bims-glucam 2024-12-15 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–12–15
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism Is essential for coronavirus replication in host cells and in mice.
Targeting pivotal amino acids metabolism for treatment of leukemia.
Deciphering molecular drivers of lactate metabolic shift in mammalian cell cultures.
Glutamine: A key player in human metabolism as revealed by hyperpolarized magnetic resonance.
Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.
Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis.
Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice.
METTL16 controls airway inflammations in smoking-induced COPD via regulating glutamine metabolism.
Ambient PM2.5 Orchestrates M1 Polarization of Alveolar Macrophages via Activating Glutaminase 1-mediated Glutaminolysis in Acute Lung Injury.
Metabolic reprogramming, sensing, and cancer therapy.
Dynamic profiling of intra- and extra-cellular L/D-amino acids metabolism in colorectal cell and intestinal epithelial cell.
AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis.
Synthesis of platinum nanoparticles functionalized with glutamine and conjugated with thiosemicarbazone and their cytotoxic effects on MDA-MB-231 breast cancer cell line and evaluation of CASP-8 gene expression.
Virus-Inspired Biodegradable Tetrasulfide-Bridged Mesoporous Organosilica with GSH Depletion for Fluorescence Imaging-Guided Sonodynamic Chemotherapy of Glioblastoma Multiforme.
Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.
Order of amino acid recruitment into the genetic code resolved by last universal common ancestor's protein domains.
Variations in brain glutamate and glutamine levels throughout the sleep-wake cycle.

J Biol Chem. 2024 Dec 09. pii: S0021-9258(24)02565-1. [Epub ahead of print] 108063

Glutamine metabolism Is essential for coronavirus replication in host cells and in mice.

Kai Su Greene, Annette Choi, Nianhui Yang, Matthew Chen, Ruizhi Li, Yijian Qiu, Shahrzad Ezzatpour, Katherine S Rojas, Jonathan Shen, Kristin F Wilson, William P Katt, Hector C Aguilar, Michael J Lukey, Gary R Whittaker, Richard A Cerione.

  Understanding the fundamental biochemical and metabolic requirements for the replication of coronaviruses within infected cells is of notable interest for the development of broad-based therapeutic strategies, given the likelihood of emergence of new pandemic-potential virus species, as well as future variants of SARS-CoV-2. Here we demonstrate members of the glutaminase family of enzymes (GLS and GLS2), which catalyze the hydrolysis of glutamine to glutamate (i.e., the first step in glutamine metabolism), play key roles in coronavirus replication in host cells. Using a range of human seasonal and zoonotic coronaviruses, we show three examples where GLS expression increases during coronavirus infection of host cells, and another where GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the 'glutamine addiction' of virus-infected cells. We demonstrate that genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, a specific GLS inhibitor, block viral replication in epithelial cells. Moreover, treatment of SARS-CoV-2 infected K18-human ACE2 transgenic mice with SU1 resulted in their complete survival compared to untreated control animals, which succumbed within 10 days post-infection. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and mice and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of broad-based anti-viral drug candidates.

Keywords:  GLS; GLS inhibitor UP4; GLS2; HCoV-229E; HCoV-OC43; SARS-CoV-2; glutamine metabolism; pan-glutaminase inhibitor SU1

DOI:  https://doi.org/10.1016/j.jbc.2024.108063
Heliyon. 2024 Dec 15. 10(23): e40492

Targeting pivotal amino acids metabolism for treatment of leukemia.

Jiankun Hong, Wuling Liu, Xiao Xiao, Babu Gajendran, Yaacov Ben-David.

  Metabolic reprogramming is a crucial characteristic of cancer, allowing cancer cells to acquire metabolic properties that support their survival, immune evasion, and uncontrolled proliferation. Consequently, targeting cancer metabolism has become an essential therapeutic strategy. Abnormal amino acid metabolism is not only a key aspect of metabolic reprogramming but also plays a significant role in chemotherapy resistance and immune evasion, particularly in leukemia. Changes in amino acid metabolism in tumor cells are typically driven by a combination of signaling pathways and transcription factors. Current approaches to targeting amino acid metabolism in leukemia include inhibiting amino acid transporters, blocking amino acid biosynthesis, and depleting specific amino acids to induce apoptosis in leukemic cells. Different types of leukemic cells rely on the exogenous supply of specific amino acids, such as asparagine, glutamine, arginine, and tryptophan. Therefore, disrupting the supply of these amino acids may represent a vulnerability in leukemia. This review focuses on the pivotal role of amino acids in leukemia metabolism, their impact on leukemic stem cells, and their therapeutic potential.

Keywords:  Amino-acid metabolism; Amino-acid transporters; Chemo-resistance; Immune invasion; Leukemia; Leukemic stem cells; Metabolic reprogramming; Signaling pathways

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40492
Metab Eng. 2024 Dec 04. pii: S1096-7176(24)00164-2. [Epub ahead of print]88 25-39

Deciphering molecular drivers of lactate metabolic shift in mammalian cell cultures.

Mauro Torres, Ellie Hawke, Robyn Hoare, Rachel Scholey, Leon P Pybus, Alison Young, Andrew Hayes, Alan J Dickson.

  Lactate metabolism plays a critical role in mammalian cell bioprocessing, influencing cellular performance and productivity. The transition from lactate production to consumption, known as lactate metabolic shift, is highly beneficial and has been shown to extend culture lifespan and enhance productivity, yet its molecular drivers remain poorly understood. Here, we have explored the mechanisms that underpin this metabolic shift through two case studies, illustrating environmental- and genetic-driven factors. We characterised these study cases at process, metabolic and transcriptomic levels. Our findings indicate that glutamine depletion coincided with the timing of the lactate metabolic shift, significantly affecting cell growth, productivity and overall metabolism. Transcriptome analysis revealed dynamic regulation the ATF4 pathway, involved in the amino acid (starvation) response, where glutamine depletion activates ATF4 gene and its targets. Manipulating ATF4 expression through overexpression and knockdown experiments showed significant changes in metabolism of glutamine and lactate, impacting cellular performance. Overexpression of ATF4 increased cell growth and glutamine consumption, promoting a lactate metabolic shift. In contrast, ATF4 downregulation decreased cell proliferation and glutamine uptake, leading to production of lactate without any signs of lactate shift. These findings underscore a critical role for ATF4 in regulation of glutamine and lactate metabolism, related to phasic patterns of growth during CHO cell culture. This study offers unique insight into metabolic reprogramming during the lactate metabolic shift and the molecular drivers that determine cell status during culture.

Keywords:  Biopharmaceuticals; CHO cells; Glutamine; Lactate metabolic shift; Metabolome; Transcriptome

DOI:  https://doi.org/10.1016/j.ymben.2024.12.001
Prog Nucl Magn Reson Spectrosc. 2024 Nov-Dec;144-145:pii: S0079-6565(24)00012-8. [Epub ahead of print]144-145 15-39

Glutamine: A key player in human metabolism as revealed by hyperpolarized magnetic resonance.

Karen Dos Santos, Gildas Bertho, Mathieu Baudin, Nicolas Giraud.

In recent years, there has been remarkable progress in the field of dissolution dynamic nuclear polarization (D-DNP). This method has shown significant potential for enhancing nuclear polarization by over 10,000 times, resulting in a substantial increase in sensitivity. The unprecedented signal enhancements achieved with D-DNP have opened new possibilities for in vitro analysis. This method enables the monitoring of structural and enzymatic kinetics with excellent time resolution at low concentrations. Furthermore, these advances can be straightforwardly translated to in vivo magnetic resonance imaging and magnetic resonance spectroscopy (MRI and MRS) experiments. D-DNP studies have used a range of 13C labeled molecules to gain deeper insights into the cellular metabolic pathways and disease hallmarks. Over the last 15 years, D-DNP has been used to analyze glutamine, a key player in the cellular metabolism, involved in many diseases including cancer. Glutamine is the most abundant amino acid in blood plasma and the major carrier of nitrogen, and it is converted to glutamate inside the cell, where the latter is the most abundant amino acid. It has been shown that increased glutamine consumption by cells is a hallmark of tumor cancer metabolism. In this review, we first highlight the significance of glutamine in metabolism, providing an in-depth description of its use at the cellular level as well as its specific roles in various organs. Next, we present a comprehensive overview of the principles of D-DNP. Finally, we review the state of the art in D-DNP glutamine analysis and its application in oncology, neurology, and perfusion marker studies.

DOI: https://doi.org/10.1016/j.pnmrs.2024.05.003
Cell Death Differ. 2024 Dec 07.

Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.

Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Zhang Yang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A Schmid, Thomas M Marti, Patrick Dorn, Ren-Wang Peng.

Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat KRAS-driven lung cancer.

DOI: https://doi.org/10.1038/s41418-024-01427-x
iScience. 2024 Dec 20. 27(12): 111359

Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis.

Yue Gao, Siyu Zhang, Xianhong Zhang, Yitian Du, Ting Ni, Shuailin Hao.

  Genetic mutations arising from various internal and external factors drive cells to become cancerous. Cancerous cells undergo numerous changes, including metabolic reprogramming and epigenetic modifications, to support their abnormal proliferation. This metabolic reprogramming leads to the altered expression of many metabolic enzymes and the accumulation of metabolites. Recent studies have shown that these enzymes and metabolites can serve as substrates or cofactors for chromatin-modifying enzymes, thereby participating in epigenetic modifications and promoting carcinogenesis. Additionally, epigenetic modifications play a role in the metabolic reprogramming and immune evasion of cancer cells, influencing cancer progression. This review focuses on the origins of cancer, particularly the metabolic reprogramming of cancer cells and changes in epigenetic modifications. We discuss how metabolites in cancer cells contribute to epigenetic remodeling, including lactylation, acetylation, succinylation, and crotonylation. Finally, we review the impact of epigenetic modifications on tumor immunity and the latest advancements in cancer therapies targeting these modifications.

Keywords:  Epigenetics; Molecular genetics

DOI:  https://doi.org/10.1016/j.isci.2024.111359
bioRxiv. 2024 Nov 25. pii: 2024.11.25.625088. [Epub ahead of print]

Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice.

Seung-Chul Choi, Yong Ge, Milind V Joshi, Damian Jimenez, Lauren T Padilla, Cassandra LaPlante, Jeffery C Rathmell, Mansour Mohamadzadeh, Laurence Morel.

Glutamine metabolism is essential for T cell activation and functions. The inhibition of glutaminolysis impairs Th17 cell differentiation and alters Th1 cell functions. There is evidence for an active glutaminolysis in the immune cells of lupus patients. Treatment of lupus-prone mice with glutaminolysis inhibitors ameliorated disease in association with a reduced frequency of Th17 cells. This study was performed to determine the role of glutaminolysis in murine Tfh cells, a critical subset of helper CD4 + T cells in lupus that provide help to autoreactive B cells to produce autoantibodies. We showed that lupus Tfh present a high level of glutamine metabolism. The pharmacological inhibition of glutaminolysis with DON had little effect on the Tfh cells of healthy mice, but it reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production, germinal center B cell dynamics, as well as a reduction of the frequency of atypical age-related B cells and plasma cells. Accordingly, profound transcriptomic and metabolic changes, including an inhibition of glycolysis, were induced in lupus Tfh cells by DON, while healthy Tfh cells showed little changes. The T cell-specific inhibition of glutaminolysis by deletion of the gene encoding for the glutaminase enzyme GLS1 largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with little effect in a congenic control background. These results were confirmed in an induced model of lupus. Finally, we showed that T cell-specific Gls1 deletion impaired T- dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results demonstrated a greater intrinsic requirement of lupus Tfh cells for their helper functions, and they suggest that targeting glutaminolysis may be beneficial to treat lupus.

DOI: https://doi.org/10.1101/2024.11.25.625088
Ecotoxicol Environ Saf. 2024 Dec 11. pii: S0147-6513(24)01594-X. [Epub ahead of print]289 117518

METTL16 controls airway inflammations in smoking-induced COPD via regulating glutamine metabolism.

Xinyu Jia, Shan Liu, Chunan Sun, Manni Zhu, Qi Yuan, Min Wang, Tingting Xu, Zhengxia Wang, Zhongqi Chen, Mao Huang, Ningfei Ji, Mingshun Zhang.

  The persistent airway inflammation is the main characteristic of chronic obstructive pulmonary disease (COPD), typically caused by an indoor environment pollution cigarette smoke (CS). METTL16 is an m6A methyltransferase that has been proven to be closely associated with the occurrence of various diseases. However, its exact role in smoking-induced COPD remains to be investigated. In this study, we found that the level of METTL16 was aberrantly decreased in lung tissues of COPD smokers. Similarly, murine model induced by CS and lung epithelial cell model induced by cigarette smoke extract (CSE) also confirmed this discovery. Moreover, in the Mettl16-deficient (Mettl16+/-) mice challenged with CS, airway inflammation was aggravated. To identify the potential target genes and regulatory pathways through METTL16, methylated RNA immunoprecipitation sequencing (meRIP-seq), RNA sequencing (RNA-seq) and metabolomic profiling were used. Knockdown of METTL16 significantly reduced the stability of glutamic-oxaloacetic transaminase 2 (GOT2) and downregulated its expression through m6A modification, while reprogramed glutamine metabolism in lung epithelial cells. Significant reduction in inflammation levels was observed in the 3-month COPD murine model fed a glutamine-supplemented diet. Mechanistically, METTL16 could regulate lung epithelial mitochondrial function by participating in the reprogramming of glutamine metabolism. Our study characterized the role of the METTL16/GOT2/glutamine axis in the occurrence and development of COPD, and emphasized the potential value of METTL16 and glutamine in the therapy of chronic airway inflammation in smoking-induced COPD.

Keywords:  Airway inflammations; COPD; Cigarette smoke; Glutamine; METTL16

DOI:  https://doi.org/10.1016/j.ecoenv.2024.117518
Environ Pollut. 2024 Dec 07. pii: S0269-7491(24)02184-5. [Epub ahead of print] 125467

Ambient PM2.5 Orchestrates M1 Polarization of Alveolar Macrophages via Activating Glutaminase 1-mediated Glutaminolysis in Acute Lung Injury.

Jingran Su, Yikun Tu, Xiaoqi Hu, Yuanli Wang, Mo Chen, Xue Cao, Mengyao Shao, Fang Zhang, Wenjun Ding.

  The temporary explosive growth events of atmospheric fine particulate matter (PM2.5) pollution during late autumn and winter seasons still frequently occur in China. High-concentration exposure to PM2.5 aggravates lung inflammation, leading to acute lung injury (ALI). Alveolar macrophages (AMs) participate in PM2.5-induced pulmonary inflammation and injury. The polarization of AMs is dependent on metabolic reprogramming. However, the mechanism underlying the PM2.5-induced glutaminase-mediated glutaminolysis in AM polarization are still largely obscure. In his study, we found that PM2.5-treated mice exhibited pulmonary dysfunction and inflammation. The concentraions of glutamate and succinate were increased in PM2.5-treated lungs and AMs compared with the controls, whereas glutamine and α-ketoglutarate (α-KG) levels were decreased, indicating that glutaminolysis in AMs was aberrantly activated as evidenced by increased mRNA and protein levels of GLS1 after PM2.5 exposure. Moreover, we deterimined that the GLS1/nuclear factor kappa-B (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway regulated M1 polarization of AMs upon PM2.5 exposure. Inhibition of glutaminolysis by GLS1 specific inhibitor CB-839 and GLS1 siRNA significantly decreased PM2.5-induced M1 macrophage polarization and attenuated pulmonary damage. Taken together, our findings reveal a novel mechanism by which a metabolic program regulates M1 polarization of AMs and suggest that GLS1-mediated glutaminolysis is a potential therapeutic target for treating PM2.5-induced ALI.

Keywords:  ALI; GLS1; Glutaminolysis; M1 macrophage polarization; PM(2.5)

DOI:  https://doi.org/10.1016/j.envpol.2024.125467
Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064

Metabolic reprogramming, sensing, and cancer therapy.

Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.

  The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy

DOI:  https://doi.org/10.1016/j.celrep.2024.115064
J Pharm Biomed Anal. 2024 Dec 09. pii: S0731-7085(24)00664-2. [Epub ahead of print]255 116622

Dynamic profiling of intra- and extra-cellular L/D-amino acids metabolism in colorectal cell and intestinal epithelial cell.

Wenchan Deng, Rongrong Huang, Yuanjiang Pan, Cuirong Sun.

  The metabolism process of amino acids is closely related to the growth of normal and cancer cells. It is still not clear how L/D-configuration amino acids participate in the metabolism of colorectal cell. Herein, intra- and extra-cellular metabolic distribution of L/D-amino acids in colorectal cell (HCT116) and human normal intestinal epithelial cell (NCM460) were profiled utilizing HPLC-MS/MS coupled with a chiral probe. The results displayed the differential metabolic portrayal for the two cell lines. Compared with NCM460 cell, 13 kinds of significant differential amino acids were founded in a lower concentration within HCT116 cell, and L-Gln was even not detected for intra-cell; as for extra-cell culture medium, the HCT116 cell consumed more L-Gln, D-Phe and D-Leu, while L-Met was low ingested in HCT116 cell. L-Ala and Gly were excretion in both two cell lines, excepted L-Cit which was uptake in HCT116 and excretion in NCM460 cell. Furthermore, the dynamic changes of chiral amino acids displayed that phenylalanine, tyrosine and tryptophan biosynthesis and arginine biosynthesis is the major pathway for intra-cellular metabolites and extra-cellular metabolites, respectively. Moreover, with additional D-amino acids in culture medium, the results exhibited that high concentration of D-amino acids have no significant effect on the proliferation of NCM460 cell, but could influence the profiling of amino acids metabolites, and further affect the proliferation of HCT116 cell. This present work enhances the understanding of these differential amino acids metabolic network and depicts a dynamic process of metabolic dysregulation of HCT116 and NCM460 cell.

Keywords:  Cellular metabolism; Chiral amino acids; Colorectal cancer; HPLC-MS/MS

DOI:  https://doi.org/10.1016/j.jpba.2024.116622
Ecotoxicol Environ Saf. 2024 Dec 10. pii: S0147-6513(24)01587-2. [Epub ahead of print]289 117511

AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis.

Xiangting Zhang, Yuan Zeng, Huiya Ying, Yiwen Hong, Jun Xu, Rong Lin, Yuhao Chen, Xiao Wu, Weimin Cai, Ziqiang Xia, Qian Zhao, Yixiao Wang, Ruoru Zhou, Dandan Zhu, Fujun Yu.

  AdipoRon has been validated for its ability to reverse liver fibrosis, yet the underlying mechanisms remain to be thoroughly investigated. Collagen, predominantly synthesized and secreted in hepatic stellate cells (HSCs), relies on glycine as a crucial constituent. Activating transcription factor 4 (ATF4) serves as a pivotal transcriptional regulator in amino acid metabolism. Therefore, our objective is to explore the impact of AdipoRon on ATF4-mediated endoplasmic reticulum stress and amino acid metabolism in HSCs. We induced liver fibrosis in mice through intraperitoneal injection of CCl4 and administered AdipoRon (50 mg/kg) via gavage. In vitro studies were predominantly conducted using LX-2 cells. Our findings demonstrated that AdipoRon effectively suppressed ATF4-mediated endoplasmic reticulum stress in HSCs and assumed a crucial role in hindering serine/glycine biosynthesis. Interestingly, this inhibitory effect of AdipoRon on serine/glycine biosynthesis is regulated by PSAT1-mediated glutaminolysis, resulting in a subsequent decrease in collagen synthesis within HSCs. This study provides potential mechanistic insights into the treatment of liver fibrosis with AdipoRon.

Keywords:  Hepatic stellate cells; collagen; endoplasmic reticulum stress; glutaminolysis; liver fibrosis

DOI:  https://doi.org/10.1016/j.ecoenv.2024.117511
Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 12.

Synthesis of platinum nanoparticles functionalized with glutamine and conjugated with thiosemicarbazone and their cytotoxic effects on MDA-MB-231 breast cancer cell line and evaluation of CASP-8 gene expression.

Nabeel Rahi Mashkoor, Salwan Ali Abed, Arash Davoudi, Zahraa Aqeel Adel Jassim, Zainab Yousif Faraj, Fatemeh Akbari, Fahimeh Abedini Bajgiran, Mohammad Hedayati, Ali Salehzadeh.

  Breast cancer (BC) is the most prevalent form of cancer among women and is a major contributor to cancer-related fatalities. Nanotechnology has provided novel approaches to drug delivery to cancer cells. In this work, we synthesized platinum (Pt) nanoparticles, functionalized them with glutamine, conjugated them with thiosemicarbazone (TSC), and characterized their anticancer effects on the MDA-MB-231 breast cancer cell line. Characteristics of the nanoparticles were assessed by FT-IR, XRD, EDS mapping, SEM, TEM, DLS, and zeta potential measurement. Cell viability was characterized by MTT assay, and cell necrosis/apoptosis levels were determined by flow cytometry. The expression level of the CASP-8 gene was investigated by real-time PCR. Pt@Gln-TSC nanoparticles are spherical, 20-70 nm in diameter in dry form, 662 nm after hydration, and their zeta potential was - 6.6 mV. The 50% inhibitory concentration (IC50) for MDA-MB-231 (breast cancer) and HDF (normal) cell lines was 170 and 348µg/ml, respectively. Also, the IC50 of oxaliplatin drug and TSC on MDA-MB-231 cells was 184 µg/ml and 307 µg/ml, respectively. Treatment with Pt@Gln-TSC nanoparticles caused an increase in cell necrosis and primary apoptosis and elevated the expression of the CASP-8 gene by 2.54 folds. This study shows that Pt@Gln-TSC nanoparticles are significantly more toxic to breast cancer cells than to normal cells and can inhibit MDA-MB-231 cells by activating extrinsic apoptosis.

Keywords:  Apoptosis; Breast cancer; Flow cytometry; Platinum nanoparticles; Thiosemicarbazone

DOI:  https://doi.org/10.1007/s00210-024-03629-z
ACS Appl Mater Interfaces. 2024 Dec 13.

Virus-Inspired Biodegradable Tetrasulfide-Bridged Mesoporous Organosilica with GSH Depletion for Fluorescence Imaging-Guided Sonodynamic Chemotherapy of Glioblastoma Multiforme.

Feng Wei, Yanling Lin, Rujun Pan, Yilong Peng, E Chen, Junlong Kang, Jiang Zhu, Jiayin Wang, Baofang Wu, Wenwen Shen, Jinyan Lin, Hongzhi Gao, Xinhua Tian.

  Glioblastoma multiforme (GBM), a highly prevalent and lethal form of malignant tumor, is typically treated with Temozolomide (TMZ), a chemotherapeutic agent. Nevertheless, the effectiveness of TMZ is hampered by inadequate cell entry, systemic adverse effects, and monotherapy constraints. Previous clinical studies have demonstrated that combination therapy can significantly enhance the therapeutic efficacy. Herein, we developed ultrasmall virus-inspired biodegradable tetrasulfide-bridged mesoporous organosilica coloaded with TMZ and indocyanine green (ICG) (designated as vMSTI) for fluorescence imaging-guided sonodynamic chemotherapy and glutathione (GSH) depletion, aiming to enhance the therapeutic efficiency of GBM. Once accumulated within the tumors, the vMSTI nanosystem efficiently entered tumor cells via "spike surface"-assisted endocytosis. Subsequently, intracellular overproduction of GSH within tumor cells triggered the degradation of vMSTI, resulting in the release of both TMZ and ICG, while simultaneously depleting intracellular GSH levels. Upon ultrasound (US) irradiation, the released ICG generated abundant reactive oxygen species (ROS) for sonodynamic therapy, which could be further potentiated by GSH depletion. Furthermore, released TMZ effectively elicited DNA damage to enable chemotherapy. Consequently, the vMSTI effectively triggered apoptosis, suppressing GBM growth under the guidance of fluorescence imaging. Our nanosystems offered a promising strategy for imaging-guided combination therapy for GBM.

Keywords:  GSH depletion; chemotherapy; sonodynamic therapy; ultrasmall; virus-inspired nanopartiles

DOI:  https://doi.org/10.1021/acsami.4c19480
Nat Rev Drug Discov. 2024 Dec 12.

Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.

Sébastien Viel, Eric Vivier, Thierry Walzer, Antoine Marçais.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

DOI: https://doi.org/10.1038/s41573-024-01098-w
Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2410311121

Order of amino acid recruitment into the genetic code resolved by last universal common ancestor's protein domains.

Sawsan Wehbi, Andrew Wheeler, Benoit Morel, Nandini Manepalli, Bui Quang Minh, Dante S Lauretta, Joanna Masel.

  The current "consensus" order in which amino acids were added to the genetic code is based on potentially biased criteria, such as the absence of sulfur-containing amino acids from the Urey-Miller experiment which lacked sulfur. More broadly, abiotic abundance might not reflect biotic abundance in the organisms in which the genetic code evolved. Here, we instead identify which protein domains date to the last universal common ancestor (LUCA) and then infer the order of recruitment from deviations of their ancestrally reconstructed amino acid frequencies from the still-ancient post-LUCA controls. We find that smaller amino acids were added to the code earlier, with no additional predictive power in the previous consensus order. Metal-binding (cysteine and histidine) and sulfur-containing (cysteine and methionine) amino acids were added to the genetic code much earlier than previously thought. Methionine and histidine were added to the code earlier than expected from their molecular weights and glutamine later. Early methionine availability is compatible with inferred early use of S-adenosylmethionine and early histidine with its purine-like structure and the demand for metal binding. Even more ancient protein sequences-those that had already diversified into multiple distinct copies prior to LUCA-have significantly higher frequencies of aromatic amino acids (tryptophan, tyrosine, phenylalanine, and histidine) and lower frequencies of valine and glutamic acid than single-copy LUCA sequences. If at least some of these sequences predate the current code, then their distinct enrichment patterns provide hints about earlier, alternative genetic codes.

Keywords:  astrobiology; early life; origins of life; phylostratigraphy; translation

DOI:  https://doi.org/10.1073/pnas.2410311121
Biol Psychiatry. 2024 Dec 04. pii: S0006-3223(24)01785-2. [Epub ahead of print]

Variations in brain glutamate and glutamine levels throughout the sleep-wake cycle.

Sujung Yoon, Suji Lee, Yoonji Joo, Eunji Ha, Haejin Hong, Yumi Song, Hyangwon Lee, Shinhye Kim, Chaewon Suh, C Justin Lee, In Kyoon Lyoo.

   BACKGROUND: Glutamatergic signaling is essential for modulating synaptic plasticity and cognition. However, the dynamics of glutamatergic activity over the 24-hour sleep-wake cycle, particularly in relation to sleep, remain poorly understood. This study aims to investigate diurnal variations in brain Glx levels-representing the combined concentrations of glutamate and glutamine-in humans and to explore their implications for cognitive performance and sleep pressure.
METHODS: We conducted two independent experiments to measure Glx levels across the sleep-wake cycle using proton magnetic resonance spectroscopy. In Experiment 1, 14 participants underwent 13 hours of Glx measurements during a typical sleep-wake cycle. Experiment 2 extended these measurements to an around-the-clock observation over a 6-day period. This period included two days of normal sleep-wake cycles, 24 hours of enforced wakefulness, and a three-day recovery phase. Seven participants took part in Experiment 2.
RESULTS: The study observed that brain Glx levels increased during wakefulness and decreased during sleep. Notably, Glx levels were lower during enforced wakefulness compared to those during normal wakefulness. Reduced Glx levels were associated with diminished cognitive performance, while greater Glx exposure over the preceding 24 hours correlated with increased sleep pressure.
CONCLUSIONS: These findings suggest that Glx accumulation may contribute to increased sleep pressure, while its reduction appears to support wakefulness. These observations, together with the diurnal variations in Glx levels, underscore the dynamic nature of glutamatergic activity across the daily cycle. Further research is warranted to explore the potential role of sleep in regulating glutamatergic homeostasis.

Keywords:  Glutamate; Glutamine; Glx; Human brain; Magnetic resonance spectroscopy; Sleep; Wakefulness

DOI:  https://doi.org/10.1016/j.biopsych.2024.11.016