Metabolic Modulation of Cellular Function

Editorial

18 March 2024

Editorial: Metabolic modulation of cellular function

Or Kakhlon

Ann Saada

and

Pablo V. Escriba

698 views

0 citations

Editors

Or Kakhlon

Hadassah Medical Center

Ann Saada

Hebrew University of Jerusalem

Pablo Vicente Escriba

University of the Balearic Islands

Impact

Original Research

11 December 2023

Sex hormone-binding globulin improves lipid metabolism and reduces inflammation in subcutaneous adipose tissue of metabolic syndrome-affected horses

Lynda Bourebaba

, 6 more and

Krzysztof Marycz

2,640 views

4 citations

Effect of Valproic acid (VPA), cisplatin, and their combination on cell cycle distribution of MDA-MB-231 and MDA-MB-436 cells. The cells were treated with 1 mM of VPA, 5 µM cisplatin (for MDA-MB-436), 10 µM cisplatin (for MDA-MB-231), or their combination for 72 h. The cell cycle phases were analyzed by flow cytometry and propidium iodide (PI) labeling. (A,B) Cell cycle analysis of MBA-MB-231 (A) and MBA-MB-436 cells (B). Results are presented as the percent of control (mean ± standard deviation [SD]); *p < 0.05; N = 6/group. (C) Representative flow cytometry histograms.

Brief Research Report

26 October 2023

Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells

Avital Granit Mizrahi

, 13 more and

Tamar Peretz

2,076 views

4 citations

Natural products as co-adjuvant therapy in acute leukemia with a metabolic and immunomodulatory approach. Treatment with chemotherapeutic agents may favor the selection of chemoresistant clones characterized by an increase in glycolytic flux or an increase in mitochondrial activity. Combined treatment with natural products can lead to the regulation of tumor metabolism by decreasing glycolysis and/or altering mitochondrial function, making cells more sensitive to cell death, and promoting the recognition and elimination of tumor cells by cells of the immune system. DC, Dendritic cells; MDSC-LCs, Myeloid-derived suppressor-like cells; N2 neutrophils, Anti-tumor phenotype; NK, Natural killer; Tregs, Regulators T cells.

Review

13 July 2023

Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance

Cindy Mayerli Arévalo

, 2 more and

Susana Fiorentino

2,494 views

2 citations

Review

16 June 2023

Metabolomics in aging research: aging markers from organs

Weicheng Fang

, 4 more and

Beidong Liu

Metabolism plays an important role in regulating aging at several levels, and metabolic reprogramming is the main driving force of aging. Due to the different metabolic needs of different tissues, the change trend of metabolites during aging in different organs and the influence of different levels of metabolites on organ function are also different, which makes the relationship between the change of metabolite level and aging more complex. However, not all of these changes lead to aging. The development of metabonomics research has opened a door for people to understand the overall changes in the metabolic level in the aging process of organisms. The omics-based “aging clock” of organisms has been established at the level of gene, protein and epigenetic modifications, but there is still no systematic summary at the level of metabolism. Here, we reviewed the relevant research published in the last decade on aging and organ metabolomic changes, discussed several metabolites with high repetition rate, and explained their role in vivo, hoping to find a group of metabolites that can be used as metabolic markers of aging. This information should provide valuable information for future diagnosis or clinical intervention of aging and age-related diseases.

7,322 views

12 citations

Hypoxia-dependent expression of glycolytic genes in the mouse embryo. (A) Expression of Aldoa, Ldha, and Pfkfb3 mRNA was detected in whole-mount (Dorsal view) and cryosection (Section) in situ hybridization of E8.25 (six to eight somite stage) embryos. Scale bars, 500 μm (Dorsal view) and 100 μm (Section). Data are representative of six independent experiments. NP, neural plate; NNE, non-neural ectoderm; M, cranial mesenchyme. (B) Expression of Aldoa, Ldha, Pfkfb3, and Nqo1 after the whole-embryo culture with 5% or 20% O2 determined by RT-qPCR. Messenger RNA levels of genes were normalized to that of Gapdh, and the relative values are presented as white (5% O2) and gray (20% O2) bars. Data are shown as means ± S.E.M of five embryos. Statistical differences were assessed using Student’s t-tests, **p < 0.001. (C) Embryos were cultured under hypoxia (5% O2) or normoxia (20% O2) from E8.0 (three to five somite stage) to E8.25 (six to eight somite stage). Expression of Aldoa, Ldha, and Pfkfb3 mRNA was detected by in situ hybridization. Neural plates are indicated by gray dotted lines. Scale bars, 100 μm. Data are representative of four independent experiments. NP, neural plate; M, cranial mesenchyme.

Original Research

03 July 2023

Glycolytic activity is required for the onset of neural plate folding during neural tube closure in mouse embryos

Daisuke Sakai

, 5 more and

Hiroki Shoji

2,267 views

6 citations

Original Research

18 January 2023

Perturbed actin cap as a new personalized biomarker in primary fibroblasts of Huntington’s disease patients

Saja Gharaba

, 10 more and

Miguel Weil

High content image based analysis of primary skin fibroblast samples of HD patients compared to HC (A) Representative images of skin fibroblast cells stained with 4 different fluorescent vital dyes (Hoechst 22,342 to label the cell nuclei, Calcein AM to label cytoplasm of living cells, TMRE to label functional mitochondria, and Mitotracker far-red to label mitochondria). The images were acquired by 20x magnification using INCell 2200 image analyzer. Scale bar = 50 µm. (B) Principal component analysis of 12HD vs. 11HC phenotypic data (PCA graph on the right) The analysis shows a separation between the two groups. Each sample is represented by 6 circles each circle is the median of phenotypic data extracted from 20 fields coming from one well, each field contain 10–40 cells, blue circles represent HC samples, red circles represent HD samples. (C) (Histogram graphs on the right) represent the distribution of the analyzed PCA data of the two populations in the two dimensions (PC1, PC2), blue histogram represents HC and red histogram represents HD. (D) Plot of feature importance in the two PCA dimensions PC1 & PC2, organized from the most important (orange) to the least important feature (black) to the significant difference between the two populations in the PCA analysis.

Primary fibroblasts from patient’s skin biopsies are directly isolated without any alteration in the genome, retaining in culture conditions their endogenous cellular characteristics and biochemical properties. The aim of this study was to identify a distinctive cell phenotype for potential drug evaluation in fibroblasts from Huntington’s Disease (HD) patients, using image-based high content analysis. We show that HD fibroblasts have a distinctive nuclear morphology associated with a nuclear actin cap deficiency. This in turn affects cell motility in a similar manner to fibroblasts from Hutchinson-Gilford progeria syndrome (HGPS) patients used as known actin cap deficient cells. Moreover, treatment of the HD cells with either Latrunculin B, used to disrupt actin cap formation, or the antioxidant agent Mitoquinone, used to improve mitochondrial activity, show expected opposite effects on actin cap associated morphological features and cell motility. Deep data analysis allows strong cluster classification within HD cells according to patients’ disease severity score which is distinct from HGPS and matching controls supporting that actin cap is a biomarker in HD patients’ cells correlated with HD severity status that could be modulated by pharmacological agents as tool for personalized drug evaluation.

2,634 views

7 citations

The distribution of Paneth cell in epithelium of the small intestine. Differentiated cells migrate from the base of the crypt to the villus, whereas PCs remain at the base of the crypt and are distributed between Lgr5+ stem cells. In the development of NEC, the microbial dysbiosis decrease binding of bacteria by IgA, and the mucosal layer becomes thinner. Increased inflammatory infiltration reduce the secretion of immune cells in the intestinal lumen, which is not enough to resist the invasion of pathogenic microorganisms. Large numbers of microbiota pass through the disrupted intestinal barrier (Created with BioRender.com).

Review

17 May 2023

Paneth cell development in the neonatal gut: pathway regulation, development, and relevance to necrotizing enterocolitis

Jiahui Yang

and

Yongyan Shi

2,687 views

0 citations

Brief Research Report

05 December 2022

Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin

Avital Granit

, 4 more and

Or Kakhlon

Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deacetylase inhibitor (HDACi) valproic acid (VPA) can counter the cisplatin-induced metabolic changes leading to its resistance. We performed targeted metabolomic and real time PCR analyses on MDA-MB-231 TNBC cells treated with cisplatin, VPA or their combination. 22 (88%) out of the 25 metabolites most significantly modified by the treatments, were acylcarnitines (AC) and three (12%) were phosphatidylcholines (PCs). The most discernible effects were up-modulation of AC by cisplatin and, contrarily, their down-modulation by VPA, which was partial in the VPA-cisplatin combination. Furthermore, the VPA-cisplatin combination increased PCs, sphingomyelins (SM) and hexose levels, as compared to the other treatments. These changes predicted modulation of different metabolic pathways, notably fatty acid degradation, by VPA. Lastly, we also show that the VPA-cisplatin combination increased mRNA levels of the fatty acid oxidation (FAO) promoting enzymes acyl-CoA synthetase long chain family member 1 (ACSL1) and decreased mRNA levels of fatty acid synthase (FASN), which is the rate limiting enzyme of long-chain fatty acid synthesis. In conclusion, VPA supplementation altered lipid metabolism, especially fatty acid oxidation and lipid synthesis, in cisplatin-treated MDA-MB-231 TNBC cells. This metabolic reprogramming might reduce cisplatin resistance. This finding may lead to the discovery of new therapeutic targets, which might reduce side effects and counter drug tolerance in TNBC patients.

3,547 views

13 citations