bims-kishpe 2024-12-08 papers

bims-kishpe

Biomed News

on HSP70 role in hypoxia and metabolism in ECs

Issue of 2024–12–08
sixteen papers selected by
Alia Ablieh, Universität Heidelberg

THBS1 mediates hypoxia driven EndMT in pulmonary hypertension.
Death-associated protein kinase 1 prevents hypoxia-induced metabolic shift and pulmonary arterial smooth muscle cell proliferation in PAH.
Transcriptional and post-transcriptional regulation of whiB6 by a response regulator PhoP and a small noncoding RNA MTS1338 in Mycobacterium tuberculosis.
Ang-(1-7) and ET-1 Interplay Through Mas and ETB Receptor Interaction Defines a Novel Vasoprotective Mechanism.
MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α.
Plasma exosomes from patients with coronary artery disease promote atherosclerosis via impairing vascular endothelial junctions.
Potential of Anthocyanin-rich Products to Prevent and Improve Endothelial Function and Senescence: Focus on Anthocyanins.
Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.
Glucose Metabolism Reprogramming of Vascular Endothelial Cells and Its Implication in Development of Atherosclerosis.
FTO-mediated demethylation of MTUS1/ATIP1 promotes tumor progression in head and neck squamous cell carcinoma.
NOS3 regulates angiogenic potential of human induced pluripotent stem cell-derived endothelial cells.
Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.
Valproic Acid Inhibits Endoplasmic Reticulum Stress and Reduces Ferroptosis After Traumatic Brain Injury.
Diverting glial glycolytic flux towards neurons is a memory-relevant role of Drosophila CRH-like signalling.
Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease.
Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.

Pulm Circ. 2024 Oct;14(4): e70019

THBS1 mediates hypoxia driven EndMT in pulmonary hypertension.

Bingming Peng, Yingzhen Zhou, Xingmeng Fu, Li Chen, Zhengxia Pan, Qijian Yi, Tengteng Zhao, Zhou Fu, Ting Wang.

  Long-term hypoxia is one of the main causes of pulmonary vascular remodeling in pulmonary hypertension (PH) associated with congenital heart disease (CHD) children. Endothelial to mesenchymal transition (EndMT) is an important pathological basis of pulmonary vascular remodeling in PH. We observed that Fibronectin 1 (FN1) had strong protein-protein interactions with both Thrombospondin 1 (THBS1) and Transglutaminase 2 (TGM2) in PH with venous peripheral bloods samples from pediatric patients and healthy children. LungMAP CellCards and heatmaps of human PAEC in PH patients and lung tissues in hypoxia induced PH mice model were used to show that THBS1 and FN1 were significantly elevated. We studied the relationship between THBS1 and FN1 in vivo, by using SUHX-induced PH mice model, and in vitro, by using hypoxia-induced human PAEC. The results showed that hypoxia could result in EndMT and inhibiting THBS1 could reverse EndMT in vivo and in vitro, verifying our transcriptome results. Taken together, our research demonstrated that THBS1 could mediate hypoxia driven EndMT of PH, providing a new insight of research in the pathophysiology of PH.

Keywords:  EndMT; THBS1; hypoxia; pulmonary hypertension; pulmonary vascular remodeling

DOI:  https://doi.org/10.1002/pul2.70019
Cell Signal. 2024 Nov 30. pii: S0898-6568(24)00502-3. [Epub ahead of print]127 111527

Death-associated protein kinase 1 prevents hypoxia-induced metabolic shift and pulmonary arterial smooth muscle cell proliferation in PAH.

Laura-Marie Seidel, Jana Thudium, Caroline Smith, Vandna Sapehia, Natascha Sommer, Magdalena Wujak, Norbert Weissmann, Werner Seeger, Ralph T Schermuly, Tatyana Novoyatleva.

  Pulmonary hypertension (PH) is a general term used to describe high blood pressure in the lungs from any cause. Pulmonary arterial hypertension (PAH) is a progressive, and fatal disease that causes the walls of the pulmonary arteries to tighten and stiffen. One of the major characteristics of PAH is the hyperproliferation and resistance to apoptosis of vascular cells, which trigger excessive pulmonary vascular remodeling and vasoconstriction. The death-associated protein DAP-kinase (DAPK) is a tumor suppressor and Ser/Thr protein kinase, which was previously shown to regulate the hypoxia inducible factor (HIF)-1α. Against this background, we now show that DAPK1 regulates human pulmonary arterial smooth muscle cell (hPASMC) proliferation and energy metabolism in a HIF-dependent manner. DAPK1 expression is downregulated in pulmonary vessels and PASMCs of human and experimental PH lungs. Reduced expression of DAPK1 in hypoxia and non-hypoxia PAH-PASMCs correlates with increased expression of HIF-1/2α. RNA interference-mediated depletion of DAPK1 leads to fundamental metabolic changes, including a significantly decreased rate of oxidative phosphorylation associated with enhanced expression of both HIF-1α and HIF-2α and glycolytic enzymes, as hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and an integrator between the glycolysis and citric acid cycle, pyruvate dehydrogenase kinase 1 (PDK1). DAPK1 ablation in healthy donor hPASMCs leads to an increase in proliferation, while its overexpression provides the opposite effects. Together our data indicate that DAPK1 serves as a new inhibitor of the pro-proliferative and glycolytic phenotype of PH in PASMCs acting via HIF-signaling pathway.

Keywords:  DAPK1; HIF; Metabolic shift; Mitochondrial respiration; Proliferation; Pulmonary artery smooth muscle cells

DOI:  https://doi.org/10.1016/j.cellsig.2024.111527
Biochem Biophys Res Commun. 2024 Nov 29. pii: S0006-291X(24)01629-2. [Epub ahead of print]741 151093

Transcriptional and post-transcriptional regulation of whiB6 by a response regulator PhoP and a small noncoding RNA MTS1338 in Mycobacterium tuberculosis.

Krishan Kumar, Tanmay Dutta.

  WhiB6 in pathogenic mycobacteria is highly upregulated during NO stress, hypoxia, and macrophage infection. Its expression primarily results from transcriptional control by a two-component response regulator PhoP in response to the various stresses exerted on mycobacterial cells inside phagosomes. Herein, we investigated the transcriptional and posttranscriptional regulatory mechanism of whiB6 expression. We found that PhoP binds to the PhoP-signature sequences located upstream to the core promoter region of whiB6 gene and controls its expression at the transcriptional level. Phosphorylation of PhoP is obligatory for binding to whiB6 promoter. A dormancy regulatory factor DosR, although doesn't bind to whiB6 gene, can bind to the PhoP-bound whiB6 gene implicating its potential role in whiB6 expression. A virulence-associated sRNA MTS1338 directly binds to the coding region of whiB6 gene presumably protecting it from cellular ribonucleases. Induction of MTS1338 in response to low pH and oxidative stress increases whiB6 accumulation likely through the stabilization of whiB6 transcript at the posttranscriptional level. This study substantially increases our knowledge of the regulation of whiB6 expression in M. tuberculosis.

Keywords:  DosR; Mycobacteria; Redox sensor; Small RNA

DOI:  https://doi.org/10.1016/j.bbrc.2024.151093
Hypertension. 2024 Dec 05.

Ang-(1-7) and ET-1 Interplay Through Mas and ETB Receptor Interaction Defines a Novel Vasoprotective Mechanism.

Augusto C Montezano, Jithin Kuriakose, Katie Y Hood, Yuan Yan Sin, Livia L Camargo, Yoon Namkung, Carlos H Castro, Robson A Santos, Rheure Alves-Lopes, Gonzalo Tejeda, Patricia Passaglia, Sehrish Basheer, Emily Gallen, Jane E Findlay, Fazli R Awan, Stéphane A Laporte, Margaret R MacLean, George S Baillie, Rhian M Touyz.

   BACKGROUND: Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B).
METHODS/RESULTS: To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells. Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290-314). Binding sites for MasR on ETBR were identified (amino acids 176-200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.
CONCLUSIONS: We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.

Keywords:  endothelial cells; hypertension, pulmonary; nitric oxide; nitric oxide synthase type III; vascular remodeling

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.124.22693
J Mol Cell Cardiol. 2024 Nov 30. pii: S0022-2828(24)00203-7. [Epub ahead of print]198 74-88

MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α.

Wesam Bassiouni, Zabed Mahmud, Thomas Simmen, John M Seubert, Richard Schulz.

  Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death.

Keywords:  ER stress; Matrix metalloproteinase-2; Myocardial cell death; Proteolysis

DOI:  https://doi.org/10.1016/j.yjmcc.2024.11.013
Sci Rep. 2024 11 30. 14(1): 29813

Plasma exosomes from patients with coronary artery disease promote atherosclerosis via impairing vascular endothelial junctions.

Jian Han, Xiaoyan Kang, Yazhen Su, Jing Wang, Xiaogang Cui, Yunfei Bian, Changxin Wu.

  The underlying mechanism of vascular endothelial hyperpermeability caused by decrease of endothelial junctions occurring in atherosclerosis remains elusive. Our findings identified that plasma exosomes from patients with stable coronary artery disease (ExoSCAD) contain differentially expressed miRNAs that are clustered with genes related to cell junctions, prompting us to investigate the role of ExoSCAD in regulating vascular endothelial junctions and to elucidate the underlying mechanisms. Here, we show that ExoSCAD markedly impair vascular endothelial junctions via suppressing VE-Cadherin and ZO-1 in endothelial cells in vitro and in vivo, consequently increases endothelial permeability. Critically, exosomal miR-140-3p plays a crucial role in ExoSCAD-induced inhibition of ZO-1, and may be an important causative factor in the development of endothelial hyperpermeability during atherosclerosis. Additionally, exosomal miR-140-3p level coordinates with severity of SCAD. Targeting miR-140-3p in circulating exosomes might open novel options for treatment of atherosclerosis.

Keywords:  Atherosclerosis; Endothelial cell junctions; Plasma exosomes; Stable coronary artery disease; miR-140-3p

DOI:  https://doi.org/10.1038/s41598-024-81352-8
J Agric Food Chem. 2024 Dec 04.

Potential of Anthocyanin-rich Products to Prevent and Improve Endothelial Function and Senescence: Focus on Anthocyanins.

Cyril Auger, Hira Muzammel, Ibrahima Diouf, Valérie B Schini-Kerth.

  Endothelial dysfunction is a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, diabetes, and aging. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors, including nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH), and vasocontracting factors, such as arachidonic acid-derived mediators generated by cyclooxygenases, and an increased level of oxidative stress. Recently, endothelial senescence was reported to be an early trigger of endothelial dysfunction. Preclinical studies indicate that polyphenol-rich food, including anthocyanin-rich products, can activate pathways promoting an increased formation of vasoprotective factors and can prevent the induction of endothelial dysfunction in endothelial cells and isolated blood vessels. Similarly, intake of anthocyanin-rich products has been associated with the prevention and/or the improvement of an endothelial dysfunction in several experimental models of cardiovascular diseases, including physiological aging. Moreover, clinical data indicate that polyphenol-rich and anthocyanin-rich products can improve endothelial function and vascular health in humans with cardiovascular diseases. The present review will discuss both experimental and clinical evidence indicating that several polyphenol-rich foods and natural products, and especially anthocyanin-rich products, can promote endothelial and vascular health, as well as the underlying mechanisms.

Keywords:  anthocyanins; cardiovascular diseases; endothelium; polyphenols; vascular health

DOI:  https://doi.org/10.1021/acs.jafc.4c04727
Nat Commun. 2024 Dec 03. 15(1): 10516

Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.

Rinako Nakagawa, Miriam Llorian, Sunita Varsani-Brown, Probir Chakravarty, Jeannie M Camarillo, David Barry, Roger George, Neil P Blackledge, Graham Duddy, Neil L Kelleher, Robert J Klose, Martin Turner, Dinis P Calado.

To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.

DOI: https://doi.org/10.1038/s41467-024-54937-0
Rev Cardiovasc Med. 2024 Nov;25(11): 423

Glucose Metabolism Reprogramming of Vascular Endothelial Cells and Its Implication in Development of Atherosclerosis.

Shiwen Luo, Liu Li, Huiqing Chen, Jingyue Wei, Dongmei Yang.

  Atherosclerosis (AS) is an important cause of morbidity and mortality in cardiovascular diseases such as coronary atherosclerotic heart disease and stroke. As the primary natural barrier between blood and the vessel wall, damage to vascular endothelial cells (VECs) is one of the initiating factors for the development of AS. VECs primarily use aerobic glycolysis for energy supply, but several diseases can cause altered glucose metabolism in VECs. Glucose metabolism reprogramming of VECs is the core event of AS, which is closely related to the development of AS. In this review, we review how glucose metabolism reprogramming of VECs promotes the development of AS by inducing VEC barrier dysfunction, autophagy, altering the inflammatory response, and proliferation of VECs, in the hopes of providing new ideas and discovering new targets for the prevention and treatment of AS.

Keywords:  atherosclerosis; glucose metabolism; vascular endothelial cells

DOI:  https://doi.org/10.31083/j.rcm2511423
BMC Cancer. 2024 Dec 03. 24(1): 1489

FTO-mediated demethylation of MTUS1/ATIP1 promotes tumor progression in head and neck squamous cell carcinoma.

Dongxiao Tang, Congyuan Cao, Wuguo Li, Anxun Wang.

   BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) has been recognized as the seventh most prevalent malignant tumor globally. It is a malignant neoplasm that arises from the mucosal epithelium of head and neck region. In our previous research, we have demonstrated that MTUS1/ATIP1 exhibits anti-cancer properties in HNSCC. Nevertheless, the underlying mechanism responsible for the reduction of MTUS1/ATIP1 expression has not been investigated.
METHODS: HNSCC and adjacent normal tissues were collected and examined using m6A MeRIP-seq, qRT-PCR, and IHC to investigate the relationship between MTUS1/ATIP1 and FTO. MeRIP-qPCR, m6A dot blot, RNA and protein stability assays, and RNC-qRT-PCR were employed to elucidate the mechanism by which FTO mediates demethylation of MTUS1/ATIP1 in HNSCC. Functional assays, subcutaneous tumorigenesis, and in situ tongue cancer models were conducted to assess the impact of the FTO-MTUS1/ATIP1 pathway on proliferative capacity of HNSCC tumors.
RESULTS: FTO was observed to be markedly upregulated and showed a negative correlation with MTUS1/ATIP1 expression in HNSCC. FTO was responsible for mediating m6A demethylation in the 3'UTR of MTUS1/ATIP1, leading to its degradation. Additionally, silencing MTUS1/ATIP1 successfully reversed the tumor-promoting effects on HNSCC triggered by FTO in in vitro and in vivo.
CONCLUSIONS: Our research elucidated the functional importance of FTO-mediated m6A demethylation of MTUS1/ATIP1, suggesting that targeting the FTO-MTUS1/ATIP1 axis could be a prospective novel approach for treating HNSCC.

Keywords:  Demethylation; FTO; Head and neck squamous cell carcinoma; MTUS1/ATIP1; N6-methyladenosine

DOI:  https://doi.org/10.1186/s12885-024-13253-y
Biochem Biophys Rep. 2024 Dec;40 101876

NOS3 regulates angiogenic potential of human induced pluripotent stem cell-derived endothelial cells.

Anne M Kong, Zulhusni A Idris, Daniel Urrutia-Cabrera, Jarmon G Lees, Ren Jie Phang, Geraldine M Mitchell, Raymond C B Wong, Shiang Y Lim.

  Incorporation of blood capillaries in engineered tissues and their functional connection to host blood vessels is essential for success in engineering vascularized tissues, a process which involves spatial patterning of endothelial cells (ECs) to form functional and integrated vascular networks. Different types of ECs have been employed for vascular network formation and each source offers advantages and disadvantages. While ECs derived from induced pluripotent stem cells (iPSC-ECs) offer advantages over primary ECs in that they can be generated in large quantities for autologous applications, their suitability for disease modelling and cell replacement therapies is not well-explored. The present study compares the angiogenic capacity of iPSC-ECs and primary ECs (cardiac microvascular ECs and lymphatic microvascular ECs) using an in vitro tubulogenesis assay, revealing comparable performance in forming a pseudo-capillary network on Matrigel. Analysis of genes encoding angiogenic factors (VEGFA, VEGFC, VEGFD and ANG), endothelial cell markers (PECAM1, PCDH12 and NOS3) and proliferation markers (AURKB and MKI67) indicates a significant positive correlation between NOS3 mRNA expression levels and various tubulogenic parameters. Further experimentation using a CRISPR activation system demonstrates a positive impact of NOS3 on tubulogenic activity of ECs, suggesting that iPSC-ECs can be enhanced with endogenous NOS3 activation. Collectively, these findings highlight the potential of iPSC-ECs in generating vascularized tissues and advancing therapeutic vascularization.

Keywords:  CRISPR; Endothelial cells; Induced pluripotent stem cells; NOS3; Tubulogenesis

DOI:  https://doi.org/10.1016/j.bbrep.2024.101876
J Clin Invest. 2024 Dec 03. pii: e183409. [Epub ahead of print]

Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.

Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y Eugene Chen, Lin Chang.

  Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease (CVD). Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain-containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMC), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16 knockout (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor alpha 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibits a remarkable circadian expression pattern and regulates the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMC causes disrupted BP circadian variation through reduced response to adrenergic signaling and clock gene regulation. Our findings offer substantial insights into the intricate molecular pathways that govern circadian fluctuations in BP.

Keywords:  Cardiovascular disease; Hypertension; Vascular biology

DOI:  https://doi.org/10.1172/JCI183409
Dose Response. 2024 Oct-Dec;22(4):22(4): 15593258241303646

Valproic Acid Inhibits Endoplasmic Reticulum Stress and Reduces Ferroptosis After Traumatic Brain Injury.

Jie Chen, Lei Li, Lei Huang, Chengyu Zhao, Zhanwei Ruan.

   Backgound: Traumatic brain injury (TBI) is a severe neurological disorders, which invloving complicated molecular mechanisms, such as endoplasmic reticulum (ER) stress and ferroptosis. , However, the mechanism underlying TBI remains unclear.
Objectives: The Objective was to determine the effect of VPA on ER stress and ferroptosis, and affirm the relationship between ER stress and ferroptosis. Methods: The expression levels of GRP78, ATF6, CHOP and GPX4 in brain tissues were detected via western blot, histological staining, and immunofluorescence. The effect of VPA on ER stress and ferroptosis on OS cellswas evaluated in vitro and in vivo.
Results: In our study, we found that VPA suppressed ER stress after TBI by inhibiting the GRP78-ATF6-CHOP signaling pathway, which ameliorated ferroptosis by reversing the reduction of the ferroptosis protein GPX4. Furthermore, tissue defects, bleeding, and iron accumulation also reduced. Moreover, 4-phenylbutyric acid was used to further confirm our assumption.
Conclusion: VPA plays a neuroprotective role by inhibiting ER stress levels and subsequently inhibiting ferroptosis.

Keywords:  endoplasmic reticulum; ferroptosis; traumatic brain injury; valproic acid

DOI:  https://doi.org/10.1177/15593258241303646
Nat Commun. 2024 Dec 02. 15(1): 10467

Diverting glial glycolytic flux towards neurons is a memory-relevant role of Drosophila CRH-like signalling.

Raquel Francés, Yasmine Rabah, Thomas Preat, Pierre-Yves Plaçais.

An essential role of glial cells is to comply with the large and fluctuating energy needs of neurons. Metabolic adaptation is integral to the acute stress response, suggesting that glial cells could be major, yet overlooked, targets of stress hormones. Here we show that Dh44 neuropeptide, Drosophila homologue of mammalian corticotropin-releasing hormone (CRH), acts as an experience-dependent metabolic switch for glycolytic output in glia. Dh44 released by dopamine neurons limits glial fatty acid synthesis and build-up of lipid stores. Although basally active, this hormonal axis is acutely stimulated following learning of a danger-predictive cue. This results in transient suppression of glial anabolic use of pyruvate, sparing it for memory-relevant energy supply to neurons. Diverting pyruvate destination may dampen the need to upregulate glial glycolysis in response to increased neuronal demand. Although beneficial for the energy efficiency of memory formation, this mechanism reveals an ongoing competition between neuronal fuelling and glial anabolism.

DOI: https://doi.org/10.1038/s41467-024-54778-x
Arterioscler Thromb Vasc Biol. 2024 Dec 05.

Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease.

Pei Zhu, Calvin L Chao, Adam W T Steffeck, Caitlyn Dang, Noah X Hamlish, Eric M Pfrender, Bin Jiang, Clara B Peek.

   BACKGROUND: Peripheral artery disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia.
METHODS: We performed secondary analysis of publicly available RNA-sequencing data sets derived from patients with PAD to identify the differential expression of circadian-related genes in endothelial cells and ischemic limb skeletal muscles. We used mice with specific genetic loss of the circadian clock activator, BMAL1 (brain and muscle ARNT-like 1), in adult skeletal muscle tissues (Bmal1muscle). Bmal1muscle mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser Doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and assay for transposase-accessible chromatin with sequencing analyses in primary myotube culture model.
RESULTS: Disrupted expression of circadian rhythm-related genes was observed in existing RNA-sequencing data sets from endothelial cells and ischemic limb skeletal muscles derived from patients with PAD. Genetic loss of Bmal1 specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in Bmal1muscle mouse muscles in the ischemic limbs but not in their contralateral nonischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia adaptation in Bmal1muscle mouse muscles. These changes were corroborated in Bmal1-deficient cultured primary myotubes cultured under hypoxic conditions.
CONCLUSIONS: Circadian clock in skeletal muscle is crucial for the muscle's response to hypoxia during hindlimb ischemia. Targeting the muscle circadian clock may have therapeutic potential for enhancing muscle response to reduced blood flow and promoting recovery in conditions such as PAD.

Keywords:  atherosclerosis; femoral artery; ischemia; perfusion; reperfusion

DOI:  https://doi.org/10.1161/ATVBAHA.124.321772
Anticancer Res. 2024 Dec;44(12): 5241-5252

Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.

Makoto Fujiwara, Takahiro Mimae, Kei Kushitani, Norifumi Tsubokawa, Yoshihiro Miyata, Yukio Takeshima, Morihito Okada.

   BACKGROUND/AIM: Oxidative phosphorylation (OXPHOS) is implicated in cancer progression and metastasis. However, its role in lung adenocarcinoma (LUAD) is unknown. We assessed OXPHOS in LUAD cases and cell lines and investigated the effect of OXPHOS inhibition on LUAD cells.
MATERIALS AND METHODS: The cases with high expression of OXPHOS-related genes and peroxisome proliferator-activated receptor gamma (PPAR-γ) were extracted using RNA-seq data from The Cancer Genome Atlas (TCGA) LUAD dataset and the clinicopathological features and survival were assessed. Resected LUAD specimens were stained for PPAR-γ. Real-time qPCR and western blot were used to examine the expression of OXPHOS- and glycolysis-related genes and proteins in four LUAD cell lines. Cell proliferation was evaluated in LUAD cells treated with OXPHOS inhibitors.
RESULTS: The TCGA database analysis revealed that cases with high OXPHOS or PPAR-γ expression had a worse prognosis (p=0.07 and p=0.01, respectively). High OXPHOS cases were associated with lymph node metastasis (p<0.01). PPAR-γ was expressed only in the peripheral area of the papillary component of LUAD. We identified A549, HTB181 and H322 as OXPHOS-high type cells and H596 as OXPHOS-low type cells. Oligomycin treatment inhibited cell proliferation in the OXHOS-high cells (0.72-, 0.69-, and 0.77- fold change in oligomycin vs. DMSO, for A549, HTB181, and H322 cells, respectively, p<0.01) but not in the OXPHOS-low cells.
CONCLUSION: High expression of OXPHOS-related genes and PPAR-γ is a poor prognostic factor in LUAD. The levels of OXPHOS vary among cases and within different areas of the tumor. Targeting OXPHOS metabolism may represent a novel therapeutic approach for treating LUAD.

Keywords:  Lung neoplasms; adenocarcinoma of lung; oxidative phosphorylation; therapeutics

DOI:  https://doi.org/10.21873/anticanres.17352