ACS Pharmacology and Translational Science最新文献

{"title":"A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.","authors":"Jianing Wu, Xin Zhou, Xin Xu, Jing Xie","doi":"10.1021/acsptsci.4c00706","DOIUrl":"10.1021/acsptsci.4c00706","url":null,"abstract":"<p><p>Cartilage-related osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are typical degenerative diseases that cause a heavy socioeconomic burden for lack of disease-modifying treatments. Due to the avascular and hypoxic microenvironment of cartilage, chondrocytes primarily achieve energy supply through cytoplasmic anaerobic glycolysis; thus, mitochondria, energy producers through aerobic phosphorylation, have received little attention until recently. Mitochondria carry out a crucial role in the regulation of cellular bioenergetics, metabolism, and signaling while also serving as a central platform where diverse biological processes converge, thereby contributing significantly to cellular homeostasis and cartilage physiology. Mitochondrial functionality is intertwined with mitochondrial morphology, which is determined by a dynamic balance between mitochondrial fusion and fission. Disruption of the equilibrium leads to mitochondrial dysfunction and the onset of diseases. Although the potential role of mitochondria in the pathogenesis of cartilage-related diseases has been proposed and sporadic studies have begun to focus on the underlying molecular mechanisms of mitochondrial fusion/fission, the importance of the physiological and pathological functions of mitochondrial fusion-fission dynamics in cartilage biological processes is little discussed. This review aims to bridge the gap by characterizing its interplay with mitochondrial quality control, energy metabolism, redox homeostasis regulation, cellular senescence, and apoptosis, which are all closely associated with cartilage physiology and pathology. Moreover, its role in cartilage-related diseases, especially OA and IVDD, is further discussed. This review emphasizes the emerging field of mitochondrial fusion-fission dynamics in skeletal systems and possibly provides new cues for disease control and clinical intervention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1473-1497"},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases","authors":"Jianing Wu,&nbsp;Xin Zhou,&nbsp;Xin Xu and Jing Xie*,&nbsp;","doi":"10.1021/acsptsci.4c0070610.1021/acsptsci.4c00706","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00706https://doi.org/10.1021/acsptsci.4c00706","url":null,"abstract":"<p >Cartilage-related osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are typical degenerative diseases that cause a heavy socioeconomic burden for lack of disease-modifying treatments. Due to the avascular and hypoxic microenvironment of cartilage, chondrocytes primarily achieve energy supply through cytoplasmic anaerobic glycolysis; thus, mitochondria, energy producers through aerobic phosphorylation, have received little attention until recently. Mitochondria carry out a crucial role in the regulation of cellular bioenergetics, metabolism, and signaling while also serving as a central platform where diverse biological processes converge, thereby contributing significantly to cellular homeostasis and cartilage physiology. Mitochondrial functionality is intertwined with mitochondrial morphology, which is determined by a dynamic balance between mitochondrial fusion and fission. Disruption of the equilibrium leads to mitochondrial dysfunction and the onset of diseases. Although the potential role of mitochondria in the pathogenesis of cartilage-related diseases has been proposed and sporadic studies have begun to focus on the underlying molecular mechanisms of mitochondrial fusion/fission, the importance of the physiological and pathological functions of mitochondrial fusion-fission dynamics in cartilage biological processes is little discussed. This review aims to bridge the gap by characterizing its interplay with mitochondrial quality control, energy metabolism, redox homeostasis regulation, cellular senescence, and apoptosis, which are all closely associated with cartilage physiology and pathology. Moreover, its role in cartilage-related diseases, especially OA and IVDD, is further discussed. This review emphasizes the emerging field of mitochondrial fusion-fission dynamics in skeletal systems and possibly provides new cues for disease control and clinical intervention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1473–1497 1473–1497"},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spotlight on Glycan Pairing: The Generation and Impact of Monoclonal Antibody Asymmetrical Fc N‑Glycan Pairs on Fc Receptor Interaction.","authors":"Maximilian Meudt, Julia Baumeister, Erik M F Machal, Matthias J Knape, Boris Mizaikoff, Sybille Ebert, Frank Rosenau, Michaela Blech, Fabian Higel","doi":"10.1021/acsptsci.5c00185","DOIUrl":"10.1021/acsptsci.5c00185","url":null,"abstract":"<p><p>Monoclonal antibodies' Fc N-glycans play a crucial role in their therapeutic efficacy, as they influence effector functions through Fc receptor binding. However, the impact of asymmetrical Fc glyco-pairs is often overlooked in assessing Fc receptor binding and effector functions. This study addresses this gap by generating pure asymmetrical Fc glyco-pairs and evaluating their Fc receptor binding properties, thereby providing a comprehensive understanding of the impact of Fc N-glycans. Utilizing redox pairing and affinity chromatography, homogeneously asymmetrical Fc glyco-pairs were generated, and their interaction properties toward Fcγ receptors IIIa, IIa, IIb, and I were determined by surface plasmon resonance. The results underscore the importance of considering the apparent glycan distribution of Fc N-glycans as glycan pairing was found to individually influence Fc receptor binding. Notably, single afucosylation significantly increased the affinity for FcγRIIIa, while the effect of galactosylation was detectable but less pronounced. Galactosylation, however, played a crucial role in FcγRIIa binding, with asymmetrical galactosylation being sufficient for the whole effect. In contrast, for FcγRIIb, afucosylation was more important, while galactosylation played a minor role. Furthermore, glycosylation-dependent Fc-FcγRI complex stability differences could be resolved, challenging the commonly held belief that this interaction is glycosylation independent.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1756-1767"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spotlight on Glycan Pairing: The Generation and Impact of Monoclonal Antibody Asymmetrical Fc N-Glycan Pairs on Fc Receptor Interaction","authors":"Maximilian Meudt,&nbsp;Julia Baumeister,&nbsp;Erik M.F. Machal,&nbsp;Matthias J. Knape,&nbsp;Boris Mizaikoff,&nbsp;Sybille Ebert,&nbsp;Frank Rosenau,&nbsp;Michaela Blech and Fabian Higel*,&nbsp;","doi":"10.1021/acsptsci.5c0018510.1021/acsptsci.5c00185","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00185https://doi.org/10.1021/acsptsci.5c00185","url":null,"abstract":"<p >Monoclonal antibodies’ Fc N-glycans play a crucial role in their therapeutic efficacy, as they influence effector functions through Fc receptor binding. However, the impact of asymmetrical Fc glyco-pairs is often overlooked in assessing Fc receptor binding and effector functions. This study addresses this gap by generating pure asymmetrical Fc glyco-pairs and evaluating their Fc receptor binding properties, thereby providing a comprehensive understanding of the impact of Fc N-glycans. Utilizing redox pairing and affinity chromatography, homogeneously asymmetrical Fc glyco-pairs were generated, and their interaction properties toward Fcγ receptors IIIa, IIa, IIb, and I were determined by surface plasmon resonance. The results underscore the importance of considering the apparent glycan distribution of Fc N-glycans as glycan pairing was found to individually influence Fc receptor binding. Notably, single afucosylation significantly increased the affinity for FcγRIIIa, while the effect of galactosylation was detectable but less pronounced. Galactosylation, however, played a crucial role in FcγRIIa binding, with asymmetrical galactosylation being sufficient for the whole effect. In contrast, for FcγRIIb, afucosylation was more important, while galactosylation played a minor role. Furthermore, glycosylation-dependent Fc-FcγRI complex stability differences could be resolved, challenging the commonly held belief that this interaction is glycosylation independent.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1756–1767 1756–1767"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formoterol, the Most Effective Bronchodilator, Has No Anti-Inflammatory nor Metabolic Modulatory Effects in Severe Asthma Induced by Aspergillus fumigatus","authors":"Phyllis X. L. Gan,&nbsp;Kira M. Linke,&nbsp;Wupeng Liao and W. S. Fred Wong*,&nbsp;","doi":"10.1021/acsptsci.4c0067210.1021/acsptsci.4c00672","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00672https://doi.org/10.1021/acsptsci.4c00672","url":null,"abstract":"<p >In an increasing number of asthma studies, modulation of pulmonary metabolic reprogramming using therapeutic agents targeting metabolic enzymes promoted bronchodilatory, anti-inflammatory, and antiremodeling effects. Although formoterol is the bronchodilator of choice for asthma management, its anti-inflammatory and metabolic modulatory effects in severe asthma have not been investigated. The present study aimed to explore formoterol’s anti-inflammatory and metabolic modulatory potential in <i>Aspergillus fumigatus</i> (Af)-induced severe asthma model to establish additional benefits in the difficult-to-treat severe asthma subtype. Formoterol was administered via nebulization in an Af-induced severe asthma mouse model. Airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and metabolic pathways on glycolysis and oxidative phosphorylation in the lungs were assessed. An in-depth analysis of formoterol’s effect on airway smooth muscle metabolism was also performed. Inhaled formoterol significantly inhibited methacholine-induced AHR in Af-induced severe asthma in a dose-dependent manner (<i>p</i> &lt; 0.001). However, it did not reduce airway immune cell counts, inflammation score of hematoxylin and eosin-stained lung sections, airway mucus hypersecretion, lung levels of proinflammatory cytokines and chemokines, and α-smooth muscle actin-positive airway smooth muscle wall thickness. In addition, formoterol did not show any effects on lung single-cell glycolytic and oxidative phosphorylation activities or on the levels of metabolic enzymes in lung tissues and α-smooth muscle actin-positive airway smooth muscle in Af-induced severe asthma. Inhaled formoterol is an entirely potent and effective bronchodilator against Af-induced severe asthma, with no effect on airway inflammation, airway remodeling, and pulmonary metabolism.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1556–1566 1556–1566"},"PeriodicalIF":4.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formoterol, the Most Effective Bronchodilator, Has No Anti-Inflammatory nor Metabolic Modulatory Effects in Severe Asthma Induced by Aspergillus fumigatus.","authors":"Phyllis X L Gan, Kira M Linke, Wupeng Liao, W S Fred Wong","doi":"10.1021/acsptsci.4c00672","DOIUrl":"10.1021/acsptsci.4c00672","url":null,"abstract":"<p><p>In an increasing number of asthma studies, modulation of pulmonary metabolic reprogramming using therapeutic agents targeting metabolic enzymes promoted bronchodilatory, anti-inflammatory, and antiremodeling effects. Although formoterol is the bronchodilator of choice for asthma management, its anti-inflammatory and metabolic modulatory effects in severe asthma have not been investigated. The present study aimed to explore formoterol's anti-inflammatory and metabolic modulatory potential in Aspergillus fumigatus (Af)-induced severe asthma model to establish additional benefits in the difficult-to-treat severe asthma subtype. Formoterol was administered via nebulization in an Af-induced severe asthma mouse model. Airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and metabolic pathways on glycolysis and oxidative phosphorylation in the lungs were assessed. An in-depth analysis of formoterol's effect on airway smooth muscle metabolism was also performed. Inhaled formoterol significantly inhibited methacholine-induced AHR in Af-induced severe asthma in a dose-dependent manner (<i>p</i> < 0.001). However, it did not reduce airway immune cell counts, inflammation score of hematoxylin and eosin-stained lung sections, airway mucus hypersecretion, lung levels of proinflammatory cytokines and chemokines, and α-smooth muscle actin-positive airway smooth muscle wall thickness. In addition, formoterol did not show any effects on lung single-cell glycolytic and oxidative phosphorylation activities or on the levels of metabolic enzymes in lung tissues and α-smooth muscle actin-positive airway smooth muscle in Af-induced severe asthma. Inhaled formoterol is an entirely potent and effective bronchodilator against Af-induced severe asthma, with no effect on airway inflammation, airway remodeling, and pulmonary metabolism.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1556-1566"},"PeriodicalIF":4.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis.","authors":"Radoslaw Wesolowski, Anja Schütz, Michael Lisurek, Marc Nazaré, Udo Heinemann, Dirk Pleimes, Michael Bader, Edgar Specker","doi":"10.1021/acsptsci.5c00043","DOIUrl":"10.1021/acsptsci.5c00043","url":null,"abstract":"<p><p>Serotonin (5-HT), a crucial neurotransmitter and peripheral mediator, regulates various physiological processes and is synthesized by tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for its production. 5-HT overproduction is implicated in multiple diseases, making TPH1 a promising therapeutic target. However, selectivity remains a challenge due to the structural similarity of TPH1 with other members of the aromatic amino acid hydroxylase (AAAH) family, including TPH2, phenylalanine hydroxylase (PAH), and tyrosine hydroxylase (TH). This study aimed to evaluate the selectivity and inhibitory potential of TPT-004, a novel TPH inhibitor, compared with Telotristat (LP778902) and its prodrug (LX1606). We developed high-throughput fluorescence assays to evaluate the inhibitory effects of the test compounds on TPH1, TPH2, PAH, and TH enzymes. TPT-004 demonstrated high selectivity for TPHs compared to LP778902 and LX1606. Structural analysis based on a detailed sequence alignment within the AAAH enzyme family, combined with cocrystal structures of TPH1 and TPH2 bound to different generations of inhibitors, enhances our understanding of the molecular basis of inhibitor binding and provides a framework for explaining TPT-004's selectivity for TPHs. Selectivity profiling against 97 targets confirmed that TPT-004 showed minimal off-target interactions, underscoring its specificity. A dose-range finding (DRF) study in rats assessed the <i>in vivo</i> safety profile of TPT-004, showing no adverse effects on survival and body weight at doses up to 400 mg/kg/day. Hematology parameters remained normal, with only minor liver changes observed. These results highlight TPT-004's potential as a selective and safe TPH inhibitor, offering a promising therapeutic option for serotonin-related disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1678-1693"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selectivity and Safety Characterization of a Xanthine–Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis","authors":"Radoslaw Wesolowski,&nbsp;Anja Schütz,&nbsp;Michael Lisurek,&nbsp;Marc Nazaré,&nbsp;Udo Heinemann,&nbsp;Dirk Pleimes,&nbsp;Michael Bader* and Edgar Specker*,&nbsp;","doi":"10.1021/acsptsci.5c0004310.1021/acsptsci.5c00043","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00043https://doi.org/10.1021/acsptsci.5c00043","url":null,"abstract":"<p >Serotonin (5-HT), a crucial neurotransmitter and peripheral mediator, regulates various physiological processes and is synthesized by tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for its production. 5-HT overproduction is implicated in multiple diseases, making TPH1 a promising therapeutic target. However, selectivity remains a challenge due to the structural similarity of TPH1 with other members of the aromatic amino acid hydroxylase (AAAH) family, including TPH2, phenylalanine hydroxylase (PAH), and tyrosine hydroxylase (TH). This study aimed to evaluate the selectivity and inhibitory potential of TPT-004, a novel TPH inhibitor, compared with Telotristat (LP778902) and its prodrug (LX1606). We developed high-throughput fluorescence assays to evaluate the inhibitory effects of the test compounds on TPH1, TPH2, PAH, and TH enzymes. TPT-004 demonstrated high selectivity for TPHs compared to LP778902 and LX1606. Structural analysis based on a detailed sequence alignment within the AAAH enzyme family, combined with cocrystal structures of TPH1 and TPH2 bound to different generations of inhibitors, enhances our understanding of the molecular basis of inhibitor binding and provides a framework for explaining TPT-004’s selectivity for TPHs. Selectivity profiling against 97 targets confirmed that TPT-004 showed minimal off-target interactions, underscoring its specificity. A dose–range finding (DRF) study in rats assessed the <i>in vivo</i> safety profile of TPT-004, showing no adverse effects on survival and body weight at doses up to 400 mg/kg/day. Hematology parameters remained normal, with only minor liver changes observed. These results highlight TPT-004’s potential as a selective and safe TPH inhibitor, offering a promising therapeutic option for serotonin-related disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1678–1693 1678–1693"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydrozingerone Improves Mood and Memory in Diabetic Mice via Modulating Core Neuroimmune Genes and Their Associated Proteins.","authors":"Anuradha Kesharwani, Bottu Kavya Sree, Nivedita Singh, Rahul Laxman Gajbhiye, Krishna Murti, Ramalingam Peraman, Krishna Pandey, Charles L Limoli, Ravichandiran Velayutham, Vipan Kumar Parihar","doi":"10.1021/acsptsci.5c00046","DOIUrl":"10.1021/acsptsci.5c00046","url":null,"abstract":"<p><p>Patients with poorly managed diabetes are at a greater risk of developing dementia and experiencing accelerated brain aging due to elevated blood glucose levels. Furthermore, patients with diabetes frequently encounter challenges with memory, recall, and concentration while carrying out their daily activities. The goal of this study was to investigate whether dehydrozingerone, a structural half-analog of curcumin, might improve mood and cognition in diabetics using a well-established mouse model of type 2 diabetes (T2DM) induced by a high-fat diet (HFD) and low streptozotocin (STZ) doses. Dehydrozingerone (DH) at 50 mg/kg orally for 2 weeks improved hippocampal and medial prefrontal cortex (mPFC)-dependent mood and memory in diabetic mice. An integrated transcriptome and proteome analysis revealed that 26 genes encoding mitochondrial energetics (Cox6), insulin resistance (Etnppl), lipid metabolism (Apod, Plin4), accelerated brain aging (Gm11639), and inflammation (Ighg2c) are differentially expressed in the diabetic mouse brain at both the mRNA and protein levels. Further, bioinformatic analysis revealed that these differentially expressed genes (DEGs) and proteins (DEPs) play a critical role in a variety of biological functions, including ion transport, calcium signaling, cellular senescence, mitochondrial energy, autophagy, neuronal plasticity, and cognition. Additionally, anomalies in the glutamine-glutamate/GABA cycle could exacerbate diabetes-related cognitive deficits. Treatment with DH had a variety of advantages, including decreased neuroinflammation and neuronal cell death as well as the promotion of critical genes and proteins necessary to promote cognitive performance. As a consequence, DH may be a potential treatment option for diabetics with persistent neuroinflammation and cognitive impairments.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1694-1710"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydrozingerone Improves Mood and Memory in Diabetic Mice via Modulating Core Neuroimmune Genes and Their Associated Proteins","authors":"Anuradha Kesharwani,&nbsp;Bottu Kavya Sree,&nbsp;Nivedita Singh,&nbsp;Rahul Laxman Gajbhiye,&nbsp;Krishna Murti,&nbsp;Ramalingam Peraman,&nbsp;Krishna Pandey,&nbsp;Charles L. Limoli,&nbsp;Ravichandiran Velayutham and Vipan Kumar Parihar*,&nbsp;","doi":"10.1021/acsptsci.5c0004610.1021/acsptsci.5c00046","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00046https://doi.org/10.1021/acsptsci.5c00046","url":null,"abstract":"<p >Patients with poorly managed diabetes are at a greater risk of developing dementia and experiencing accelerated brain aging due to elevated blood glucose levels. Furthermore, patients with diabetes frequently encounter challenges with memory, recall, and concentration while carrying out their daily activities. The goal of this study was to investigate whether dehydrozingerone, a structural half-analog of curcumin, might improve mood and cognition in diabetics using a well-established mouse model of type 2 diabetes (T2DM) induced by a high-fat diet (HFD) and low streptozotocin (STZ) doses. Dehydrozingerone (DH) at 50 mg/kg orally for 2 weeks improved hippocampal and medial prefrontal cortex (mPFC)-dependent mood and memory in diabetic mice. An integrated transcriptome and proteome analysis revealed that 26 genes encoding mitochondrial energetics (Cox6), insulin resistance (Etnppl), lipid metabolism (Apod, Plin4), accelerated brain aging (Gm11639), and inflammation (Ighg2c) are differentially expressed in the diabetic mouse brain at both the mRNA and protein levels. Further, bioinformatic analysis revealed that these differentially expressed genes (DEGs) and proteins (DEPs) play a critical role in a variety of biological functions, including ion transport, calcium signaling, cellular senescence, mitochondrial energy, autophagy, neuronal plasticity, and cognition. Additionally, anomalies in the glutamine-glutamate/GABA cycle could exacerbate diabetes-related cognitive deficits. Treatment with DH had a variety of advantages, including decreased neuroinflammation and neuronal cell death as well as the promotion of critical genes and proteins necessary to promote cognitive performance. As a consequence, DH may be a potential treatment option for diabetics with persistent neuroinflammation and cognitive impairments.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1694–1710 1694–1710"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}