Edited by Judit Ovádi Keywords:Hypoxia-inducible factor Protein phosphatase 1, regulatory subunit 3C Glycogen accumulation Hypoxia Human MCF7 cell a b s t r a c t Hundreds of genes can be regulated by hypoxia-inducible factor 1 (HIF1) under hypoxia. Here we demonstrated a HIF1-mediated induction of protein phosphatase 1, regulatory subunit 3C gene (PPP1R3C) in human MCF7 cells under hypoxia. By mutation analysis we confirmed the presence of a functional hypoxia response element that is located 229 bp upstream from the PPP1R3C gene. PPP1R3C induction correlates with a significant glycogen accumulation in MCF7 cells under hypoxia. Knockdown of either HIF1a or PPP1R3C attenuated hypoxia-induced glycogen accumulation significantly. Knockdown of HIF2a reduced hypoxia-induced glycogen accumulation slightly (but not significantly). Our results demonstrated that HIF1 promotes glycogen accumulation through regulating PPP1R3C expression under hypoxia, which revealed a novel metabolic adaptation of cells to hypoxia.

Metabolism under hypoxia is significantly different from that under normoxia. It has been well elucidated that HIF-1 (hypoxia-inducible factor-1) plays a central role in regulating glucose metabolism under hypoxia; however, the role of HIF-1 in lipid metabolism has not yet been well addressed. In the present study we demonstrate that HIF-1 promotes LDL (low-density lipoprotein) and VLDL (very-LDL) uptake through regulation of VLDLR (VLDL receptor) gene expression under hypoxia. Increased VLDLR mRNA and protein levels were observed under hypoxic or DFO (deferoxamine mesylate salt) treatment in MCF7, HepG2 and HeLa cells. Using dual-luciferase reporter and ChIP (chromatin immunoprecipitation) assays we confirmed a functional HRE (hypoxia-response element) which is localized at +405 in exon 1 of the VLDLR gene. Knockdown of HIF1A (the α subunit of HIF-1) and VLDLR, but not HIF2A (the α subunit of HIF-2), attenuated hypoxia-induced lipid accumulation through affecting LDL and VLDL uptake. Additionally we also observed a correlation between HIF-1 activity and VLDLR expression in hepatocellular carcinoma specimens. The results of the present study suggest that HIF-1-mediated VLDLR induction influences intracellular lipid accumulation through regulating LDL and VLDL uptake under hypoxia.

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite‐mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α‐ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2‐oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss‐of‐function and gain‐of‐function mouse models, we showed that OXGR1 is essential for AKG‐mediated exercise‐induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

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Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development.

It has been demonstrated that dietary fat affects pubertal mammary gland development. However, the role of lauric acid (LA) in this process remains unclear. Thus, this study aimed to investigate the effects of LA on mammary gland development in pubertal mice and to explore the underlying mechanism. In vitro, 100 μM LA significantly promoted proliferation of mouse mammary epithelial cell line HC11 by regulating expression of proliferative markers (cyclin D1/3, p21, PCNA). Meanwhile, LA activated the G protein-coupled receptor 84 (GPR84) and PI3K/Akt signaling pathway. In agreement, dietary 1% LA enhanced mammary duct development, increased the expression of GPR84 and cyclin D1, and activated PI3K/Akt in mammary gland of pubertal mice. Furthermore, knockdown of GPR84 or inhibition of PI3K/Akt totally abolished the promotion of HC11 proliferation induced by LA. These results showed that LA stimulated mammary gland development of pubertal mice through activation of GPR84 and PI3K/Akt signaling pathway.

Mild aqueous Zn batteries have attracted increasing attention for energy storage due to the advantages of high safety and low cost; however, the rechargeability of Zn anodes is one major issue for practical applications. In this work, an effective approach is proposed to improve the reversibility and stability of Zn anodes using advanced acidic electrolytes. A trace amount of acetic acid (HAc) is employed as a buffering agent to provide a stable pH environment in aqueous Zn electrolytes, and thus suppress passivation from precipitation reactions on Zn electrodes. Meanwhile, tetramethylene sulfone (TMS) is introduced as the critical component to stabilize the Zn anodes in the acidic electrolyte. TMS greatly strengthens the hydrogen‐bonding network with reduced H2O activity and extends the electrochemical window of acidic electrolytes. With the optimal 3 m Zn(OTF)2 in (H2O‐HAc)/TMS acidic electrolyte (pH 1.6), the Zn electrode exhibits a coulombic efficiency of >99.8% and smooth Zn deposition. The Zn‐V2O5 full cell demonstrates ultra‐stable cycling over 20 000 cycles with a low decay rate of 0.0009% for each cycle at a negative/postive capacity ratio of 6.5. This work provides an insightful perspective to stabilize Zn electrodes by regulating the pH environment and limiting the H2O activity simultaneously for long‐life Zn anodes.

BackgroundDocetaxel (DOC) is widely used as a chemotherapy drug for various tumors, including gastric cancer (GC), but the clinical application of DOC has been limited due to the hydrophobicity of the drug. We aimed to formulate a multifunctional nanoparticle (NP) system to reduce the side effects of the chemotherapy agent, to promote synergistic therapeutic effects, and to achieve targeted delivery of the therapy.MethodsThe polyethylene glycol-poly(ε-caprolactone) NPs (PEG-PCL NPs) were prepared by a ring opening copolymerization technique and were then conjugated with a programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb). The effects of the surface coating on particle size, size distribution, zeta potential, drug encapsulation efficiency, loading capacity, and the drug release kinetics were investigated. By using a panel of PD-L1-expressing human GC cell lines and PD-L1-overexpressing cells, we studied cellular uptake, cytotoxic effects, and cellular apoptosis in the presence of PD-L1 mAb-conjugated NPs.ResultsThe characterization of the structure and biological functions of DOC-PEG-PCL-mAb NPs was investigated in vitro. X-ray photoelectron spectroscopy validated the presence of the PD-L1 mAbs on the NP surface. The cellular uptake analysis showed that the antibody-conjugated NPs achieved significantly higher cellular uptake. The results of an in vitro cytotoxicity experiment on three GC lines further proved the targeting effects of the antibody conjugation. In addition, we found that the DOC-PEG-PCL-mAb NPs induced cell apoptosis and enhanced G2-M arrest in cancer cells, indicating the inhibition of microtubule synthesis. When compared with the control groups, DOC-PEG-PCL-mAb NPs are more effective in inhibiting PD-L1 expression in GC cells.ConclusionOur results reported here highlight the biological and clinical potential of DOC-PEG-PCL-mAb NPs using PD-L1 mAbs in GC treatment.