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Keywords = transcription factor EB

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11 pages, 3264 KiB  
Article
An Oncolytic Vaccinia Virus Expressing Aphrocallistes Vastus Lectin Modulates Hepatocellular Carcinoma Metabolism via ACSS2/TFEB-Mediated Autophagy and Lipid Accumulation
by Qiang Wang, Simeng Zhou, Yin Wang, Yajun Gao, Yanrong Zhou, Ting Ye, Gongchu Li and Kan Chen
Mar. Drugs 2025, 23(8), 297; https://doi.org/10.3390/md23080297 - 24 Jul 2025
Viewed by 294
Abstract
Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we [...] Read more.
Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article
(This article belongs to the Special Issue Marine Glycobiology)
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16 pages, 4508 KiB  
Article
Tension Force Stress Downregulates the Expression of Osteogenic Markers and Mineralization in Embryonic Stem-Cell-Derived Embryoid Bodies
by Ju-Hyeon An, Chun-Choo Kim, Junil Lee, Junhyeok Kim, Jeong-Chae Lee and Sung-Ho Kook
Cells 2025, 14(13), 991; https://doi.org/10.3390/cells14130991 - 28 Jun 2025
Viewed by 377
Abstract
Mechanical stresses affect a variety of cellular events in relation to the frequency, magnitude, and duration of the stimuli applied. Embryonic stem cell (ESC)-derived embryoid bodies (EBs) are pluripotent stem cell aggregates and comprise all somatic cells. Numerous studies have highlighted the effects [...] Read more.
Mechanical stresses affect a variety of cellular events in relation to the frequency, magnitude, and duration of the stimuli applied. Embryonic stem cell (ESC)-derived embryoid bodies (EBs) are pluripotent stem cell aggregates and comprise all somatic cells. Numerous studies have highlighted the effects of mechanosignals on stem cells, whereas their impact on EBs has been barely investigated. Here, we examined how cyclic tensile stress affects the behavior of EBs to differentiate into mineralized osteocytes by applying 2% elongation at 0.5 Hz frequency for 1 h once or 1 h every other day for 5 or 14 days in osteogenic medium. EBs that expressed undifferentiated markers, Oct4 and Sox2, were differentiated into mineralized cells, along with the accumulation of runt-related transcription factor 2 (RUNX2) and β-catenin in osteogenic medium. The application of tensile force inhibited EB’ mineralization via the downregulation of bone sialoprotein, osteocalcin, osterix, and RUNX2. While the transfection with si-β-catenin did not affect the osteogenic potency of EBs at a significant level, treatment with 10 μM of PD98059, but not of SP600125 or SB203580, diminished the mineralization of EBs and the expression of RUNX2 and RUNX2-regulated osteoblastic genes. The level of phosphorylated extracellular signal-regulated kinase-1 (p-ERK1) rather than p-ERK2 was more apparently diminished in tension-applied EBs. The transfection with si-ERK1, but not with si-ERK2, suppressed the mineralization of osteogenic medium-supplied EBs and the expression of osteoblast-specific genes. Collectively, this study demonstrates that tensile stress inhibits osteogenic potency of EBs by downregulating ERK1-mediated signaling and osteogenic gene expression. Full article
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22 pages, 8293 KiB  
Article
Time-Dependent Impact of Betulin and Its Derivatives on IL-8 Expression in Colorectal Cancer Cells with Molecular Docking Studies
by Marcel Madej, Adrianna Halama, Elwira Chrobak and Joanna Magdalena Gola
Int. J. Mol. Sci. 2025, 26(13), 6186; https://doi.org/10.3390/ijms26136186 - 27 Jun 2025
Viewed by 362
Abstract
Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and [...] Read more.
Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and metastasis. Elevated IL-8 expression is frequently associated with advanced CRC stages. This study investigated the effects of betulin and its semi-synthetic derivatives, EB5 and ECH147, on IL-8 expression in CRC cell lines characterized by differing malignancy grades. IL-8 transcript and protein levels were quantified using real-time RT-qPCR and a proximity ligation assay, respectively, following compound exposure at 2, 8, and 24 h. Basal IL-8 levels were significantly higher in low-grade CRC cell lines. Among the compounds tested, ECH147 exerted the most pronounced, time-dependent inhibitory effect on CXCL8 expression. Furthermore, molecular docking analyses revealed that ECH147 exhibits stronger binding affinity toward the IL-8 protein compared to conventional chemotherapeutics. These findings suggest that the modification of the betulin structure via the incorporation of a propynoyl moiety enhances both its molecular interaction with CXCL8 and its anti-inflammatory potential. ECH147 and EB5 thus emerge as promising candidates for further development as immunomodulatory agents targeting the IL-8-associated pathway in CRC. Full article
(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)
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18 pages, 2600 KiB  
Article
c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors
by Miguel V. Guerra, Juan Castro, Antonio Moreno, Elisa Balboa, Juan J. Marugan, Alejandra R. Alvarez and Silvana Zanlungo
Antioxidants 2025, 14(5), 611; https://doi.org/10.3390/antiox14050611 - 20 May 2025
Viewed by 521
Abstract
Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and [...] Read more.
Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction. Full article
(This article belongs to the Special Issue Oxidative Stress and Lysosomal Function in Health and Disease)
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20 pages, 2030 KiB  
Review
Targeting Lysosomal Dysfunction and Oxidative Stress in Age-Related Macular Degeneration
by Ana S. Falcão, Margarida L. Pedro, Sandra Tenreiro and Miguel C. Seabra
Antioxidants 2025, 14(5), 596; https://doi.org/10.3390/antiox14050596 - 16 May 2025
Viewed by 968
Abstract
Age-related macular degeneration (AMD) is the leading cause of vision loss in the Western world, and it currently lacks effective therapy. It is believed that AMD initiates in the aged retinal pigment epithelium (RPE), which presents lysosomal dysfunction and oxidative stress (OxS) that [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the Western world, and it currently lacks effective therapy. It is believed that AMD initiates in the aged retinal pigment epithelium (RPE), which presents lysosomal dysfunction and oxidative stress (OxS) that ultimately leads to RPE damage and AMD progression. AMD is a complex pathology, so multitarget treatments are required to act on different pathways, presenting several challenges. In this review, we discuss the current knowledge on the pathogenesis of this disease, focusing mainly on lysosomal dysfunction and OxS. Because transcription factors regulate homeostasis, the transcription factor EB (TFEB), which controls lysosomal function and biogenesis, and the nuclear factor erythroid 2-related factor 2 (NRF2), which manages OxS, have been proposed as promising targets for disease intervention. Finally, we discuss the interplay of these pathways for a potential synergistic effect on AMD-targeted therapies, as they could change the course of today’s available treatments for AMD. Full article
(This article belongs to the Special Issue Oxidative Stress and Lysosomal Function in Health and Disease)
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23 pages, 1705 KiB  
Review
Lysosomal Stress in Cardiovascular Diseases: Therapeutic Potential of Cardiovascular Drugs and Future Directions
by Toshiki Otoda, Ken-ichi Aihara and Tadateru Takayama
Biomedicines 2025, 13(5), 1053; https://doi.org/10.3390/biomedicines13051053 - 27 Apr 2025
Viewed by 1031
Abstract
Lysosomal dysfunction has emerged as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), particularly due to its involvement in chronic inflammation, lipid dysregulation, and oxidative stress. This review highlights the multifaceted roles of lysosomes in CVD pathophysiology, focusing on key mechanisms [...] Read more.
Lysosomal dysfunction has emerged as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), particularly due to its involvement in chronic inflammation, lipid dysregulation, and oxidative stress. This review highlights the multifaceted roles of lysosomes in CVD pathophysiology, focusing on key mechanisms such as NLRP3 inflammasome activation, TFEB-mediated autophagy regulation, ferroptosis, and the role of apolipoprotein M (ApoM) in preserving lysosomal integrity. Additionally, we discuss how impaired lysosomal acidification, mediated by V-ATPase, contributes to lipid-induced cardiac dysfunction. Therapeutically, several pharmacological agents, such as statins, SGLT2 inhibitors, TRPML1 agonists, resveratrol, curcumin, and ferroptosis modulators (e.g., GLS1 activators and icariin), have demonstrated promise in restoring lysosomal function, enhancing autophagic flux, and reducing inflammatory and oxidative injury in both experimental models and early clinical settings. However, key challenges remain, including limitations in drug delivery systems, the absence of lysosome-specific biomarkers, and insufficient clinical validation of these strategies. Future research should prioritize the development of reliable diagnostic tools for lysosomal dysfunction, the optimization of targeted drug delivery, and large-scale clinical trials to validate therapeutic efficacy. Incorporating lysosome-modulating approaches into standard cardiovascular care may offer a new precision medicine paradigm for managing CVD progression. Full article
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17 pages, 7042 KiB  
Article
Acid Sphingomyelinase Regulates AdipoRon-Induced Differentiation of Arterial Smooth Muscle Cells via TFEB Activation
by Xiang Li, Wei Zhao, Zhengchao Wang, Alexandra K. Moura, Kiana Roudbari, Rui Zuo, Jenny Z. Hu, Yun-Ting Wang, Pin-Lan Li and Yang Zhang
Int. J. Mol. Sci. 2025, 26(5), 2147; https://doi.org/10.3390/ijms26052147 - 27 Feb 2025
Viewed by 1005
Abstract
AdipoRon is a selective adiponectin receptor agonist that inhibits vascular remodeling by promoting the differentiation of arterial smooth muscle cells (SMCs). Our recent studies have demonstrated that activation of TFEB and its downstream autophagy–lysosomal signaling contribute to adipoRon-induced differentiation of SMCs. The present [...] Read more.
AdipoRon is a selective adiponectin receptor agonist that inhibits vascular remodeling by promoting the differentiation of arterial smooth muscle cells (SMCs). Our recent studies have demonstrated that activation of TFEB and its downstream autophagy–lysosomal signaling contribute to adipoRon-induced differentiation of SMCs. The present study was designed to examine whether acid sphingomyelinase (ASM; gene symbol Smpd1) is involved in mediating adipoRon-induced activation of TFEB–autophagy signaling and inhibition of proliferation/migration in arterial SMCs. Our results showed that adipoRon induced ASM expression and ceramide production in Smpd1+/+ SMCs, which were abolished in Smpd1−/− SMCs. Compared to Smpd1+/+ SMCs, Smpd1−/− SMCs exhibited less TFEB nuclear translocation and activation of autophagy signaling induced by adipoRon stimulation. SMC differentiation was further characterized by retarded wound healing, reduced proliferation, F-actin reorganization, and MMP downregulation. The results showed that Smpd1−/− SMCs were less responsive to adipoRon-induced differentiation than Smpd1+/+ SMCs. Mechanistically, adipoRon increased the expression of protein phosphatases such as calcineurin and PP2A in Smpd1+/+ SMCs. The calcineurin inhibitor FK506/cyclosporin A or PP2A inhibitor okadaic acid significantly attenuated adipoRon-induced activation of TFEB–autophagy signaling. In addition, adipoRon-induced expressions of calcineurin and PP2A were not observed in Smpd1−/− SMCs. However, activation of calcineurin by lysosomal TRPML1-Ca2+ channel agonist ML-SA1 rescued the activation of TFEB–autophagy signaling and the effects of adipoRon on cell differentiation in Smpd1−/− SMCs. Taken together, these data suggested that ASM regulates adipoRon-induced SMC differentiation through TFEB activation. This study provided novel mechanistic insights into the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling. Full article
(This article belongs to the Special Issue Smooth Muscle Cells in Vascular Disease)
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16 pages, 3834 KiB  
Article
Melatonin Mitigates Acidosis-Induced Neuronal Damage by Up-Regulating Autophagy via the Transcription Factor EB
by Yan Shi, Zhaoyu Mi, Wei Zhao, Yue Hu, Hui Xiang, Yaoxue Gan and Shishan Yuan
Int. J. Mol. Sci. 2025, 26(3), 1170; https://doi.org/10.3390/ijms26031170 - 29 Jan 2025
Viewed by 998
Abstract
Acidosis, a common feature of cerebral ischemia and hypoxia, results in neuronal damage and death. This study aimed to investigate the protective effects and mechanisms of action of melatonin against acidosis-induced neuronal damage. SH-SY5Y cells were exposed to an acidic environment to simulate [...] Read more.
Acidosis, a common feature of cerebral ischemia and hypoxia, results in neuronal damage and death. This study aimed to investigate the protective effects and mechanisms of action of melatonin against acidosis-induced neuronal damage. SH-SY5Y cells were exposed to an acidic environment to simulate acidosis, and a photothrombotic (PT) infarction model was used to establish an animal model of cerebral ischemia of male C57/BL6J mice. Both in vivo and in vitro studies demonstrated that acidosis increased cytoplasmic transcription factor EB (TFEB) levels, reduced nuclear TFEB levels, and suppressed autophagy, as evidenced by elevated p62 levels, a higher LC3-II/LC3-I ratio, decreased synapse-associated proteins (PSD-95 and synaptophysin), and increased neuronal apoptosis. In contrast, melatonin promoted the nuclear translocation of TFEB, enhanced autophagy, and reversed neuronal apoptosis. Moreover, the role of TFEB in melatonin’s neuroprotective effects was validated by modulating TFEB nuclear translocation. In conclusion, melatonin mitigates acidosis-induced neuronal damage by promoting the nuclear translocation of TFEB, thereby enhancing autophagy. These findings offer new insights into potential treatments for acidosis. Full article
(This article belongs to the Special Issue Metabolism, Synthesis and Function of Melatonin)
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2 pages, 551 KiB  
Correction
Correction: Zhang et al. Hepatitis B Virus X Protein (HBx) Suppresses Transcription Factor EB (TFEB) Resulting in Stabilization of Integrin Beta 1 (ITGB1) in Hepatocellular Carcinoma Cells. Cancers 2021, 13, 1181
by Chunyan Zhang, Huan Yang, Liwei Pan, Guangfu Zhao, Ruofei Zhang, Tianci Zhang, Zhixiong Xiao, Ying Tong, Yi Zhang, Richard Hu, Stephen J. Pandol and Yuan-Ping Han
Cancers 2025, 17(1), 103; https://doi.org/10.3390/cancers17010103 - 31 Dec 2024
Viewed by 780
Abstract
In the original publication [...] Full article
(This article belongs to the Section Molecular Cancer Biology)
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21 pages, 10076 KiB  
Article
Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity
by Hao Chen, Kaitlyn Hinz, Chen Zhang, Yssa Rodriguez, Sha Neisha Williams, Mengwei Niu, Xiaowen Ma, Xiaojuan Chao, Alexandria L. Frazier, Kenneth E. McCarson, Xiaowan Wang, Zheyun Peng, Wanqing Liu, Hong-Min Ni, Jianhua Zhang, Russell H. Swerdlow and Wen-Xing Ding
Biomolecules 2024, 14(12), 1537; https://doi.org/10.3390/biom14121537 - 30 Nov 2024
Cited by 2 | Viewed by 1500
Abstract
Alcohol consumption is believed to affect Alzheimer’s disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity [...] Read more.
Alcohol consumption is believed to affect Alzheimer’s disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption. Full article
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19 pages, 7515 KiB  
Article
Deciphering Transcriptomic Variations in Hematopoietic Lineages: HSCs, EBs, and MKs
by Swati Dahariya, Anton Enright, Santosh Kumar and Ravi Kumar Gutti
Int. J. Mol. Sci. 2024, 25(18), 10073; https://doi.org/10.3390/ijms251810073 - 19 Sep 2024
Viewed by 1358
Abstract
In the realm of hematopoiesis, hematopoietic stem cells (HSCs) serve as pivotal entities responsible for generating various blood cell types, initiating both the myeloid and lymphoid branches within the hematopoietic lineage. This intricate process is marked by genetic variations that underscore the crucial [...] Read more.
In the realm of hematopoiesis, hematopoietic stem cells (HSCs) serve as pivotal entities responsible for generating various blood cell types, initiating both the myeloid and lymphoid branches within the hematopoietic lineage. This intricate process is marked by genetic variations that underscore the crucial role of genes in regulating cellular functions and interactions. Recognizing the significance of genetic factors in this context, this article delves into a genetic perspective, aiming to unravel the biological factors that govern the transition from one cell’s fate to another within the hematopoietic system. To gain deeper insights into the genetic traits of three distinct blood cell types—HSCs, erythroblasts (EBs), and megakaryocytes (MKs)—we conducted a comprehensive transcriptomic analysis. Leveraging diverse hematopoietic cell datasets from healthy individuals, sourced from The BLUEPRINT consortium, our investigation targeted the identification of genetic variants responsible for changes in gene expression levels and epigenetic modifications across the entire human genome in each of these cell types. The total number of normalized expressed transcripts includes 14,233 novel trinity lncRNAs, 13,749 mRNAs, and 3092 lncRNAs. This scrutiny revealed a total of 31,074 transcripts, with a notable revelation that 14,233 of them were previously unidentified or novel lncRNAs, highlighting a substantial reservoir of genetic information yet to be explored. Examining their expression across distinct lineages further unveiled 2845 differentially expressed (DE) mRNAs and 354 DE long noncoding RNAs (lncRNAs) notably enriched among the three distinct blood cell types: HSCs, EBs, and MKs. Our investigation extended beyond mRNA to focus on the dynamic expression of lncRNAs, revealing a well-defined pattern that played a significant role in regulating differentiation and cell-fate specification. This coordination of lncRNA dynamics extended to aberrations in both mRNA and lncRNA transcriptomes within HSCs, EBs, and MKs. We specifically characterized lncRNAs with preferential expression in HSCs, as well as in various downstream differentiated lineage progenitors of EBs and MKs, providing a comprehensive perspective on lncRNAs in human hematopoietic cells. Notably, the expression of lncRNAs exhibited substantial cell-to-cell variation, a phenomenon discernible only through single-cell analysis. The comparative analysis undertaken in this study provides valuable insights into the distinctive genetic signatures guiding the differentiation of these crucial hematopoietic cell types. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 743 KiB  
Review
Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
by Nadia Papini, Paola Giussani and Cristina Tringali
Int. J. Mol. Sci. 2024, 25(16), 8884; https://doi.org/10.3390/ijms25168884 - 15 Aug 2024
Cited by 3 | Viewed by 2348
Abstract
Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, [...] Read more.
Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future. Full article
(This article belongs to the Special Issue Advances in Molecular and Translational Medicine: 2nd Edition)
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27 pages, 6189 KiB  
Article
Bhlhe40 Regulates Proliferation and Angiogenesis in Mouse Embryoid Bodies under Hypoxia
by Bárbara Acosta-Iborra, Ana Isabel Gil-Acero, Marta Sanz-Gómez, Yosra Berrouayel, Laura Puente-Santamaría, Maria Alieva, Luis del Peso and Benilde Jiménez
Int. J. Mol. Sci. 2024, 25(14), 7669; https://doi.org/10.3390/ijms25147669 - 12 Jul 2024
Cited by 2 | Viewed by 1809
Abstract
Knowledge of the molecular mechanisms that underlie the regulation of major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused [...] Read more.
Knowledge of the molecular mechanisms that underlie the regulation of major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused on the functional role of the transcriptional repressor basic-helix-loop-helix family member e40 (Bhlhe40), which we previously identified in a meta-analysis as one of the most consistently upregulated genes in response to hypoxia across various cell types. We investigated the role of Bhlhe40 in controlling proliferation and angiogenesis using a gene editing strategy in mouse embryonic stem cells (mESCs) that we differentiated in embryoid bodies (EBs). We observed that hypoxia-induced Bhlhe40 expression was compatible with the rapid proliferation of pluripotent mESCs under low oxygen tension. However, in EBs, hypoxia triggered a Bhlhe40-dependent cell cycle arrest in most progenitor cells and endothelial cells within vascular structures. Furthermore, Bhlhe40 knockout increased the basal vascularization of the EBs in normoxia and exacerbated the hypoxia-induced vascularization, supporting a novel role for Bhlhe40 as a negative regulator of blood vessel formation. Our findings implicate Bhlhe40 in mediating key functional adaptive responses to hypoxia, such as proliferation arrest and angiogenesis. Full article
(This article belongs to the Section Molecular Biology)
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17 pages, 1154 KiB  
Article
Integrative Bioinformatics Analysis Reveals a Transcription Factor EB-Driven MicroRNA Regulatory Network in Endothelial Cells
by Teresa Gravina, Francesco Favero, Stefania Rosano, Sushant Parab, Alejandra Diaz Alcalde, Federico Bussolino, Gabriella Doronzo and Davide Corà
Int. J. Mol. Sci. 2024, 25(13), 7123; https://doi.org/10.3390/ijms25137123 - 28 Jun 2024
Cited by 1 | Viewed by 2023
Abstract
Various human diseases are triggered by molecular alterations influencing the fine-tuned expression and activity of transcription factors, usually due to imbalances in targets including protein-coding genes and non-coding RNAs, such as microRNAs (miRNAs). The transcription factor EB (TFEB) modulates human cellular networks, overseeing [...] Read more.
Various human diseases are triggered by molecular alterations influencing the fine-tuned expression and activity of transcription factors, usually due to imbalances in targets including protein-coding genes and non-coding RNAs, such as microRNAs (miRNAs). The transcription factor EB (TFEB) modulates human cellular networks, overseeing lysosomal biogenesis and function, plasma–membrane trafficking, autophagic flux, and cell cycle progression. In endothelial cells (ECs), TFEB is essential for the maintenance of endothelial integrity and function, ensuring vascular health. However, the comprehensive regulatory network orchestrated by TFEB remains poorly understood. Here, we provide novel mechanistic insights into how TFEB regulates the transcriptional landscape in primary human umbilical vein ECs (HUVECs), using an integrated approach combining high-throughput experimental data with dedicated bioinformatics analysis. By analyzing HUVECs ectopically expressing TFEB using ChIP-seq and examining both polyadenylated mRNA and small RNA sequencing data from TFEB-silenced HUVECs, we have developed a bioinformatics pipeline mapping the different gene regulatory interactions driven by TFEB. We show that TFEB directly regulates multiple miRNAs, which in turn post-transcriptionally modulate a broad network of target genes, significantly expanding the repertoire of gene programs influenced by this transcription factor. These insights may have significant implications for vascular biology and the development of novel therapeutics for vascular disease. Full article
(This article belongs to the Special Issue Genes and Human Diseases 2.0)
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12 pages, 1893 KiB  
Review
Role of TFEB in Huntington’s Disease
by Javier Ojalvo-Pacheco, Sokhna M. S. Yakhine-Diop, José M. Fuentes, Marta Paredes-Barquero and Mireia Niso-Santano
Biology 2024, 13(4), 238; https://doi.org/10.3390/biology13040238 - 4 Apr 2024
Viewed by 3310
Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the [...] Read more.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy–lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models. Full article
(This article belongs to the Special Issue Lysosomes and Diseases Associated with Its Dysfunction)
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