generates more tax revenue and water savings than does BAU. A time-dependent global sensitivity analysis quantifies the importance of socioeconomic variables on the adoption rate of apartment homes. The top influential factors are the annual pay rates (or capital recovery factor) for single-family houses and apartment homes. The ABM can be used by city managers and policymakers for scenario exploration in accordance with local conditions to evaluate the effectiveness of impact fees and other policies in promoting LID and compact growth.