bims-glucam 2023-06-18 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–06–18
fiveteen papers selected by
Sreeparna Banerjee, Middle East Technical University

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis.
Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.
Amino acid metabolism in tumor: New shine in the fog?
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.
Circ_0091579 Knockdown Inhibited HCC Proliferation and Glutamine Metabolism Through miR-1270/YAP1 Axis.
Mutant IDH in Gliomas: Role in Cancer and Treatment Options.
Mutant Tau protein-induced abnormalities in the Na+-dependent glutamine translocation and recycling and their impact on astrocyte-neuron integrity in vitro.
Effects of glutamine and arginine combination on pro- and anti-inflammatory cytokines.
Amino acid homeostasis is a target of metformin therapy.
Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.
A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells.
Glutamine boosts intestinal stem cell-mediated small intestinal epithelial development during early weaning: Involvement of WNT signaling.
Tumor Steatosis and Glutamine Synthetase Expression in Patients with Advanced HCC Receiving Atezolizumab plus Bevacizumab Therapy.
xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

Cell Death Discov. 2023 Jun 12. 9(1): 182

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis.

Yiqing Cai, Liemei Lv, Tiange Lu, Mengfei Ding, Zhuoya Yu, Xiaomin Chen, Xiangxiang Zhou, Xin Wang.

Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.

DOI: https://doi.org/10.1038/s41420-023-01475-1
Blood Adv. 2023 Jun 14. pii: bloodadvances.2023010083. [Epub ahead of print]

Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.

Dheerendra Gupta, Ahmed Elwakiel, Satish Ranjan, Manish Kumar Pandey, Shruthi Krishnan, Saira Ambreen, Reinhard Henschler, Rajiv Rana, Maria Keller, Uta Ceglarek, Khurrum Shahzad, Shrey Kohli, Berend Isermann.

A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. T-cell pre-incubation with aPC for 1 hour prior to transplantation increases FOXP3+ Tregs and reduces acute graft versus host disease (aGvHD) in mice, but the underlying mechanism remains unknown. As cellular metabolism modulates epigenetic gene regulation and plasticity in T-cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation and ex vivo using T-cells isolated from aGvHD mice without and with aPC preincubation or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of Th1-cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced TCA metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, while FOXP3 expression in splenic T-cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T-cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic marks, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.

DOI: https://doi.org/10.1182/bloodadvances.2023010083
Clin Nutr. 2023 Jun 07. pii: S0261-5614(23)00184-X. [Epub ahead of print]

Amino acid metabolism in tumor: New shine in the fog?

Hui Qiu, Nan Shao, Jing Liu, Juanjuan Zhao, Chao Chen, Qihong Li, Zhixu He, Xu Zhao, Lin Xu.

  Alterations in amino acid metabolism is closely related to the occurrence of clinical diseases. The mechanism of tumorigenesis is complex, involving the complicated relationship between tumor cells and immune cells in local tumor microenvironment. A series of recent studies have shown that metabolic remodeling is intimately related to tumorigenesis. And amino acid metabolic reprogramming is one of the important characteristics of tumor metabolic remodeling, which participates in tumor cells growth, survival as well as the immune cell activation and function in the local tumor microenvironment, thereby affecting tumor immune escape. Recent studies have further shown that controlling the intake of specific amino acids can significantly improve the effect of clinical intervention in tumors, suggesting that amino acid metabolism is gradually becoming one of the new promising targets of clinical intervention in tumors. Therefore, developing new intervention strategies based on amino acid metabolism has broad prospects. In this article, we review the abnormal changes in the metabolism of some typical amino acids, including glutamine, serine, glycine, asparagine and so on in tumor cells and summarize the relationship among amino acid metabolism, tumor microenvironment and the function of T cells. In particular, we discuss the current issues that need to be addressed in the related fields of tumor amino acid metabolism, aiming to provide a theoretical basis for the development of new strategies for clinical interventions in tumors based on amino acid metabolism reprogramming.

Keywords:  Amino acid metabolism; Immune cells; Immune escape; Tumor

DOI:  https://doi.org/10.1016/j.clnu.2023.06.011
Cell Metab. 2023 Jun 07. pii: S1550-4131(23)00185-7. [Epub ahead of print]

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R Flint, Lisa Young, Claire M Connell, Michael J Lukey, Marcus D Goncalves, Eileen P White, Ashok R Venkitaraman, Tobias Janowitz.

  Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Keywords:  GDF-15; IL-6; NADPH; cachexia; cancer; corticosterone; ferroptosis; ketogenic diet; lipid peroxidation; steroid

DOI:  https://doi.org/10.1016/j.cmet.2023.05.008
Int J Mol Sci. 2023 May 27. pii: 9365. [Epub ahead of print]24(11):

Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.

Zhujun Li, Zhiyan Gu, Lan Wang, Yun Guan, Yingying Lyu, Jialong Zhang, Yin Wang, Xin Wang, Ji Xiong, Ying Liu.

  Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs' metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs.

Keywords:  GBM; IDH-wild type; branched-chain amino acid transaminase 1; glutamate; lactate dehydrogenase A; redox balance; thioredoxin

DOI:  https://doi.org/10.3390/ijms24119365
Biochem Genet. 2023 Jun 14.

Circ_0091579 Knockdown Inhibited HCC Proliferation and Glutamine Metabolism Through miR-1270/YAP1 Axis.

Ming Liu, Bing Guo, Ge Zhang, Huanpeng Qi.

  A growing number of studies have indicated that circRNAs play an important role in the progression of malignant tumors, including hepatocellular carcinoma (HCC). In this study, we designed to explore the abnormal expression of hsa_circ_0091579 (circ_0091579) and its role in the pathogenesis of HCC. In this study, the mRNA levels of circ_0091579, miR-1270, and Yes-associated protein (YAP1) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R and Actinomycin D were used to test the stability of circ_0091579. Cell Counting Kit-8 (CCK-8) was used to measure cell viability. Tubule formation assay was used to determine the effect of HCC cells on the number of tubes. Cell apoptosis was detected by flow cytometry. Western blot was used for the protein levels. Transwell and wound healing tests were used to measure the abilities of invasion and migration. The effect of circ_0091579 knockdown on tumor growth was verified in vivo by xenograft tumor assay and Immunohistochemistry (IHC) analysis. Dual-luciferase reporter or RIP assay was used to detect the relationship between miR-1270 and circ_0091579 or YAP1. Glutamine metabolism was determined by ELISA and western blot assays. In the present study, we found that circ_0091579 was upregulated in HCC tissues and cells. Inhibited circ_0091579 expression significantly suppressed proliferation and promoted apoptosis of HCC cells. Moreover, circ_0091579 knockdown inhibited tumor growth in vivo. Bioinformatic prediction and luciferase assay showed that circ_0091579 acted as a molecular sponge for miR-1270 and YAP1 was a target gene of miR-1270. MiR-1270 silencing could reverse the inhibitory effect of circ_0091579 knockdown on HCC progression, and YAP1 overexpression also could reverse the suppressive effect of circ_0091579 silencing on HCC progression. Meanwhile, miR-1270 inhibitor could invert the negative regulation effect of circ_0091579 silencing on YAP1 expression. Circ_0091579 promoted HCC progression by regulating the miR-1270/YAP1 axis, and our study might offer novel biomarkers and therapeutic targets for HCC.

Keywords:  HCC; YAP1; circ_0091579; miR-1270

DOI:  https://doi.org/10.1007/s10528-023-10386-w
Cancers (Basel). 2023 May 23. pii: 2883. [Epub ahead of print]15(11):

Mutant IDH in Gliomas: Role in Cancer and Treatment Options.

Georgios Solomou, Alina Finch, Asim Asghar, Chiara Bardella.

  Altered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas.

Keywords:  cancer metabolism; gliomas; hydroxyglutarate; isocitrate dehydrogenase; oncometabolites

DOI:  https://doi.org/10.3390/cancers15112883
Neurochem Int. 2023 Jun 07. pii: S0197-0186(23)00079-7. [Epub ahead of print]168 105551

Mutant Tau protein-induced abnormalities in the Na+-dependent glutamine translocation and recycling and their impact on astrocyte-neuron integrity in vitro.

Marta Sidoryk-Węgrzynowicz, Beata Dąbrowska-Bouta, Grzegorz Sulkowski, Lidia Strużyńska.

  Tau-dependent neurodegeneration is accompanied by astrocytosis in a mouse trans-genic model, which replicates the neuropathological characteristic of tauopathy and other human neurodegenerative disorders where astrocyte activation precedes neuronal loss and is associated with disease progression. This indicates an important role of astrocytes in the development of the disease. Astrocytes derived from a transgenic mouse model expressing human Tau, exhibit changes in cellular markers of astrocyte neuroprotective function related to the glutamate-glutamine cycle (GGC), representing a key part of astrocyte-neuron integrity. Here, we focused on investigating the functional properties of key GGC components involved in the astrocyte-neuron network associated with Tau pathology in vitro. Mutant recombinant Tau (rTau) carrying the P301L mutation was added to the neuronal cultures, with or without control astrocyte-conditioned medium (ACM), to study glutamine translocation through the GGC. We demonstrated that mutant Tau in vitro induces neuronal degeneration, while control astrocytes response in neuroprotective way by preventing neurodegeneration. In parallel with this observation, we noticed the Tau-dependent decline of neuronal microtubule associated protein 2 (MAP2), followed by changes in glutamine (Gln) transport. Exposure to rTau decreases sodium-dependent Gln uptake in neurons and that effect was reversed when cells were co-incubated with control ACM after induction of rTau dependent pathology. Further, we found that neuronal Na+-dependent system A is the most specific system that is affected under rTau exposure. In addition, in rTau-treated astrocytes total Na+-dependent uptake of Gln, which is mediated by the N system, increases. Altogether, our study suggest mechanisms operating in Tau pathology may be related to the alterations in glutamine transport and recycling that affect neuronal-astrocytic integrity.

Keywords:  Astrocyte- Neuron integrity; Glutamate; Glutamine; Neurodegeneration; Tauopathy

DOI:  https://doi.org/10.1016/j.neuint.2023.105551
Open Vet J. 2023 May;13(5): 613-619

Effects of glutamine and arginine combination on pro- and anti-inflammatory cytokines.

Maulydia Maulydia, Nancy Margarita Rehatta, Subijanto Marto Soedarmo.

   Background: Cytokines were beneficial for diagnosis and treatment, which in clinical situations introduced from the perspective of pro and anti-inflammatory effects. An inflammatory response is commonly associated with various severe traumatic insults that consequently recruit the immune cells into the target organs and causing systemic inflammatory response that can lead to sepsis. Immune-modulating nutrients, such as glutamine and arginine, are known as pathophysiological modulate in inflammation.
Aim: The aim of this study was to evaluate the effect of oral gavage supplementation with a combination of glutamine and arginine on inflammatory cytokines in intestinal mucosa, specifically jejunum.
Methods: Sixteen Rattus norvegicus rats (average weight 150-200 g) were randomly divided into two groups: groups A and B, both intraperitoneal injected by 2 ml NaCl 0.9%. Group A orally supplemented with 1 ml dextrose 5% daily, meanwhile, group B orally supplemented with 1 ml combination of glutamine and arginine (contains 250 mg/kg glutamine and 250 mg/kg arginine) daily. The experiment lasted for 3 days. We compared the pro and anti-inflammatory cytokines (IL-10, NF-κB, TNF-α, IL-8, and MMP-8) between the two groups by the Mann-Whitney test.
Results: More IL-10, TNF-α, and IL-8 cytokine-produced cells found in group A. Group B produced significantly lower TNF-α (p = 0.009) and IL-8 (p = 0.003). The number of NF-κB and MMP-8 were slightly higher in group B.
Conclusion: Giving a combination of glutamine and arginine as nutrition supplementation has beneficial effects in decreasing almost half of the cells that produce TNF-α and IL-8. Further studies must be carried out to support a standard guideline for this recommendation.

Keywords:  Arginine; Cytokine; Glutamine; Immunonutrient; Inflammatory

DOI:  https://doi.org/10.5455/OVJ.2023.v13.i5.14
Mol Metab. 2023 Jun 09. pii: S2212-8778(23)00084-4. [Epub ahead of print] 101750

Amino acid homeostasis is a target of metformin therapy.

Calum Forteath, Ify Mordi, Raid Nisr, Erika J Gutierrez-Lara, Noor Alqurashi, Iain R Phair, Amy R Cameron, Craig Beall, Ibrahim Nisr, Mohapradeep Mohan, Aaron K F Wong, Adel Dihoum, Anwar Mohammad, Colin N A Palmer, Douglas Lamont, Kei Sakamoto, Benoit Viollet, Marc Foretz, Chim C Lang, Graham Rena.

  Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we demonstrate that metformin restricts tertiary control of BCAA cellular uptake, contributing towards therapeutic actions of the drug. In cell studies, we observed diminished uptake of amino acids following metformin treatment of a variety of cell types. Supplementation of media with amino acids attenuated metformin effects, providing an explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics demonstrated that SNAT2 was the most strongly suppressed amino acid transporter in liver cells following metformin treatment, although other transporters were affected. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of metformin.

Keywords:  AMPK; SNAT2; branched chain amino acids; glutamine; mTOR; metformin; rapamycin

DOI:  https://doi.org/10.1016/j.molmet.2023.101750
Cancers (Basel). 2023 Jun 02. pii: 3037. [Epub ahead of print]15(11):

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Giovanni Tossetta, Sonia Fantone, Daniela Marzioni, Roberta Mazzucchelli.

  Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.

Keywords:  KEAP1; NRF2; antioxidants; chemotherapy; compounds; natural; prostate cancer; signaling; synthetic

DOI:  https://doi.org/10.3390/cancers15113037
Small. 2023 Jun 16. e2301600

A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells.

Chongzhi Wu, Fu Zhang, Bowen Li, Zhiyao Li, Xin Xie, Yong Huang, Zhuo Yao, Yuan Chen, Yuan Ping, Weidong Pan.

  Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.

Keywords:  cancer stem cells; combination therapy; ferroptosis; nano-prodrug; triple-negative breast cancer

DOI:  https://doi.org/10.1002/smll.202301600
Stem Cell Reports. 2023 May 27. pii: S2213-6711(23)00191-1. [Epub ahead of print]

Glutamine boosts intestinal stem cell-mediated small intestinal epithelial development during early weaning: Involvement of WNT signaling.

Junquan Tian, Yuying Li, Xuetai Bao, Fan Yang, Xiongzhuo Tang, Qian Jiang, Chengbo Yang, Yulong Yin, Kang Yao.

  Early weaning usually causes small intestine epithelial development abnormality, increasing the risk of gastrointestinal diseases. Glutamine (Gln), enriching in plasma and milk, is widely reported to benefit intestinal health. However, whether Gln affects intestinal stem cell (ISC) activity in response to early weaning is unclear. Here, both the early weaning mice and intestinal organoids were used to study the role of Gln in regulating ISC activities. Results showed that Gln ameliorated early weaning-induced epithelial atrophy and augmented the ISC-mediated epithelial regeneration. Gln deprivation disabled ISC-mediated epithelial regeneration and crypt fission in vitro. Mechanistically, Gln augmented WNT signaling in a dose-dependent manner to regulate ISC activity, while WNT signaling blockage abolished the effects of Gln on ISCs. Together, Gln accelerates stem cell-mediated intestinal epithelial development associated with the augmentation of WNT signaling, which provides novel insights into the mechanism by which Gln promotes intestinal health.

Keywords:  WNT signaling; early weaning; glutamine; intestinal epithelial development; intestinal stem cell

DOI:  https://doi.org/10.1016/j.stemcr.2023.05.012
Hepatol Res. 2023 Jun 09.

Tumor Steatosis and Glutamine Synthetase Expression in Patients with Advanced HCC Receiving Atezolizumab plus Bevacizumab Therapy.

Yutaka Kurebayashi, Hanako Tsujikawa, Katsutoshi Sugimoto, Daisuke Yunaiyama, Yoichi Araki, Kazuhiro Saito, Hiroshi Takahashi, Tatsuya Kakegawa, Takuya Wada, Yusuke Tomita, Masakazu Abe, Yu Yoshimasu, Hirohito Takeuchi, Taiki Hirata, Kentaro Sakamaki, Kazuhiro Kakimi, Toshitaka Nagao, Takao Itoi, Michiie Sakamoto.

   BACKGROUND AND AIM: The anti-PD-L1 antibody atezolizumab and VEGF-neutralizing antibody bevacizumab in combination (Atezo+Bev) have become the first-line therapy in advanced HCC. Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo+Bev therapy.
METHODS: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo+Bev therapy were included in this study. Pre-treatment tumor biopsy, pre- and post-treatment diffusion-weighted MRI with nine b values (0-1500 s/mm2 ), and other clinicopathological factors were analyzed.
RESULTS: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival. Furthermore, changes in the pre- and post-treatment true diffusion coefficients on MRI, which may reflect changes in TIME after treatment, were significantly associated with better PFS.
CONCLUSIONS: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically-determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo+Bev therapy in advanced HCC. This article is protected by copyright. All rights reserved.

Keywords:  Hepatocellular carcinoma; Immune microenvironment; Immunotherapy; Intravoxel incoherent motion; Magnetic resonance imaging

DOI:  https://doi.org/10.1111/hepr.13933
Cell Rep. 2023 Jun 12. pii: S2211-1247(23)00647-2. [Epub ahead of print]42(6): 112636

xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

Hee-Hoon Kim, Young-Ri Shim, Ha Neul Kim, Keungmo Yang, Tom Ryu, Kyurae Kim, Sung Eun Choi, Min Jeong Kim, Chaerin Woo, Katherine Po Sin Chung, Song Hwa Hong, Hyemi Shin, Jae Myoung Suh, Youngae Jung, Geum-Sook Hwang, Won Kim, Seok-Hwan Kim, Hyuk Soo Eun, Je Kyung Seong, Won-Il Jeong.

  Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.

Keywords:  CP: Immunology; CP: Metabolism; glutamate; interferon-γ; metabolic disorders; metabotropic glutamate receptor; natural killer cells; obesity

DOI:  https://doi.org/10.1016/j.celrep.2023.112636