Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.

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Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague. The aging signaling pathways were conservative from yeast and worms to mammals. So, we tested if CGA had an effect on aging in Caenorhabditis elegans. We found that CGA could extend the lifespan of C. elegans by up to 20.1%, delay the age-related decline of body movement, and improve stress resistance. We conducted genetic analysis with a series of worm mutants and found that CGA could extend the lifespan of the mutants of eat-2, glp-1, and isp-1, but not of daf-2, pdk-1, akt-1, akt-2, sgk-1, and clk-1. CGA could activate the FOXO transcription factors DAF-16, HSF-1, SKN-1, and HIF-1, but not SIR-2.1. Taken together, CGA might extend the lifespan of C. elegans mainly via DAF-16 in insulin/IGF-1 signaling pathway.

5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine. While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD). We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, we have identified disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/β-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD.

ORCID IDs: 0000-0002-4656-3189 (H.S.); 0000-0003-0518-5924 (C.Z.); 0000-0001-9320-9628 (W.J.).Anther cuticle and pollen exine are protective barriers for pollen development and fertilization. Despite that several regulators have been identified for anther cuticle and pollen exine development in rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana), few genes have been characterized in maize (Zea mays) and the underlying regulatory mechanism remains elusive. Here, we report a novel male-sterile mutant in maize, irregular pollen exine1 (ipe1), which exhibited a glossy outer anther surface, abnormal Ubisch bodies, and defective pollen exine. Using map-based cloning, the IPE1 gene was isolated as a putative glucose-methanolcholine oxidoreductase targeted to the endoplasmic reticulum. Transcripts of IPE1 were preferentially accumulated in the tapetum during the tetrad and early uninucleate microspore stage. A biochemical assay indicated that ipe1 anthers had altered constituents of wax and a significant reduction of cutin monomers and fatty acids. RNA sequencing data revealed that genes implicated in wax and flavonoid metabolism, fatty acid synthesis, and elongation were differentially expressed in ipe1 mutant anthers. In addition, the analysis of transfer DNA insertional lines of the orthologous gene in Arabidopsis suggested that IPE1 and their orthologs have a partially conserved function in male organ development. Our results showed that IPE1 participates in the putative oxidative pathway of C16/C18 v-hydroxy fatty acids and controls anther cuticle and pollen exine development together with MALE STERILITY26 and MALE STERILITY45 in maize.Male sterility is a common biological phenomenon in plants and widely used in the production of hybrid seeds, which can reduce costs and enhance seed purity (Tester and Langridge, 2010). According to inheritance or origin, male sterility includes three types: genic male sterility, cytoplasmic male sterility, and cytoplasmicgenic male sterility (Rhee et al., 2015). The generation of mature pollen grains relies on anther development. The start of anther formation occurs in differentiated flower tissues (floral meristem), which consist of three histogenic layers: L1, L2, and L3. After continuous cell division and differentiation, L1 forms the epidermis and the L3 layer develops into the stomium and vascular bundles. L2 is the most important layer; it undergoes a series of periclinal and anticlinal divisions and eventually grows into the endothecium, the middle layer, the tapetum, and the pollen mother cells. When anther morphogenesis is completed, the anther has centrally localized pollen mother cells enclosed by four somatic layers, which are, from the surface to the interior, the epidermis, endothecium, middle layer, and tapetum. Then, the pollen mother cells undergo meiosis and mitosis, resulting in trinucleate pollen grains, and the endothecium, middle layer, and tapetum are gradually degraded (Goldberg et al., 1993(Goldberg et al., , 1995Ma, 2005).The anther cuticle and poll...

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The Rem, Rem2, Rad, and Gem/Kir (RGK) family of small GTP-binding proteins potently inhibits high voltage-activated (HVA) Ca 2+ channels, providing a powerful means of modulating neural, endocrine, and muscle functions. The molecular mechanisms of this inhibition are controversial and remain largely unclear. RGK proteins associate directly with Ca 2+ channel β subunits (Ca v β), and this interaction is widely thought to be essential for their inhibitory action. In this study, we investigate the molecular underpinnings of Gem inhibition of P/Q-type Ca 2+ channels. We find that a purified Gem protein markedly and acutely suppresses P/Q channel activity in inside-out membrane patches, that this action requires Ca v β but not the Gem/Ca v β interaction, and that Gem coimmunoprecipitates with the P/Q channel α 1 subunit (Ca v α 1 ) in a Ca v β-independent manner. By constructing chimeras between P/Q channels and Gem-insensitive low voltage-activated T-type channels, we identify a region encompassing transmembrane segments S1, S2, and S3 in the second homologous repeat of Ca v α 1 critical for Gem inhibition. Exchanging this region between P/Q and T channel Ca v α 1 abolishes Gem inhibition of P/Q channels and confers Ca v β-dependent Gem inhibition to a chimeric T channel that also carries the P/Q I-II loop (a cytoplasmic region of Ca v α 1 that binds Ca v β). Our results challenge the prevailing view regarding the role of Ca v β in RGK inhibition of high voltage-activated Ca 2+ channels and prompt a paradigm in which Gem directly binds and inhibits Ca v β-primed Ca v α 1 on the plasma membrane.

Mitochondrial DNA control region segment I sequences and melanocortin 1 receptor (MC1R) gene polymorphism were examined in ethnic populations in the silk road region of China. Both the frequencies of the MC1R variants and the results of mtDNA data in this region presented intermediate values between those of Europe and East and Southeast Asia, which suggested extensive gene admixture in this area and was in general agreement with previous studies. Phylogenetic analysis of the ethnic populations in the Silk Road region that based on mtDNA data didn't show expected cluster pattern according to their ethnogenesis. We suspect that a high migration rate in female among these closely related populations and other three demographic events might account for it.