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Heteronemin promotes iron-dependent cell death in pancreatic cancer

Naunyn-Schmiedeberg's Archives of Pharmacology 2024年第3期397卷 1865-1874页

作者： Kaftan, Gizem Erdoğan, Mümin Alper El-Shazly, Mohamed Lu, Mei-Chin Shih, Shou-Ping Lin, Hung-Yu Saso, Luciano Armagan, Güliz Doctoral Degree Program in Biochemistry Graduate School of Health Sciences Ege University Izmir Bornova 35100 Turkey Department of Biochemistry Faculty of Pharmacy Afyonkarahisar Health Sciences University Afyonkarahisar 03100 Turkey Department of Physiology Faculty of Medicine Izmir Katip Çelebi University Izmir Çiğli Turkey Department of Pharmacognosy Faculty of Pharmacy Ain-Shams University Organization of African Unity Street Cairo Abassia 11566 Egypt Department of Pharmaceutical Biology Faculty of Pharmacy and Biotechnology German University in Cairo Cairo 11835 Egypt Graduate Institute of Marine Biology National Dong Hwa University Pingtung 944 Taiwan National Museum of Marine Biology & Aquarium Pingtung 944 Taiwan Doctoral Degree Program in Marine Biotechnology National Sun Yat-Sen University (NSYSU) 70 Lien-Hai Road Kaohsiung 80424 Taiwan Doctoral Degree Program in Marine Biotechnology Academia Sinica 128 Academia Road Section 2 Taipei Nankang 11529 Taiwan School of Medicine College of Medicine I-SHOU University Kaohsiung Taiwan Division of Urology Department of Surgery E-Da Cancer & E-Da Hospital Kaohsiung 824 Taiwan Department of Physiology and Pharmacology “Vittorio Erspamer” Sapienza University of Rome P. Le Aldo Moro 5 Rome 00185 Italy Department of Biochemistry Faculty of Pharmacy Ege University Izmir Bornova 35100 Turkey

The marine environment has been recognized as a prolific source of potent bioactive compounds with significant anticancer properties. Among these, heteronemin, a sesterterpenoid-type natural product, has shown promise. This study delves into the potential of heteronemin as a ferroptotic agent against pancreatic cancer, using the Panc-1 cell line as a model. The cytotoxic potential of heteronemin was assessed using cell viability assays. Furthermore, its effect on lipid peroxidation was determined spectrophotometrically, while the changes it induced in autophagy- and ferritin-related protein expressions were evaluated using immunoblotting techniques. Various cell-based tests were employed to scrutinize its anticancer efficacy. Heteronemin displayed a notable cytotoxic effect, reducing cell viability by 50% at a concentration of 55 nM. This cytotoxicity was discernibly linked to ferroptosis, as evidenced by the reversal of cell death upon treatment with the ferroptosis inhibitor, ferrostatin-1. Heteronemin treatment led to a marked increase in ferroptosis markers and malondialdehyde (MDA) levels. Conversely, the expression of glutathione peroxidase-4 (GPX4), a key anti-ferroptotic protein, was suppressed. Furthermore, significant modulations in the expression of ferritinophagy- and iron-related proteins such as Atg5, Atg7, FTL, STEAP3, and DMT-1 were evident post-treatment (p < 0.05). This study underscores the potential of heteronemin as a ferroptosis inducer in pancreatic cancer cells. Given its robust cytotoxicity, heteronemin emerges as a promising lead compound for further exploration in cancer therapeutics. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

关键词： Ferroptosis Heteronemin Pancreatic ductal adenocarcinoma Sesterterpenoid-type natural product

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Dysregulated microRNAs in type 2 diabetes and breast cancer:Potential associated molecular mechanisms

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World Journal of Diabetes 2024年第6期15卷 1187-1198页

作者： Alex Cleber Improta-Caria Filipe Ferrari João Lucas Penteado Gomes Paloma Brasilio Villalta Úrsula Paula RenóSoci Ricardo Stein Edilamar M Oliveira Laboratory of Biochemistry and Molecular Biology of the Exercise Physical Education and Sport SchoolUniversity of São PauloSão Paulo 05508-030Brazil Graduate Program in Cardiology and Cardiovascular Sciences Federal University of Rio Grande do SulHospital de Clínicas de Porto AlegrePorto Alegre 90035003Brazil Laboratory of Metabolic Disorders(Labdime) School of Applied SciencesUniversity of Campinas-UNICAMPCampinas 13484-350Brazil Departments of Internal Medicine Molecular Pharmacology and PhysiologyCenter for Regenerative MedicineUSF Health Heart InstituteMorsani College of MedicineUniversity of South FloridaTampaFL 33602United States

Type 2 diabetes(T2D)is a multifaceted and heterogeneous syndrome associated with complications such as hypertension,coronary artery disease,and notably,breast cancer(BC).The connection between T2D and BC is established through processes that involve insulin resistance,inflammation and other *** this comprehension the specific cellular and molecular mechanisms linking T2D to BC,especially through microRNAs(miRNAs),remain *** are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological ***,the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been *** review aims to identify dysregulated miRNAs in both T2D and BC,exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

关键词： Type 2 diabetes Breast cancer MicroRNAs Molecular mechanisms

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Undernutrition during development modulates endoplasmic reticulum stress genes in the hippocampus of juvenile rats: Involvement of oxidative stress

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Brain Research 2022年第0期1797卷 000-000页

作者： Fernandes, Matheus Santos Pedroza, Anderson Apolônio de Andrade Silva, Severina Cássia de Lemos, Maria Daniele Teixeira Bernardo, Elenilson M. Pereira, Allifer R dos Santos, Tony Meireles Lagranha, Claudia Graduate Program in Neuropsychiatry and Behavioral Sciences Federal University of Pernambuco PE Recife Brazil Graduate Program in Biochemistry and Physiology Federal University of Pernambuco PE Recife Brazil Laboratory of Biochemistry and Exercise Biochemistry / CAV Federal University of Pernambuco Vitoria de Santo Antão PE Brazil Physical Education and Sport Department Federal University of Pernambuco PE Recife Brazil

To evaluate whether exercise training mitigates the deleterious effects of undernutrition during the developmental period in juvenile Wistar rats. Pregnant Wistar rats were fed with a diet containing 17 % or 8 % casein during pregnancy and lactation. At 30 days of life, male offspring were divided into 4 groups: Low-Protein non-trained (LS), Low-Protein Trained (LT), Normoprotein non-trained (NS), and Normoprotein Trained (NT). Trained rats performed aerobic exercise training (AET) for 4 weeks, 5 days a week, 1 h a day. 24 h from the last day of training, the animals were sacrificed. The tissues were removed to analyze indicators of mitochondrial metabolism, oxidative stress, and gene expression of GRP78, PERK, ATF6 ER stress markers, and BDNF. The results showed that undernutrition during development promotes deleterious effects on mitochondrial oxidative metabolism and induces reticulum stress in the hippocampus of juvenile rats. On the other hand, AET improves mitochondrial function and increases enzymatic and non-enzymatic antioxidant capacity, as well as declines ER stress. AET at moderate intensity for 4 weeks in male juvenile Wistar rats acts as a lifestyle intervention opposing the negative effects induced by a protein-restricted maternal diet. © 2022

关键词： Brain ER Stress Maternal Low Protein Diet Mitochondria Oxidative Stress Physical Exercise

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Single-image example-based superresolution of hyperpolarized 13C images

arXiv

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arXiv 2023年

作者： Deh, Kofi Coffee, Elizabeth Zhang, Guannan Kim, Nathaniel Miloushev, Vesselin Keshari, Kayvan R. Department of Radiology Memorial Sloan Kettering Cancer Center New York CityNY United States Department of Neurology Memorial Sloan Kettering Cancer Center New York CityNY United States Department of Physiology & Biophysics Weill Cornell Graduate School New York CityNY United States Department of Biochemistry & Structural Biology Weill Cornell Graduate School NYCNY United States Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center NYCNY United States

The transient signal available for hyperpolarized (HP) 13C imaging limits the image spatial resolution. This paper demonstrates a method of increasing spatial resolution by post-processing the HP 13C metabolic map using a corresponding anatomic image as a high-resolution example. The proposed method is tested with a Shepp-Logan digital phantom and for an MR image of a tumor in a mouse brain acquired at 3 Tesla using 13C Chemical Shift Imaging. The results are compared to the results of standard image rescaling methods using peak-signal-to-noise ratio and structural similarity index (SSIM) image quality metrics. In vivo, the method reduced blur resulting in a better match between the metabolite biodistribution and the anatomy. It is concluded that the image quality of hyperpolarized 13C MRI in vivo images can be improved with single image superresolution using the anatomic image as an example. © 2023, CC0.

关键词： Magnetic resonance imaging

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A Superoxide-Driven Redox State Promotes Geroconversion and Resistance to Senolysis in Replication-Stress Associated Senescence

SSRN

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SSRN 2023年

作者： Luo, Le Pervaiz, Shazib Clement, Marie-Veronique Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore117596 Singapore Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Singapore NUS Medicine Healthy Longevity Program National University of Singapore Singapore Integrated Science and Engineering Program NUS Graduate School National University of Singapore Singapore Yong Loo Lin School of Medicine National University of Singapore Singapore National University Cancer Institute National University Health System Singapore

Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we unravel the existence of a redox state associated with replication stress-induced senescence that we have coined senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe DCFH-DA. Moreover, measurement of GSH and GSSH reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Further supporting the key role of superoxide (O2.-) in the generation of SA-redox state, we show that incubation of senescent RPE1-hTERT with the O2.- scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidantś reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. Moreover, SA-redox state activates NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases the rate of TFEB protein synthesis, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and renders cells resistant to senolysis. However, SA-redox state does not prevent the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-βGal activity. Furthermore, while p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis. The latter is validated by the increased rate of p21 synthesis leading to p21 abundance upon the acquisition of SA-redox status, while maintaining low levels of p53 through an increase in the rate of p53 degradation despite buffering a decrease in p53 mRNA. © 2023, The Authors. All rights reserved.

关键词： Probes

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Effect of nutmeg extract on the white adipose tissue (WAT) browning process of aging rats

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Nutrition and Healthy Aging 2021年第4期6卷 285-291页

作者： Pratiwi, Yuni Susanti Siannoto, Melisa Goenawan, Hanna Sylviana, Nova Tarawan, Vita Murniati Nurhayati, Titing Setiawan, Iwan Nugraha, Gaga Irawan Dwipa, Lazuardhi Purba, Ambrosius Supratman, Unang Lesmana, Ronny Physiology Division Department of Biomedical Sciences Faculty of Medicine Universitas Padjadjaran Jatinangor Indonesia Physiology Molecular Laboratory Biological Activity Division Central Laboratory Universitas Padjadjaran Jatinangor Indonesia Graduate Program of Anti Aging and Aesthetic Medicine Faculty of Medicine Universitas Padjadjaran Bandung Indonesia Biochemistry Division Department of Biomedical Sciences Faculty of Medicine Universitas Padjadjaran Jatinangor Indonesia Geriatric Subdivision Department of Internal Medicine Faculty of Medicine-Hasan Sadikin Hospital Universitas Padjadjaran Jatinangor Indonesia Department of Chemistry Faculty of Mathematics and Natural Sciences Universitas Padjadjaran Jatinangor Indonesia

The white adipose tissue (WAT) browning process has become one of the promising methods for managing obesity. During this process, WAT is transformed into brown-like adipose tissue, which is also known as beige adipose tissue. The browning process can be activated by several inducers. One of the best candidates is peroxisome proliferator-activated receptor γ (PPARγ) agonist. Nutmeg (Myristica fragrans Houtt) is a natural PPARα/γ partial agonist that is known to contribute to the browning effect. This study aimed to explore the potential effect of nutmeg seed extract (NuSE) on body weight reduction and uncoupling protein (UCP)1, UCP2, UCP3, and peroxisome proliferator-activated receptor gamma coactivator-1 PGC-1α levels in aging rats. Eight male Wistar rats (80 weeks old) were divided into control and treatment groups. Both groups were fed a standard diet, and the treatment group was given 8.1 mg/kg body weight/day of NuSE via oral gavage for 12 weeks. After 12 weeks, the levels of UCP1, UCP2, UCP3, and PGC-1α from both inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) were examined. We observed that the administration of NuSE has no significant effect to the decreasement of rats body weights (p = 0.464), levels of UCP1 (p = 0.686), UCP2 (p = 0.360), UCP3 (p = 0.076), and PGC-1α (p = 0.200). © 2021 - The authors. Published by IOS Press.

关键词： Adipose tissue aging browning nutmeg

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Successive responses of three coral holobiont components (coral hosts, symbiotic algae, and bacteria) to daily temperature fluctuations

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Ecological Indicators 2024年 158卷

作者： Hsieh, Yunli Eric Lu, Chih-Ying Liu, Po-Yu Kao, Jia-Min Yang, Sung-Yin Wu, Chien-Yi Wong, Jing-Wen Michelle Shikina, Shinya Fan, Tung-Yung Yang, Shan-Hua Systems Biology and Mathematical Modelling group Max Planck Institute of Molecular Plant Physiology Potsdam Germany Institute of Biochemistry and Biology Bioinformatics Department University of Potsdam Potsdam Germany School of BioSciences The University of Melbourne ParkvilleVIC Australia Molecular and Biological Agricultural Sciences Program Taiwan International Graduate Program National Chung Hsing University and Academia Sinica Taipei Taiwan Graduate Institute of Biotechnology National Chung Hsing University Taichung Taiwan Biodiversity Research Center Academia Sinica Taipei Taiwan School of Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Institute of Fisheries Science National Taiwan University Taipei Taiwan Department of Aquatic Bioscience National Chiayi University Chiayi Taiwan Institute of Marine Environment and Ecology National Taiwan Ocean University Keelung Taiwan National Museum of Marine Biology and Aquarium Pingtung Taiwan

Corals and their associated microbiota form a "holobiont," which includes symbiotic algae and other associated microbiota dominated by bacteria. The composition of holobiont is influenced by various environmental factors, such as increasing sea water temperatures. Previous studies of the effects of temperature changes on coral physiology and associated bacterial communities have been conducted based on stable water temperatures set by mean temperatures, or by slowly increasing/decreasing temperatures. However, the daily temperature fluctuations that corals experience in nature are not stable. The current understanding of the effects of large daily temperature fluctuations on coral and associated bacterial community dynamics is limited. Hence, we conducted a four-week tank experiment using different large daily temperature fluctuations (±5 °C and ±7 °C) accompanied by continuous warming conditions (26 °C to 29 °C) to investigate the effects on two common reef-building corals, Stylophora pistillata and Pocillopora acuta. During the experiment, the activity of coral host catalase and superoxide dismutase were measured, the photosynthetic ability of symbiotic algae was recorded, and the variation in bacterial communities was analyzed using the V6-V8 region of 16S rDNA. According to the results, different parts of the holobionts of two coral species exhibited varying response rates to the continuous warming conditions and diurnal temperature fluctuations. Additionally, it was found that diurnal temperature fluctuations may mitigate the heat stress on the host and reduce the changes in bacterial response to warming. Therefore, it is suggested that the holobionts of different coral species may adopt different adaptation and survival strategies in response to diurnal temperature fluctuations and warming. Finally, based on the response of these two coral species under the conditions of diurnal temperature fluctuations and continuous warming, Acinetobacter and Rhodobacteracea

关键词： Temperature distribution

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Glucocorticoid Enhances Presenilin1-Dependent Aβ Production at Er's Mitochondrial-Associated Membrane by Downregulating Rer1 in Neuronal Cells

SSRN

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SSRN 2023年

作者： Choi, Gee Euhn Park, Ji Yong Park, Mo Ran Yoon, Jee Hyeon Han, Ho Jae Laboratory of Veterinary Biochemistry College of Veterinary Medicine Veterinary Medical Research Institute Jeju National University Jeju63243 Korea Republic of Interdisciplinary Graduate Program in Advanced Convergence Technology & Science Jeju National University Jeju63243 Korea Republic of Department of Veterinary Physiology College of Veterinary Medicine Research Institute for Veterinary Science BK21 Four Future Veterinary Medicine Leading Education & Research Center Seoul National University Seoul08826 Korea Republic of

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and β secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer’s disease (AD) by increasing ER-mitochondria connectivity, in which amyloid β (Aβ) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances γ-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial Aβ is unclear. In this study, we determined how glucocorticoid enhances Aβ production in MAM using SH-SY5Y cells and ICR mice. First, we observed that cortisol-induced Aβ accumulation in mitochondria preceded its extracellular apposition by enhancing γ-secretase activity, which was the result of increased presenilin 1 (PSEN1) localization in MAM. Screening data revealed that cortisol selectively downregulated the ER retrieval protein Rer1, which triggered its maturation and subsequent entry into the endocytic secretory pathway of PSEN1. Accordingly, overexpression of RER1 reversed the deleterious effects of mitochondrial Aβ on mitochondrial respiratory function and neuronal cell viability. Notably, we found that cortisol guided the glucocorticoid receptor (GR) to bind directly to the RER1 promoter, thus trans-repressing its expression. Inhibiting GR function reduced Aβ accumulation at mitochondria and improved the outcome of a spatial memory task in mice exposed to corticosterone. Taken together, glucocorticoid enhances PSEN1-mediated Aβ generation at MAM by downregulating Rer1, which is a potential target at early stages of AD pathogenesis. © 2023, The Authors. All rights reserved.

关键词： Mitochondria

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TMEM16 scramblases thin the membrane to enable lipid scrambling

Research Square

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Research Square 2021年

作者： Falzone, Maria E. Feng, Zhang Alvarenga, Omar E. Pang, Yangang Lee, ByoungCheol Cheng, Xiaolu Fortea, Eva Scheuring, Simon Accardi, Alessio Department of Anesthesiology Weill Cornell Medical College United States Department of Biochemistry Weill Cornell Medical College United States Physiology Biophysics and Systems Biology Graduate Program Weill Cornell Medical College United States Department of Physiology and Biophysics Weill Cornell Medical College United States

TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. It was proposed that lipid headgroups move between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryoEM structure of the Ca2+-bound afTMEM16 scramblase in nanodiscs showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not entail specific protein-lipid interactions with the extracellular vestibule. Further, we find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes despite an open pathway. Our results show how afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove. © 2021, CC BY.

关键词： Lipids

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Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity

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Cell Reports 2025年第6期44卷 115746页

作者： Tsukahara, Takao Kethireddy, Saini Bonefas, Katherine M. Chen, Alex Sutton, Brendan L.M. Bandow, Kenjiro Dou, Yali Iwase, Shigeki Sutton, Michael A. Michigan Neuroscience Institute University of Michigan Medical School Ann Arbor MI United States Department of Human Genetics University of Michigan Ann Arbor 48109 MI United States Department of Molecular & Integrative Physiology University of Michigan Ann Arbor MI United States Neuroscience Graduate Program University of Michigan Ann Arbor 48109 MI United States College of Literature Science and the Arts University of Michigan Ann Arbor 48109 MI United States Meikai University School of Dentistry Department of Oral Biology and Tissue Engineering Division of Biochemistry Saitama Sakado 350-0283 Japan Department of Medicine and Department of Biochemistry and Molecular Medicine Keck School of Medicine University of Southern California Los Angeles 90033 CA United States

Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating non-redundant yet poorly understood roles of this enzyme family in neurodevelopment. However, the specific cellular role of KMT2 enzymes in the brain remains poorly understood, owing to the clear non-catalytic functions of each family member and the potential for functional redundancy in installing H3K4 methylation (H3K4me). Here, we identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling. Using RNAi screening, conditional genetics, small-molecule inhibitors, and transcriptional profiling, our data reveal that individual KMT2 enzymes have unique roles and operate in specific phases to control distinct facets of homeostatic scaling. Together, our results suggest that the expansion of this enzyme family in mammals is key to coupling fine-tuned gene expression changes to adaptive modifications of synaptic function. © 2025 The Author(s)

关键词： chromatin CP: Neuroscience histone methylation homeostatic plasticity KMT2 lysine methyltransferase 2 neurodevelopmental disorders transcription

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