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Cigarette smoke-induced dysbiosis: comparative analysis of lung and intestinal microbiomes in COPD mice and patients

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Respiratory Research 2024年第1期25卷 1-14页

作者： Laiman, Vincent Chuang, Hsiao-Chi Lo, Yu-Chun Yuan, Tzu-Hsuen Chen, You-Yin Heriyanto, Didik Setyo Yuliani, Fara Silvia Chung, Kian Fan Chang, Jer-Hwa Department of Radiology Faculty of Medicine Public Health and Nursing Universitas Gadjah Mada – Dr. Sardjito Hospital Yogyakarta Indonesia School of Respiratory Therapy College of Medicine Taipei Medical University 250 Wuxing Street Taipei 11031 Taiwan Division of Pulmonary Medicine Department of Internal Medicine Shuang Ho Hospital Taipei Medical University New Taipei Taiwan Cell Physiology and Molecular Image Research Center Wan Fang Hospital Taipei Medical University Taipei Taiwan National Heart and Lung Institute Imperial College London London United Kingdom The Ph.D. Program for Neural Regenerative Medicine College of Medical Science and Technology Taipei Medical University Taipei Taiwan Department of Health and Welfare College of City Management University of Taipei Taipei Taiwan Industrial Ph.D. Program of Biomedical Science and Engineering National Yang Ming Chiao Tung University Taipei Taiwan Department of Biomedical Engineering National Yang Ming Chiao Tung University Taipei Taiwan Department of Anatomical Pathology Faculty of Medicine Public Health and Nursing Universitas Gadjah Mada – Dr. Sardjito Hospital Yogyakarta Indonesia Department of Pharmacology and Therapy Faculty of Medicine Public Health and Nursing Universitas Gadjah Mada Yogyakarta Indonesia Division of Pulmonary Medicine Departments of Internal Medicine Wan Fang Hospital Taipei Medical University Taipei Taiwan Collaboration Research Center for Precision Oncology based Omics- PKR Promics Universitas Gadjah Mada Yogyakarta Indonesia

Background: The impact of cigarette smoke (CS) on lung diseases and the role of microbiome dysbiosis in chronic obstructive pulmonary disease (COPD) have been previously reported;however, the relationships remain unclear. Methods: Our research examined the effects of 20-week cigarette smoke (CS) exposure on the lung and intestinal microbiomes in C57BL/6JNarl mice, alongside a comparison with COPD patients’ intestinal microbiome data from a public dataset. Results: The study found that CS exposure significantly decreased forced vital capacity (FVC), thickened airway walls, and induced emphysema. Increased lung damage was observed along with higher lung keratinocyte chemoattractant (KC) levels by CS exposure. Lung microbiome analysis revealed a rise in Actinobacteriota, while intestinal microbiome showed significant diversity changes, indicating dysbiosis. Principal coordinate analysis highlighted distinct intestinal microbiome compositions between control and CS-exposed groups. In the intestinal microbiome, notable decreases in Patescibacteria, Campilobacterota, Defferibacterota, Actinobacteriota, and Desulfobacterota were observed. We also identified correlations between lung function and dysbiosis in both lung and intestinal microbiomes. Lung interleukins, interferon-ɣ, KC, and 8-isoprostane levels were linked to lung microbiome dysbiosis. Notably, dysbiosis patterns in CS-exposed mice were similar to those in COPD patients, particularly of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 patients. This suggests a systemic impact of CS exposure. Conclusion: In summary, CS exposure induces significant dysbiosis in lung and intestinal microbiomes, correlating with lung function decline and injury. These results align with changes in COPD patients, underscoring the important role of microbiome in smoke-related lung diseases. © The Author(s) 2024.

关键词： Cigarette smoke Emphysema Inflammation Intestine Lung Microbiome

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Impact of transgenic sugarcane overexpressing SoSPS1 gene on bacterial diversity, enzyme activity and minerals content in soil rhizosphere

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Journal of Crop science and Biotechnology 2021年第1期24卷 61-69页

作者： Wulandari, Fitria Ekawati Suherman Handoyo, Tri Kim, Kyung-Min Sugiharto, Bambang Postgraduate Program in Biotechnology University of Jember Jl. Kalimantan No. 37 Kampus Tegalboto Jember 68121 Indonesia Laboratory of Molecular Biology and Biotechnology Center for Development of Advanced Science and Technology (CDAST) University of Jember Jl. Kalimantan No. 37 Kampus Tegalboto Jember 68121 Indonesia Division of Plant Biosciences School of Applied BioSciences College of Agriculture and Life Science Kyungpook National University Daegu South Korea Department of Biology Faculty of Mathematics and Natural Sciences University of Jember Jl. Kalimantan No. 37 Kampus Tegalboto Jember 68121 Indonesia

The transgenic sugarcane overexpressing SoSPS1 gene increased sugar content which may alter the root exudation that interact with soil rhizosphere microorganism. The microbial plays an important role in biochemical cycling and nutrient transformation in the soil. Therefore, it is important to investigate the potential risk of the transgenic sugarcane on soil ecosystem. This study is designed to evaluate the impact of overexpressing gene for sucrose-phosphate synthesis (SoSPS1) on the bacterial diversity, enzyme activity and nutrient contents. The transgenic sugarcane showed no significant difference in the population of culturable bacteria in the soil rhizosphere compared to non-transgenic counterpart. The populations of total, nitrogen-fixing and phosphate-solubilizing bacteria were similar in transgenic and non-transgenic sugarcane, although the bacterial population tends to increase at later sugarcane growth stage may due to the rise in nutrition from the root exudation. The PCR analysis showed no detection of horizontal gene flow in the bacteria. However, urease activity was significantly decreased in the transgenic sugarcane concomitant with lower nitrogen content in the soil rhizosphere at a later growth stage might due to the transgenic sugarcane lines increased nitrogen absorption for higher growth rate. Furthermore, the nutrient contents, such as organic carbon, phosphorus, potassium, magnesium and calcium, slightly varied in the soil rhizosphere but did not affected by the transgenic sugarcane. The results suggested that the transgenic sugarcane overexpressing SoSPS1 gene may not affect the bacterial diversity, nutrient contents and soil ecosystem. © 2020, Korean Society of Crop science (KSCS).

关键词： Bacterial diversity Soil fertility Sucrose-phosphate synthase Sugarcane

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Bloch-Grüneisen temperature and universal scaling of normalized resistivity in doped graphene revisited

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Physical Review B 2021年第4期103卷 045425-045425页

作者： Khoe Van Nguyen Yia-Chung Chang Research Center for Applied Sciences Academia Sinica Taipei 115 Taiwan Molecular Science and Technology Taiwan International Graduate Program Academia Sinica Taipei 115 Taiwan Department of Physics National Central University Chungli 320 Taiwan Department of Physics National Cheng-Kung University Tainan 701 Taiwan

We resolved some controversial issues on the Bloch-Grüneisen (BG) temperature in doped graphene via analytical and numerical calculations based on full inelastic electron-acoustic-phonon (EAP) scattering rate and various approximation schemes. Analytic results for BG temperature obtained by semi-inelastic (SI) approximation (which gives scattering rates in excellent agreement with the full inelastic scattering rates) are compared with those obtained by quasielastic (QE) approximation and the commonly adopted value of ΘFLA=2ℏvLAkF/kB. It is found that the commonly adopted BG temperature in graphene (ΘFLA) is about 5 times larger than the value obtained by the QE approximation and about 2.5 times larger than that by the SI approximation, when using the crossing-point temperature where low-temperature and high-temperature limits of the resistivity (ρ) meet. The corrected analytic relation based on SI approximation agrees extremely well with the transition temperatures determined by fitting the low- and high-T behavior of available experimental data of graphene's resistivity. Using the analytic expression of ΘBG we can prove that the normalized resistivity defined as R=ρ(T)/ρ(ΘBG) plotted as a function of (T/ΘBG) is independent of the carrier density. We also introduced a way to determine the BG temperature including the full inelastic EAP scattering rate when the deviation of electron energy from the chemical potential is taken into account by finding the maximum of ∂ρ/∂T.

关键词： Electrical conductivity Graphene Scaling methods

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ABCB1 Regulates Immune Genes in Breast Cancer

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Breast cancer (Dove Medical Press) 2023年 15卷 801-811页

作者： Han-Kun Chen Yi-Ling Chen Chih-Yang Wang Wei-Pang Chung Jung-Hua Fang Ming-Derg Lai Hui-Ping Hsu Department of Surgery Chi Mei Medical Center Tainan Taiwan. Department of Health and Nutrition Chia Nan University of Pharmacy and Science Tainan Taiwan. PhD Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan. Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan. Department of Oncology National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 70403 Taiwan. Center of Applied Nanomedicine National Cheng Kung University Tainan Taiwan. Laboratory Animal Center College of Medicine National Cheng Kung University Tainan Taiwan. Department of Biochemistry and Molecular Biology National Cheng Kung University Tainan Taiwan. Institute of Basic Medical Sciences College of Medicine National Cheng Kung University Tainan Taiwan. Department of Surgery National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan.

Background:Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and immune genes in breast cancer has not been widely studied. Methods:Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2 breast cancer was established to investigate the association between and immune genes in breast cancer. Results:Expression of increased in doxorubicin-selected MCF-7/ADR cells. High expression of mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. is positively correlated with , and . In the HER2 stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11bLy6G and CD11bLy6C cells, were more abundant than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well controlled after paclitaxel-trastuzumab combined therapy. Conclusion:ABCB1 was a poor predictor of HER2 LN breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.

关键词： ABC transporters ABCB1 breast cancer myeloid-derived suppressor cells patient-derived xenograft

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Theoretical insights into the chemical bonding, electronic structure, and spectroscopic properties of the lanarkite Pb2SO5 structure

arXiv

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arXiv 2023年

作者： Fabris, Guilherme S.L. Ferrer, Mateus M. Sambrano, Julio R. Almeida, Cláudio R.R. Paskocimas, Carlos A. La Porta, Felipe A. Graduate Program in Materials Science and Engineering Technological Development Center Universidade Federal de Pelotas RS Pelotas96010-610 Brazil Modeling and Molecular Simulation Group São Paulo State University Bauru São Paulo17033-360 Brazil Department of Materials Engineering Federal University of Rio Grande do Norte RN Natal59078-970 Brazil Postgraduate Program in Science and Engineering of Materials Federal University of Rio Grande do Norte RN Natal59078-970 Brazil Federal University of Technology - Paraná Nanotechnology and Computational Chemistry Laboratory Avenida dos Pioneiros 3131 CEP PR Londrina86036-370 Brazil State University of Londrina Post-Graduation Program in Chemistry Rodovia Celso Garcia Cid 445 km 380 CEP PR Londrina86057-970 Brazil

Lanarkite is a mineral formed by a combination of lead, sulphur, and oxygen atoms arranged in the general chemical formula Pb2SO5 (PSO) that crystallises with monoclinic symmetry (belonging to the C2/m space group, No. 12). This mineral was first discovered in Lanarkshire, Scotland and was named after its location. PSO has a unique structure comprising alternating penta-coordinated lead [PbO5] and tetra-coordinated sulphur [SO4] clusters. This lanarkite-type structure has recently attracted significant scientific interest and has been the focus of the superconducting material research community. However, its chemistry needs to be explored further. This article presents a comprehensive investigation on the chemical bonding, electronic structure, and spectroscopic properties of the lanarkite-type PSO structure from a computational perspective. Thus, different functionals in the DFT (e.g., PBE, PBE0, PBESOL, PBESOL0, BLYP, WC1LYP37, and B3LYP) were assessed to accurately predict their fundamental properties. All the DFT calculations were performed using a triple-zeta valence plus polarisation basis set. Among all the DFT functionals tested in this study, PBE showed the best agreement with the experimental data available in the literature. Our results also reveal that the [PbO5] clusters are formed with three Pb–O bond lengths, with values of about 2.32, 2.59, and 2.84 Å, respectively, while the [SO4] clusters have the same S–O bond length of 1.57 Å. We performed a complete topological analysis of this system to comprehend these structural differences. Additionally, the PSO structure has an indirect band gap energy of 2.9 eV and an effective mass ratio (mℎ∗ /me∗) of about 0.415 (using PBE calculations) which may, in principle, indicate a low recombination of electron-hole pairs in the lanarkite structure. Therefore, we believe that a detailed understanding of their electronic structures, spectroscopic properties as well as their chemical bonding is critically important

关键词： Lead compounds

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Volume electron microscopy (vol 2, 51, 2022)

NATURE REVIEWS METHODS PRIMERS

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NATURE REVIEWS METHODS PRIMERS 2022年第1期2卷 1页

作者： Peddie, Christopher J. Genoud, Christel Kreshuk, Anna Meechan, Kimberly Micheva, Kristina D. Narayan, Kedar Pape, Constantin Parton, Robert G. Schieber, Nicole L. Schwab, Yannick Titze, Benjamin Verkade, Paul Weigel, Aubrey Collinson, Lucy M. Electron Microscopy Science Technology Platform The Francis Crick Institute London UK Electron Microscopy Facility Faculty of Biology and Medicine University of Lausanne Lausanne Switzerland Cell Biology and Biophysics Unit European Molecular Biology Laboratory Heidelberg Germany Department of Molecular and Cellular Physiology Stanford University Palo Alto CA USA Center for Molecular Microscopy Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA Cancer Research Technology Program Frederick National Laboratory for Cancer Research Frederick MD USA The Institute for Molecular Bioscience The University of Queensland Brisbane Queensland Australia Centre for Microscopy and Microanalysis The University of Queensland Brisbane Queensland Australia Cell Biology and Biophysics Unit/ Electron Microscopy Core Facility European Molecular Biology Laboratory Heidelberg Germany Nanosurf AG Liestal Switzerland School of Biochemistry University of Bristol Bristol UK Janelia Research Campus Howard Hughes Medical Institute Ashburn VA USA

Life exists in three dimensions, but until the turn of the century most electron microscopy methods provided only 2D image data. Recently, electron microscopy techniques capable of delving deep into the structure of cells and tissues have emerged, collectively called volume electron microscopy (vEM). Developments in vEM have been dubbed a quiet revolution as the field evolved from established transmission and scanning electron microscopy techniques, so early publications largely focused on the bioscience applications rather than the underlying technological breakthroughs. However, with an explosion in the uptake of vEM across the biosciences and fast-paced advances in volume, resolution, throughput and ease of use, it is timely to introduce the field to new audiences. In this Primer, we introduce the different vEM imaging modalities, the specialized sample processing and image analysis pipelines that accompany each modality and the types of information revealed in the data. We showcase key applications in the biosciences where vEM has helped make breakthrough discoveries and consider limitations and future directions. We aim to show new users how vEM can support discovery science in their own research fields and inspire broader uptake of the technology, finally allowing its full adoption into mainstream biological imaging.

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Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma:the PLANET study

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National science Review 2022年第3期9卷 96-109页

作者： Weiwei Zhai Hannah Lai Neslihan Arife Kaya Jianbin Chen Hechuan Yang Bingxin Lu Jia Qi Lim Siming Ma Sin Chi Chew Khi Pin Chua Jacob Josiah Santiago Alvarez Pauline Jieqi Chen Mei Mei Chang Lingyan Wu Brian K.P.Goh Alexander Yaw-Fui Chung Chung Yip Chan Peng Chung Cheow Ser Yee Lee Juinn Huar Kam Alfred Wei-Chieh Kow Iyer Shridhar Ganpathi Rawisak Chanwat Jidapa Thammasiri Boon Koon Yoong Diana Bee-Lan Ong Vanessa H.de Villa Rouchelle D.Dela Cruz Tracy Jiezhen Loh Wei Keat Wan Zeng Zeng Anders Jacobsen Skanderup Yin Huei Pang Krishnakumar Madhavan Tony Kiat-Hon Lim Glenn Bonney Wei Qiang Leow Valerie Chew Yock Young Dan Wai Leong Tam Han Chong Toh Roger Sik-Yin Foo Pierce Kah-Hoe Chow Genome Institute of Singapore Agency for Science Technology and Research Key Laboratory of Zoological Systematics and Evolution Institute of Zoology Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences School of Biological Sciences Nanyang Technological University Division of Biosciences Faculty of Life Sciences Division of Surgery and Surgical Oncology National Cancer Centre Department of Hepato-Pancreato-Biliary and Transplant Surgery Singapore General Hospital Division of Hepatobiliary and Pancreatic Surgery Department of Surgery University Surgical Cluster National University Health System Hepato-Pancreato-Biliary Surgery Unit Department of Surgery National Cancer Institute Division of Pathology National Cancer Institute Department of Surgery Faculty of Medicine University of Malaya Department of Surgery and Center for Liver Disease Management and Transplantation The Medical City Department of Laboratories The Medical City Department of Pathology Singapore General Hospital Institute for Infocomm Research ASTAR Department of Pathology National University Health System Translational Immunology Institute (TII) Sing Health Duke-NUS Academic Medical Centre Division of Gastroenterology and Hepatology University Medicine Cluster National University Hospital Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Cancer Science Institute of Singapore National University of Singapore Division of Medical Oncology National Cancer Center Singapore Cardiovascular Research Institute National University of Singapore National University Healthcare System Singhealth-Duke-NUS Academic Surgery Program Duke-NUS Graduate Medical School Institute of Molecular and Cell Biology Agency for Science Technology and Research

Intra-tumor heterogeneity(ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic(transcriptomic and immune)heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma(HCC)with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients(331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage Ⅱ patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.

关键词： hepatocellular carcinoma intra-tumor heterogeneity phenotypic evolution tumor evolution

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TGR5 potentiates GLP-1 secretion and cause pancreatic islet regeneration in response to Tithonia diversifolia saponin-rich extract in diabetic model mice

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Phytomedicine Plus 2022年第1期2卷 100203-100203页

作者： Ejelonu, Oluwamodupe Cecilia Elekofehinti, Olusola Olalekan Adanlawo, Isaac Gbadura Kundu, Rakesh Cell signaling laboratory Zoology Department Siksha Bhavana. Visva Bharati University WB Santiniketan India Phytomedicine/Molecular Biology &Bioinformatics Lab. Department of Chemical Sciences (Biochemistry Program) Olusegun Agagu University of Science and Technology Okitipupa Ondo State Nigeria Molecular Biology and Bioinformatics Unit Department of Biochemistry Federal University of Technology Akure Ondo State Nigeria Department of Biochemistry Ekiti State University Ado-Ekiti Ekiti State Nigeria

Background: Activation of Takeda G-protein bile acid receptor 5 (TGR5) secretes glucagon-like peptide-1 (GLP1) downstream insulin release. Saponin which has been indicated as the antidiabetic principle in plant shared similar steroidal scaffold with cholic acid (primary agonist of TGR5), hence antidiabetic mechanism of Tithonia diversifolia leaves saponin-rich extract (TDS) was investigated via TGR5/GLP-1 pathway. Methods: Insulin secretion and expression of GLP1 were measured in MIN6 β-cells incubated with TDS and cholic acid a known agonist of TGR5 at (25, 75, 125, 325) µg/ml and treatment were compared to incubation with insulin secretagogue metformin (50 mM). The action of TDS on TGR5 was studied in vivo using swiss albino mice. Results: β-cell assay showed dose dependent increase in insulin secretion/1 × 10⁶cells incubated with TDS (25, 75, 125, 325 µg/ml) when compared with positive control (50 mM metformin) and vehicle control (Cholic acid). TDS increased GLP-1 and insulin expression and decrease the percentage of%HbA1c in treated mice when compared with control (p < 0.05). TGR5 gene were highly expressed in cell incubated with 20–60 mg/kg body weight of TDS compared to STZ-induced diabetic mice and immunoblotting of TGR5 protein showed higher expression in all groups treated with TDS compared to STZ-induced diabetic mice. Conclusion: TDS exhibit its antidiabetic mechanism via TGR5 agonism leading to increase GLP-1 expression and subsequently insulin release. Hence TDS may represent a new therapeutic strategy for type-2 diabetes, a finding which could be further investigated in clinical trials. © 2021 The Author(s)

关键词： Antidiabetic GLP1 Insulin TGR5 Tithonia diversifolia

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Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2

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Nature Communications 2024年第1期15卷 7463页

作者： Wang, Rong-Hsuan Chen, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chu, Yu-Hsin Chien, Chia-Chen Chien, Po-Chen Lo, Shao-Yun Wang, Zhong-Liang Tsou, Min-Chen Chen, Ssu-Yu Chiu, Guang-Shen Chen, Wen-Ling Wu, Yi-Hsuan Wang, Lily Hui-Ching Wang, Wen-Ching Lin, Shu-Yi Kung, Hsing-Jien Wang, Lu-Hai Cheng, Hui-Chun Lin, Kai-Ti Institute of Biotechnology National Tsing Hua University Hsinchu Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu Taiwan Institute of Molecular and Genomic Medicine National Health Research Institutes Zhunan Taiwan Institute of Molecular and Cellular Biology National Tsing Hua University Hsinchu Taiwan Department of Medical Science National Tsing Hua University Hsinchu Taiwan School of Medicine National Tsing Hua University Hsinchu Taiwan Department of Life Science National Tsing Hua University Hsinchu Taiwan Institute of Biomedical Engineering and Nanomedicine National Health Research Institutes Zhunan Taiwan College of Medical Science and Technology PhD Program for Cancer Biology and Drug Discovery Taipei Medical University Taipei Taiwan Chiese Medicine Research Center and Institute of Integrated Medicine China Medical University Taichung City Taiwan

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H₂S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H₂S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism. © The Author(s) 2024.

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Investigation of Aframomum melegueta compounds as ERK5 inhibitor related to breast cancer via molecular docking and dynamic simulation

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In silico pharmacology 2025年第1期13卷 18页

作者： Paul Olamide Ottu Olorunfemi Oyewole Babalola Cecilia Oluwamodupe Ayodeji Folasade Oluwatobiloba Idayat Oyinkansola Kehinde Olufemi Adebisi Akinola Sulyman Olalekan Ibrahim Olusola Olalekan Elekofehinti Teady Bioscience Research Laboratory Ilara Mokin Ondo State Nigeria. Phytomedicine Molecular Biology and Bioinformatics lab Department of Chemical Science (Biochemistry program) Olusegun Agagu University of Science and Technology Okitipupa Ondo State Nigeria. Bioinformatics and Molecular Biology Lab Department of Biochemistry Federal University of Technology Akure Akure Ondo State Nigeria. Department of Industrial Chemistry University of Ilorin Ilorin Kwara State Nigeria.

Breast cancer remains a global health challenge, with rising cases predicted in the coming decades. The complexity of breast cancer treatment arises from its complex nature, often involving multiple therapeutic strategies. One promising approach is targeting the ERK5 pathway, a key regulator in cancer cell proliferation and survival. In this study, we explored the anticancer potential of bioactive compounds from Aframomum melegueta, a plant traditionally used in West African medicine. The 3D structure of ERK5 (PDB ID: 4B99) was prepared and optimized using the Schrödinger Protein Preparation Wizard. Six phytochemicals from Aframomum melegueta were screened for their binding affinities to ERK5 using GlideXP docking. Dihydrogingerenone A,1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4-dihydroxyphenyl) heptane-3,5-diyldiacetate and Dihydrogingerenone C emerged as the lead compound, demonstrating a high docking score of − 9.659 kcal/mol, − 9.383 kcal/mol, and − 8.264 kcal/mol compared to standard anticancer drugs like Docetaxel (− 4.175 kcal/mol) and Temozolomide (− 5.443 kcal/mol). Post-docking analyses using MM-GBSA free energy calculations confirmed the compound’s high binding stability, with van der Waals interactions and hydrogen bonding at critical residues such as Met140 playing a significant role. Pharmacokinetic profiling using ADME analysis showed that our compounds exhibited favorable drug-likeness properties, adhering to Lipinski’s Rule of Five without violations. QSAR modeling and molecular dynamics (MD) simulations further validated its pharmacological potential. These findings suggest that Aframomum melegueta contains bioactive compounds with strong potential as ERK5 inhibitors, offering a novel approach to breast cancer treatment.

关键词： Aframomum melegueta Breast cancer Dihydrogingerenone A ERK5 molecular dynamic simulation

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