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16 pages, 2609 KiB  
Article
MicroRNA210 Suppresses Mitochondrial Metabolism and Promotes Microglial Activation in Neonatal Hypoxic–Ischemic Brain Injury
by Shirley Hu, Yanelly Lopez-Robles, Guofang Shen, Elena Liu, Lubo Zhang and Qingyi Ma
Cells 2025, 14(15), 1202; https://doi.org/10.3390/cells14151202 - 5 Aug 2025
Abstract
Neuroinflammation is the major contributor to the pathology of neonatal hypoxic–ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms [...] Read more.
Neuroinflammation is the major contributor to the pathology of neonatal hypoxic–ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen–glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1β and rescued OGD-mediated downregulation of mitochondrial iron–sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury. Full article
(This article belongs to the Special Issue Non-Coding RNAs as Regulators of Cellular Function and Disease)
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18 pages, 2745 KiB  
Article
Obesity-Induced MASLD Is Reversed by Capsaicin via Hepatic TRPV1 Activation
by Padmamalini Baskaran, Ryan Christensen, Kimberley D. Bruce and Robert H. Eckel
Curr. Issues Mol. Biol. 2025, 47(8), 618; https://doi.org/10.3390/cimb47080618 - 4 Aug 2025
Abstract
Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, [...] Read more.
Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article
(This article belongs to the Special Issue Mechanisms and Pathophysiology of Obesity)
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22 pages, 1078 KiB  
Review
The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine
by Gabriel Urreola, Michael Le, Alan Harris, Jose A. Castillo, Augustine M. Saiz, Hania Shahzad, Allan R. Martin, Kee D. Kim, Safdar Khan and Richard Price
Biomedicines 2025, 13(8), 1891; https://doi.org/10.3390/biomedicines13081891 - 3 Aug 2025
Viewed by 21
Abstract
Background/Objectives: Cannabinoid use is rising among patients undergoing spinal fusion, yet its influence on bone healing is poorly defined. The endocannabinoid system (ECS)—through cannabinoid receptors 1 (CB1) and 2 (CB2)—modulates skeletal metabolism. We reviewed preclinical, mechanistic and clinical evidence to clarify how individual [...] Read more.
Background/Objectives: Cannabinoid use is rising among patients undergoing spinal fusion, yet its influence on bone healing is poorly defined. The endocannabinoid system (ECS)—through cannabinoid receptors 1 (CB1) and 2 (CB2)—modulates skeletal metabolism. We reviewed preclinical, mechanistic and clinical evidence to clarify how individual cannabinoids affect fracture repair and spinal arthrodesis. Methods: PubMed, Web of Science and Scopus were searched from inception to 31 May 2025 with the terms “cannabinoid”, “CB1”, “CB2”, “spinal fusion”, “fracture”, “osteoblast” and “osteoclast”. Animal studies, in vitro experiments and clinical reports that reported bone outcomes were eligible. Results: CB2 signaling was uniformly osteogenic. CB2-knockout mice developed high-turnover osteoporosis, whereas CB2 agonists (HU-308, JWH-133, HU-433, JWH-015) restored trabecular volume, enhanced osteoblast activity and strengthened fracture callus. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with CB2 bias, accelerated early posterolateral fusion in rats and reduced the RANKL/OPG ratio without compromising final union. In contrast, sustained or high-dose Δ9-tetrahydrocannabinol (THC) activation of CB1 slowed chondrocyte hypertrophy, decreased mesenchymal-stromal-cell mineralization and correlated clinically with 6–10% lower bone-mineral density and a 1.8–3.6-fold higher pseudarthrosis or revision risk. Short-course or low-dose THC appeared skeletal neutral. Responses varied with sex, age and genetic background; no prospective trials defined safe perioperative dosing thresholds. Conclusions: CB2 activation and CBD consistently favor bone repair, whereas chronic high-THC exposure poses a modifiable risk for nonunion in spine surgery. Prospective, receptor-specific trials stratified by THC/CBD ratio, patient sex and ECS genotype are needed to establish evidence-based cannabinoid use in spinal fusion. Full article
(This article belongs to the Topic Cannabis, Cannabinoids and Its Derivatives)
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10 pages, 503 KiB  
Brief Report
RAGE Knockout Mitigates Diet-Induced Obesity and Metabolic Disruption
by Isabelle L. Palmer, Genevieve Parker, Alden T. Chiu, Colson G. Beus, Ethan P. Evans, Jack H. Radford, Cameron R. Braithwaite, Ryan D. van Slooten, Elijah T. Cooper-Leavitt, Zachary E. Moore, Derek M. Clarke, R. Ryley Parrish, Juan A. Arroyo, Paul R. Reynolds and Benjamin T. Bikman
Metabolites 2025, 15(8), 524; https://doi.org/10.3390/metabo15080524 - 2 Aug 2025
Viewed by 153
Abstract
Background/Objectives: The receptor for advanced glycation end products (RAGEs) has been implicated in obesity and metabolic dysfunction. However, its precise role in diet-induced obesity remains unclear. Methods: In this study, we investigated the metabolic consequences of RAGE knockout (RAGE KO) in mice subjected [...] Read more.
Background/Objectives: The receptor for advanced glycation end products (RAGEs) has been implicated in obesity and metabolic dysfunction. However, its precise role in diet-induced obesity remains unclear. Methods: In this study, we investigated the metabolic consequences of RAGE knockout (RAGE KO) in mice subjected to a Western diet (WD). Results: Our findings demonstrate that RAGE KO mice remained significantly leaner than their wild-type (WT) counterparts when fed a WD, exhibiting reduced body weight gain and smaller adipocyte size. Indirect calorimetry revealed that RAGE KO mice had increased oxygen consumption and locomotor activity compared to WT mice, indicating enhanced energy expenditure. Mitochondrial respiration assays indicated significantly greater oxygen consumption in RAGE KO animals. Additionally, systemic inflammation markers, such as TNF-α, were significantly lower in RAGE KO mice when fed a WD, indicating a reduction in diet-induced inflammatory responses. Conclusions: These findings suggest that RAGE plays a key role in metabolic homeostasis, and its deletion confers resistance to obesity and metabolic disruption induced by a Western diet. Targeting RAGE may provide a novel therapeutic approach for combating obesity and related metabolic disorders. Full article
(This article belongs to the Special Issue Fat and Glucose Metabolism)
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14 pages, 2113 KiB  
Article
NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria
by Victoria E. Stefan, Victoria Klepsch, Nikolaus Thuille, Martina Steinlechner, Sebastian Peer, Kerstin Siegmund, Peter Lackner, Erich Schmutzhard, Karin Albrecht-Schgör and Gottfried Baier
Cells 2025, 14(15), 1162; https://doi.org/10.3390/cells14151162 - 28 Jul 2025
Viewed by 243
Abstract
Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8+ T cells in the pathophysiology of [...] Read more.
Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8+ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood–brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM. Full article
(This article belongs to the Section Cell Signaling)
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16 pages, 4271 KiB  
Article
Considering Litter Effects in Preclinical Research: Evidence from E17.5 Acid-Sensing Ion Channel 2a Knockout Mice Exposed to Acute Seizures
by Junie P. Warrington, Tyranny Pryor, Maria Jones-Muhammad and Qingmei Shao
Brain Sci. 2025, 15(8), 802; https://doi.org/10.3390/brainsci15080802 - 28 Jul 2025
Viewed by 169
Abstract
Background: The reproducibility of research findings continues to be a challenge in many fields, including neurosciences. It is now required that biological variables such as sex and age be considered in preclinical and clinical research. Rodents are frequently used to model clinical conditions; [...] Read more.
Background: The reproducibility of research findings continues to be a challenge in many fields, including neurosciences. It is now required that biological variables such as sex and age be considered in preclinical and clinical research. Rodents are frequently used to model clinical conditions; however, litter information is rarely presented. Some studies utilize entire litters with each animal treated as an independent sample, while others equally assign animals from each litter to different groups/treatments, and others use averaged data. These methods can yield different results. Methods: This study used different analysis methods to evaluate embryo and placenta weights from E17.5 acid-sensing ion channel 2a (ASIC2a) mice with or without seizure exposure. Results: When each embryo was treated as an individual sample, fetal and placental weight significantly differed following seizures in the ASIC2a heterozygous (+/−) and homozygous (−/−) groups. Differences in fetal weight were driven by females in the ASIC2a+/− group and both sexes in the ASIC2a−/− group. These differences were lost when an average per sex/genotype/litter was used. There was no difference in placental weight when treated individually; however, female ASIC2a−/− placentas weighed less following seizures. This difference was lost with averaged data. ASIC2a−/− fetuses from −/− dams had reduced weights post-seizure exposure. Position on the uterine horn influenced embryo and placental weight. Conclusions: Our results indicate that using full litters analyzed as individual data points should be avoided, as it can lead to Type I errors. Furthermore, studies should account for litter effects and be transparent in their methods and results. Full article
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16 pages, 13113 KiB  
Article
Ambient Particulate Matter Exposure Impairs Gut Barrier Integrity and Disrupts Goblet Cell Function
by Wanhao Gao, Wang Lin, Miao Tian, Shilang Fan, Sabrina Edwards, Joanne Tran, Yuanjing Li and Xiaoquan Rao
Biomedicines 2025, 13(8), 1825; https://doi.org/10.3390/biomedicines13081825 - 25 Jul 2025
Viewed by 323
Abstract
Background: As a well-known environmental hazard, ambient fine particulate matter (PM2.5, aerodynamic diameter ≤ 2.5 µm) has been positively correlated with an increased risk of digestive system diseases, including appendicitis, inflammatory bowel disease, and gastrointestinal cancer. Additionally, PM2.5 exposure [...] Read more.
Background: As a well-known environmental hazard, ambient fine particulate matter (PM2.5, aerodynamic diameter ≤ 2.5 µm) has been positively correlated with an increased risk of digestive system diseases, including appendicitis, inflammatory bowel disease, and gastrointestinal cancer. Additionally, PM2.5 exposure has been shown to alter microbiota composition and diversity in human and animal models. However, its impact on goblet cells and gut mucus barrier integrity remains unclear. Methods: To address this, 8-week-old male and female interleukin-10 knockout (IL10−/−) mice, serving as a spontaneous colitis model, were exposed to concentrated ambient PM2.5 or filtered air (FA) in a whole-body exposure system for 17 weeks. Colon tissues from the PM2.5-exposed mice and LS174T goblet cells were analyzed using H&E staining, transmission electron microscopy (TEM), and transcriptomic profiling. Results: The average PM2.5 concentration in the exposure chamber was 100.20 ± 13.79 µg/m3. PM2.5 exposure in the IL10−/− mice led to pronounced colon shortening, increased inflammatory infiltration, ragged villi brush borders, dense goblet cells with sparse enterocytes, and lipid droplet accumulation in mitochondria. Similar ultrastructure changes were exhibited in the LS174T goblet cells after PM2.5 exposure. Transcriptomic analysis revealed a predominantly upregulated gene expression spectrum, indicating an overall enhancement rather than suppression of metabolic activity after PM2.5 exposure. Integrated enrichment analyses, including GO, KEGG, and GSEA, showed enrichment in pathways related to oxidative stress, xenobiotic (exogenous compound) metabolism, and energy metabolism. METAFlux, a metabolic activity analysis, further substantiated that PM2.5 exposure induces a shift in cellular energy metabolism preference and disrupts redox homeostasis. Conclusions: The findings of exacerbated gut barrier impairment and goblet cell dysfunction following PM2.5 exposure provide new evidence of environmental factors contributing to colitis, highlighting new perspectives on its role in the pathogenesis of colitis. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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12 pages, 1017 KiB  
Article
Forebrain-Specific B-raf Deficiency Reduces NMDA Current and Enhances Small-Conductance Ca2+-Activated K+ (SK) Current
by Cornelia Ruxanda, Christian Alzheimer and Fang Zheng
Int. J. Mol. Sci. 2025, 26(15), 7172; https://doi.org/10.3390/ijms26157172 - 25 Jul 2025
Viewed by 235
Abstract
B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired [...] Read more.
B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired hippocampal long-term potentiation (LTP). To elucidate the mechanism(s) underlying diminished synaptic plasticity in B-raf-deficient mice, we performed whole-cell recordings from CA1 pyramidal cells in hippocampal slices of control and B-raf mutant mice. We found that the NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) at the Schaffer collateral—CA1 pyramidal cell synapses was significantly reduced in B-raf mutants, which would at least partially account for their impaired LTP. Interestingly, the reduced NMDA component of field postsynaptic potentials in mutant preparations was partially reinstated by blocking the apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels, which have also been reported to modulate hippocampal LTP and learning tasks. To determine the impact of B-raf-dependent signaling on SK current, we isolated the apamin-sensitive tail current after a strong depolarizing event and found indeed a significantly bigger SK current in B-raf-deficient cells compared to controls, which is consistent with the reduced action potential firing and the stronger facilitating effect of apamin on CA1 somatic excitability in B-raf-mutant hippocampus. Our data suggest that B-raf signaling readjusts the delicate balance between NMDA receptors and SK channels to promote synaptic plasticity and facilitate hippocampal learning and memory. Full article
(This article belongs to the Special Issue Advances in Synaptic Transmission and Plasticity)
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21 pages, 3499 KiB  
Article
Auricularia auricula’s Exopolysaccharide Mitigates DSS-Induced Colitis Through Dectin–1-Mediated Immunomodulation and Microbiota Remodeling
by Luísa Coutinho Coelho, Luísa Dan Favilla, Thais Bergmann de Castro, Maria Carolina B. Di Medeiros Leal, Christian Hoffmann and Anamélia Lorenzetti Bocca
Pharmaceuticals 2025, 18(8), 1085; https://doi.org/10.3390/ph18081085 - 22 Jul 2025
Viewed by 245
Abstract
Background/Objectives: Ulcerative colitis (UC) is characterized by the interplay between immune responses and dysbiosis in disease development. Aiming to provide additional insights into disease development and potential treatment strategies, the present study investigates the local effect of oral treatment with polysaccharides obtained from [...] Read more.
Background/Objectives: Ulcerative colitis (UC) is characterized by the interplay between immune responses and dysbiosis in disease development. Aiming to provide additional insights into disease development and potential treatment strategies, the present study investigates the local effect of oral treatment with polysaccharides obtained from Auricularia auricula’s submerged culture in an experimental model of DSS-induced colitis and its impact on lesion resolution. Methods: The structure and monosaccharide composition of Auricularia polysaccharides were characterized through Nuclear Magnetic Resonance (NMR). To evaluate the effect of this polysaccharide on the murine model, wild-type and Dectin-1 knockout mice were treated or not with the exopolysaccharide (EPS) while under DSS consumption. During the experimental period, feces samples were collected to evaluate microbial shifts during disease development, and, finally, the colonic tissue was analyzed to assess the inflammatory process and cytokine production. Results: The EPS composition showed a polymeric mixture of glucans and fucogalactomannans. The treatment of the wild-type DSS-induced colitis group improved the inflammatory response by increasing gut–homeostatic cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α). The Dectin-1 KO mice group did not show the same enhancement after EPS treatment. The microbiome analysis revealed a difference in the genotype, and the treatment modified the DSS microbiome modulation, with nine and four ASVs in WT and Dectin-1 KO mice, respectively. Conclusions: The EPS treatment demonstrated therapeutic potential in treating inflammatory intestinal diseases by modulating cytokine secretion and microbiota composition, which is dependent on the Dectin-1 receptor’s carbohydrate recognition. Full article
(This article belongs to the Special Issue Natural Products Derived from Fungi and Their Biological Activities)
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17 pages, 4451 KiB  
Article
Phenotype Differences Between ATP13A2 Heterozygous and Knockout Mice Across Aging
by Kristina Croucher, Josephine K. Lepp, Jennifer Bechtold, Edward J. Hamad, Sophia Scott, Christian Bittner, Sara Rogers, Christian Ong, Shannon Boehme, Zhuo Wang, Li Lin, Xinwen Wang and Sheila M. Fleming
Int. J. Mol. Sci. 2025, 26(15), 7030; https://doi.org/10.3390/ijms26157030 - 22 Jul 2025
Viewed by 276
Abstract
ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (αSyn) pathology. However, few [...] Read more.
ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (αSyn) pathology. However, few studies have included ATP13A2 heterozygous mice as a comparison. In the present study, the effect of reduced or complete loss of ATP13A2 function on behavior, αSyn, gliosis, dopamine, and polyamines were determined in mice. Male and female ATP13A2 wildtype (WT), heterozygous (Het), and knockout (KO) mice were assessed behaviorally at 3, 12, and 18 months of age. In the brain, αSyn, phosphorylated αSyn, and GFAP were measured in the prefrontal cortex, striatum, ventral midbrain, and cerebellum. Polyamine and neurotransmitter analyses were performed in the same brain regions. Similar to previous studies, KO mice developed motor impairments and widespread gliosis in the brain. In addition, polyamine content was altered in Het and KO mice. In contrast, Het mice showed impairments in cognitive function and an age-related increase in αSyn in the brain. These results indicate potentially different pathological mechanisms when ATP13A2 is reduced compared to when it is knocked out and may have important implications for disease modification in synucleinopathies including PD. Full article
(This article belongs to the Special Issue Optimizing Mechanistic Rationale for Parkinson’s Disease Treatment)
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17 pages, 7940 KiB  
Article
Carbohydrate-Responsive Element-Binding Protein-Associated Metabolic Changes in Chemically Induced Hepatocarcinogenesis Mouse Model
by Maren Engeler, Majedul Karim, Marcel Gischke, Franziska Willer, Helen Leiner, Jessica Prey, Paul Friedrich Ziegler, Frank Dombrowski and Silvia Ribback
Int. J. Mol. Sci. 2025, 26(14), 6932; https://doi.org/10.3390/ijms26146932 - 18 Jul 2025
Viewed by 366
Abstract
The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the [...] Read more.
The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; p < 0.05). L-KO hepatocytes exhibited lower proliferation, while KO tumors showed the downregulation of AKT/mTOR signaling, glycolysis, and lipogenesis compared to WT tumors. Our results showed that the liver-specific loss of ChREBPα, while ChREBPβ remained active, significantly reduced the tumor progression, suggesting an oncogenic role for ChREBPα. In contrast, the systemic knockout of both ChREBPα and ChREBPβ reduced the tumor initiation but did slightly prevent tumor progression, indicating that ChREBPβ may exert tumor-suppressive functions. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment of Primary Liver Cancer)
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14 pages, 1708 KiB  
Article
Investigation of the Mouse Infection Model for Echovirus 18
by Lei Xiang, Linlin Zhai, Guanyong Ou, Wei Zhao, Yang Yang and Chenguang Shen
Viruses 2025, 17(7), 1011; https://doi.org/10.3390/v17071011 - 18 Jul 2025
Viewed by 335
Abstract
Echovirus 18, a member of the B group of enteroviruses, is a significant etiological agent of aseptic meningitis and viral encephalitis in children. In this study, we investigated the pathogenicity of E18 by establishing a mouse infection model after comparing various mouse strains [...] Read more.
Echovirus 18, a member of the B group of enteroviruses, is a significant etiological agent of aseptic meningitis and viral encephalitis in children. In this study, we investigated the pathogenicity of E18 by establishing a mouse infection model after comparing various mouse strains and injection methods. Two-day-old IFNAR1 knockout mice infected with clinical isolates of E18 exhibited symptoms such as lethargy, hind limb paralysis, and even mortality. Similarly, some two-day-old C57BL/6J mice displayed comparable symptoms; however, the incidence was lower than that observed in IFNAR1 knockout mice. No similar symptoms were noted in any Balb/c mice. Significant pathological changes were observed in skeletal muscle, brain tissue, and other organs of symptomatic mice; among these tissues, skeletal muscle demonstrated the highest viral load. The established infection model using two-day-old IFNAR1 knockout mice provides valuable insights into further investigations regarding its pathological injury mechanisms as well as the protective effects conferred by antibodies. Full article
(This article belongs to the Section Animal Viruses)
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21 pages, 3512 KiB  
Article
IP3R2-Mediated Astrocytic Ca2+ Transients Are Critical to Sustain Modulatory Effects of Locomotion on Neurons in Mouse Somatosensory Cortex
by Mario Fernández de la Puebla, Xiaoyi Zhang, Erlend A. Nagelhus, Magnar Bjørås and Wannan Tang
Cells 2025, 14(14), 1103; https://doi.org/10.3390/cells14141103 - 18 Jul 2025
Viewed by 932
Abstract
Accumulating studies have shown that astrocytes are essential for regulating neurons at both synaptic and circuit levels. The main mechanism of brain astrocytic intracellular Ca2+ activity is through the release of Ca2+ via the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) from [...] Read more.
Accumulating studies have shown that astrocytes are essential for regulating neurons at both synaptic and circuit levels. The main mechanism of brain astrocytic intracellular Ca2+ activity is through the release of Ca2+ via the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) from the endoplasmic reticulum (ER). Studies using IP3R2 knockout mouse models (Itpr2−/−) have shown that eliminating IP3R2 leads to a significant reduction in astrocytic Ca2+ activity However, there is ongoing controversy regarding the effect of this IP3R2-dependent reduction in astrocytic Ca2+ transients on neuronal activity. In our study, we employed dual-color two-photon Ca2+ imaging to study astrocytes and neurons simultaneously in vibrissa somatosensory cortex (vS1) in awake-behaving wild-type and Itpr2−/− mice. We systematically characterized and compared both recorded astrocytic and neuronal Ca2+ activities in wild-type and Itpr2−/− mice during various animal behaviors, particularly during the transition period from stillness to locomotion. We report that vS1 astrocytic Ca2+ elevation in both wild-type and Itpr2−/− mice was significantly modulated by free whisking and locomotion. However, vS1 neurons were only significantly modulated by locomotion in wild-type mice, but not in Itpr2−/− mice. Our study suggests a non-synaptic modulatory mechanism on functions of astrocytic IP3R2-dependent Ca2+ transients to local neurons. Full article
(This article belongs to the Section Cells of the Nervous System)
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14 pages, 4042 KiB  
Article
Conditional Deletion of Translin/Trax in Dopaminergic Neurons Reveals No Impact on Psychostimulant Behaviors or Adiposity
by Yunlong Liu, Renkun Wu, Gaiyuan Geng, Helian Yang, Chunmiao Wang, Mengtian Ren and Xiuping Fu
Biomolecules 2025, 15(7), 1040; https://doi.org/10.3390/biom15071040 - 17 Jul 2025
Viewed by 321
Abstract
Despite the abundant expression of the microRNA-degrading Translin (TN)/Trax (TX) complex in midbrain dopaminergic (DA) neurons and its implication in neuropsychiatric disorders, its cell-autonomous roles in metabolic and behavioral responses remain unclear. To address this, we generated DA neuron-specific conditional knockout (cKO) mice [...] Read more.
Despite the abundant expression of the microRNA-degrading Translin (TN)/Trax (TX) complex in midbrain dopaminergic (DA) neurons and its implication in neuropsychiatric disorders, its cell-autonomous roles in metabolic and behavioral responses remain unclear. To address this, we generated DA neuron-specific conditional knockout (cKO) mice for Tsn (TN) or Tsnax (TX) using DAT-Cre. Immunostaining confirmed efficient TX loss in Tsnax cKO DA neurons without affecting TN, while Tsn deletion abolished TX expression, revealing asymmetric protein dependency. Body composition analysis showed no alterations in adiposity in either cKO model. Locomotor responses to acute or repeated administration of cocaine (20 mg/kg) or amphetamine (2.5 mg/kg) were unchanged in Tsn or Tsnax cKO mice. Furthermore, amphetamine-induced conditioned place preference (1 mg/kg) was unaffected. These results demonstrate that the TN/TX complex within DA neurons is dispensable for regulating adiposity, psychostimulant-induced locomotion (both acute and sensitized), or amphetamine reward-related behavior, suggesting its critical functions may lie outside these specific domains. Full article
(This article belongs to the Section Molecular Genetics)
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18 pages, 2314 KiB  
Article
Deletion of Clock Gene Period 2 (Per2) in Astrocytes Shortens Clock Period but Does Not Affect Light-Mediated Phase Shifts in Mice
by Soha A. Hassan, Katrin S. Wendrich and Urs Albrecht
Clocks & Sleep 2025, 7(3), 37; https://doi.org/10.3390/clockssleep7030037 - 17 Jul 2025
Viewed by 304
Abstract
The circadian clock is a self-sustaining oscillator with a period of approximately 24 h, enabling organisms to anticipate daily recurring events, such as sunrise and sunset. Since the circadian period is not exactly 24 h and the environmental day length varies throughout the [...] Read more.
The circadian clock is a self-sustaining oscillator with a period of approximately 24 h, enabling organisms to anticipate daily recurring events, such as sunrise and sunset. Since the circadian period is not exactly 24 h and the environmental day length varies throughout the year, the clock must be periodically reset to align an organism’s physiology with the natural light/dark cycle. This synchronization, known as entrainment, is primarily regulated by nocturnal light, which can be replicated in laboratory settings using a 15 min light pulse (LP) and by assessing locomotor activity. An LP during the early part of the dark phase delays the onset of locomotor activity, resulting in a phase delay, whereas an LP in the late dark phase advances activity onset, causing a phase advance. The clock gene Period 2 (Per2) plays a key role in this process. To investigate its contributions, we examined the effects of Per2 deletion in neurons versus astrocytes using glia-specific GPer2 (Per2/GfapCre) knockout (KO) and neuronal-specific NPer2KO (Per2/NesCre) mice. All groups were subjected to Aschoff type II protocol, where an LP was applied at ZT14 or ZT22 and the animals were released into constant darkness. As control, no LP was applied. Phase shift, period, amplitude, total activity count, and rhythm instability were assessed. Our findings revealed that mice lacking Per2 in neurons (NPer2) exhibited smaller phase delays and larger phase advances compared to control animals. In contrast, mice with Per2 deletion specifically in glial cells including astrocytes (GPer2) displayed normal clock resetting. Interestingly, the absence of Per2 in either of the cell types resulted in a shorter circadian period compared to control animals. These results suggest that astrocytic Per2 is important for maintaining the circadian period but is not required for phase adaptation to light stimuli. Full article
(This article belongs to the Section Animal Basic Research)
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