Pub Date : 2025-12-08DOI: 10.1016/j.bbrep.2025.102402
Mahsa Mohammadian , Shima Asfia , Ralf Seemann
Lipid droplets (LDs) maintain cellular lipid homeostasis through dynamic interactions with other organelles. Understanding how these contact sites form is crucial for uncovering the mechanisms of lipid exchange and signaling. In this study, we used an in vitro model to investigate how lipid composition and the LD-associated protein perilipin 5 (PLIN5) influence contact formation between an LD monolayer and a bilayer membrane. Artificial LDs consisting of triolein and coated with either a DOPE or DOPC monolayer containing PLIN5 or not were incubated with large unilamellar vesicles (LUVs) that mimic the bilayer membrane of the organelle. Using double fluorescence labeling of the LUV bilayer and the core, we can distinguish between fusion of the LUV bilayer with the LDs and stable attachment of LUVs to the LD’s surface. Our results show that the probability of fusion between LDs and LUVs is greatly increased for DOPE-coated LDs, while PLIN5 promotes the stable attachment of LUVs to the LD’s surface and prevents fusion. These observations illustrate how certain lipid and protein components can modulate contact formation between LDs and membranes in a controlled in vitro system, and provide a basis for future studies on the molecular mechanisms of organelle communication.
{"title":"Influence of PLIN5 and lipid composition on lipid droplet contact sites with other organelles","authors":"Mahsa Mohammadian , Shima Asfia , Ralf Seemann","doi":"10.1016/j.bbrep.2025.102402","DOIUrl":"10.1016/j.bbrep.2025.102402","url":null,"abstract":"<div><div>Lipid droplets (LDs) maintain cellular lipid homeostasis through dynamic interactions with other organelles. Understanding how these contact sites form is crucial for uncovering the mechanisms of lipid exchange and signaling. In this study, we used an in vitro model to investigate how lipid composition and the LD-associated protein perilipin 5 (PLIN5) influence contact formation between an LD monolayer and a bilayer membrane. Artificial LDs consisting of triolein and coated with either a DOPE or DOPC monolayer containing PLIN5 or not were incubated with large unilamellar vesicles (LUVs) that mimic the bilayer membrane of the organelle. Using double fluorescence labeling of the LUV bilayer and the core, we can distinguish between fusion of the LUV bilayer with the LDs and stable attachment of LUVs to the LD’s surface. Our results show that the probability of fusion between LDs and LUVs is greatly increased for DOPE-coated LDs, while PLIN5 promotes the stable attachment of LUVs to the LD’s surface and prevents fusion. These observations illustrate how certain lipid and protein components can modulate contact formation between LDs and membranes in a controlled in vitro system, and provide a basis for future studies on the molecular mechanisms of organelle communication.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102402"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748904","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}
Pub Date : 2025-12-08DOI: 10.1016/j.bbrep.2025.102393
Jennifer L. Goeckeler-Fried , Xuemei Zeng , Jeong S. Hong , Disha Joshi , Zhengrong Yang , Fan Jiang , John C. Kappes , Eric J. Sorscher , Jeffrey L. Brodsky
Background
The most common loss-of-function mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) is F508del. The misfolded F508del-CFTR protein is targeted for endoplasmic reticulum associated degradation (ERAD), a pathway in which non-native proteins are ubiquitinated and degraded by the proteasome. Because the identification of ubiquitinated residues would highlight how F508del-CFTR is selected for premature degradation, ubiquitination profiles in CFTR- and F508del-CFTR-expressing cells have been examined. Several ubiquitin ligases modify CFTR, however, the relative CFTR-directed activity of each ligase is unknown.
Methods
We reconstituted CFTR ubiquitination using purified CFTR and components of the ubiquitination machinery. Since prior work implicated the Carboxyl terminus of Hsp70-Interacting Protein (CHIP) ubiquitin ligase in both ERAD and plasma membrane turnover, CFTR ubiquitination was examined in the presence of CHIP and a companion ubiquitin conjugating enzyme.
Results
Mass spectrometry identified 16 modified lysines, half of which were previously identified after CFTR was isolated from cells. One lysine, K420, which resides in the regulatory insertion, had been implicated in cyclic nucleotide-dependent activation of CFTR. Here, we find that mutation of K420 increases cell surface levels of CFTR, an effect which in turn increases forskolin-dependent short circuit current.
Conclusions
We establish a system in which residue-specific modifications of CFTR by any component of the ubiquitin machinery can now be surveyed.
{"title":"Reconstitution of CFTR ubiquitination identifies lysine-420 as a regulator of cell surface residence and current","authors":"Jennifer L. Goeckeler-Fried , Xuemei Zeng , Jeong S. Hong , Disha Joshi , Zhengrong Yang , Fan Jiang , John C. Kappes , Eric J. Sorscher , Jeffrey L. Brodsky","doi":"10.1016/j.bbrep.2025.102393","DOIUrl":"10.1016/j.bbrep.2025.102393","url":null,"abstract":"<div><h3>Background</h3><div>The most common loss-of-function mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) is F508del. The misfolded F508del-CFTR protein is targeted for endoplasmic reticulum associated degradation (ERAD), a pathway in which non-native proteins are ubiquitinated and degraded by the proteasome. Because the identification of ubiquitinated residues would highlight how F508del-CFTR is selected for premature degradation, ubiquitination profiles in CFTR- and F508del-CFTR-expressing cells have been examined. Several ubiquitin ligases modify CFTR, however, the relative CFTR-directed activity of each ligase is unknown.</div></div><div><h3>Methods</h3><div>We reconstituted CFTR ubiquitination using purified CFTR and components of the ubiquitination machinery. Since prior work implicated the Carboxyl terminus of Hsp70-Interacting Protein (CHIP) ubiquitin ligase in both ERAD and plasma membrane turnover, CFTR ubiquitination was examined in the presence of CHIP and a companion ubiquitin conjugating enzyme.</div></div><div><h3>Results</h3><div>Mass spectrometry identified 16 modified lysines, half of which were previously identified after CFTR was isolated from cells. One lysine, K420, which resides in the regulatory insertion, had been implicated in cyclic nucleotide-dependent activation of CFTR. Here, we find that mutation of K420 increases cell surface levels of CFTR, an effect which in turn increases forskolin-dependent short circuit current.</div></div><div><h3>Conclusions</h3><div>We establish a system in which residue-specific modifications of CFTR by any component of the ubiquitin machinery can now be surveyed.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102393"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748902","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}
The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.
{"title":"In vitro 3D models of neuron-astrocyte interactions","authors":"Tong Su, Zhixiang Li, Yujie Yang, Yangfan Dai, Yueqi Li, Huan Zhao","doi":"10.1016/j.bbrep.2025.102400","DOIUrl":"10.1016/j.bbrep.2025.102400","url":null,"abstract":"<div><div>The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of <em>in vitro</em> 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of <em>in vitro</em> 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102400"},"PeriodicalIF":2.2,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691575","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}
Pub Date : 2025-12-05DOI: 10.1016/j.bbrep.2025.102404
Xianlong Gao , Matthias Majetschak
We reported previously that many chemokine receptors can form heteromeric complexes with α1B-adrenoceptor (α1B-AR) and arginine vasopressin receptor 1 A (AVPR1A). To gain initial insight into the relative proportions of receptors that may participate in the formation of such heteromers, we performed molecular Boolean (MolBoolean) analyses of receptor-receptor interactions in an expression system and in primary human aortic vascular smooth muscle cells (hVSMCs), utilizing chemokine (C–C motif) receptor 1, α1B-adrenoceptor and AVPR1A as representative receptor partners. In HEK293T cells co-expressing all three receptors, 60–70 % of each recombinant receptor were located proximal enough to permit heteromerization with the other two receptor partners. In primary human vascular smooth muscle cells, 30–50 % of each receptor were located proximal enough to permit heteromerization with the other two receptor partners. The MolBoolean analyses of receptor-receptor interactions provides new insights into the spatial distribution of GPCRs in the plasma membrane. Our finding that large proportions of the receptor partners may be able to participate in heteromerization supports the concept that such hetero-oligomeric complexes composed of CCR1, α1B-AR and AVPR1A could be of physiological relevance.
{"title":"Molecular Boolean analyses of chemokine (C–C motif) receptor 1, α1B-adrenoceptor and arginine vasopressin receptor 1A heteromers","authors":"Xianlong Gao , Matthias Majetschak","doi":"10.1016/j.bbrep.2025.102404","DOIUrl":"10.1016/j.bbrep.2025.102404","url":null,"abstract":"<div><div>We reported previously that many chemokine receptors can form heteromeric complexes with α<sub>1B</sub>-adrenoceptor (α<sub>1B</sub>-AR) and arginine vasopressin receptor 1 A (AVPR1A). To gain initial insight into the relative proportions of receptors that may participate in the formation of such heteromers, we performed molecular Boolean (MolBoolean) analyses of receptor-receptor interactions in an expression system and in primary human aortic vascular smooth muscle cells (hVSMCs), utilizing chemokine (C–C motif) receptor 1, α<sub>1B</sub>-adrenoceptor and AVPR1A as representative receptor partners. In HEK293T cells co-expressing all three receptors, 60–70 % of each recombinant receptor were located proximal enough to permit heteromerization with the other two receptor partners. In primary human vascular smooth muscle cells, 30–50 % of each receptor were located proximal enough to permit heteromerization with the other two receptor partners. The MolBoolean analyses of receptor-receptor interactions provides new insights into the spatial distribution of GPCRs in the plasma membrane. Our finding that large proportions of the receptor partners may be able to participate in heteromerization supports the concept that such hetero-oligomeric complexes composed of CCR1, α<sub>1B</sub>-AR and AVPR1A could be of physiological relevance.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102404"},"PeriodicalIF":2.2,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691631","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}
Pub Date : 2025-12-03DOI: 10.1016/j.bbrep.2025.102394
Jiafang Cui, Ling Shen, Bing Han
Circular RNAs (circRNAs) are a class of covalently closed, non-coding RNA molecules characterized by their exceptional stability and tissue-specific expression. Once considered splicing artifacts, they have emerged as pivotal regulators in cellular pathophysiology, particularly within the central nervous system (CNS), where they are highly abundant. This review synthesizes the current understanding of the biogenesis, molecular functions, and regulatory roles of circRNAs in major CNS disorders, underscores their significant potential as next-generation diagnostic and prognostic biomarkers, as well as promising therapeutic targets. Moving from bench to bedside, the review critically examines the burgeoning landscape of circRNA-based therapeutics. We assess the promise and limitations of current delivery platforms, including exosomes and lipid nanoparticles (LNPs), with special attention to the formidable challenge of traversing the blood-brain barrier (BBB). To conclude, we outline the prevailing challenges and future perspectives, emphasizing that the development of more sensitive detection methods and optimized delivery systems is paramount to translating the immense potential of circRNAs into tangible clinical solutions for CNS diseases.
{"title":"CircRNAs: Novel biomarkers and therapeutic targets for diseases of the central nervous system","authors":"Jiafang Cui, Ling Shen, Bing Han","doi":"10.1016/j.bbrep.2025.102394","DOIUrl":"10.1016/j.bbrep.2025.102394","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) are a class of covalently closed, non-coding RNA molecules characterized by their exceptional stability and tissue-specific expression. Once considered splicing artifacts, they have emerged as pivotal regulators in cellular pathophysiology, particularly within the central nervous system (CNS), where they are highly abundant. This review synthesizes the current understanding of the biogenesis, molecular functions, and regulatory roles of circRNAs in major CNS disorders, underscores their significant potential as next-generation diagnostic and prognostic biomarkers, as well as promising therapeutic targets. Moving from bench to bedside, the review critically examines the burgeoning landscape of circRNA-based therapeutics. We assess the promise and limitations of current delivery platforms, including exosomes and lipid nanoparticles (LNPs), with special attention to the formidable challenge of traversing the blood-brain barrier (BBB). To conclude, we outline the prevailing challenges and future perspectives, emphasizing that the development of more sensitive detection methods and optimized delivery systems is paramount to translating the immense potential of circRNAs into tangible clinical solutions for CNS diseases.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102394"},"PeriodicalIF":2.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691574","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}
Pub Date : 2025-12-03DOI: 10.1016/j.bbrep.2025.102395
Zhimin Song , Yaofeng Wang , Yun Zhang , Jingjing Chen , Tinghong Zhang , Shu Meng
Nuclear reprogramming to pluripotency holds great promise for regenerative medicine. However, innate immune overactivation may impair nuclear reprogramming efficiency but the underlying mechanism is not fully understood. Here we used mouse embryonic fibroblasts isolated from doxycycline-inducible OSKM transgenic mice as the nuclear reprogramming system and administered a high dosage of Polyinosinic polycytidylic acid (PIC) to stimulate TLR3 as the innate immune overactivation. PIC treatment reduced nuclear reprogramming efficiency. We identified that PIC treatment upregulated type I interferon transcription and secretion, IFNAR1 cell surface expression, and nuclear Stat1 level. Importantly, the introduction of Ifnar1 blocking antibody completely reversed this impaired nuclear reprogramming efficiency. Similarly, Ifn-β neutralizing antibody substantially ameliorated the impaired nuclear reprogramming efficiency caused by PIC treatment. Our data suggest that innate immune overactivation impairs nuclear reprogramming through the IFN-IFNAR1 axis. Blocking this signaling pathway can be used as a general strategy to enhance nuclear reprogramming efficiency.
{"title":"Innate immune overactivation hinders nuclear reprogramming through IFN-IFNAR1 axis","authors":"Zhimin Song , Yaofeng Wang , Yun Zhang , Jingjing Chen , Tinghong Zhang , Shu Meng","doi":"10.1016/j.bbrep.2025.102395","DOIUrl":"10.1016/j.bbrep.2025.102395","url":null,"abstract":"<div><div>Nuclear reprogramming to pluripotency holds great promise for regenerative medicine. However, innate immune overactivation may impair nuclear reprogramming efficiency but the underlying mechanism is not fully understood. Here we used mouse embryonic fibroblasts isolated from doxycycline-inducible OSKM transgenic mice as the nuclear reprogramming system and administered a high dosage of Polyinosinic polycytidylic acid (PIC) to stimulate TLR3 as the innate immune overactivation. PIC treatment reduced nuclear reprogramming efficiency. We identified that PIC treatment upregulated type I interferon transcription and secretion, IFNAR1 cell surface expression, and nuclear Stat1 level. Importantly, the introduction of Ifnar1 blocking antibody completely reversed this impaired nuclear reprogramming efficiency. Similarly, Ifn-β neutralizing antibody substantially ameliorated the impaired nuclear reprogramming efficiency caused by PIC treatment. Our data suggest that innate immune overactivation impairs nuclear reprogramming through the IFN-IFNAR1 axis. Blocking this signaling pathway can be used as a general strategy to enhance nuclear reprogramming efficiency.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102395"},"PeriodicalIF":2.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691632","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}
Pub Date : 2025-12-03DOI: 10.1016/j.bbrep.2025.102399
Sijin Kong , Lijin Wang , ZiXuan Ren
Background
Depression is a prevalent and debilitating mental disorder with limited treatment options. Curcumin, a natural compound with neuroprotective and anti-inflammatory properties, has shown potential antidepressant effects, though the underlying mechanisms remain incompletely understood.
Methods and results
In this study, we investigated the therapeutic effects and molecular mechanisms of curcumin in a chronic unpredictable mild stress (CUMS)-induced rat model of depression. Behavioral assessments, including the sucrose preference test, forced swim test, and open field test, demonstrated that curcumin (50 and 100 mg/kg, orally administered for 21 days) alleviated CUMS-induced anhedonia, behavioral despair, and anxiety-like behaviors, in a dose-dependent manner, with the 100 mg/kg dose exhibiting superior efficacy. Metabolomic profiling of the prefrontal cortex revealed significant metabolic disturbances in CUMS rats, particularly in starch and sucrose metabolism, which were progressively restored by curcumin. Functional enrichment analysis highlighted modulation of neuroinflammation, bioenergetic homeostasis, and signal transduction pathways as key biological processes associated with curcumin's effects. Integrated multi-omics and machine learning approaches identified the MAPK signaling pathway as a central regulatory node. qPCR validation confirmed that curcumin normalized the expression of key MAPK-related genes, including BDNF, EGFR, ERK2, JUN, RAF1, and TNF, with high-dose curcumin consistently showing the most pronounced therapeutic effects.
Conclusion
Our findings demonstrate that curcumin exerts potent antidepressant effects through multi-target mechanisms involving metabolic reprogramming and coordinated regulation of the MAPK signaling pathway. This study provides novel mechanistic insights into curcumin's polypharmacological actions, supporting its potential as a multi-modal therapeutic agent for depression by simultaneously modulating neurotrophic support, inflammatory responses, and intracellular signaling cascades.
{"title":"Curcumin reprograms metabolic pathways and MAPK signaling to exert antidepressant effects","authors":"Sijin Kong , Lijin Wang , ZiXuan Ren","doi":"10.1016/j.bbrep.2025.102399","DOIUrl":"10.1016/j.bbrep.2025.102399","url":null,"abstract":"<div><h3>Background</h3><div>Depression is a prevalent and debilitating mental disorder with limited treatment options. Curcumin, a natural compound with neuroprotective and anti-inflammatory properties, has shown potential antidepressant effects, though the underlying mechanisms remain incompletely understood.</div></div><div><h3>Methods and results</h3><div>In this study, we investigated the therapeutic effects and molecular mechanisms of curcumin in a chronic unpredictable mild stress (CUMS)-induced rat model of depression. Behavioral assessments, including the sucrose preference test, forced swim test, and open field test, demonstrated that curcumin (50 and 100 mg/kg, orally administered for 21 days) alleviated CUMS-induced anhedonia, behavioral despair, and anxiety-like behaviors, in a dose-dependent manner, with the 100 mg/kg dose exhibiting superior efficacy. Metabolomic profiling of the prefrontal cortex revealed significant metabolic disturbances in CUMS rats, particularly in starch and sucrose metabolism, which were progressively restored by curcumin. Functional enrichment analysis highlighted modulation of neuroinflammation, bioenergetic homeostasis, and signal transduction pathways as key biological processes associated with curcumin's effects. Integrated multi-omics and machine learning approaches identified the MAPK signaling pathway as a central regulatory node. qPCR validation confirmed that curcumin normalized the expression of key MAPK-related genes, including BDNF, EGFR, ERK2, JUN, RAF1, and TNF, with high-dose curcumin consistently showing the most pronounced therapeutic effects.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that curcumin exerts potent antidepressant effects through multi-target mechanisms involving metabolic reprogramming and coordinated regulation of the MAPK signaling pathway. This study provides novel mechanistic insights into curcumin's polypharmacological actions, supporting its potential as a multi-modal therapeutic agent for depression by simultaneously modulating neurotrophic support, inflammatory responses, and intracellular signaling cascades.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102399"},"PeriodicalIF":2.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691633","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}
Prosaposin (PSAP), a precursor of saposins, is essential for lysosomal hydrolysis of sphingolipids. It binds with progranulin (PGRN) and transports from the Golgi to lysosomes, where it is processed into saposins. PSAP is also secreted and functions on various cells, including neurons. We found that PSAP is highly expressed in the subfornical organ (SFO), a thirst center, in SAP-D-deficient (SAP-D−/−) mice, which develop primary polydipsia. As polyuria progresses, CD68-positive active microglia infiltrate the SFO and strongly express PSAP and PGRN. Lysosomal marker LAMP1 analysis in the SFO of mice with advanced polydipsia showed increased LAMP1 expression and decreased co-localization of PSAP and LAMP1 in microglia and neurons. This suggests that SAP-D-deficient PSAP struggles to reach lysosomes, causing intracellular accumulation. c-Fos-positive cell counts in the SFO remained significantly higher in SAP-D−/− mice, reflecting altered drinking behavior. These findings imply that PSAP may drive polydipsia progression.
{"title":"Accumulation of prosaposin and progranulin around the subfornical organ induces polydipsia in SAP-D-deficient mice","authors":"Harumi Hisaki , Takao Susa , Noriyuki Okudaira , Miho Akimoto , Masayoshi Iizuka , Junko Matsuda , Shunya Uchida , Hiroko Okinaga , Tomoki Okazaki , Mimi Tamamori-Adachi","doi":"10.1016/j.bbrep.2025.102388","DOIUrl":"10.1016/j.bbrep.2025.102388","url":null,"abstract":"<div><div>Prosaposin (PSAP), a precursor of saposins, is essential for lysosomal hydrolysis of sphingolipids. It binds with progranulin (PGRN) and transports from the Golgi to lysosomes, where it is processed into saposins. PSAP is also secreted and functions on various cells, including neurons. We found that PSAP is highly expressed in the subfornical organ (SFO), a thirst center, in SAP-D-deficient (SAP-D<sup>−/−</sup>) mice, which develop primary polydipsia. As polyuria progresses, CD68-positive active microglia infiltrate the SFO and strongly express PSAP and PGRN. Lysosomal marker LAMP1 analysis in the SFO of mice with advanced polydipsia showed increased LAMP1 expression and decreased co-localization of PSAP and LAMP1 in microglia and neurons. This suggests that SAP-D-deficient PSAP struggles to reach lysosomes, causing intracellular accumulation. c-Fos-positive cell counts in the SFO remained significantly higher in SAP-D<sup>−/−</sup> mice, reflecting altered drinking behavior. These findings imply that PSAP may drive polydipsia progression.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102388"},"PeriodicalIF":2.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691572","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}
Pub Date : 2025-12-02DOI: 10.1016/j.bbrep.2025.102381
Kundlik Rathod, Aswar Urmila
The objective of the study is to develop and evaluate a polyherbal formulation (PHF) for Parkinson's disease (PD). The present research provides preliminary studies which includes exhaustive literature survey leading to the selection of seven medicinal plants. Hydroalcoholic extracts of these plants were subsequently evaluated for their efficacy using haloperidol catalepsy and antioxidant assay. Based on results, four potent extracts, Asparagus racemosus, Convolvulus prostratus, Bacopa monnieri, and Nigella sativa, were chosen for further research. A PHF containing the above extracts was prepared and assessed for physicochemical properties, microbial load, and bioactive constituents. HPTLC analysis confirmed the presence of quercetin, kaempferol, rutin, and β-sitosterol. Molecular docking was performed for the promising actives present in the above extracts, such as kaempferol, quercetin, rutin, and β-sitosterol, highlighting their potential interactions with the PD-related targets. Antioxidant activity was evaluated using DPPH, ABTS, and FRAP assays, confirming potent free radical scavenging properties. Anti-inflammatory effects were demonstrated via heat-induced hemolysis, albumin denaturation, and proteinase inhibition assays. Additionally, the MAO-B enzyme inhibition assay indicated significant antiparkinsonian potential. PHF, combined with antioxidant, anti-inflammatory, and MAO-B inhibitory activities, supports its therapeutic application in neuronal protection. Acute oral toxicity was assessed as per OECD 425 guidelines, confirming its safety.
{"title":"Neuroprotective potential of polyherbal formulation: Evidence from preliminary in-vitro and in-vivo studies","authors":"Kundlik Rathod, Aswar Urmila","doi":"10.1016/j.bbrep.2025.102381","DOIUrl":"10.1016/j.bbrep.2025.102381","url":null,"abstract":"<div><div>The objective of the study is to develop and evaluate a polyherbal formulation (PHF) for Parkinson's disease (PD). The present research provides preliminary studies which includes exhaustive literature survey leading to the selection of seven medicinal plants. Hydroalcoholic extracts of these plants were subsequently evaluated for their efficacy using haloperidol catalepsy and antioxidant assay. Based on results, four potent extracts, <em>Asparagus racemosus</em>, <em>Convolvulus prostratus</em>, <em>Bacopa monnieri</em>, and <em>Nigella sativa,</em> were chosen for further research. A PHF containing the above extracts was prepared and assessed for physicochemical properties, microbial load, and bioactive constituents. HPTLC analysis confirmed the presence of quercetin, kaempferol, rutin, and β-sitosterol. Molecular docking was performed for the promising actives present in the above extracts, such as kaempferol, quercetin, rutin, and β-sitosterol, highlighting their potential interactions with the PD-related targets. Antioxidant activity was evaluated using DPPH, ABTS, and FRAP assays, confirming potent free radical scavenging properties. Anti-inflammatory effects were demonstrated via heat-induced hemolysis, albumin denaturation, and proteinase inhibition assays. Additionally, the MAO-B enzyme inhibition assay indicated significant antiparkinsonian potential. PHF, combined with antioxidant, anti-inflammatory, and MAO-B inhibitory activities, supports its therapeutic application in neuronal protection. Acute oral toxicity was assessed as per OECD 425 guidelines, confirming its safety.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"45 ","pages":"Article 102381"},"PeriodicalIF":2.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691636","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}
Pub Date : 2025-12-02DOI: 10.1016/j.bbrep.2025.102355
Bingyan Yang, Hongyang Zhang, Lingdi Dong, Jianjun Wang, Nan Yu
Background
Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer. Considering the substantial improvement in prognosis when detected at an early stage, identifying biomarkers for an early diagnosis of cSCC is crucial. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in cSCC progression; This study aimed to identify PI3K/AKT/mTOR-related genes that may serve as diagnostic indicators for cSCC, thereby providing a diagnostic framework for this disease.
Methods/results
A total of 33 PI3K/AKT/mTOR-related differentially expressed genes (DEGs) in cSCC were acquired by intersecting the DEGs from the Gene Expression Omnibus database between normal and cSCC groups and genes reported to be associated with the PI3K/AKT/mTOR pathway in the literature. LASSO regression identified 11 hub genes (AKT1, AKT3, EIF4EBP1, GFRA1, GRSF1, HIF1A, IGF1, IL11, IL24, KRT75, and MMP3), which were used to construct the diagnostic model. Receiver operating curve analysis revealed that these hub genes displayed strong diagnostic capacity. Quantitative polymerase chain reaction validation confirmed significant differences in mRNA expression of HIF1A, MMP3, IL11, GRSF1, and EIF4EBP1 between cSCC and normal cell lines.
Conclusion
These five PI3K/AKT/mTOR-related genes have the potential to serve as clinical biomarkers for the diagnosis of cSCC and as candidate therapeutic targets. This study offers valuable insights for further research to elucidate the specific pathological mechanisms and establish innovative treatment approaches for cSCC.
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