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

{"title":"Anxa10 and neuropathic pain: Insights into dysregulation of endoplasmic reticulum-mitochondria contact tethering complex and therapeutic potential","authors":"Fei-Fei Wu ,&nbsp;Bo-Zhi Liu ,&nbsp;Yun-Qiang Huang ,&nbsp;Chang-Lei Zhu ,&nbsp;Yu-Lu Xia ,&nbsp;Kun-Long Zhang ,&nbsp;Shu-Jiao Li ,&nbsp;Yan-Ling Yang ,&nbsp;Ya-Yun Wang","doi":"10.1016/j.bbadis.2025.167856","DOIUrl":"10.1016/j.bbadis.2025.167856","url":null,"abstract":"<div><div>The stability of membrane contact sites is critically dependent on Endoplasmic Reticulum mitochondria contact tethering complexes (EMCTCs), and dysregulation of these sites has been implicated in neuropathic diseases. In this study, we examined the role of Annexin A10 (Anxa10), a calcium-dependent protein, in neuropathic pain by investigating its influence on EMCTCs dysregulation. Using RNA sequencing, western blotting, and behavioral assays, we observed that spared nerve injury (SNI)-induced neuropathic pain significantly increased Anxa10 expression levels within the spinal dorsal horn (SDH) of mice. By employing cell-specific gene regulation via the Cre/loxp system, we utilized loxp-modified adeno-associated virus vectors to modulate Anxa10 expression in GAD2-Cre (inhibitory neurons), vGlut2-Cre (excitatory neurons), and Fos-Cre (activity-induced neurons) transgenic mice. Our results demonstrated that specific down-regulation of Anxa10 in excitatory neurons within the SDH alleviated neuropathic pain, whereas up-regulation of Anxa10, regardless of cell type, induced spontaneous pain in mice. Ultrastructural analysis of the endoplasmic reticulum (ER) and mitochondria, as well as double immunofluorescence staining, revealed that downregulation of Anxa10 mitigated the SNI-induced reduction in ER-mitochondrial distance. Additionally, it attenuated the SNI-induced upregulation of key components of EMCTCs, including IP3R, GRP75, and VDAC1, while preventing the SNI-induced downregulation of NCX3 expression. Furthermore, we formulated and validated the hypothesis that SGK1 and PI3K are positioned downstream of Anxa10. The up-regulation of Anxa10 compromised mitochondrial integrity and disrupted mitochondrial networks, ultimately leading to elevated oxidative stress. Collectively, these findings suggest that Anxa10 represents a promising therapeutic target for correcting EMCTCs dysregulation and mitigating neuropathic pain.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167856"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863481","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":"Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation","authors":"Wenying Shan ,&nbsp;Shao-Lin Zhang ,&nbsp;Yehuda G. Assaraf ,&nbsp;Kin Yip Tam","doi":"10.1016/j.bbadis.2025.167859","DOIUrl":"10.1016/j.bbadis.2025.167859","url":null,"abstract":"<div><div>KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the <em>in vitro</em> and <em>in vivo</em> efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation <em>in vitro</em>, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167859"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855682","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":"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":"The voltage-gated sodium channel β3 subunit modulates C6 glioma cell motility independently of channel activity","authors":"Hengrui Liu ,&nbsp;Samir W. Hamaia ,&nbsp;Lisa Dobson ,&nbsp;Jieling Weng ,&nbsp;Federico López Hernández ,&nbsp;Christopher A. Beaudoin ,&nbsp;Samantha C. Salvage ,&nbsp;Christopher L.-H. Huang ,&nbsp;Laura M. Machesky ,&nbsp;Antony P. Jackson","doi":"10.1016/j.bbadis.2025.167844","DOIUrl":"10.1016/j.bbadis.2025.167844","url":null,"abstract":"<div><h3>Background</h3><div>Voltage-gated sodium channels (VGSCs) initiate action potentials in nerve and muscle cells and are regulated by auxiliary β subunits. VGSC β subunits are also expressed in some cancer types, suggesting potential functions distinct from their role in electrophysiological excitability. This study investigated the occurrence and functional implications of the VGSC β3 subunit (the product of <em>SCN3B</em> gene) in glioma, focusing on the role of its extracellular immunoglobulin domain (β3 Ig).</div></div><div><h3>Methods</h3><div>Data mining explored associations between β3 expression and glioma severity at patient, tissue, and single-cell levels. Using C6 glioma cells expressing β3 or β3 without its Ig domain, we examined the effects on cell viability, mobility, and actin-based cell protrusions. A single-chain variable fragment (scFv) antibody targeting the β3 Ig was selected by phage display to interfere with its functions. The interacting proteins with β3 Ig were identified by immunoprecipitation-mass spectrometry.</div></div><div><h3>Results</h3><div>Data mining revealed negative correlations between β3 expression and glioma severity and aggressiveness. Expression of β3 in C6 cells reduced cell migration and invasion without affecting cell viability. Filopodia were significantly increased while lamellipodia/ruffles were decreased, producing striking cell morphological changes. These effects were abrogated by expression of the β3 subunit lacking the β3 Ig domain or exogenous application of an scFv targeting β3 Ig. Most of the plasma membrane-associated proteins immunoprecipitated with the β3 subunit are known regulators of actin polymerization.</div></div><div><h3>Conclusion</h3><div>Our data reveals a novel and unexpected role for the VGSC β3 subunit in orchestrating actin organization and negatively regulating cell migration in glioma cells which may potentially explain clinical correlations with glioma severity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167844"},"PeriodicalIF":4.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868767","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}