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In order to study the effect of Hericium erinaceuspolysaccharide (HEP) on the immune and antioxidation functions of immunosuppressed mice. The control group received distilled water orally and the model and experimental groups I, II, and III received 0, 80, 160, and 320 mg/kg HEP respectively for a fortnight after re-molding with cyoclphosphnalide (CTX). Compared with the control group, the secretion of IL-2, IL-4, and IFN-γ, the activity or content of T-AOC, T-SOD, and GSH-PX, and the expression of PCNA mRNA in the thymus and spleen were reduced in immunosuppressed mice (P< .05 or P< .01). Compared with immunosuppressed mice, the levels of IL-2, IFN-γ, and GSH-PX and the PCNA mRNA expression of spleen and thymus were increased (P< .05 or P< .01), and the microstructure were also obviously improved in the experimental group III. Overall, 320 mg/kg of HEP significantly improved the immune and antioxidant functions.Graphical AbstractHEP can improve cytokine secretion by regulating antioxidant function and expression of apoptosis-related genes, thereby ameliorating tissue microstructure of thymus and spleen.

Tissues derive ATP from two pathways—glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue’s major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

Tectochrysin (TEC) is a natural flavonoid with anti-inflammatory, antioxidant, antitumor, and wound-healing activity. However, little is known about the therapeutic effects of TEC on inflammatory bowel disease (IBD). This study investigated the anti-inflammatory effect of TEC on IBD. Mice with dextran sulfate sodium (DSS)-induced chronic colitis served as an in vivo model of IBD. Lipopolysaccharide (LPS)-stimulated J774A.1 macrophages and mouse bone marrow-derived macrophages (BMDMs) served as in vitro models of inflammation. In vivo, 0.5% (w/w) TEC ameliorated DSS-induced colitis in mice by decreasing lipocalin-2 levels, disease activity index, colon shorten, weight loss, histological scores, and the apoptosis of colonic mucosal cells; it improved intestinal barrier function by increasing the expression of ZO-1 and occludin, decreasing the Th17/Treg ratio, and reducing the protein expression of NLRP3 and caspase-1 in the colon. Moreover, TEC decreased inflammation by reducing the serum levels of pro-inflammatory cytokines IFN-γ, IL-1β, G-CSF, IL-6, IL-8, iNOS, and TNF-α and increasing the levels of anti-inflammatory cytokines Bcl-2 and IL-10. TEC increased the relative abundance of the beneficial bacteria norank_f_Muribaculaceae in the mouse intestine. In vitro, 500 ng/mL TEC reduced oxidative stress by decreasing LPS-induced mitochondrial ROS production in BMDMs. TEC alleviated the increased levels of IL-1β, IL-6, and TNF-α and increased IL-10 levels in the culture supernatant of LPS-stimulated J774A.1 macrophages and BMDMs. These results indicate that TEC has a protective effect on DSS-induced chronic colitis by inhibiting inflammation, improving intestinal barrier function, and regulating intestinal microbial composition. Therefore, TEC has a high potential to treat IBD.

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes, and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin (SOST) that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influenceaA osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or “osteokines” from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin (OCN) secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2 (LCN2) is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain. We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process. Proteins secreted from bone cells (osteoblasts, osteocytes, and osteoclasts) regulate the formation of osteoblasts, osteoclasts, and new blood vessels in a paracrine (local hormonal action) manner. The human skeleton is constantly being modeled, and that remodeling involves the removal of old or damaged bone by osteoclasts and its subsequent replacement with new bone by osteoblasts. Osteocytes inhibit osteoblast differentiation and promote osteoclast differentiation. A team headed by Weiguo Zou of the Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, reviewed recent progress that has been made regarding the hormonal functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. The authors highlight the growing awareness of how bone functions as both a paracrine and endocrine (distant hormonal action) organ, which is of great importance in developing treatments for metabolic disorders and degenerative diseases.

Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells (BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2 (Msi2) regulates BMSC lineage commitment. Msi2is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2deficiency led to increased PPARγ signaling. RNA-interacting protein immunoprecipitation assays demonstrated that Msi2could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2decreased significantly during the aging process of mice, indicating that decreased Msi2function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2function may benefit the treatment of bone aging.

Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APCCdh1E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc.