Chemico-Biological Interactions最新文献

{"title":"Alkaloid-based modulators of the PI3K/Akt/mTOR pathway for cancer therapy: Understandings from pharmacological point of view","authors":"Fatima Zohra Mokhfi ,&nbsp;Md Al Amin ,&nbsp;Mehrukh Zehravi ,&nbsp;Sherouk Hussein Sweilam ,&nbsp;Uppuluri Varuna Naga Venkata Arjun ,&nbsp;Jeetendra Kumar Gupta ,&nbsp;Bhaskar Vallamkonda ,&nbsp;Anitha Balakrishnan ,&nbsp;Manjula Challa ,&nbsp;Jyoti Singh ,&nbsp;P. Dharani Prasad ,&nbsp;Syed Salman Ali ,&nbsp;Irfan Ahmad ,&nbsp;Koula Doukani ,&nbsp;Talha Bin Emran","doi":"10.1016/j.cbi.2024.111218","DOIUrl":"10.1016/j.cbi.2024.111218","url":null,"abstract":"<div><p>This review aims to summarize the role of alkaloids as potential modulators of the PI3K/Akt/mTOR (PAMT) pathway in cancer therapy. The PAMT pathway plays a critical role in cell growth, survival, and metabolism, and its dysregulation contributes to cancer hallmarks. In healthy cells, this pathway is tightly controlled. However, this pathway is frequently dysregulated in cancers and becomes abnormally active. This can happen due to mutations in genes within the pathway itself or due to other factors. This chronic overactivity promotes cancer hallmarks such as uncontrolled cell division, resistance to cell death, and increased blood vessel formation to nourish the tumor. As a result, the PAMT pathway is a crucial therapeutic target for cancer. Researchers are developing drugs that specifically target different components of this pathway, aiming to turn it off and slow cancer progression. Alkaloids, a class of naturally occurring nitrogen-containing molecules found in plants, have emerged as potential therapeutic agents. These alkaloids can target different points within the PAMT pathway, inhibiting its activity and potentially resulting in cancer cell death or suppression of tumor growth. Research is ongoing to explore the role of various alkaloids in cancer treatment. Berberine reduces mTOR activity and increases apoptosis by targeting the PAMT pathway, inhibiting cancer cell proliferation. Lycorine inhibits Akt phosphorylation and mTOR activation, increasing pro-apoptotic protein production and decreasing cell viability. In glioblastoma models, harmine suppresses mTORC1. This review focuses on alkaloids such as evodiamine, hirsuteine, chaetocochin J, indole-3-carbinol, noscapine, berberine, piperlongumine, and so on, which have shown promise in targeting the PAMT pathway. Clinical studies evaluating alkaloids as part of cancer treatment are underway, and their potential impact on patient outcomes is being investigated. In summary, alkaloids represent a promising avenue for targeting the dysregulated PAMT pathway in cancer, and further research is warranted.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111218"},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"25-Hydroxycholesterol induces oxidative stress, leading to apoptosis and ferroptosis in extravillous trophoblasts","authors":"Ki Mo Lee ,&nbsp;Tae Hoon Kim ,&nbsp;Eui-Jeong Noh ,&nbsp;Jae Won Han ,&nbsp;Jong-Seok Kim ,&nbsp;Sung Ki Lee","doi":"10.1016/j.cbi.2024.111214","DOIUrl":"10.1016/j.cbi.2024.111214","url":null,"abstract":"<div><p>25-hydroxycholesterol (25HC) is an oxysterol derived from cholesterol and plays a role in various cellular processes, such as lipid metabolism, inflammatory responses, and cell survival. Extravillous trophoblasts (EVTs) are a major cell type found in the placenta, which are highly energetic cells with proliferative and invasive properties. EVT dysfunction can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction. This study investigated the effects and underlying mechanisms of action of 25HC on EVT proliferation. Swan 71 cells, an EVT cell line, were treated with different concentrations of 25HC. Next, cell proliferation was assessed. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potentials (MMPs), lipid peroxidation (LPO), and glutathione (GSH) levels were measured. Apoptosis, ferroptosis, and autophagy were evaluated by western blotting and flow cytometry. The results revealed that 25HC significantly inhibited proliferation and decreased the metabolic activity of EVTs. Moreover, 25HC caused oxidative stress by altering mtROS, LPO, MMPs, and GSH levels. Additionally, 25HC induces apoptosis, ferroptosis, and autophagy through the modulation of relevant protein levels. Interestingly, pretreatment with Z-VAD-FMK, an apoptosis inhibitor, and ferrostatin-1, a ferroptosis inhibitor, partially restored the effects of 25HC on cell proliferation, oxidative stress, and cell death. In summary, our findings suggest that 25HC treatment inhibits EVT proliferation and triggers apoptosis, ferroptosis, and autophagy, which are attributable to oxidative stress.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111214"},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphodiesterase 4 is overexpressed in human keloids and its inhibition reduces fibroblast activation and skin fibrosis","authors":"Javier Milara ,&nbsp;Pilar Ribera ,&nbsp;Severiano Marín ,&nbsp;Paula Montero ,&nbsp;Inés Roger ,&nbsp;Herman Tenor ,&nbsp;Julio Cortijo","doi":"10.1016/j.cbi.2024.111211","DOIUrl":"10.1016/j.cbi.2024.111211","url":null,"abstract":"<div><p>There is a pressing medical need for improved treatments in skin fibrosis including keloids and hypertrophic scars (HTS). This study aimed to characterize the role of phosphodiesterase 4 (PDE4), specifically PDE4B in fibrotic skin remodeling <em>in vitro</em> and <em>in vivo</em>.</p><p><em>In vitro</em>, effects of PDE4A-D (Roflumilast) or PDE4B (siRNA) inhibition on TGFβ1-induced myofibroblast differentiation and dedifferentiation were studied in normal (NHDF) and keloid (KF) human dermal fibroblasts. <em>In vivo,</em> the role of PDE4 on HOCl-induced skin fibrosis in mice was addressed in preventive and therapeutic protocols.</p><p>PDE4B (mRNA, protein) was increased in Keloid &gt; HTS compared to healthy skin and in TGFβ-stimulated NHDF and KF. In Keloid &gt; HTS, collagen Iα1, αSMA, TGFβ1 and NOX4 mRNA were all elevated compared to healthy skin confirming skin fibrosis.</p><p><em>In vitro</em>, inhibition of PDE4A-D and PDE4B similarly prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and myofibroblast differentiation, elevated NOX4 protein and proliferation in NHDF. PDE4A-D inhibition enabled myofibroblast dedifferentiation and curbed TGFβ1-induced reactive oxygen species and fibroblast senescence. In KF PDE4A-D inhibition restrained TGFβ1-induced Smad3 and ERK1/2 phosphorylation, myofibroblast differentiation and senescence. Mechanistically, PDE4A-D inhibition rescued from TGFβ1-induced loss in PPM1A, a Smad3 phosphatase. <em>In vivo</em>, PDE4 inhibition mitigated HOCl-induced skin fibrosis in mice in preventive and therapeutic protocols.</p><p>The current study provides novel evidence evolving rationale for PDE4 inhibitors in skin fibrosis (including keloids and HTS) and delivered evidence for a functional role of PDE4B in this fibrotic condition.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111211"},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0009279724003570/pdfft?md5=c52d7886ca65adaa356dd924285ccbe0&pid=1-s2.0-S0009279724003570-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into the effects of organometallic ruthenium complexes on nicotinic acetylcholine receptors","authors":"Tomaž Trobec ,&nbsp;Nicolas Lamassiaude ,&nbsp;Evelyne Benoit ,&nbsp;Monika Cecilija Žužek ,&nbsp;Kristina Sepčić ,&nbsp;Jerneja Kladnik ,&nbsp;Iztok Turel ,&nbsp;Rómulo Aráoz ,&nbsp;Robert Frangež","doi":"10.1016/j.cbi.2024.111213","DOIUrl":"10.1016/j.cbi.2024.111213","url":null,"abstract":"<div><p>Nicotinic acetylcholine receptors (nAChRs) are expressed in excitable and non-excitable cells of the organism. Extensive studies suggest that nAChR ligands have therapeutic potential, notably for neurological and psychiatric disorders. Organometallic ruthenium complexes are known to inhibit several medically important enzymes such as cholinesterases. In addition, they can also interact with muscle- and neuronal-subtype nAChRs. The present study aimed to investigate the direct effects of three organometallic ruthenium complexes, [(η⁶-<em>p</em>-cymene)Ru(II)(5-nitro-1,10-phenanthroline)Cl]Cl (<strong>C1–Cl</strong>), [(η⁶-<em>p</em>-cymene)Ru(II)(1-hydroxypyridine-2(1<em>H</em>)-thionato)Cl] (<strong>C1a</strong>) and [(η⁶-<em>p</em>-cymene)Ru(II)(1-hydroxy-3-methoxypyridine-2(1<em>H</em>)-thionato)pta]PF₆ (<strong>C1</strong>), on muscle-subtype (<em>Torpedo</em>) nAChRs and on the two most abundant human neuronal-subtype nAChRs in the CNS (α4β2 and α7) expressed in <em>Xenopus laevis</em> oocytes, using the two-electrode voltage-clamp. The results show that none of the three compounds had agonistic activity on any of the nAChR subtypes studied. In contrast, <strong>C1–Cl</strong> reversibly blocked <em>Torpedo</em> nAChR (half-reduction of ACh-evoked peak current amplitude by 332 nM of compound). When tested at 10 μM, <strong>C1–Cl</strong> was statistically more potent to inhibit <em>Torpedo</em>nAChR than α4β2 and α7 nAChRs. Similar results of <strong>C1</strong> effects were obtained on <em>Torpedo</em> and α4β2 nAChRs, while no action of the compound was detected on α7 nAChRs. Finally, the effects of <strong>C1a</strong> were statistically similar on the three nAChR subtypes but, in contrast to <strong>C1–Cl</strong> and <strong>C1</strong>, the inhibition was hardly reversible. These results, together with our previous studies on isolated mouse neuromuscular preparations, strongly suggest that <strong>C1–Cl</strong> is, among the three compounds studied, the only molecule that could be used as a potential myorelaxant drug.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111213"},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative in vitro and in silico analysis of the ability of basic Asp49 phospholipase A2 and Lys49-phospholipase A2-like myotoxins from Bothrops diporus venom to inhibit the metastatic potential of murine mammary tumor cells and endothelial cell tubulogenesis","authors":"Daniela J. Sasovsky ,&nbsp;Emilio Angelina ,&nbsp;Laura C. Leiva ,&nbsp;Elisa Bal de Kier Joffé ,&nbsp;Bruno Lomonte ,&nbsp;Soledad Bustillo","doi":"10.1016/j.cbi.2024.111217","DOIUrl":"10.1016/j.cbi.2024.111217","url":null,"abstract":"<div><p>Snake venoms are a complex mixture of proteins and polypeptides that represent a valuable source of potential molecular tools for understanding physiological processes for the development of new drugs. In this study two major PLA₂s, named PLA₂-I (Asp49) and PLA₂-II (Lys49), isolated from the venom of <em>Bothrops diporus</em> from Northeastern Argentina, have shown cytotoxic effects on LM3 murine mammary tumor cells, with PLA₂-II-like exhibiting a stronger effect compared to PLA₂-I. At sub-cytotoxic levels, both PLA₂s inhibited adhesion, migration, and invasion of these adenocarcinoma cells. Moreover, these toxins hindered tubulogenesis in endothelial cells, implicating a potential role in inhibiting tumor angiogenesis. All these inhibitory effects were more pronounced for the catalytically-inactive toxin. Additionally, <em>in silico</em> studies strongly suggest that this PLA₂-II-like myotoxin could effectively block fibronectin binding to the integrin receptor, offering a dual advantage over PLA₂-I in interacting with the <strong><em>α</em></strong>V<strong><em>β</em></strong>3 integrin. In conclusion, this study reports for the first time, integrating both <em>in vitro</em> and <em>in silico</em> approaches, a comparative analysis of the antimetastatic and antiangiogenic potential effects of two isoforms, an Asp49 PLA₂-I and a Lys49 PLA₂-II-like, both isolated from <em>Bothrops diporus</em> venom.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111217"},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142088294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring changes in the zeta potential and the surface charge of human glioblastoma cells and phosphatidylcholine liposomes induced by curcumin as a function of pH","authors":"Joanna Kotyńska,&nbsp;Monika Naumowicz","doi":"10.1016/j.cbi.2024.111215","DOIUrl":"10.1016/j.cbi.2024.111215","url":null,"abstract":"<div><p>Curcumin (CUR) has received worldwide attention for its beneficial effects on human health. Research report possible cytotoxic activity against various cancers, including glioblastoma. So far, little attention has been given to the binding properties of CUR to lipid membranes, which influences their electrical characteristics and can provide insight into their membrane-permeation abilities. Biophysical interactions between the polyphenol and <em>in vitro</em> models (liposomes and LN-18 human glioblastoma cells) were investigated by monitoring zeta potential and the membrane's surface charge as a function of pH. We focused on practical measurements and undertook a theoretical analysis of interactions in the natural cell membrane. We used the MTT assay to evaluate the viability of CUR-treated cells. Measurements performed using the Electrophoretic Light Scattering method demonstrated the dose-dependent effect of CUR on both membrane surface charge and zeta potential analyzed <em>in vitro</em> models. We determined theoretical parameters characterizing the cell membrane based on a quantitative description of the adsorption equilibria formed due to the binding of solution ions to the membrane of glioblastoma cells. The interaction of CUR with liposomes and human cancer cells is pH-dependent.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111215"},"PeriodicalIF":4.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of MSH6 augments the antineoplastic efficacy of cisplatin in non-small cell lung cancer as autophagy modulator","authors":"Ayşegül Varol ,&nbsp;Joelle C. Boulos ,&nbsp;Chunmei Jin ,&nbsp;Sabine M. Klauck ,&nbsp;Anatoly Zhitkovich ,&nbsp;Thomas Efferth","doi":"10.1016/j.cbi.2024.111193","DOIUrl":"10.1016/j.cbi.2024.111193","url":null,"abstract":"<div><p>The altered response to chemotherapeutic agents predominantly stems from heightened single-point mutations within coding regions and dysregulated expression levels of genes implicated in drug resistance mechanisms. The identification of biomarkers based on mutation profiles and expression levels is pivotal for elucidating the underlying mechanisms of altered drug responses and for refining combinatorial therapeutic strategies in the field of oncology. Utilizing comprehensive bioinformatic analyses, we investigated the impact of eight mismatch repair (MMR) genes on overall survival across 23 cancer types, encompassing more than 7500 tumors, by integrating their mutation profiles. Among these genes, <em>MSH6</em> emerged as the most predictive biomarker, characterized by a pronounced mutation frequency and elevated expression levels, which correlated with poorer patient survival outcomes.</p><p>The wet lab experiments disclosed the impact of <em>MSH6</em> in mediating altered drug responses. Cytotoxic assays conducted revealed that the depletion of <em>MSH6</em> in H460 non-small lung cancer cells augmented the efficacy of cisplatin, carboplatin, and gemcitabine. Pathway analyses further delineated the involvement of <em>MSH6</em> as a modulator, influencing the delicate equilibrium between the pro-survival and pro-death functions of autophagy.</p><p>Our study elucidates the intricate interplay between <em>MSH6</em>, autophagy, and cisplatin efficacy, highlighting <em>MSH6</em> as a potential therapeutic target to overcome cisplatin resistance. By revealing the modulation of autophagy pathways by <em>MSH6</em> inhibition, our findings offer insights into novel approaches for enhancing the efficacy of cisplatin-based cancer therapy through targeted interventions.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111193"},"PeriodicalIF":4.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food additive salicylates inhibit human and rat placental 3β-hydroxysteroid dehydrogenase: 3D-QSAR and in silico analysis","authors":"Xiulian Yang ,&nbsp;Shaowei Wang ,&nbsp;Yunbing Tang ,&nbsp;Yingfen Ying ,&nbsp;Yang Zhu ,&nbsp;Congde Chen ,&nbsp;Ren-shan Ge ,&nbsp;Miaoqing Liu","doi":"10.1016/j.cbi.2024.111203","DOIUrl":"10.1016/j.cbi.2024.111203","url":null,"abstract":"<div><p>The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3β-HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3β-HSD4. Salicylates inhibited h3β-HSD1, depending on carbon chain number in the alcohol moiety and the IC₅₀ values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 μM, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 μM. Interestingly, only hexyl salicylate inhibited r3β-HSD4 with IC₅₀ of 31.05 μM. Bivariate analysis revealed a negative correlation between IC₅₀ and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3β-HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3β-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111203"},"PeriodicalIF":4.7,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute lead (Pb2+) exposure increases calcium oxalate crystallization in the inner medullary collecting duct, and is ameliorated by Ca2+/Mg2+-ATPase inhibition, as well as Capa receptor and SPoCk C knockdown in a Drosophila melanogaster model of nephrolithiasis","authors":"Penelope Pando,&nbsp;Anoushka S. Vattamparambil,&nbsp;Sanjana Sheth,&nbsp;Greg M. Landry","doi":"10.1016/j.cbi.2024.111201","DOIUrl":"10.1016/j.cbi.2024.111201","url":null,"abstract":"<div><p>Calcium oxalate (CaOx) kidney stones accumulate within the renal tubule due to high concentrations of insoluble deposits in the urine. Pb²⁺-induced Ca²⁺ mobilization along with Pb²⁺-induced nephrotoxic effects within the proximal tubule have been well established; however, Pb²⁺ mediated effects within the collecting duct remains insufficiently studied. Thus <em>in vitro</em> and <em>ex vivo</em> model systems were treated with increasing concentrations of lead (II) acetate (PbAc) ± sodium oxalate (Na₂C₂O₄) for 1 h, both individually and in combination. Pb²⁺-mediated solution turbidity increased 2 to 5 times greater post-exposure to 75, 100 and 200 μM Pb²⁺ with the additional co-treatment of 10 mM oxalate in mouse inner medullary collecting duct (mIMCD-3) cells. Additionally, 100 μM and 200 μM Pb²⁺ alone induced significant levels of intracellular Ca²⁺ release. To validate Pb²⁺-mediated effects on the formation of CaOx crystals, alizarin red staining confirmed the presence of CaOx crystallization. Pb²⁺-induced intracellular Ca²⁺ was also observed <em>ex vivo</em> in fly Malpighian tubules with significant increases in CaOx crystal formation via Pb²⁺-induced intracellular Ca²⁺ release significantly increasing the average crystal number, size, and total area of crystal formation, which was ameliorated by tissue-specific SPoCk C transporter and Capa receptor knockdown. These studies demonstrate Pb²⁺-induced Ca²⁺ release likely increases the formation of CaOx crystals, which is modulated by a G_q-linked mechanism with concurrent Ca²⁺ extracellular mobilization.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111201"},"PeriodicalIF":4.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141997111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of ALDH1A1 in glioblastoma proliferation and invasion","authors":"Yu-Kai Huang ,&nbsp;Tzu-Ming Wang ,&nbsp;Chi-Yu Chen ,&nbsp;Chia-Yang Li ,&nbsp;Shu-Chi Wang ,&nbsp;Khushboo Irshad ,&nbsp;Yuan Pan ,&nbsp;Kun-Che Chang","doi":"10.1016/j.cbi.2024.111202","DOIUrl":"10.1016/j.cbi.2024.111202","url":null,"abstract":"<div><p>High-grade gliomas, including glioblastoma multiforme (GBM), continue to be a leading aggressive brain tumor in adults, marked by its rapid growth and invasive nature. Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), an enzyme, plays a significant role in tumor progression, yet its function in high-grade gliomas is still poorly investigated. In this study, we evaluated <em>ALDH1A1</em> levels in clinical samples of GBM. We also assessed the prognostic significance of <em>ALDH1A1</em> expression in GBM and LGG (low grade glioma) patients using TCGA (The Cancer Genome Atlas) database analysis. The MTT and transwell assays were utilized to examine cell growth and the invasive capability of U87 cells, respectively. We quantitatively examined markers for cell proliferation (Ki-67 and cyclin D1) and invasion (MMP2 and 9). A Western blot test was conducted to determine the downstream signaling of ALDH1A1. We found a notable increase in <em>ALDH1A1</em> expression in high-grade gliomas compared to their low-grade counterparts. U87 cells that overexpressed ALDH1A1 showed increased cell growth and invasion. We found that ALDH1A1 promotes the phosphorylation of AKT, and inhibiting AKT phosphorylation mitigates the ALDH1A1's effects on tumor growth and migration. In summary, our findings suggest ALDH1A1 as a potential therapeutic target for GBM treatment.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"402 ","pages":"Article 111202"},"PeriodicalIF":4.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000927972400348X/pdfft?md5=b54593a8b7921cd38eb5e74a3cd20adc&pid=1-s2.0-S000927972400348X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}