Biological Research最新文献

{"title":"Uncovering leading compounds for alzheimer's disease treatment: mendelian randomization and virtual screening insights into plasma protein modulation.","authors":"Xiaohan Sun, Xiaofei Hu, Jianming Wei, Haoyu An","doi":"10.1186/s40659-025-00598-2","DOIUrl":"10.1186/s40659-025-00598-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder influenced by both genetic and environmental factors. Identifying therapeutic targets and interventions remains challenging. This study utilized Mendelian Randomization (MR) to investigate causal relationships between plasma proteins, lifestyle factors, and AD, along with virtual screening to identify potential drug compounds. A two-sample MR analysis assessed associations between plasma proteins, identified through genome-wide association studies (GWAS), and AD risk. Co-localization analysis (CA) confirmed the overlap between protein expression and AD susceptibility loci, and reverse MR ruled out reverse causality. A protein-protein interaction (PPI) network was constructed to explore therapeutic targets, followed by virtual screening to identify small-molecule inhibitors for selected proteins. The analysis found significant associations between eight plasma proteins and AD, with five proteins (GSTP1, BIN1, Siglec-3, SERPINF2, and GRN) showing strong evidence of involvement in AD pathogenesis. Virtual screening identified six compounds as potential inhibitors of GSTP1 and four compounds as potential inhibitors of BIN1. Furthermore, MR analysis of lifestyle factors, such as dietary behaviors and smoking cessation, indicated they may influence AD risk through their effects on specific proteins. These findings offer novel insights into the genetic mechanisms underlying AD and highlight the potential of combining MR with virtual screening to identify therapeutic targets. The study also suggests that lifestyle modifications could offer alternative prevention and treatment strategies for AD. Future research should focus on the experimental validation of the identified compounds and further explore the mechanisms linking lifestyle factors to AD.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"19"},"PeriodicalIF":4.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of two KCND3 variants associated with SCA 19/22 ataxia in Latin American families.","authors":"Felipe Arancibia, Fernanda Martin, Jenny Ruiz-Fuentes, Erbio Diaz, Tamara Hermosilla, Wendy Gonzalez, Felipe Simon, Diana Avila-Jaque, Mariana Luna-Álvarez, David José Dávila Ortiz de Montellano, Marcelo Miranda, M Leonor Bustamante, Diego Varela","doi":"10.1186/s40659-025-00589-3","DOIUrl":"10.1186/s40659-025-00589-3","url":null,"abstract":"<p><strong>Background: </strong>Spinocerebellar ataxia 19/22 (SCA19/22) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19/22 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. To date, 22 variants have been reported worldwide, with incomplete functional studies.</p><p><strong>Results: </strong>We present four Chilean and Mexican cases in whom two single-nucleotide variants were identified through whole-exome sequencing of the probands. One variant (G371R) was initially cataloged as pathogenic and the other (S357W) as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. The pathogenicity of the G371R variation was confirmed by in-silico mutagenesis. Our molecular models, that include electrostatic potential analysis and algorithms to analyze the pore dimensions (HOLE), indicated that the longer side chain of the arginine narrowed the channel's selectivity filter, while the positive charge modified its surface electrostatic potential, presumably preventing potassium flux. Functional characterization of the S357W variant was performed in AD293 cells. When overexpressed, K_V4.3^S357W channels alone showed no current. Protein electrophoresis revealed that the total number of K_V4.3 channels expressed did not differ between the wild-type and mutated phenotypes, suggesting a protein trafficking malfunction. Co-expression of the KChIP2 auxiliary subunit partially rescued the potassium currents when the variant was expressed, albeit with very different biophysical characteristics, including faster inactivation vs. wild-type channels.</p><p><strong>Conclusions: </strong>This functional characterization of two KCND3 variants associated with SCA19/22 adds new evidence for the pathogenic role of Kv4.3 loss-of-function mutations and establishes a correlation between functional dominance and clinical severity in SCA19/22.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"18"},"PeriodicalIF":4.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactive and evolutionary effect of CASZ1 gene variants on varicose veins susceptibility in South Asian Indians.","authors":"Rohit Mehra, Vikram Patra, Rishi Dhillan, Dattatraya Cvnm, Hemender Singh, Love Gupta, Garima Rastogi, Indu Sharma, Varun Sharma","doi":"10.1186/s40659-025-00599-1","DOIUrl":"10.1186/s40659-025-00599-1","url":null,"abstract":"<p><strong>Background: </strong>Varicose veins (VV) are spectrum of common vascular diseases having complex genetic etiology. The Castor Zinc Finger 1 (CASZ1) gene has been involved in vascular development and its variant has shown association with VV in various ethnicities, but CASZ1 susceptibility to VV risk is unexplored in the South Asian Indian population. The objective of this study was to estimate the association of the CASZ1 gene variations and VV susceptibility in the South Asian Indians, and to examine the evolutionary patterns of these variants compared to other populations.</p><p><strong>Methodology: </strong>Population based case control analysis was conducted on all CASZ1 variants present in the Global Screening Array, including the established VV variant rs11121615 with a focus on validating and identification of both novel and established genetic markers to capture a full spectrum of population-specific genetic markers unique to studied population group. Linkage disequilibrium patterns and cumulative variant effects were also analyzed, followed by selection pressure assessment using neutrality tests.</p><p><strong>Results: </strong>Three CASZ1 variants rs72860191 (OR 1.58, 95% CI 1.07-2.32, p = 0.01), rs7519604 (OR 1.43, 95% CI 1.05-1.94, p = 0.01), and rs11121615 (OR 0.69, 95% CI 0.50-0.95, p = 0.02) were observed to be significantly associated with VV. Haplotype analysis identified unique haplotype structure of South Asian Indians compared to other global populations. Moreover, the cumulative OR was observed to be higher than the independently estimated values (OR = 2.41, 95% CI 1.48-3.94), indicating genotypic epistasis of VV associated variants. The neutrality tests revealed balancing selection within CASZ1 in the studied population compared to other populations, CONCLUSION: The present study identified CASZ1 variants and their epistatic interactions is associated with VV susceptibility supported with evidence of balancing selection, provides crucial insights into the genetic architecture of VV in studied group, highlighting the impact of evolutionary forces on disease susceptibility.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"17"},"PeriodicalIF":4.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the synergistic effect of metformin and FX11 on PANC-1 cell lines.","authors":"Melike Bayindir-Bilgic, Ezgi Duman, Deniz Turgut, Ayse Naz Kadikoylu, Nur Ekimci-Gurcan, Utku Ozbey, Aysegul Kuskucu, Omer F Bayrak","doi":"10.1186/s40659-025-00592-8","DOIUrl":"10.1186/s40659-025-00592-8","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer is among the most aggressive and malignant tumors and is a leading cause of cancer-related mortality. It is characterized by its metabolic Warburg effect and glucose dependence. Aerobic glycolysis is a key feature of metabolic reprogramming in cancer cells. This study investigates the combined effect of metformin and FX11, hypothesizing that disrupting cancer cell energetics through complementary mechanisms may result in a synergistic therapeutic effect. The combination of metformin and FX11 affects the axis that regulates vital functions in cancer cells; thus, the uncontrolled growth of tumor cells, especially those that use a lactose-dependent energy pathway, can be controlled. Several in vitro experiments were conducted to evaluate this hypothesis. PANC-1 cell proliferation was assessed using an MTS assay, lactate levels were measured via an LDH assay, and apoptosis was determined using a flow cytometry-based PE-annexin V assay. The downstream effects of metformin and FX11 treatment were evaluated via western blot analysis.</p><p><strong>Results: </strong>The findings of this study revealed that metformin and FX11 significantly decreased the viability of PANC-1 cells when used in combination, and this effect was achieved by significantly affecting the energy mechanism of the cells through the AMPKα axis. Furthermore, the lactate levels in PANC1 cells co-treated with metformin and FX11 were significantly decreased, while the increased cellular stress led the cells to apoptosis.</p><p><strong>Conclusions: </strong>Compared with metformin treatment alone, the combination treatment of metformin and FX11 stimulates cellular stress in pancreatic cancer and targets various energy processes that encourage cancer cells to undergo apoptosis. This study provides a novel therapeutic strategy for the treatment of pancreatic cancer.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"15"},"PeriodicalIF":4.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the mechanisms of PD-L1 expression in gastric cancer: a review.","authors":"Peifeng Chen, Zhangming Chen, Wannian Sui, Wenxiu Han","doi":"10.1186/s40659-025-00597-3","DOIUrl":"10.1186/s40659-025-00597-3","url":null,"abstract":"<p><p>In the progression of gastric cancer (GC), various cell types in the tumor microenvironment (TME) exhibit upregulated expression of programmed death ligand 1 (PD-L1), leading to impaired T-cell function and evasion of immune surveillance. Infection with H. pylori and EBV leads to increased PD-L1 expression in various cell types within TME, resulting in immune suppression and facilitating immune escape of GC cells. In the TME, mesenchymal stem cells (MSCs), M1-like tumor-associated macrophages (MI-like TAM), and myeloid-derived suppressor cells (MDSCs) contribute to the upregulation of PD-L1 expression in GC cells. Conversely, mast cells, M2-like tumor-associated macrophages (M2-like TAM), and tumor-associated neutrophils (TANs) exhibit elevated levels of PD-L1 expression in response to the influence of GC cells. Together, these factors collectively contribute to the upregulation of PD-L1 expression in GC. This review aims to provide a comprehensive summary of the cellular expression patterns of PD-L1 in GC and the underlying molecular mechanisms. Understanding the complex regulatory pathways governing PD-L1 expression may offer novel insights for the development of effective immunotherapeutic interventions.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"16"},"PeriodicalIF":4.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective role of extracellular vesicles against oxidative DNA damage.","authors":"Jordi Ribas-Maynou, Ana Parra, Pablo Martínez-Díaz, Camila Peres Rubio, Xiomara Lucas, Marc Yeste, Jordi Roca, Isabel Barranco","doi":"10.1186/s40659-025-00595-5","DOIUrl":"10.1186/s40659-025-00595-5","url":null,"abstract":"<p><strong>Background: </strong>Oxidative stress, a source of genotoxic damage, is often the underlying mechanism in many functional cell disorders. Extracellular vesicles (EVs) have been shown to be key regulators of cellular processes and may be involved in maintaining cellular redox balance. Herein, we aimed to develop a method to assess the effects of EVs on DNA oxidation using porcine seminal plasma extracellular vesicles (sEVs).</p><p><strong>Results: </strong>The technique was set using a cell-free plasmid DNA to avoid the bias generated by the uptake of sEVs by sperm cells, employing increasing concentrations of hydrogen peroxide (H₂O₂) that generate DNA single-strand breaks (SSBs). Because SSBs contain a free 3'-OH end that allow the extension through quantitative PCR, such extension -and therefore the SYBR intensity- showed to be proportional to the amount of SSB. In the next stage, H₂O₂ was co-incubated with two size-differentiated subpopulations (small and large) of permeabilized and non-permeabilized sEVs to assess whether the intravesicular content (IC) or the surface of sEVs protects the DNA from oxidative damage. Results obtained showed that the surface of small sEVs reduced the incidence of DNA SSBs (P < 0.05), whereas that of large sEVs had no impact on the generation of SSBs (P > 0.05). The IC showed no protective effect against DNA oxidation (P > 0.05).</p><p><strong>Conclusions: </strong>Our results suggest that the surface of small sEVs, including the peripheral corona layer, may exert a protective function against alterations that are originated by oxidative mechanisms. In addition, our in vitro study opens path to detect, localize and quantify the protective effects against oxidation of extracellular vesicles derived from different fluids, elucidating their function in physiopathological states.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"14"},"PeriodicalIF":4.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocannabinoid system upregulates the enrichment and differentiation of human iPSC- derived spermatogonial stem cells via CB2R agonism.","authors":"Merve Gizer, Selin Önen, Özgür Doğuş Erol, Fatima Aerts-Kaya, Tuba Reçber, Emirhan Nemutlu, Petek Korkusuz","doi":"10.1186/s40659-025-00596-4","DOIUrl":"10.1186/s40659-025-00596-4","url":null,"abstract":"<p><strong>Background: </strong>Male factor infertility (MFI) is responsible for 50% of infertility cases and in 15% of the cases sperm is absent due to germ cell aplasia. Human induced pluripotent stem cell (hiPSC)-derived spermatogonial stem cells (hSSCs) could serve as an autologous germ cell source for MFI in patients with an insufficient sperm yield for assisted reproductive technology (ART). The endocannabinoid system (ECS) has been implicated to play a role in mouse embryonic stem cells (mESCs) and the human testicular environment. However, the contribution of the ECS in hiPSCs and hiPSC-derived hSSCs is currently unknown. Here, we aimed to assess whether hiPSCs and hiPSC-derived hSSCs are regulated by components of the ECS and whether manipulation of the ECS could increase the yield of hiPSC-derived SSCs and serve as an autologous cell-based source for treatment of MFI.</p><p><strong>Methods: </strong>We reprogrammed human dermal fibroblasts (hDFs) to hiPSCs, induced differentiation of hSSC from hiPSCs and evaluated the presence of ECS ligands (AEA, 2-AG) by LC/MS, receptors (CB1R, CB2R, TRPV1, GPR55) by qPCR, flow cytometry and immunofluorescent labeling. We then examined the efficacy of endogenous and synthetic selective ligands (ACPA, CB65, CSP, ML184) on proliferation of hiPSCs using real-time cell analysis (RTCA) and assessed the effects of on CB2R agonism on hiPSC pluripotency and differentiation to hSSCs.</p><p><strong>Results: </strong>hiPSCs from hDFs expressed the pluripotency markers OCT4, SOX2, NANOG, SSEA4 and TRA-1-60; and could be differentiated into ID4+, PLZF + hSSCs. hiPSCs and hiPSC-derived hSSCs secreted AEA and 2-AG at 10^- 10 - 10^- 9 M levels. Broad expression of all ECS receptors was observed in both hiPSCs and hiPSC-derived hSSCs, with a higher CB2R expression in hSSCs in comparison to hiPSCs. CB2R agonist CB65 promoted proliferation and differentiation of hiPSCs to hiPSC-hSSCs in comparison to AEA, 2-AG, ACPA, CSP and ML184. The EC₅₀ of CB65 was determined to be 2.092 × 10^- 8 M for support of pluripotency and preservation of stemness on hiPSCs from 78 h. CB65 stimulation at EC₅₀ also increased the yield of ID4 + hSSCs, PLZF + SSPCs and SCP3 + spermatocytes from day 10 to 12.</p><p><strong>Conclusions: </strong>We demonstrated here for the first time that stimulation of CB2R results in an increased yield of hiPSCs and hiPSC-derived hSSCs. CB65 is a potent CB2R agonist that can be used to increase the yield of hiPSC-derived hSSCs offering an alternative source of autologous male germ cells for patients with MFI. Increasing the male germ/stem cell pool by CB65 supplementation could be part of the ART-associated protocols in MFI patients with complete germ cell aplasia.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"13"},"PeriodicalIF":4.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small extracellular vesicles enhance the survival of Sca-1+ cardiac stem cells against ROS-induced ischemic-reoxygenation injury in vitro.","authors":"Radwa A Mehanna, Hagar Elkafrawy, Marwa M Essawy, Samar S Ibrahim, Ashraf K Awaad, Nehal A Khalil, Marwa A Kholief, Abeer Sallam, Heba A Hamed, Mona A Barkat, Mohamed F ElKady, Eman H Thabet","doi":"10.1186/s40659-025-00593-7","DOIUrl":"10.1186/s40659-025-00593-7","url":null,"abstract":"<p><strong>Background: </strong>Ischemic reperfusion (IR) generates reactive oxygen species (ROS) that inevitably result in myocardial cell death and heart failure. The regenerative power of cardiac progenitor/stem pools (CSCs), especially the Sca1⁺ population, in response to IR injury remains unclear.</p><p><strong>Methods: </strong>Our work sought to investigate whether small extracellular vesicles (sEVs) isolated from bone marrow-mesenchymal stem cells (BMMSCs) could rescue CSCs, specifically Sca-1+/CSCs, from IR by increasing their proliferative capacity and limiting their apoptosis in vitro. The Sca-1+/CSCs-IR model was induced by the oxygen-glucose deprivation/reoxygenation method (OGD/R). The effects of treatment with BMMSCs-derived sEVs on oxidative stress, cell proliferation, apoptosis, and cell cycle were assessed. To further test the mechanistic action, we assessed the PTEN/pAkt/HIF-1α pathway.</p><p><strong>Results: </strong>Compared to hypoxic untreated CSCs, BMMSCs-derived sEVs-treated cells had shifted from their quiescent to proliferative phase (p > 0.05) and showed decreased apoptosis (p < 0.001). sEVs-treated CSCs were predominately in the S phase (11.8 ± 0.9%) (p < 0.01). We identified an abundance of miRNA-21-5P in BMMSCs. HIF-1α expression was highest in CSCs treated with sEVs (p < 0.05). Moreover, miRNA-21-5p-rich sEVs shifted the redox state, reducing oxidative stress and promoting balance (p > 0.05).</p><p><strong>Conclusion: </strong>Conditioning Sca-1+/CSCs, an essential population in the postnatal heart, with sEVs rich in miRNA-21 robustly enhanced the proliferation, and synthesis phase of the cell cycle, and stabilized HIF-1α while alleviating oxidative stress and apoptosis. Such sEVs rich in miRNA-21-5p can be further used as a preconditioning tool to enhance endogenous Sca-1+/CSCs regeneration in response to IR injury.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"12"},"PeriodicalIF":4.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin regulates in a cell-type specific manner light-evoked response and synaptic activity in mouse retinal ganglion cells.","authors":"Claudia Di Berardino, Sebastián F Estay, Alejandro Alcaino, Andrés E Chávez","doi":"10.1186/s40659-025-00594-6","DOIUrl":"10.1186/s40659-025-00594-6","url":null,"abstract":"<p><strong>Background: </strong>Serotonin (5-HT) is known to be synthesized and accumulated in the vertebrate retina through the 5-HT transporter, SERT. While manipulation of the serotonergic system has been shown to impact visual processing, the role of 5-HT and SERT as modulators of retinal synaptic function remains poorly understood.</p><p><strong>Results: </strong>Using mouse retinal slices, we show that acute application of 5-HT produces a cell-type specific reduction in light-evoked excitatory responses (L-EPSC) in ON-OFF retinal ganglion cells (RGCs), but not in ON RGCs. Similarly, increasing 5-HT tone by acute application of citalopram, a selective 5-HT reuptake inhibitor, also reduces L-EPSC in ON-OFF RGCs while not affecting ON RGCs. Importantly, citalopram-mediated reduction of L-EPSC was absent in ON-OFF RGCs recorded from SERT null retina, highlighting the role of SERT in regulating light-evoked responses in RGCs. The effects of both exogenous and endogenous 5-HT on L-EPSC in ON-OFF RGCs are likely due to a presynaptic reduction in excitatory synaptic strength as 5-HT and citalopram reduced the frequency but not the amplitude of spontaneous excitatory currents (sEPSCs) in ON-OFF RGCs. Moreover, 5-HT and citalopram had no effect on currents elicited by the direct activation of postsynaptic receptors in RGCs by brief application of glutamate in the inner retina.</p><p><strong>Conclusions: </strong>Altogether these findings indicate that 5-HT modulates excitatory inputs onto RGCs in a cell-type specific manner and highlight that in the adult mouse retina, 5-HT-mediated effects onto RGCs are tightly controlled by the 5-HT transporter SERT.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"11"},"PeriodicalIF":4.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium electroporation induces stress response through upregulation of HSP27, HSP70, aspartate β-hydroxylase, and CD133 in human colon cancer cells.","authors":"Anna Szewczyk, Nina Rembiałkowska, Jolanta Saczko, Małgorzata Daczewska, Vitalij Novickij, Julita Kulbacka","doi":"10.1186/s40659-025-00591-9","DOIUrl":"10.1186/s40659-025-00591-9","url":null,"abstract":"<p><strong>Background: </strong>Electroporation (EP) leverages electric pulses to permeabilize cell membranes, enabling the delivery of therapeutic agents like calcium in cancer treatment. Calcium electroporation (CaEP) induces a rapid influx of calcium ions, disrupting cellular calcium homeostasis and triggering cell death pathways. This study aims to compare the cellular responses between microsecond (µsEP) and nanosecond (nsEP) electroporation, particularly in terms of oxidative stress, immune response activation, and cancer stem cell (CSC) viability in drug-resistant (LoVo Dx) and non-resistant (LoVo) colorectal cancer cell lines.</p><p><strong>Results: </strong>Both µsEP and nsEP, particularly when combined with Ca²⁺, significantly reduced the viability of cancer cells, with nsEP showing greater efficacy. Reactive oxygen species (ROS) levels increased 5-fold in malignant cells following nsEP, correlating with decreased ATP production and mitochondrial dysfunction. Nanosecond CaEP (nsCaEP) also induced significant expression of aspartate-β-hydroxylase (ASPH), a protein linked to calcium homeostasis and tumor progression. Moreover, nsEP led to heightened expression of heat shock proteins (HSP27/70), indicating potential immune activation. Interestingly, nsEP without calcium drastically reduced the expression of CD133, a marker for CSCs, while the addition of Ca²⁺ preserved CD133 expression. The expression of death effector domain-containing DNA binding protein (DEDD), associated with apoptosis, was significantly elevated in treated cancer cells, especially in the nucleus after nsCaEP.</p><p><strong>Conclusions: </strong>The study confirms that nsEP is more effective than µsEP in disrupting cancer cell viability, enhancing oxidative stress, and triggering immune responses, likely through HSP overexpression and ROS generation. nsEP also appears to reduce CSC viability, offering a promising therapeutic approach. However, preserving CD133 expression in the presence of calcium suggests complex interactions that require further investigation. These findings highlight the potential of nsCaEP as an innovative strategy for targeting both cancer cells and CSCs, potentially improving treatment outcomes in colorectal cancer. Further studies are needed to explore the exact cell death mechanisms and optimize protocols for clinical applications.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"58 1","pages":"10"},"PeriodicalIF":4.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}