Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia","authors":"Alicja Rabiasz ,&nbsp;Zuzanna Bukowy-Bieryłło ,&nbsp;Patrycja Kaźmierczak ,&nbsp;Hanna Przystałowska-Macioła ,&nbsp;Marcin Mikoś ,&nbsp;Irena Wojsyk-Banaszak ,&nbsp;Ewa Ziętkiewicz","doi":"10.1016/j.bbadis.2025.167855","DOIUrl":"10.1016/j.bbadis.2025.167855","url":null,"abstract":"<div><div>Primary ciliary dyskinesia (PCD) is a heritable disease caused by the dysfunction of motile cilia, with a highly heterogeneous genetic background. <em>CFAP221</em> (Cilia and Flagella Associated Protein 221) is one of the genes, whose role in the PCD pathogenesis requires further evidence.</div><div>Using whole-exome sequencing we found a novel, homozygous protein-truncating variant in <em>CFAP221</em> in a Polish PCD patient. To better understand the effect of the identified pathogenic variant on motile cilia structure and function, the proband's nasal epithelium was examined using immunofluorescence, high-speed videomicroscopy, and mucociliary transport assay. Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband; importantly, the motility of proband's sperm cells was within the normal range. To independently confirm the role of <em>CFAP221</em>, the impact of RNA interference (RNAi)-mediated knockdown of <em>CFAP221</em> homolog on motile cilia function in a ciliated flatworm, <em>Schmidtea mediterranea,</em> was analyzed<em>.</em> Knockdown of <em>CFAP221</em> homolog impaired motile cilia function and led to a visible change in the speed of worms' locomotion.</div><div>Taken together, our study provided an independent confirmation of the involvement of <em>CFAP221</em> in the PCD pathogenesis. The subtle effect of <em>Smed-cfap221</em> knockdown in worms was consistent with the mild course of PCD in the proband.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167855"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain","authors":"Lei Zhou ,&nbsp;Soroosh Mozaffaritabar ,&nbsp;Erika Koltai ,&nbsp;Smaragda Giannopoulou ,&nbsp;Attila Kolonics ,&nbsp;Yaodong Gu ,&nbsp;Ricardo A. Pinho ,&nbsp;Ildiko Miklossy ,&nbsp;Istvan Boldogh ,&nbsp;Zsolt Radák","doi":"10.1016/j.bbadis.2025.167851","DOIUrl":"10.1016/j.bbadis.2025.167851","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice.&lt;/div&gt;&lt;div&gt;We established three experimental groups: young wild-type mice (3–4 months old), aged wild-type mice (25–27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24–27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation.&lt;/div&gt;&lt;div&gt;In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mit","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167851"},"PeriodicalIF":4.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of CREB3L1 blocks key cancer pathways and suppresses metastasis of lung squamous cell carcinoma cells","authors":"Paul Mellor ,&nbsp;Stephanie Kendall ,&nbsp;S. Austin Hammond ,&nbsp;Riley Plett ,&nbsp;Liliia Kyrylenko ,&nbsp;Anurag Saxena ,&nbsp;Deborah H. Anderson","doi":"10.1016/j.bbadis.2025.167845","DOIUrl":"10.1016/j.bbadis.2025.167845","url":null,"abstract":"<div><div>Lung cancer is the leading cause of death due to cancer, with higher mortality rates than cancers of the colon, breast and prostate combined. About one quarter of lung cancers are lung squamous cell carcinomas (LUSC), with a five-year survival rate of only 16 %. We discovered that the majority of LUSCs have reduced expression of a key transcription factor CREB3L1 (cAMP responsive element binding protein 3 like 1), known to function as a metastasis suppressor in breast, bladder and ovarian cancers. In this report, we set out to determine if CREB3L1 functions as a metastasis suppressor in LUSCs. A differential gene expression analysis showed that ectopic expression of CREB3L1 in NCI-H2170 and NCI-1703 cells caused significant reductions in many signaling pathway genes involved in promoting cell viability, survival, migration and angiogenesis. Expression of CREB3L1 was able to reduce cell migration and anchorage-independent growth in soft agar in NCI-H2170, NCI-H1703 and NCI-H226 LUSC cells. Expression of CREB3L1 had less impact on the growth of primary xenograft tumors for NCI-H2170 and NCI-H1703 cells, the latter of which formed atypical masses filled with blood. In contrast, xenografts of NCI-H226 expressing CREB3L1 showed significant reductions in primary tumor growth. Finally, in a mouse metastasis assay, expression of CREB3L1 in NCI-H2170 cells significantly reduced the formation of liver metastases and in NCI-H226 cells, lung metastases, as compared to their respective CREB3L1-deficient parental LUSC cells. Taken together, these results strongly support a role for CREB3L1 as a metastasis suppressor in lung squamous cell carcinoma cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167845"},"PeriodicalIF":4.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome alterations in peripheral immune cells of DLBCL patients and evidence of cancer extracellular vesicles involvement","authors":"Mostafa Ejtehadifar ,&nbsp;Sara Zahedi ,&nbsp;Paula Gameiro ,&nbsp;José Cabeçadas ,&nbsp;Manuel S. Rodriguez ,&nbsp;Maria Gomes da Silva ,&nbsp;Hans Christian Beck ,&nbsp;Rune Matthiesen ,&nbsp;Ana Sofia Carvalho","doi":"10.1016/j.bbadis.2025.167842","DOIUrl":"10.1016/j.bbadis.2025.167842","url":null,"abstract":"<div><div>Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease and a frequent form of non-Hodgkin lymphoma. Given the primary localization of DLBCL and the effect of tumors on the systemic immune response, we investigated the proteome of DLBCL patients' and healthy donors (HDs') peripheral immune cells (PICs). Since the ubiquitin-proteasome system has a vital role in proteome regulation and immune cells' functions, this study also explores the potential impact of DLBCL secretome on the polyubiquitination level in PICs. PICs from DLBCL patients and HDs were isolated and analyzed by mass spectrometry-based proteomics. The analysis resulted in 135 down and 51 upregulated proteins (adjusted <em>p</em>-value &lt;0.05). Unsupervised principal component analysis revealed distinct proteomic profiles between DLBCL and HDs. Functional enrichment analysis for comparison between DLBCL and HDs-PICs proteome identified immune-related pathways such as innate immune system, specifically neutrophil degranulation, Fcγ receptor-dependent phagocytosis, and JAK-STAT signaling after IL-12 stimulation as downregulated. Proteomics analysis of DLBCL-PICs also showed dysregulation of proteostasis factors. This prompted the investigation of the effect of tumor secretome on viability and polyubiquitination level in mononuclear immune cells. Therefore, human HD peripheral blood mononuclear cells (PBMCs) were cultured in the presence of DLBCL cell line-derived soluble factors, small-EVs, and large-EVs in vitro. Our results revealed that exposure of mainly small-EVs, and large-EVs to HD PBMCs increased the polyubiquitination in PBMCs and decreased PIC viability. These findings suggest impaired immune responses in DLBCL-PICs, with tumor secretome-inducing polyubiquitination and reduced PIC viability.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167842"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between daily sleep-wake rhythms, γ-secretase, and amyloid-β peptide pathology point to complex underlying relationships","authors":"Savannah M. Turton ,&nbsp;Samantha Padgett ,&nbsp;M. Tyler Maisel ,&nbsp;Carrie E. Johnson ,&nbsp;Valeria A. Buzinova ,&nbsp;Sarah E. Barth ,&nbsp;Katharina Kohler ,&nbsp;Heather M. Spearman ,&nbsp;Teresa Macheda ,&nbsp;Elena C. Manauis ,&nbsp;Landys Z. Guo ,&nbsp;Haleigh R. Whitlock ,&nbsp;Adam D. Bachstetter ,&nbsp;Sridhar Sunderam ,&nbsp;Bruce F. O'Hara ,&nbsp;Marilyn J. Duncan ,&nbsp;M. Paul Murphy","doi":"10.1016/j.bbadis.2025.167840","DOIUrl":"10.1016/j.bbadis.2025.167840","url":null,"abstract":"<div><div>Disrupted or insufficient sleep is a well-documented risk factor for Alzheimer's disease (AD) and related dementias. Previous studies in our lab and others have shown that chronic fragmentation of the daily sleep-wake rhythm in mice can accelerate the development of AD-related neuropathology in the brain, including increases in the levels of amyloid-β (Aβ). Although sleep is known to increase clearance of Aβ via the glymphatic system, little is known about the effect of sleep on Aβ production and the role this might play in amyloid deposition. To examine the relationship of Aβ production and its interaction with sleep and sleep dysfunction, we treated mice from an APP × PS1 mutant knock-in line (APP^ΔNLh/ΔNLh × PS1^P264L/P264L) with an inhibitor of γ-secretase (LY-450,139; Semagacestat®) during a protocol of mild sleep fragmentation (SF). Compared to the male mice, the female mice slept less, and had more Aβ pathology. Semagacestat treatment reduced Aβ, but only in the most soluble extractable fraction. Although the female mice showed an increase in the amount of Aβ following SF, this effect was blocked by Semagacestat, an effect that was not seen in the male mice. SF also led to a significant, sex-dependent changes in the relative amounts of C-terminal fragments of the amyloid precursor protein, the immediate substrate of the γ-secretase enzyme. These findings indicate that the relationship between disruption of the daily sleep-wake rhythm and the development of AD-related pathology is complex, and may involve unappreciated interactions with biological sex. Consideration of these factors is necessary for a better understanding of AD risk, especially the elevated risk in women.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167840"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small molecule DDQ involvement of ERK-mediated signaling pathway with enhanced mitophagy in HT22 cells transfected with mTau","authors":"Jangampalli Adi Pradeepkiran ,&nbsp;Sudhir Kshirsagar ,&nbsp;Rainier Vladlen Alvir ,&nbsp;Philip Irwin Motakatla ,&nbsp;P. Hemachandra Reddy","doi":"10.1016/j.bbadis.2025.167850","DOIUrl":"10.1016/j.bbadis.2025.167850","url":null,"abstract":"<div><div>Tau hyperphosphorylation was the initial recognized pathogenic tau protein post-translational modification in Alzheimer's disease. In our present research, treatment of diethyl (3,4-dihydroxy phenethylamine) (quinolin-4-yl) methylphosphonate (DDQ) HT22 cells with mTau transfected HT22 cells decreased the phosphorylation of tau at Ser202, Thr205, p-ERK, and increased LC3B, and TOM20 as detected by Western blots. Moreover, DDQ p-tau and p-ERK inhibition of phosphorylation also contributed to significant mitochondrial protection in the presence of mTau. Taken together, for the first time, we found that DDQ is involved in phosphorylation inhibition to restore the mitophagy, which may relate to the Sirt3 activation of the ERK-CREB mediated pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167850"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis","authors":"Tomoyasu Yoshihiro ,&nbsp;Kyoko Yamaguchi ,&nbsp;Hiroshi Ariyama ,&nbsp;Sakuya Koreishi ,&nbsp;Koki Uehara ,&nbsp;Hirofumi Ohmura ,&nbsp;Mamoru Ito ,&nbsp;Kenji Tsuchihashi ,&nbsp;Taichi Isobe ,&nbsp;Koji Shindo ,&nbsp;Kenoki Ohuchida ,&nbsp;Masafumi Nakamura ,&nbsp;Yoshihiro Nagao ,&nbsp;Yoshinao Oda ,&nbsp;Koichi Akashi ,&nbsp;Eishi Baba","doi":"10.1016/j.bbadis.2025.167843","DOIUrl":"10.1016/j.bbadis.2025.167843","url":null,"abstract":"<div><h3>Background</h3><div><em>Helicobacter pylori</em> infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe <em>in vitro</em> modeling of IM, as well as <em>in vivo</em> modeling of the oncogenic transformation from AG using human gastric organoids.</div></div><div><h3>Methods</h3><div>Organoids derived from patients with AG were established and characterized by immunohistochemistry and <em>in situ</em> hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.</div></div><div><h3>Results</h3><div>AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of <em>Runt-related transcription factor 3</em> (<em>RUNX3</em>), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of <em>SMAD4</em> counteracted the induction of these markers. Organoids doubly deficient for <em>TP53</em> and <em>SMAD4</em> formed larger and more proliferative p21 -negative subcutaneous tumors than did <em>RUNX3</em>-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.</div></div><div><h3>Conclusions</h3><div>Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of <em>TP53</em> and <em>SMAD4</em> confers tumorigenic potential to AGOs by inhibiting p21 induction.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167843"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-driven integration of multi-omics and radiomics: A new hope for precision cancer diagnosis and prognosis","authors":"Jordi Camps ,&nbsp;Andrea Jiménez-Franco ,&nbsp;Raquel García-Pablo ,&nbsp;Jorge Joven ,&nbsp;Meritxell Arenas","doi":"10.1016/j.bbadis.2025.167841","DOIUrl":"10.1016/j.bbadis.2025.167841","url":null,"abstract":"<div><div>Despite advances in cancer diagnosis and treatment, the disease remains a major health challenge. Integrating multi-omics, radiomics, and artificial intelligence has improved detection, prognosis, and treatment monitoring. Molecular multi-omics provides insights into tumor biology, while radiomics extracts imaging features for outcome prediction. Liquid biopsy and circulating tumor DNA aid early detection and personalized therapy. Artificial intelligence-driven models integrate data to identify biomarkers and guide precision oncology. Despite challenges like cost and data integration, future advancements aim to enhance resolution, scalability, and non-invasive diagnostics. This mini-review explores these methodologies, their clinical impact, and their potential in personalized cancer treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167841"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of hippocampal excitatory amino acid transporter 2 in modulating anxiety and visceral pain in a mouse model of inflammatory bowel disease","authors":"Hao Jiang ,&nbsp;Feini Zhou ,&nbsp;Lingnan Guo ,&nbsp;Yiyuan Gao ,&nbsp;Ning Kong ,&nbsp;Maosheng Xu ,&nbsp;Fan Zhang","doi":"10.1016/j.bbadis.2025.167832","DOIUrl":"10.1016/j.bbadis.2025.167832","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is characterized by chronic inflammation and significantly impairs quality of life through anxiety-like behaviors and visceral pain. Early evaluation of the risk of anxiety-like behaviors and visceral pain in IBD patients, along with targeted treatment, may benefit disease management. Visceral pain and anxiety-like behavior are often accompanied by neurological damage. Previous studies have shown that abnormal accumulation of glutamate can cause excitatory neurotoxic effects, leading to central nervous system (CNS) damage. Excitatory amino acid transporters (EAATs), particularly EAAT2, are known to regulate glutamate levels. The impact of hippocampal EAAT2 modulation on these clinical features in IBD is yet to be evaluated. Therefore, we designed this experiment to test this hypothesis. This study aimed to investigate the impact of altered levels of hippocampal EAAT2 on anxiety-like behaviors and visceral pain in mice with IBD. We observed reduced EAAT2 expression, increased glutamate levels, elevated <em>N</em>-methyl-<span>d</span>-aspartate receptors (NMDAR) expression, and obvious glutamate toxicity in the hippocampus of dextran sulfate sodium (DSS) induced IBD model mice. These mice exhibited significant visceral pain and anxiety-like behaviors. In summary, the reduced expression of EAAT2 in the hippocampus of individuals with IBD leads to elevated glutamate levels, resulting in neuronal damage and ultimately contributing to visceral pain and anxiety-like behaviors. These findings suggest that EAAT2 could serve as a therapeutic target for neurologically derived IBD symptoms.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167832"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the synthesis, characterization, and antitumor mechanism investigation of QZQ-01115 via targeting sphingosine kinase 2","authors":"Caiyu Liu ,&nbsp;Yaxin Guo ,&nbsp;Yutong Dong ,&nbsp;Zhiqiang Qu ,&nbsp;Yanling Mu ,&nbsp;Bo Liu ,&nbsp;Fuwen Wang ,&nbsp;Yan Li","doi":"10.1016/j.bbadis.2025.167829","DOIUrl":"10.1016/j.bbadis.2025.167829","url":null,"abstract":"<div><div>Sphingosine kinase 2 (SphK2) is an oncogenic enzyme that plays an essential role in the development of oral squamous cell carcinoma (OSCC). Therefore, development of SphK2 inhibitors is of great significance for the treatment of OSCC. In this study, we synthesized a series of thiazolidinediones and screened compounds with good inhibitory activity against CAL-27 using cytotoxicity assay. The compounds were further investigated <em>in vitro</em> using a series of <em>in vitro</em> experiments such as Western blot and qPCR were used to investigate the <em>in vivo</em> anti-tumor mechanisms, and <em>in vivo</em> investigation was applied by using a nude mouse ectopic tumor model. The results showed that four new compounds were successfully synthesized, and among which the compound named QZQ-01115 showed the best inhibitory activity against CAL-27 at the concentration of 5.84 ± 0.042 μM. Further mechanistic studies showed that QZQ-01115 could inhibit the proliferation, migration and invasion of CAL-27 cells at a concentration of 4 μM–6 μM. QZQ-01115 affected the PI3K/AKT signaling pathway by influencing the levels of S1P and ceramides in CAL-27, which in turn affected the mTOR/p70S6K, resulting in the blockage of protein synthesis and the blockage of cell cycle at the G0/G0 level. Apoptosis was promoted by down-regulating Bcl-2 and up-regulating Bax. The <em>in vivo</em> results showed that QZQ-01115 reduced the volume and weight of xenograft tumors in nude mice. The induction of apoptosis by QZQ-01115 was further determined by HE staining and immunohistochemical analysis. These results suggest that QZQ-01115 may be a potential candidate for the treatment of OSCC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167829"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}