Tumor‐suppressive circular RNAs: Mechanisms underlying their suppression of tumor occurrence and use as therapeutic targets

Circular RNAs (circRNAs) have a covalently closed circular conformation and are structurally stable. Those circRNAs with tumor‐suppressive properties play an important role in tumorigenesis and metastasis and thus may be used as therapeutic targets of cancers. Herein, we review the current understanding of the classification of circRNAs and summarize the functions and mechanisms of circRNAs that have tumor‐suppressive roles in various cancers, including liver cancer (circARSP91, circADAMTS13, circADAMTS14, circMTO1, hsa_circ_0079299, and circC3P1), bladder cancer (circFNDC3B, circITCH, circHIPK3, circRNA‐3, cdrlas, and circLPAR1), gastric cancer (circLARP4, circYAP1, hsa_cric_0000096, hsa_circ_0000993, and circPSMC3), breast cancer (circ_000911, hsa_circ_0072309, and circASS1), lung cancer (hsa_circ_0000977, circPTK2, circ_0001649, hsa_circ_100395, and circ_0006916), glioma (circ_0001946, circSHPRH, and circFBXW7), and colorectal cancer (circITGA7 and hsa_circ_0014717). Thanks to their structural stability, these tumor‐suppressive circRNAs may be used as potential and potent therapeutic targets. Moreover, we propose a new method for the classification of circRNAs. Based on whether they can be translated, circRNAs can be divided into noncoding circRNAs and coding circRNAs.     

From mitochondria to healthy aging: The role of branched-chain amino acids treatment: MATeR a randomized study

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核糖体生物合成与肿瘤的研究进展

核糖体生物合成是细胞内重要的生物学过程，决定了细胞内蛋白质合成的速率。在肿瘤细胞旺盛的生长压力下，肿瘤中核糖体生物合成发生异常调控。有越来越多的研究表明核糖体生物合成的异常可能会促进肿瘤的发生发展，并且它也逐渐被认为是多种肿瘤的一个可行的治疗靶点。本文简要综述了核糖体生物合成过程及其在肿瘤中的异常和调控，以及药物靶向核糖体生物合成治疗肿瘤的研究进展。     

Histologic and ultrastructural features in early and advanced phases of Zellweger spectrum disorder (infantile Refsum disease)

Zellweger spectrum disorders (ZSD) are rare autosomal recessive inherited metabolic disorders and include severe (Zellweger syndrome) and milder phenotypes [neonatal adrenoleukodystrophy and infantile Refsum disease (IRD)]. ZSD are characterized by impaired peroxisomal functions and lack of peroxisomes detected by electron microscopy (EM). ZSD are caused by mutations in any of the 14 PEX genes. Patients with ZSD commonly demonstrate nonspecific hepatic symptoms within the first year, often without clinical suspicion of ZSD. Thus, recognition of pathologic findings in the liver is critical for the early diagnosis.

We herein demonstrate the histologic and ultrastructural features in liver biopsies in the early and advanced phases from a 16-year-old male with IRD. The initial biopsy at 5 months of age showed a lack of peroxisomes by EM, and this finding played a critical role in the early diagnosis. In contrast, the second biopsy at 14 years of age, after long-term diet therapy, demonstrated significant disease progression with near-cirrhotic liver. In addition to lack of peroxisomes, EM revealed abundant trilamellar inclusions within large angulated lysosomes in many of the hepatocytes and Kupffer cells. Mitochondrial abnormalities were identified only in the second biopsy and were mainly identified in damaged cells; thus they were likely nonspecific secondary changes.

This is the first report demonstrating histological and ultrastructural features of liver biopsies in the early and advanced phases from a child with ZSD. Trilamellar inclusions are considered to be an ultrastructural hallmark of ZSD, but they may not be apparent in the early phases.     

Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis

The role of mitochondrial biogenesis during naïve to effector differentiation of CD8⁺ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in supporting cytokine production of nascent activated human naïve CD8⁺ T cells. Specifically, we found that prior to the first round of cell division activated naïve CD8⁺ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter‐linked and important for CD8⁺ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL‐2 production – as well as subsequent IL‐2 dependent TNF, IFN‐γ, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8⁺ T cells.     

Loss of BRMS2 induces cell growth inhibition and translation capacity reduction in colorectal cancer cells

A variety of chemotherapeutic drugs targeting ribosome processing have been developed and applied to cancer treatment mainly based on the impaired ribosome biogenesis checkpoint (IRBC). The IMP U3 small nucleolar ribonucleoprotein 3 (IMP3, BRMS2) has been identified as a participant in pre-rRNA processing for nearly twenty years. However, the roles of BRMS2 in cancers still unknown. In this research, a tissue microarray (TMA) with 151 paired tissues showed the aberrant overexpression of BRMS2 in CRC tissues which was associated with the worse prognosis. To clarify the function of BRMS2 in CRC cells, an inducible knockdown system was introduced in vitro and in vivo and the cell growth was drastically suppressed. Mechanistically, we found depletion of BRMS2 markedly decreased the protein translation rates which can limit cell growth. Furthermore, to confirm whether the IRBC played a role, multiple approaches including detection of the p53 pathway, depletion of BRMS2 in p53-mutated SW620 cells, and co-depletion of RPL11 were taken. To our surprise, IRBC was not activated. That indicated BRMS2 may play a unique role in ribosome biosynthesis and IRBC. Taken together, our results demonstrated the oncogenic function of BRMS2 in CRC cells and supported its potential as a therapeutic target.     

丹酚酸B对MPP+所致线粒体损伤PC12细胞的保护作用

目的 研究丹酚酸B(salvianolic acid B, SalB)对1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium, MPP₊)所致PC12细胞线粒体损伤的保护作用及相关机制。方法 使用MPP 处理PC12细胞建立损伤模型,线粒体膜电位和线粒体ATP合成被用于检测线粒体功能,使用PCR检测线粒体DNA、PGC-1、NRF-1和TFAM基因表达,蛋白免疫印迹用于检测线粒体融合相关蛋白表达变化。结果 ①SalB显著减轻MPP 所致线粒体膜电位下降和线粒体ATP合成减少。②SalB明显增加MPP 处理后线粒体DNA、PGC-1、NRF-1和TFAM基因表达。③SalB增加MPP 处理后Opa-1和Mfn-1表达,而抑制Drp-1和Fis-1的表达。结论 SalB可能通过调控线粒体生物发生和线粒体融合相关蛋白对MPP 所致PC12细胞线粒体损伤发挥保护作用。     

The Lpt ABC transporter for lipopolysaccharide export to the cell surface

The surface of the outer membrane of Gram-negative bacteria is covered by a tightly packed layer of lipopolysaccharide molecules which provide a barrier against many toxic compounds and antibiotics. Lipopolysaccharide, synthesized in the cytoplasm, is assembled in the periplasmic leaflet of the inner membrane where the intermembrane Lpt system mediates its transport to the cell surface. The first step of lipopolysaccharide transport is its extraction from the outer leaflet of inner membrane powered by the atypical LptB₂FGC ABC transporter. Here we review latest advances leading to understanding at molecular level how lipopolysaccharide is transported irreversibly to the outer membrane.     

The SUF system: an ABC ATPase-dependent protein complex with a role in Fe–S cluster biogenesis

Iron-sulfur (Fe–S) clusters are considered one of the most ancient and versatile inorganic cofactors present in the three domains of life. Fe–S clusters can act as redox sensors or catalysts and are found to be used by a large number of functional and structurally diverse proteins. Here, we cover current knowledge of the SUF multiprotein machinery that synthesizes and inserts Fe–S clusters into proteins. Specific focus is put on the ABC ATPase SufC, which contributes to building Fe–S clusters, and appeared early on during evolution.     

Domains of apoE4 required for the biogenesis of apoE-containing HDL

Abstract

Introduction. We have studied the functions of truncated apoE4 forms in vitro and in vivo in order to identify the domains of apoE4 required for the biogenesis of apoE-containing high-density lipoprotein (HDL). Results. We have found that apoE4-185, -202, -229, or -259 could promote ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux in vitro, although less efficiently than Full-length apoE4, and had diminished capacity to activate lecithin cholesterol acyltransferase (LCAT). Formation of HDL in vivo was assessed by various methods following gene transfer in apolipoprotein A-I^?/? × apoE^?/? mice. Fast protein liquid chromatography of plasma showed that the truncated apoE forms, except apoE4-185, generated an apoE-containing HDL peak. Two-dimensional gel electrophoresis of plasma and electron microscopy showed that truncated apoE forms generated distinct HDL subpopulations and formed discoidal HDL particles which could be converted to spherical by co-administration of truncated apoE4-202 and LCAT. Conclusion. Overall, the in-vivo and in-vitro data are consistent and indicate that apoE4-185 is the shortest truncated form that supports formation of discoidal apoE4-containing HDL particles.