Targeting metabolism of breast cancer and its implications in T cell immunotherapy

Breast cancer is a prominent health issue amongst women around the world. Immunotherapies including tumor targeted antibodies, adoptive T cell therapy, vaccines, and immune checkpoint blockers have rejuvenated the clinical management of breast cancer, but the prognosis of patients remains dismal. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. The deprivation uptake of nutrients (such as glucose, amino acid, and lipid) by breast cancer cells has a significant impact on tumor growth and microenvironment remodeling. In recent years, in-depth researches on the mechanism of metabolic reprogramming and immune escape have been extensively conducted, and targeting metabolic reprogramming has been proposed as a new therapeutic strategy for breast cancer. This article reviews the abnormal metabolism of breast cancer cells and its impact on the anti-tumor activity of T cells, and further explores the possibility of targeting metabolism as a therapeutic strategy for breast cancer

Case report: Subcutaneous Mycobacterium haemophilum infection in an immunocompetent patient after lipolysis injections

Mycobacterium haemophilum is a slow-growing, aerobic mycobacterium that acts as a pathogen in immunocompromised adult patients and immunocompetent children. There are only a few rare cases in the literature describing this species as a cause of subcutaneous infections. Here, we describe a subcutaneous infection caused by M. haemophilum in an immunocompetent female after lipolysis injections at an unqualified beauty salon, suggesting that this bacteria can also be a potential causative agent of adverse events in medical aesthetics. In addition, M. haemophilum caused lesions not only at the injection sites and adjacent areas but also invaded distant sections through the subcutaneous sinus tracts. Thus, early diagnosis and appropriate treatment are vital to prevent further deterioration and improve prognosis

Translocase of the Outer Mitochondrial Membrane 40 Is Required for Mitochondrial Biogenesis and Embryo Development in Arabidopsis

In eukaryotes, mitochondrion is an essential organelle which is surrounded by a double membrane system, including the outer membrane, intermembrane space and the inner membrane. The translocase of the outer mitochondrial membrane (TOM) complex has attracted enormous interest for its role in importing the preprotein from the cytoplasm into the mitochondrion. However, little is understood about the potential biological function of the TOM complex in Arabidopsis. The aim of the present study was to investigate how AtTOM40, a gene encoding the core subunit of the TOM complex, works in Arabidopsis. As a result, we found that lack of AtTOM40 disturbed embryo development and its pattern formation after the globular embryo stage, and finally caused albino ovules and seed abortion at the ratio of a quarter in the homozygous tom40 plants. Further investigation demonstrated that AtTOM40 is wildly expressed in different tissues, especially in cotyledons primordium during Arabidopsis embryogenesis. Moreover, we confirmed that the encoded protein AtTOM40 is localized in mitochondrion, and the observation of the ultrastructure revealed that mitochondrion biogenesis was impaired in tom40-1 embryo cells. Quantitative real-time PCR was utilized to determine the expression of genes encoding outer mitochondrial membrane proteins in the homozygous tom40-1 mutant embryos, including the genes known to be involved in import, assembly and transport of mitochondrial proteins, and the results demonstrated that most of the gene expressions were abnormal. Similarly, the expression of genes relevant to embryo development and pattern formation, such as SAM (shoot apical meristem), cotyledon, vascular primordium and hypophysis, was also affected in homozygous tom40-1 mutant embryos. Taken together, we draw the conclusion that the AtTOM40 gene is essential for the normal structure of the mitochondrion, and participates in early embryo development and pattern formation through maintaining the biogenesis of mitochondria. The findings of this study may provide new insight into the biological function of the TOM40 subunit in higher plants

Identification of Sanguinarine Metabolites in Rats Using UPLC-Q-TOF-MS/MS

Sanguinarine (SAN), as the main active component of a traditional Chinese veterinary medicine, has been widely used in the animal husbandry and breeding industry. However, the metabolites of SA are still uncertain. Therefore, this research aimed to investigate the metabolites of SA based on rats in vivo. The blood, feces, and urine of rats were collected after the oral administration of 40 mg/kg SAN. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) was employed to identify the metabolites of SAN. The elemental composition of sanguinarine metabolites was inferred by analyzing their exact molecular weight, and the structures of the metabolites were predicted based on their fragment ions and cleavage pathways. A total of 12 metabolites were identified, including three metabolites in the plasma, four in the urine, and nine in the feces. According to the possible metabolic pathways deduced in this study, SAN was mainly metabolized through reduction, oxidation, demethylation, hydroxylation, and glucuronidation. This present research has summarized the metabolism of SAN in rats, which is helpful for further studying the metabolic mechanism of SAN in vivo and in vitro

Functional divergence of chloroplast Cpn60α subunits during <i>Arabidopsis</i> embryo development

<div><p>Chaperonins are a class of molecular chaperones that assist in the folding and assembly of a wide range of substrates. In plants, chloroplast chaperonins are composed of two different types of subunits, Cpn60α and Cpn60β, and duplication of <i>Cpn60α</i> and <i>Cpn60β</i> genes occurs in a high proportion of plants. However, the importance of multiple <i>Cpn60α</i> and <i>Cpn60β</i> genes in plants is poorly understood. In this study, we found that loss-of-function of <i>CPNA2</i> (<i>AtCpn60α2</i>), a gene encoding the minor Cpn60α subunit in <i>Arabidopsis thaliana</i>, resulted in arrested embryo development at the globular stage, whereas the other <i>AtCpn60α</i> gene encoding the dominant Cpn60α subunit, <i>CPNA1</i> (<i>AtCpn60α1</i>), mainly affected embryonic cotyledon development at the torpedo stage and thereafter. Further studies demonstrated that CPNA2 can form a functional chaperonin with CPNB2 (AtCpn60β2) and CPNB3 (AtCpn60β3), while the functional partners of CPNA1 are CPNB1 (AtCpn60β1) and CPNB2. We also revealed that the functional chaperonin containing CPNA2 could assist the folding of a specific substrate, KASI (β-ketoacyl-[acyl carrier protein] synthase I), and that the KASI protein level was remarkably reduced due to loss-of-function of <i>CPNA2</i>. Furthermore, the reduction in the KASI protein level was shown to be the possible cause for the arrest of <i>cpna2</i> embryos. Our findings indicate that the two Cpn60α subunits in <i>Arabidopsis</i> play different roles during embryo development through forming distinct chaperonins with specific AtCpn60β to assist the folding of particular substrates, thus providing novel insights into functional divergence of Cpn60α subunits in plants.</p></div

Partial complementation of the <i>cpna2-2</i> mutant using an <i>ABI3pro</i>:<i>CPNA2-HA</i> vector.

<p>(A) 7 and 14 DAG seedlings of WT and <i>cpna2-2</i> homozygous mutants. Arrows indicate cotyledons, and arrowheads indicate true leaves. C, cotyledon; T, true leaf. Bars = 2 mm. (B) Genotypic analysis of <i>cpna2-2</i> homozygous seedlings carrying an <i>ABI3pro</i>:<i>CPNA2-HA</i> vector. (C and D) Protein levels of KASI in 7 (C) and 14 (D) DAG seedlings of WT and <i>cpna2-2</i> homozygous mutants. ACTIN was used as the loading control, and the protein levels of ACTIN and KASI were determined by immunoblotting using the corresponding antibodies. Numbers under lanes indicate the relative band intensities quantified by ImageJ. Each experiment was repeated at least three times with comparable results.</p

Detection of the expression levels of <i>KASI</i> and phenotypic observation of embryos in <i>CPNA2pro</i>:<i>amiR-KASI</i> transgenic lines.

<p>(A) qRT-PCR analysis of the transcript levels of <i>KASI</i> in 10 DAG seedlings of wild type, amiR-16#, amiR-18# and amiR-23# lines. <i>GAPDH</i> was used as the control gene. Error bars indicate SD of three biological replicates. (B) Phenotypic observation of the embryos in wild type and lines 16, 18, 23 of <i>CPNA2pro</i>:<i>amiR-KASI</i> transgenic plants. Bars = 20 μm.</p

Summary of chaperonin subunits and KASI detected in CPNA2 and CPNA1 immunoprecipitation fractions.

<p>Summary of chaperonin subunits and KASI detected in CPNA2 and CPNA1 immunoprecipitation fractions.</p

Subcellular localization of CPNA2 and ultrastructure of chloroplasts in wild-type and <i>cpna2-2</i> embryos.

<p>(A) Fluorescent signals in mesophyll protoplasts of <i>35Spro</i>:<i>GFP</i> and <i>35Spro</i>:<i>CPNA2-GFP</i> transgenic plants. Bars = 5 μm. (B-E) Transmission electron microscopy of chloroplasts in 6 DAP wild-type (B and C) and <i>cpna2-2</i> (D and E) embryos. (C) and (E) are the magnification of white frames in (B) and (D), respectively. The arrow indicates the abnormal chloroplast; arrowheads indicate mitochondria; Nu, nucleus; NC, normal chloroplast; M, mitochondria; AC, abnormal chloroplast. Bars in (B) and (D) = 1 μm, Bars in (C) and (E) = 0.5 μm.</p