Archives of biochemistry and biophysics最新文献_第2页

Pericentriolar material 1 aggregation maintains cell survival upon prolonged replication stress

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-14 DOI: 10.1016/j.abb.2025.110383

Yung-Chieh Tsai , Tian-Ni Kuo , Yu-Ying Chao , Ruei-Ci Lin , Han-Hsiang Chien , I-Ting Peng , Yueh-Fong Tsai , Ping-Jui Su , Chia-Yih Wang

The centrosome is essential for maintaining cell shape and facilitating cell division. Thus, precise control of centrosome copy numbers is crucial for proper chromosome segregation. Pericentriolar material 1 (PCM1) is a scaffold component of centriolar satellites—electron-dense granules dispersed around the centrosome—that regulate the centrosome or primary cilia. It has been shown that disrupting PCM1 aggregation by treating cells with sodium orthovanadate inhibits centrosome amplification. However, sodium orthovanadate is a protein tyrosine phosphatase and may have off-target effects on the centrosome. To further confirm the role of PCM1 aggregation in promoting centrosome amplification, we disrupted PCM1 aggregation by interfering with microtubule networks, inhibiting the dynactin motor complex, or depleting PCM1. Centrosome copy numbers were then examined under conditions of prolonged replication stress. Our data suggest that PCM1 aggregation does not promote centrosome amplification in osteosarcoma U2-OS or pancreatic ductal adenocarcinoma PANC-1 cell lines. Instead, we found that centrosome amplification promoted PCM1 aggregation in a PLK4-dependent manner. Furthermore, we observed that PCM1 depletion inhibited U2-OS cell survival under prolonged replication stress. Prolonged replication stress induced DNA damage signaling via the ATM-CHK1 axis and autophagy to maintain cell survival, while PCM1 depletion alleviated ATM, CHK1, and autophagy activity, thereby reducing cell survival. Our findings propose that PCM1 does not facilitate centrosome amplification but instead induces activation of the ATM-CHK1 axis and autophagy to sustain osteosarcoma cell viability during prolonged replication stress.

{"title":"Pericentriolar material 1 aggregation maintains cell survival upon prolonged replication stress","authors":"Yung-Chieh Tsai , Tian-Ni Kuo , Yu-Ying Chao , Ruei-Ci Lin , Han-Hsiang Chien , I-Ting Peng , Yueh-Fong Tsai , Ping-Jui Su , Chia-Yih Wang","doi":"10.1016/j.abb.2025.110383","DOIUrl":"10.1016/j.abb.2025.110383","url":null,"abstract":"<div><div>The centrosome is essential for maintaining cell shape and facilitating cell division. Thus, precise control of centrosome copy numbers is crucial for proper chromosome segregation. Pericentriolar material 1 (PCM1) is a scaffold component of centriolar satellites—electron-dense granules dispersed around the centrosome—that regulate the centrosome or primary cilia. It has been shown that disrupting PCM1 aggregation by treating cells with sodium orthovanadate inhibits centrosome amplification. However, sodium orthovanadate is a protein tyrosine phosphatase and may have off-target effects on the centrosome. To further confirm the role of PCM1 aggregation in promoting centrosome amplification, we disrupted PCM1 aggregation by interfering with microtubule networks, inhibiting the dynactin motor complex, or depleting PCM1. Centrosome copy numbers were then examined under conditions of prolonged replication stress. Our data suggest that PCM1 aggregation does not promote centrosome amplification in osteosarcoma U2-OS or pancreatic ductal adenocarcinoma PANC-1 cell lines. Instead, we found that centrosome amplification promoted PCM1 aggregation in a PLK4-dependent manner. Furthermore, we observed that PCM1 depletion inhibited U2-OS cell survival under prolonged replication stress. Prolonged replication stress induced DNA damage signaling via the ATM-CHK1 axis and autophagy to maintain cell survival, while PCM1 depletion alleviated ATM, CHK1, and autophagy activity, thereby reducing cell survival. Our findings propose that PCM1 does not facilitate centrosome amplification but instead induces activation of the ATM-CHK1 axis and autophagy to sustain osteosarcoma cell viability during prolonged replication stress.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110383"},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hippuric acid, a uremic toxin, binds to aggregation prone region of human lysozyme and potentiates the fibrillation: A biophysical insight

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-14 DOI: 10.1016/j.abb.2025.110392

Nida Zaidi , Nawaz Akhter , Muhammad Uzair Ashraf , Owais Ahmad , Md Nadir Hassan , Maryam Khursheed , Rizwan Hasan Khan

End-stage renal disease (ESRD) and human lysozyme (HL) amyloidosis are often interconnected, typically marked by elevated levels of uremic toxins in patients' blood. In this context, hippuric acid (HA), a uremic toxin derived from the metabolism of aromatic compounds, was investigated in vitro for its effect on HL fibrillation using spectroscopic, calorimetric, and computational methods. The results indicate that HA enhances HL fibrillation in a concentration-dependent manner, evidenced by increased ThT fluorescence and the detection of amyloid fibrils with a hydrodynamic radius of approximately 840.8 nm through dynamic light scattering and right-angle light scattering. Furthermore, HA promotes the conversion of HL's α+β structure into a predominantly β-sheet configuration, as confirmed by far-UV CD spectroscopy. This interaction occurs through the formation of a complex between HA and HL, stabilized by hydrogen bonds and hydrophobic interactions, as demonstrated by isothermal titration calorimetry (ITC) and computational studies. Specifically, HA binds to Q58 and N60 in the aggregation-prone region 2 (APR2) and Trp64 in non-aggregation-prone region, inducing conformational changes that favours fibrillation. The relative lytic activity of HL increase in presence of HA which further confirm the non-involvement of key residues, D35 and E53 in binding of HA to HL. Also, HL fibrils formed in presence of HA increases the hemolysis of RBCs and the appearance of more mis-shaped RBCs. Consequently, HA significantly enhances amyloid fibrillation in HL which provides valuable insights for future research focusing on in vivo studies, pre-clinical trials, and clinical applications.

{"title":"Hippuric acid, a uremic toxin, binds to aggregation prone region of human lysozyme and potentiates the fibrillation: A biophysical insight","authors":"Nida Zaidi , Nawaz Akhter , Muhammad Uzair Ashraf , Owais Ahmad , Md Nadir Hassan , Maryam Khursheed , Rizwan Hasan Khan","doi":"10.1016/j.abb.2025.110392","DOIUrl":"10.1016/j.abb.2025.110392","url":null,"abstract":"<div><div>End-stage renal disease (ESRD) and human lysozyme (HL) amyloidosis are often interconnected, typically marked by elevated levels of uremic toxins in patients' blood. In this context, hippuric acid (HA), a uremic toxin derived from the metabolism of aromatic compounds, was investigated <em>in vitro</em> for its effect on HL fibrillation using spectroscopic, calorimetric, and computational methods. The results indicate that HA enhances HL fibrillation in a concentration-dependent manner, evidenced by increased ThT fluorescence and the detection of amyloid fibrils with a hydrodynamic radius of approximately 840.8 nm through dynamic light scattering and right-angle light scattering. Furthermore, HA promotes the conversion of HL's α+β structure into a predominantly β-sheet configuration, as confirmed by far-UV CD spectroscopy. This interaction occurs through the formation of a complex between HA and HL, stabilized by hydrogen bonds and hydrophobic interactions, as demonstrated by isothermal titration calorimetry (ITC) and computational studies. Specifically, HA binds to Q58 and N60 in the aggregation-prone region 2 (APR2) and Trp64 in non-aggregation-prone region, inducing conformational changes that favours fibrillation. The relative lytic activity of HL increase in presence of HA which further confirm the non-involvement of key residues, D35 and E53 in binding of HA to HL. Also, HL fibrils formed in presence of HA increases the hemolysis of RBCs and the appearance of more mis-shaped RBCs. Consequently, HA significantly enhances amyloid fibrillation in HL which provides valuable insights for future research focusing on <em>in vivo</em> studies, pre-clinical trials, and clinical applications.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110392"},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interaction of novel N-acridine thiosemicarbazones with lipid membrane: NMR and molecular dynamics simulations

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-14 DOI: 10.1016/j.abb.2025.110390

Vladimir E. Koshman , Alexey A. Dmitriev , Viktor A. Timoshnikov , Alina S. Arkhipova , Olga Yu Selyutina , Nikolay E. Polyakov

NMR and molecular dynamics simulations revealed differences in the localization of the novel thiosemicarbazones: 2-benzoyl ((E)-N-(acridin-9-yl)-2-(phenyl(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AOBP) and 2-dipyridyl ((E)-N-(acridin-9-yl)-2-(di(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AODP) within the lipid membrane. It turned out that both thiosemicarbazones can penetrate inside the membrane, but AOBP is able to pass into the center of the hydrophobic region of the lipid bilayer, while AODP is distributed closer to the surface and freely leaves the membrane into the aqueous environment. The presence of cholesterol was also found to prevent both thiosemicarbazones from penetrating the membrane. The mechanism of anti-proliferative activity of some TSCs is related to the penetration through the lysosomal membrane and formation of cytotoxic copper complexes, which generate ROS resulting in lysosomal membrane permeabilization and cell death. Hydrophobic drugs, including TSCs, could penetrate through lysosomal membrane via passive diffusion, thus the affinity of drug to the hydrophobic interior of the lipid membrane could be important for their activity. Since the mechanism of thiosemicarbazones anticancer activity is associated with their penetration into lysosomes, the results obtained are important for a better understanding of the mechanisms of activity of these compounds and the development of new drug agents.

{"title":"Interaction of novel N-acridine thiosemicarbazones with lipid membrane: NMR and molecular dynamics simulations","authors":"Vladimir E. Koshman , Alexey A. Dmitriev , Viktor A. Timoshnikov , Alina S. Arkhipova , Olga Yu Selyutina , Nikolay E. Polyakov","doi":"10.1016/j.abb.2025.110390","DOIUrl":"10.1016/j.abb.2025.110390","url":null,"abstract":"<div><div>NMR and molecular dynamics simulations revealed differences in the localization of the novel thiosemicarbazones: 2-benzoyl ((E)-N-(acridin-9-yl)-2-(phenyl(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AOBP) and 2-dipyridyl ((E)-N-(acridin-9-yl)-2-(di(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AODP) within the lipid membrane. It turned out that both thiosemicarbazones can penetrate inside the membrane, but AOBP is able to pass into the center of the hydrophobic region of the lipid bilayer, while AODP is distributed closer to the surface and freely leaves the membrane into the aqueous environment. The presence of cholesterol was also found to prevent both thiosemicarbazones from penetrating the membrane. The mechanism of anti-proliferative activity of some TSCs is related to the penetration through the lysosomal membrane and formation of cytotoxic copper complexes, which generate ROS resulting in lysosomal membrane permeabilization and cell death. Hydrophobic drugs, including TSCs, could penetrate through lysosomal membrane via passive diffusion, thus the affinity of drug to the hydrophobic interior of the lipid membrane could be important for their activity. Since the mechanism of thiosemicarbazones anticancer activity is associated with their penetration into lysosomes, the results obtained are important for a better understanding of the mechanisms of activity of these compounds and the development of new drug agents.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110390"},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dysregulated circular RNA and long non-coding RNA-Mediated regulatory competing endogenous RNA networks (ceRNETs) in ovarian and cervical cancers: A non-coding RNA-Mediated mechanism of chemotherapeutic resistance with new emerging clinical capacities

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-14 DOI: 10.1016/j.abb.2025.110389

Danial Amiri Manjili , Fatemeh Naghdi Babaei , Tayebeh Younesirad , Sara Ghadir , Hamid Askari , Abdolreza Daraei

Cervical cancer (CC) and ovarian cancer (OC) are among the most common gynecological cancers with significant mortality in women, and their incidence is increasing. In addition to the prominent role of the malignant aspect of these cancers in cancer-related women deaths, chemotherapy drug resistance is a major factor that contributes to their mortality and presents a clinical obstacle. Although the exact mechanisms behind the chemoresistance in these cancers has not been revealed, accumulating evidence points to the dysregulation of non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as key contributors. These ncRNAs perform the roles of regulators of signaling pathways linked to tumor formation and chemoresistance. Strong data from various recent studies have uncovered that the main mechanism of these ncRNAs in the induction of chemoresistance of CC and OC is done through a dysregulated miRNA sponge activity as competing endogenous RNA (ceRNA) in the competing endogenous RNA networks (ceRNETs), where a miRNA regulating a messenger RNA (mRNA) is trapped, thereby removing its inhibitory effect on the desired mRNA. Understanding these mechanisms is essential to enhancing treatment outcomes and managing the problem of drug resistance.

This review provides a comprehensive overview of lncRNA- and circRNA-mediated ceRNETs as the core process of chemoresistance against the commonly used chemotherapeutics, including cisplatin, paclitaxel, oxaliplatin, carboplatin, and docetaxel in CC and OC. Furthermore, we highlight the clinical potential of these ncRNAs serving as diagnostic indicators of chemotherapy responses and therapeutic targets.

{"title":"Dysregulated circular RNA and long non-coding RNA-Mediated regulatory competing endogenous RNA networks (ceRNETs) in ovarian and cervical cancers: A non-coding RNA-Mediated mechanism of chemotherapeutic resistance with new emerging clinical capacities","authors":"Danial Amiri Manjili , Fatemeh Naghdi Babaei , Tayebeh Younesirad , Sara Ghadir , Hamid Askari , Abdolreza Daraei","doi":"10.1016/j.abb.2025.110389","DOIUrl":"10.1016/j.abb.2025.110389","url":null,"abstract":"<div><div>Cervical cancer (CC) and ovarian cancer (OC) are among the most common gynecological cancers with significant mortality in women, and their incidence is increasing. In addition to the prominent role of the malignant aspect of these cancers in cancer-related women deaths, chemotherapy drug resistance is a major factor that contributes to their mortality and presents a clinical obstacle. Although the exact mechanisms behind the chemoresistance in these cancers has not been revealed, accumulating evidence points to the dysregulation of non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as key contributors. These ncRNAs perform the roles of regulators of signaling pathways linked to tumor formation and chemoresistance. Strong data from various recent studies have uncovered that the main mechanism of these ncRNAs in the induction of chemoresistance of CC and OC is done through a dysregulated miRNA sponge activity as competing endogenous RNA (ceRNA) in the competing endogenous RNA networks (ceRNETs), where a miRNA regulating a messenger RNA (mRNA) is trapped, thereby removing its inhibitory effect on the desired mRNA. Understanding these mechanisms is essential to enhancing treatment outcomes and managing the problem of drug resistance.</div><div>This review provides a comprehensive overview of lncRNA- and circRNA-mediated ceRNETs as the core process of chemoresistance against the commonly used chemotherapeutics, including cisplatin, paclitaxel, oxaliplatin, carboplatin, and docetaxel in CC and OC. Furthermore, we highlight the clinical potential of these ncRNAs serving as diagnostic indicators of chemotherapy responses and therapeutic targets.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110389"},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of oxidized phosphatidylcholine supplementation on the lipidome of RAW264.7 macrophages

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-14 DOI: 10.1016/j.abb.2025.110384

Matilde Santos , Tatiana Maurício , Rosário Domingues , Pedro Domingues

Oxidized phospholipids (OxPLs) have emerged as critical damage-associated molecular patterns (DAMPs) and modulators of numerous biological processes, including inflammation, playing a significant role in health and disease. Despite their recognized influence on macrophage polarization, the precise mechanisms by which distinct OxPL species shape macrophage behavior remains poorly understood. The present study investigates the impact of two oxidized phosphatidylcholines (OxPC): omega 3 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (OxPC22:6), and omega 6 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (OxPC18:2), on the lipidomic profile of RAW264.7 macrophages, through an LC-MS lipidomic analysis. Our findings demonstrate that the OxPCs under study modulate macrophage lipidome differently, highlighting the significance of the sn-2 acyl chain composition for their biological function. When administered alone, neither of the OxPCs induced a pro-inflammatory phenotype in macrophages. OxPC22:6 appears to induce a preparatory pro-inflammatory state in macrophages, improving their subsequent inflammatory responses, while OxPC18:2 seems to induce a resting state on macrophages. Under LPS stimulation, both OxPCs were found to selectively attenuate certain LPS-driven lipidomic changes (PC.O, PC.P, PI.P, PE.P) while amplifying others (DG, Cer, LPC, PE.O, PI.O, TG, PC, PI) and introducing unique alterations to the macrophage lipidome (SM, PE, LPE). Core lipidomic changes, crucial for macrophages' LPS response, were identified, with sustained elevation of TG, DG, Cer, PC, LPC, and PI.O and reduction of PE.O, PI, and CAR. These observations suggest that, in the presence of LPS, mainly OxPC22:6 amplifies the pro-inflammatory lipidomic signature of macrophages. Further research is needed to clarify whether the observed lipidomic adaptations improve, impair, or inhibit macrophages' inflammatory capacities and response.

{"title":"Impact of oxidized phosphatidylcholine supplementation on the lipidome of RAW264.7 macrophages","authors":"Matilde Santos , Tatiana Maurício , Rosário Domingues , Pedro Domingues","doi":"10.1016/j.abb.2025.110384","DOIUrl":"10.1016/j.abb.2025.110384","url":null,"abstract":"<div><div>Oxidized phospholipids (OxPLs) have emerged as critical damage-associated molecular patterns (DAMPs) and modulators of numerous biological processes, including inflammation, playing a significant role in health and disease. Despite their recognized influence on macrophage polarization, the precise mechanisms by which distinct OxPL species shape macrophage behavior remains poorly understood. The present study investigates the impact of two oxidized phosphatidylcholines (OxPC): omega 3 1-stearoyl-2-docosahexaenoyl-<em>sn</em>-glycero-3-phosphatidylcholine (OxPC22:6), and omega 6 1-stearoyl-2-linoleoyl-<em>sn</em>-glycero-3-phosphatidylcholine (OxPC18:2), on the lipidomic profile of RAW264.7 macrophages, through an LC-MS lipidomic analysis. Our findings demonstrate that the OxPCs under study modulate macrophage lipidome differently, highlighting the significance of the sn-2 acyl chain composition for their biological function. When administered alone, neither of the OxPCs induced a pro-inflammatory phenotype in macrophages. OxPC22:6 appears to induce a preparatory pro-inflammatory state in macrophages, improving their subsequent inflammatory responses, while OxPC18:2 seems to induce a resting state on macrophages. Under LPS stimulation, both OxPCs were found to selectively attenuate certain LPS-driven lipidomic changes (PC.O, PC.P, PI.P, PE.P) while amplifying others (DG, Cer, LPC, PE.O, PI.O, TG, PC, PI) and introducing unique alterations to the macrophage lipidome (SM, PE, LPE). Core lipidomic changes, crucial for macrophages' LPS response, were identified, with sustained elevation of TG, DG, Cer, PC, LPC, and PI.O and reduction of PE.O, PI, and CAR. These observations suggest that, in the presence of LPS, mainly OxPC22:6 amplifies the pro-inflammatory lipidomic signature of macrophages. Further research is needed to clarify whether the observed lipidomic adaptations improve, impair, or inhibit macrophages' inflammatory capacities and response.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110384"},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Amyloid β fragments that suppress oligomers but not fibrils are cytoprotective

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-13 DOI: 10.1016/j.abb.2025.110386

Maria C. Zabala-Rodriguez , Ken Teter , Suren A. Tatulian

Neurotoxic aggregates of amyloid beta (Aβ) peptide contribute to the etiology of Alzheimer's disease (AD). In this work, we examined how seven overlapping fragments derived from Aβ_1-42 affect the oligomerization and toxicity of the full-length peptide. Four fragments inhibited the toxicity of oligomeric Aβ_1-42 to various degrees, two others conferred no cellular protection against Aβ_1-42 toxicity, and one fragment enhanced both Aβ_1-42 oligomerization and toxicity. The structural and aggregation propensities of the peptides that support strong inhibition of Aβ_1-42 toxicity have been identified. Data analysis allowed elucidation of the mechanisms of action of each of the seven peptide fragments on Aβ_1-42 cytotoxicity. Our work establishes the potential therapeutic value of four Aβ fragments and supports the notion that agents directed to disruption of Aβ oligomers may be more effective AD drug candidates than those targeting Aβ fibrils.

淀粉样 beta（Aβ）肽的神经毒性聚集体是阿尔茨海默病（AD）的病因之一。在这项工作中，我们研究了从 Aβ1-42 提取的七个重叠片段如何影响全长肽的寡聚和毒性。四个片段在不同程度上抑制了寡聚 Aβ1-42 的毒性，另外两个片段对 Aβ1-42 的毒性没有细胞保护作用，一个片段增强了 Aβ1-42 的寡聚和毒性。我们已经确定了支持强力抑制 Aβ1-42 毒性的多肽的结构和聚集倾向。通过数据分析，阐明了七种肽片段对 Aβ1-42 细胞毒性的作用机制。我们的工作确定了四种 Aβ 片段的潜在治疗价值，并支持了这样一种观点，即破坏 Aβ 寡聚体的药物可能比针对 Aβ 纤维的药物更有效。

引用次数: 0

Metabolic role of a genetically conserved aldehyde dehydrogenase in bacterial assimilation of various primary amines 基因保守的醛脱氢酶在细菌同化各种伯胺中的代谢作用

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-12 DOI: 10.1016/j.abb.2025.110387

Tadashi Nakai , Naoya Miyagi , Kota Hisamura , Shoya Matsuba , Kanji Nishimoto , Emi Nakai , Katsuyuki Tanizawa , Toshihide Okajima

Primary amines such as n-butylamine and 2-phenylethylamine serve as good nitrogen, carbon, and energy sources for bacterial growth. In many Gram-negative bacterial species, these amines are first oxidized by a periplasmic enzyme, quinohemoprotein amine dehydrogenase (QHNDH), encoded in an operon termed ‘qhp’, consisting of eight genes (qhpABCDEFGR). A gene predicted to encode an aldehyde dehydrogenase is also highly conserved in the vicinity of the qhp operon. In this study, we found that a 5′-upstream region of the aldehyde dehydrogenase gene in Paracoccus denitrificans has a high promoter activity that responds to n-butylamine supplementation in the culture medium, indicating co-regulation with the qhp genes by the transcriptional regulator QhpR. Hence, we designate this gene as the ninth member of the qhp operon, qhpH. Disruption of qhpH in P. denitrificans neither affected bacterial growth on primary amines, nor impaired QHNDH activity, suggesting the presence of another constitutive aldehyde dehydrogenase(s) compensating for the defect of qhpH. Nevertheless, heterologous expression of qhpH along with the eight qhp genes in an amine non-assimilating bacterium, Rhodobacter sphaeroides, significantly enhanced the growth on n-butylamine, as compared to the slow growth without qhpH. The recombinant QhpH purified from Escherichia coli cells showed high aldehyde dehydrogenase activities toward various aldehydes. These findings demonstrate that the qhpH gene encodes an aldehyde dehydrogenase with broad substrate specificity and is evolutionarily conserved with the qhp operon to play a role in an efficient metabolism of various primary amines in Gram-negative bacteria.

{"title":"Metabolic role of a genetically conserved aldehyde dehydrogenase in bacterial assimilation of various primary amines","authors":"Tadashi Nakai , Naoya Miyagi , Kota Hisamura , Shoya Matsuba , Kanji Nishimoto , Emi Nakai , Katsuyuki Tanizawa , Toshihide Okajima","doi":"10.1016/j.abb.2025.110387","DOIUrl":"10.1016/j.abb.2025.110387","url":null,"abstract":"<div><div>Primary amines such as <em>n</em>-butylamine and 2-phenylethylamine serve as good nitrogen, carbon, and energy sources for bacterial growth. In many Gram-negative bacterial species, these amines are first oxidized by a periplasmic enzyme, quinohemoprotein amine dehydrogenase (QHNDH), encoded in an operon termed ‘<em>qhp</em>’, consisting of eight genes (<em>qhpABCDEFGR</em>). A gene predicted to encode an aldehyde dehydrogenase is also highly conserved in the vicinity of the <em>qhp</em> operon. In this study, we found that a 5′-upstream region of the aldehyde dehydrogenase gene in <em>Paracoccus denitrificans</em> has a high promoter activity that responds to <em>n</em>-butylamine supplementation in the culture medium, indicating co-regulation with the <em>qhp</em> genes by the transcriptional regulator QhpR. Hence, we designate this gene as the ninth member of the <em>qhp</em> operon, <em>qhpH</em>. Disruption of <em>qhpH</em> in <em>P. denitrificans</em> neither affected bacterial growth on primary amines, nor impaired QHNDH activity, suggesting the presence of another constitutive aldehyde dehydrogenase(s) compensating for the defect of <em>qhpH</em>. Nevertheless, heterologous expression of <em>qhpH</em> along with the eight <em>qhp</em> genes in an amine non-assimilating bacterium, <em>Rhodobacter sphaeroides</em>, significantly enhanced the growth on <em>n</em>-butylamine, as compared to the slow growth without <em>qhpH</em>. The recombinant QhpH purified from <em>Escherichia coli</em> cells showed high aldehyde dehydrogenase activities toward various aldehydes. These findings demonstrate that the <em>qhpH</em> gene encodes an aldehyde dehydrogenase with broad substrate specificity and is evolutionarily conserved with the <em>qhp</em> operon to play a role in an efficient metabolism of various primary amines in Gram-negative bacteria.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110387"},"PeriodicalIF":3.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High-altitude chronic hypoxia prevents myocardial dysfunction in experimental model of type 2 diabetes.

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-12 DOI: 10.1016/j.abb.2025.110371

Yixuan Wan, Lisha Zhang, Lei Wang, Yu Zhang, FaBao Gao

Background: High-altitude chronic hypoxia (CHH) has a favorable impact on the lower prevalence of diabetes together with the better glucose tolerance. However, whether it prevents diabetic cardiomyopathy remains unclear. This study aimed to investigate the effects of CHH on left ventricular (LV) function in experimental model of type 2 diabetes.

Methods: Sprague-Dawley rats were randomly divided into control (altitude 500 m), DM (diabetes mellitus and altitude 500 m), CHH (altitude 4250 m and non-diabetic for 2 weeks), CHH-DM2 (altitude 4250 m and DM for 2 weeks), and CHH-DM8 (altitude 4250 m and DM for 8 weeks) groups. The experimental model of type 2 diabetes was induced by a high-fat diet plus low-dose streptozotocin (35mg/kg, intraperitoneal) after fasted overnight. Left ventricular cardiac function and global myocardial strain were evaluated at 2, and 8 weeks by 7.0 T cardiovascular magnetic resonance. Subsequently, biochemical indices, histological evaluation, and levels of hypoxia-induced factor (HIF)-1α were assessed.

Results: Left ventricular ejection fraction (LVEF), global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains significantly decreased in the DM group compared with the controls. However, these abnormalities in DM rats were significantly prevented in the CHH-DM2 group, and were further improved in CHH-DM8 group. Mechanistically, prolonged CHH at high altitude further reduced cardiac apoptosis, and oxidative stress, and increased autophagy, and the expression of HIF-1α in diabetic myocardial tissue.

Conclusions: CHH exerted cardioprotective effects by improving LV function, increasing myocardial strain and attenuating cardiac hypertrophy in type 2 diabetic rats, likely through reducing apoptosis and oxidative stress, activating autophagy and HIF-1α signaling in diabetic rats.

背景：高海拔慢性缺氧（CHH）对降低糖尿病发病率和改善葡萄糖耐量有积极影响。然而，它是否能预防糖尿病心肌病仍不清楚。本研究旨在探讨高海拔对 2 型糖尿病实验模型左心室功能的影响：将 Sprague-Dawley 大鼠随机分为对照组（海拔 500 米）、DM 组（糖尿病和海拔 500 米）、CHH 组（海拔 4250 米和非糖尿病 2 周）、CHH-DM2 组（海拔 4250 米和 DM 2 周）和 CHH-DM8 组（海拔 4250 米和 DM 8 周）。2 型糖尿病的实验模型是通过高脂饮食加小剂量链脲佐菌素（35 毫克/千克，腹腔注射）诱导的。通过 7.0 T 心血管磁共振在 2 周和 8 周时评估左心室心功能和整体心肌应变。随后，对生化指标、组织学评价和缺氧诱导因子（HIF）-1α的水平进行了评估：结果：与对照组相比，DM 组的左心室射血分数（LVEF）、整体纵向（GLS）、周向（GCS）和径向（GRS）应变显著下降。然而，CHH-DM2 组能明显防止 DM 大鼠的这些异常，CHH-DM8 组则得到进一步改善。从机理上讲，长期高海拔CHH可进一步减少糖尿病心肌组织中的心脏凋亡和氧化应激，增加自噬和HIF-1α的表达：CHH通过改善2型糖尿病大鼠的左心室功能、增加心肌应变和减轻心肌肥厚发挥了心脏保护作用，这可能是通过减少糖尿病大鼠的细胞凋亡和氧化应激、激活自噬和HIF-1α信号传导实现的。

{"title":"High-altitude chronic hypoxia prevents myocardial dysfunction in experimental model of type 2 diabetes.","authors":"Yixuan Wan, Lisha Zhang, Lei Wang, Yu Zhang, FaBao Gao","doi":"10.1016/j.abb.2025.110371","DOIUrl":"https://doi.org/10.1016/j.abb.2025.110371","url":null,"abstract":"<p><strong>Background: </strong>High-altitude chronic hypoxia (CHH) has a favorable impact on the lower prevalence of diabetes together with the better glucose tolerance. However, whether it prevents diabetic cardiomyopathy remains unclear. This study aimed to investigate the effects of CHH on left ventricular (LV) function in experimental model of type 2 diabetes.</p><p><strong>Methods: </strong>Sprague-Dawley rats were randomly divided into control (altitude 500 m), DM (diabetes mellitus and altitude 500 m), CHH (altitude 4250 m and non-diabetic for 2 weeks), CHH-DM2 (altitude 4250 m and DM for 2 weeks), and CHH-DM8 (altitude 4250 m and DM for 8 weeks) groups. The experimental model of type 2 diabetes was induced by a high-fat diet plus low-dose streptozotocin (35mg/kg, intraperitoneal) after fasted overnight. Left ventricular cardiac function and global myocardial strain were evaluated at 2, and 8 weeks by 7.0 T cardiovascular magnetic resonance. Subsequently, biochemical indices, histological evaluation, and levels of hypoxia-induced factor (HIF)-1α were assessed.</p><p><strong>Results: </strong>Left ventricular ejection fraction (LVEF), global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains significantly decreased in the DM group compared with the controls. However, these abnormalities in DM rats were significantly prevented in the CHH-DM2 group, and were further improved in CHH-DM8 group. Mechanistically, prolonged CHH at high altitude further reduced cardiac apoptosis, and oxidative stress, and increased autophagy, and the expression of HIF-1α in diabetic myocardial tissue.</p><p><strong>Conclusions: </strong>CHH exerted cardioprotective effects by improving LV function, increasing myocardial strain and attenuating cardiac hypertrophy in type 2 diabetic rats, likely through reducing apoptosis and oxidative stress, activating autophagy and HIF-1α signaling in diabetic rats.</p>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":" ","pages":"110371"},"PeriodicalIF":3.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PANoptosis-related gene biomarkers in aortic dissection 主动脉夹层中与细胞凋亡相关的基因生物标志物

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-12 DOI: 10.1016/j.abb.2025.110385

Yuting Pu , Yang Zhou , Tuo Guo , Xiangping Chai , Guifang Yang

Introduction

Programmed cell death of vascular smooth muscle cells (VSMCs) is critical in the pathogenesis of aortic dissection (AD), yet the role of PANoptosis—comprising pyroptosis, apoptosis, and necroptosis—remains unclear.

Methods

We utilized the GSE213740 single-cell sequencing dataset to assess PANoptosis levels in VSMCs. Datasets GSE153434 and GSE147026 were employed to identify differentially expressed genes (DEGs) and perform weighted gene co-expression network analysis. PANoptosis gene sets were sourced from the GSEA website, with GSE52093 serving as the validation cohort. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction analyses were conducted, along with assessments of upstream regulators and immune cell infiltration. Validation was performed on aortic tissues from AD patients and mouse models.

Results

The single-cell dataset revealed an increased PANoptosis score in VSMCs in AD. Nineteen PANoptosis-related DEGs (PANDEGs) were identified, contributing to VSMC differentiation, DNA damage response, and apoptosis. KEGG analysis highlighted the P53 and TGF-β pathways, with PANDEGs positively correlating with immune cell infiltration. Key PANDEGs GADD45B, CDKN1A, and SOD2 were validated, showing co-expression with α-SMA.

Conclusion

The increased PANoptosis score in VSMCs suggests that GADD45B, CDKN1A, and SOD2 play crucial roles in AD.

{"title":"PANoptosis-related gene biomarkers in aortic dissection","authors":"Yuting Pu , Yang Zhou , Tuo Guo , Xiangping Chai , Guifang Yang","doi":"10.1016/j.abb.2025.110385","DOIUrl":"10.1016/j.abb.2025.110385","url":null,"abstract":"<div><h3>Introduction</h3><div>Programmed cell death of vascular smooth muscle cells (VSMCs) is critical in the pathogenesis of aortic dissection (AD), yet the role of PANoptosis—comprising pyroptosis, apoptosis, and necroptosis—remains unclear.</div></div><div><h3>Methods</h3><div>We utilized the GSE213740 single-cell sequencing dataset to assess PANoptosis levels in VSMCs. Datasets GSE153434 and GSE147026 were employed to identify differentially expressed genes (DEGs) and perform weighted gene co-expression network analysis. PANoptosis gene sets were sourced from the GSEA website, with GSE52093 serving as the validation cohort. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction analyses were conducted, along with assessments of upstream regulators and immune cell infiltration. Validation was performed on aortic tissues from AD patients and mouse models.</div></div><div><h3>Results</h3><div>The single-cell dataset revealed an increased PANoptosis score in VSMCs in AD. Nineteen PANoptosis-related DEGs (PANDEGs) were identified, contributing to VSMC differentiation, DNA damage response, and apoptosis. KEGG analysis highlighted the P53 and TGF-β pathways, with PANDEGs positively correlating with immune cell infiltration. Key PANDEGs GADD45B, CDKN1A, and SOD2 were validated, showing co-expression with α-SMA.</div></div><div><h3>Conclusion</h3><div>The increased PANoptosis score in VSMCs suggests that GADD45B, CDKN1A, and SOD2 play crucial roles in AD.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110385"},"PeriodicalIF":3.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

microRNA-34 family: A multifunctional miRNA family

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-03-10 DOI: 10.1016/j.abb.2025.110382

Chen Wang, Ximei Yuan, Yuejun Fu

MicroRNAs are endogenous non-coding small RNAs composed of about 22 nucleotides, which are widely found in eukaryotic cells and regulate gene expression at the post-transcriptional level through complementary pairing with target genes, leading to mRNA degradation or translation inhibition. MiR-34 family is a highly conserved miRNA family during evolution. Recent studies have found that members of the miR-34 family are involved in regulating biological processes such as aging, ciliogenesis, and immunity. To have a more comprehensive understanding of miR-34 family, this paper reviewed the functional evolution of miR-34 family, and provided a reference for further research on the related functions of miR-34.

引用次数: 0