bims-stacyt 2024-06-30 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024‒06‒30
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice.
Beta-adrenergic stimulation promotes an endoplasmic reticulum stress-dependent inflammatory program in salivary gland epithelial cells.
Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling in C. neoformans during thermal stress.
Mammary adipocytes promote breast tumor cell invasion and angiogenesis in the context of menopause and obesity.
Activation of the receptor KIT induces the secretion of exosome-like small extracellular vesicles.
GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.
Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.
Activating transcription factor 3 is an antitumor gene synergizing with growth differentiation factor 15 to modulate cell growth in human bladder cancer.
ATF4 Contributes to Abdominal Aortic Aneurysm Formation via Modulating M1 Macrophage Polarization and Inflammation.
ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts.
Activation of NF-κB signaling regulates ovariectomy-induced bone loss and weight gain.

Int J Mol Sci. 2024 Jun 12. pii: 6461. [Epub ahead of print]25(12):

REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice.

Shaunaci A Stevens, Siddharth Sunilkumar, Sandeep M Subrahmanian, Allyson L Toro, Omer Cavus, Efosa V Omorogbe, Elisa A Bradley, Michael D Dennis.

  Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3β. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3β variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3β at S9 and upregulation of IL-1β and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.

Keywords:  DDIT4; RTP801; diabetic cardiomyopathy; heart disease; inflammation

DOI:  https://doi.org/10.3390/ijms25126461
Clin Exp Immunol. 2024 Jun 24. pii: uxae054. [Epub ahead of print]

Beta-adrenergic stimulation promotes an endoplasmic reticulum stress-dependent inflammatory program in salivary gland epithelial cells.

Kalliopi Moustaka, Athanasios Stergiopoulos, Roxane Tenta, Sophia Havaki, Stergios Katsiougiannis, Fotini N Skopouli.

  The effect of beta-adrenergic stimulation on human labial minor salivary gland epithelial cells (LMSGEC) on IL-6 production, and its dependency to endoplasmic reticulum (ER) stress were investigated. Primary LMSGEC from Sjögren's syndrome (SS) patients and controls in culture were stimulated with epinephrine and IL-6 expression was evaluated by qPCR and ELISA. The expression of β-ARs in cultured LMSGEC was tested by qPCR, while adrenoceptors and cAMP levels were examined in LMSGs by immunofluorescence. ER evaluation was performed by Transmission electron microscopy (TEM) and ER stress by Western blot. Adrenergic induced IL-6 production by cultured LMSGEC was evaluated after alleviation of the ER stress by applying Tauroursodeoxycholic acid (TUDCA) and silencing of PKR-like ER kinase (PERK) and activating transcription factor 4 (ATF4) RNAs. Expression of IL-6 by LMSGEC was upregulated after β-adrenergic stimulation, while the silencing of adrenoreceptors downregulated IL-6. The amelioration of ER stress, as well as the silencing of PERK/ATF4, prevented epinephrine-induced upregulation of IL-6. Adrenergic stimulation led to higher and sustained IL-6 levels secreted by LMSGEC of SS patients compared to controls. Adrenergic signaling was endogenously enhanced in LMSGEC of SS patients (expression of β-ARs in situ, intracellular cAMP in cultured LMSGEC). In parallel, SS-LMSGEC expressed dilated ER (TEM) and higher levels of GRP78/BiP. PERK/ATF4 pathway of the ER stress emerged a considerable mediator of adrenergic stimulation for IL-6 production by the LMSGEC. An enhanced endogenous adrenergic activation and a stressed ER observed in SS-LMSGEC may contribute to a sustained IL-6 production by these cells after adrenergic stimulation.

Keywords:  PERK/ATF4 pathway; Sjögren’s syndrome; endoplasmic reticulum stress; interleukin-6; salivary gland epithelial cells; β-adrenergic stimulation

DOI:  https://doi.org/10.1093/cei/uxae054
bioRxiv. 2024 Jun 11. pii: 2024.06.11.598457. [Epub ahead of print]

Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling in C. neoformans during thermal stress.

David Goich, Amanda L M Bloom, Sean R Duffy, Maritza N Ventura, John C Panepinto.

The fungus Cryptococcus neoformans is an opportunistic pathogen of people that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of Hog1/p38 in reprogramming translation during thermal stress adaptation, and found that this pathway acts on translation via crosstalk with the Gcn2 pathway, a well-studied regulator of general translation control. Using a combination of molecular assays and phenotypic analysis, we show that increased output from the Gcn2 pathway in a Hog1 deletion mutant is associated with rescue of thermal stress adaptation at both molecular and phenotypic scales. We characterize known outputs of the Hog1 pathway during thermal stress as either Gcn2-dependent or Gcn2-independent, and demonstrate that Hog1 activation regulates the Gcn2 pathway even in the absence of thermal stress. Finally, we implicate this phenomenon in another Hog1-regulated process, morphogenesis, and recapitulate Hog1-Gcn2 crosstalk in the distantly related fungal pathogen, Candida albicans. Our results point to an important link between the stress response machinery and translation control, and clarify the etiology of phenotypes associated with Hog1 deletion. More broadly, this study highlights complex interplay between core conserved signal transduction pathways and the utility of molecular assays to better understand how these pathways are connected.Importance: Cryptococcus neoformans is an opportunistic pathogen of people that causes deadly cryptococcal meningitis, which is is responsible for an estimated 19% of AIDS-related mortality. When left untreated, cryptococcal meningitis is uniformly fatal, and in patients receiving the most effective antifungal regimens, mortality remains high. Thus, there is a critical need to identify additional targets that play a role in adaptation to the human host and virulence. This study explores the role of the stress response kinases Hog1 and Gcn2 in thermoadaptation, which is pre-requisite for virulence. Our results show that compensatory signaling occurs via the Gcn2 pathway when Hog1 is deleted, and that disruption of both pathways increases sensitivity to thermal stress. Importantly, our study highlights the insufficiency of using single gene deletion mutants to study gene function, since many phenotypes associated with Hog1 deletion were driven by Gcn2 signaling in this background, rather than loss of direct Hog1 activity.

DOI: https://doi.org/10.1101/2024.06.11.598457
Biochim Biophys Acta Mol Basis Dis. 2024 Jun 24. pii: S0925-4439(24)00318-1. [Epub ahead of print] 167325

Mammary adipocytes promote breast tumor cell invasion and angiogenesis in the context of menopause and obesity.

Roopali Roy, Emily Man, Rama Aldakhlallah, Katherine Gonzalez, Lauren Merritt, Cassandra Daisy, Michael Lombardo, Victoria Yordanova, Liang Sun, Biju Isaac, Shira Rockowitz, Margaret Lotz, Susan Pories, Marsha A Moses.

  The mechanism(s) underlying obesity-related postmenopausal (PM) breast cancer (BC) are not clearly understood. We hypothesized that the increased local presence of 'obese' mammary adipocytes within the BC microenvironment promotes the acquisition of an invasive and angiogenic BC cell phenotype and accelerates tumor proliferation and progression. BC cells, treated with primary mammary adipocyte secretome from premenopausal (Pre-M) and PM obese women (ObAdCM; obese adipocyte conditioned-media) upregulated the expression of several pro-tumorigenic factors including VEGF, lipocalin-2 and IL-6. Both Pre-M and PM ObAdCM stimulated endothelial cell recruitment and proliferation and significantly stimulated BC cell proliferation, migration and invasion. IL-6 and LCN2 induced STAT3/Akt signaling in BC cells and STAT3 inhibition abrogated the ObAdCM-stimulated BC cell proliferation and migration. Expression of proangiogenic regulators including VEGF, NRP1, NRP2, IL8RB, TGFβ2, and TSP-1 were found to be differentially regulated in mammary adipocytes from obese PM women. Comparative RNAseq indicated an upregulation of PI3K/Akt signaling, ECM-receptor interactions and lipid/fatty acid metabolism in PM versus Pre-M mammary adipocytes. Our results demonstrate that irrespective of menopausal status, cross-talk between obese mammary adipocytes and BC cells promotes tumor aggressiveness and suggest that targeting the LCN2/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumorigenesis.

Keywords:  Breast cancer; Mammary adipocyte; Obesity; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167325
J Extracell Biol. 2024 Jan;3(1): e139

Activation of the receptor KIT induces the secretion of exosome-like small extracellular vesicles.

Annika Pfeiffer, Geethani Bandara, Jennifer D Petersen, Guido H Falduto, Joshua Zimmerberg, Dean D Metcalfe, Ana Olivera.

  The receptor tyrosine kinase (RTK) KIT and its ligand stem cell factor (SCF) are essential for human mast cell (huMC) survival and proliferation. HuMCs expressing oncogenic KIT variants secrete large numbers of extracellular vesicles (EVs). The role KIT plays in regulating EV secretion has not been examined. Here, we investigated the effects of stimulation or inhibition of KIT activity on the secretion of small EVs (sEVs). In huMCs expressing constitutively active KIT, the quantity and quality of secreted sEVs positively correlated with the activity status of KIT. SCF-mediated stimulation of KIT in huMCs or murine MCs, or of transiently expressed KIT in HeLa cells, enhanced the release of sEVs expressing exosome markers. In contrast, ligand-mediated stimulation of the RTK EGFR in HeLa cells did not affect sEV secretion. The release of sEVs induced by either constitutively active or ligand-activated KIT was remarkably decreased when cells were treated with KIT inhibitors, concomitant with reduced exosome markers in sEVs. Similarly, inhibition of oncogenic KIT signalling kinases like PI3K, and MAPK significantly reduced the secretion of sEVs. Thus, activation of KIT and its early signalling cascades stimulate the secretion of exosome-like sEVs in a regulated fashion, which may have implications for KIT-driven functions.

Keywords:  KIT; cell activation; exosome; extracellular vesicle; mast cell; signalling pathway; stem cell factor

DOI:  https://doi.org/10.1002/jex2.139
J Hepatocell Carcinoma. 2024 ;11 1171-1183

GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Yi-Ning Du, Jin-Wei Zhao.

  Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

Keywords:  GDF15; HCC; growth differentiation factor 15; hepatocellular carcinoma; immune suppression; immunotherapy

DOI:  https://doi.org/10.2147/JHC.S471239
Mol Metab. 2024 Jun 24. pii: S2212-8778(24)00107-8. [Epub ahead of print] 101976

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.

Luca J Delfinis, Leslie M Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C Garibotti, Arshdeep K Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G Jones, Arthur J Cheng, Thomas J Hawke, Nicholas P Greene, Kevin A Murach, Jeremy A Simpson, Jim Petrik, Christopher G R Perry.

  OBJECTIVES: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.METHODS: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ∼45, ∼75 and ∼90 days after EOC injection.
RESULTS: Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.
CONCLUSION: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.

Keywords:  Ovarian cancer cachexia; metastasis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101976
Biomed J. 2024 Jun 26. pii: S2319-4170(24)00059-3. [Epub ahead of print] 100756

Activating transcription factor 3 is an antitumor gene synergizing with growth differentiation factor 15 to modulate cell growth in human bladder cancer.

Syue-Ting Chen, Kang-Shuo Chang, Wei-Yin Lin, Shu-Yuan Hsu, Hsin-Ching Sung, Yu-Hsiang Lin, Tsui-Hsia Feng, Chen-Pang Hou, Horng-Heng Juang.

  BACKGROUND: The functions of activating transcription factor 3 (ATF3) within the human bladder remain unexplored. This study delves into the expressions, functions, and regulatory mechanisms of ATF3 in human bladder cancer.MATERIAL AND METHODS: Gene expressions were determined by immunoblot, RT-qPCR, and reporter assays. Assays of Ki67, colony formation, Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis in vitro and in vivo. Silico analysis from TCGA database examined the correlations between GDF15 and ATF3 expressions, clinicopathologic features, and progression-free survival rates.
RESULTS: Silico analysis confirmed that ATF3 is an antitumor gene, and the expression positively correlates with GDF15 in bladder cancer tissues. Multivariate analysis revealed that low ATF3/GDF15 but not a single low expression of ATF3 is an independent prognostic factor for progression-free survival of bladder cancer patients. Ectopic overexpression of ATF3 downregulated cell proliferation and invasion in bladder cancer cells in vitro, while ATF3-knockdown reversed these results. Knockdown of ATF3 upregulated EMT markers to enhance cell invasion in vitro and downregulated GDF15, NDRG1, and KAI-1 to elevate tumor growth in vivo. The activation of metformin on ATF3 and GDF15 in bladder cancer cells was blocked by SB431542, a TGFβ receptor inhibitor. ATF3 positively regulated GDF15 expression in bladder cancer cells through a feedback loop.
CONCLUSIONS: Our results identify that ATF3 is a metformin-upregulated antitumor gene. Results of Silico analysis align with cell-based studies suggesting that low ATF3/GDF15 could be a negative prognostic marker for bladder cancer.

Keywords:  ATF3; Bladder; EMT; GDF15; in silico; tumorigenesis

DOI:  https://doi.org/10.1016/j.bj.2024.100756
Aging Dis. 2024 Jun 20.

ATF4 Contributes to Abdominal Aortic Aneurysm Formation via Modulating M1 Macrophage Polarization and Inflammation.

Huahui Yu, Xiaolu Jiao, Qianwen Lv, Linyi Li, Yunhui Du, Chaowei Hu, Zhiyong Du, Fan Li, Yu Wang, Xiaoqian Gao, Lijie Han, Xuechun Sun, Dong Chen, Yanwen Qin.

Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular disease primarily in the male elderly population, but there is a lack of approved medical therapies to prevent the progression and rupture of AAA. Activating Transcription Factor 4 (ATF4) has been established to be involved in cardiovascular diseases, such as heart failure and calcific aortic valve disease. However, the role of ATF4 in the pathogenesis of AAA remains unclear. We found that ATF4 expression was significantly increased in patients with AAA and mouse models of AAA and was mainly confined to macrophages in arteries. ATF4 knockdown significantly attenuated aneurysm formation in experimental mouse model of AAA, while ATF4 overexpression promoted the development of AAA. RNA sequencing suggested that ATF4 was strongly related to the biological function of acute inflammatory response. Macrophages-specific ATF4 knockout significantly reduced the incidence and development of AAA, and decreased M1 polarization of macrophages in mice. Sphingomyelin phosphodiesterase 3 (SMPD3), a regulator of inflammatory responses in monocytes/macrophages, has been identified as a target gene of ATF4 through RNA sequencing, ChIP sequencing, and standard ChIP analyses. ATF4 induces M1 polarization of macrophages through the activation of SMPD3, thereby promoting inflammatory responses. Together, these results suggest that ATF4 mediated macrophage M1 polarization by regulating the expression of target genes SMPD3, leading to an increased inflammatory response, which further promotes the formation and development of AAA. These findings suggest ATF4 may be a new therapeutic target for AAA.

DOI: https://doi.org/10.14336/AD.2024.0116
bioRxiv. 2024 Jun 13. pii: 2024.06.12.598694. [Epub ahead of print]

ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts.

Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.

Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that fibroblast activation is supported by metabolic reprogramming, including the upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. How fibroblast metabolic reprogramming is regulated downstream of TGF-β is incompletely understood. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote increased expression of the enzymes required for de novo glycine synthesis; however, whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single cell RNAseq data sets and found increased expression of ATF4 and mTOR metabolic targets in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

DOI: https://doi.org/10.1101/2024.06.12.598694
Biochim Biophys Acta Mol Basis Dis. 2024 Jun 25. pii: S0925-4439(24)00313-2. [Epub ahead of print] 167320

Activation of NF-κB signaling regulates ovariectomy-induced bone loss and weight gain.

Fei Huang, Jing Gao, Aonan Li, Akiko Mizokami, Miho Matsuda, Kazuhiro Aoki, Takenobu Katagiri, Tomoyo Kawakubo-Yasukochi, Eijiro Jimi.

  Postmenopausal women experience bone loss and weight gain. To date, crosstalk between estrogen receptor signals and nuclear factor-κB (NF-κB) has been reported, and estrogen depletion enhances bone resorption by osteoclasts via NF-κB activation. However, it is unclear when and in which tissues NF-κB is activated after menopause, and how NF-κB acts as a common signaling molecule for postmenopausal weight gain and bone loss. Therefore, we examined the role of NF-κB in bone and energy metabolism following menopause. NF-κB reporter mice, which can be used to measure NF-κB activation in vivo, were ovariectomized (OVX) and the luminescence intensity after OVX increased in the metaphyses of the long bones and perigonadal white adipose tissue, but not in the other tissues. OVX was performed on wild-type (WT) and p65 mutant knock-in (S534A) mice, whose mutation enhances the transcriptional activity of NF-κB. Weight gain with worsening glucose tolerance was significant in S534A mice after OVX compared with those of WT mice. The bone density of the sham group in WT or S534A mice did not change, whereas in the S534A-OVX group it significantly decreased due to the suppression of bone formation and increase in bone marrow adipocytes. Disulfiram, an anti-alcoholic drug, suppressed OVX-induced activation of NF-κB in the metaphyses of long bones and white adipose tissue (WAT), as well as weight gain and bone loss. Overall, the activation of NF-κB in the metaphyses of long bones and WAT after OVX regulates post-OVX weight gain and bone loss (241 words).

Keywords:  Bone loss; Disulfiram; Glucose tolerance; NF-κB activation; Postmenopausal osteoporosis; Weight gain

DOI:  https://doi.org/10.1016/j.bbadis.2024.167320