Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon cancer.

BACKGROUND: The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear. METHODS: Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization. RESULTS: Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization. CONCLUSIONS: PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.

Wireless neuromodulation in vitro and in vivo by intrinsic TRPC-mediated magnetomechanical stimulation.

Various magnetic deep brain stimulation (DBS) methods have been developing rapidly in the last decade for minimizing the invasiveness of DBS. However, current magnetic DBS methods, such as magnetothermal and magnetomechanical stimulation, require overexpressing exogeneous ion channels in the central nervous system (CNS). It is unclear whether magnetomechanical stimulation can modulate non-transgenic CNS neurons or not. Here, we reveal that the torque of magnetic nanodiscs with weak and slow alternative magnetic field (50 mT at 10 Hz) could activate neurons through the intrinsic transient receptor potential canonical channels (TRPC), which are mechanosensitive ion channels widely expressed in the brain. The immunostaining with c-fos shows the increasement of neuronal activity by wireless DBS with magnetomechanical approach in vivo. Overall, this research demonstrates a magnetic nanodiscs-based magnetomechanical approach that can be used for wireless neuronal stimulation in vitro and untethered DBS in vivo without implants or genetic manipulation.

Blockade of the pentraxin 3/CD44 interaction attenuates lung injury-induced fibrosis.

BACKGROUND: Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. METHODS: Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin-exposed conditional Ptx3-deficient and PTX3-neutralizing antibody (αPTX3i)-treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44-involved PTX3-induced fibrosis in HFL1 and primary mouse fibroblasts. RESULTS: PTX3 was upregulated in the lungs and plasma of bleomycin-exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin-exposed conditional Ptx3-deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen-expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K-AKT1, NF-κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic-based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin-induced pulmonary fibrosis. CONCLUSIONS: The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.

Effects of dietary and exercise intervention on weight loss and body composition in obese postmenopausal women: a systematic review and meta-analysis.

OBJECTIVE: This study examined the effects of dietary and exercise interventions on weight loss and body composition in overweight/obese peri- and postmenopausal women. METHODS: Medline, Central, Embase, and Google Scholar databases were searched for relevant trials conducted until December 31, 2016. Randomized controlled trials (RCTs) and prospective studies of overweight/obese peri- or postmenopausal women that examined the effects of dietary or exercise interventions, alone or combined, on weight loss were included. The primary outcome was percentage reduction in body weight. RESULTS: From 292 studies initially identified, 11 studies with 12 sets of participants were included. Both dietary and exercise intervention groups had significantly greater weight loss than control groups (diet vs control: difference in means = -6.55, 95% CI, -9.51 to -3.59, P < 0.001; exercise vs control: difference in means = -3.49, 95% CI, -6.96 to -0.02, P = 0.049). Combined dietary and exercise interventions resulted in greater weight loss than dietary interventions alone (diet plus exercise vs diet: difference in means = -1.22, 95% CI, -2.14 to -0.29, P = 0.010). Diet plus exercise resulted in greater fat loss (difference in means = -0.44, 95% CI, -0.67 to -0.20, P < 0.001) and greater lean mass loss (difference in means = -0.84, 95% CI, -1.13 to -0.55, P < 0.001) than diet alone. CONCLUSIONS: Dietary interventions reduced body weight and body composition profile parameters in peri- and postmenopausal women more than exercise alone. The addition of exercise reinforced the effect of dietary interventions on changing body weight and composition.

Danggui buxue tang inhibits 2,4-dinitrochlorobenzene: induced atopic dermatitis in mice.

Danggui Buxue Tang (DBT) is a herbal decoction that has been used in Chinese medicine to enhance qi and blood circulation. Previously, we found that DBT can suppress allergy-related asthma in mice, leading us to hypothesize that DBT might ameliorate allergy disease. In this study, we evaluated whether DBT can attenuate atopic dermatitis (AD) symptoms and have an anti-inflammatory effect on AD-like mice. The dorsal skin of female mice was shaved and sensitized cutaneously (skin smear) with 1-chloro-2,4-dinitrobenzene. Mice were then given various doses of DBT from days 14 to 29 cutaneously. DBT treatment suppressed ear swelling and skin inflammation and decreased mast cell and eosinophil infiltration into skin and ear tissue. DBT also inhibited levels of IgE and Th2-associated cytokine levels in serum. These results demonstrate that cutaneous administration of DBT reduced the development of AD-like skin lesions in mice.

Production of high-content galacto-oligosaccharide by enzyme catalysis and fermentation with Kluyveromyces marxianus.

Of three beta-galactosidases from Aspergillus oryzae, Kluyveromyces lactis and Bacillus sp., used for the production of low-content galacto- oligosaccharides (GOS) from lactose, the latter produced the highest yield of trisaccharides and tetrasaccharides. GOS production was enhanced by mixing beta-galactosidase glucose oxidase. The low-content GOS syrups, produced either by beta-galactosidase alone or by the mixed enzyme system, were subjected to the fermentation by Kluyveromyces marxianus, whereby glucose, galactose, lactose and other disaccharides were depleted, resulting in up to 97% and 98% on a dry weight basis of high-content GOS with the yields of 31% and 32%, respectively.