Biology Direct[JOURNAL]
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200 papers
Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?
Peggion C, Marchionni I, Carafoli E … +2 more , Brini M, Calì T
Biol Direct · 2025 Nov · PMID 41199322 · Full text
Ca²⁺ signaling is essential for neuronal development, migration, synaptic activity, spine plasticity, neurotransmitter release, membrane excitability, and long-term synaptic plasticity, as well as for the coupling betwee...
Ca²⁺ signaling is essential for neuronal development, migration, synaptic activity, spine plasticity, neurotransmitter release, membrane excitability, and long-term synaptic plasticity, as well as for the coupling between membrane depolarization and downstream signaling. Traditionally, Plasma Membrane Ca²⁺ ATPases (PMCAs) were considered high-affinity, low-capacity calcium extruders. However, recent evidence reveals that the PMCA-Neuroplastin complex facilitates ultrafast Ca²⁺ clearance at kilohertz frequencies, reshaping our understanding of calcium regulation, in particular in neurons. For bulk Ca²⁺ clearance, they are overshadowed by more powerful low-affinity/high-capacity systems on the plasma membrane. This raises key questions: what is the specific physiological and pathological role of PMCAs? Why do cells require a high-affinity/low-capacity, ATP-dependent extrusion mechanism? What is the functional meaning of the diversity of isoforms (four) and splice variants (over thirty)? And why do neurons localize distinct PMCA pumps to pre- and postsynaptic sites? The prevailing hypothesis is that PMCAs fine-tune Ca²⁺ microdomains through local regulation and interactions with specific protein partners. Finally, understanding their role in Purkinje cells (PCs) is particularly relevant, as alterations in PMCA function have been implicated in cerebellar pathology and ataxia.
Horizontal transfer of matrix metalloproteinase genes links early animal and microbial evolution.
Parsons C, Fournier GP
Biol Direct · 2025 Nov · PMID 41194257 · Full text
BACKGROUND: The early evolution of animals is characterized by the emergence of complex tissues, organs, and integument, made possible in part by the diversification of groups of structural proteins. The abundance of thi...
BACKGROUND: The early evolution of animals is characterized by the emergence of complex tissues, organs, and integument, made possible in part by the diversification of groups of structural proteins. The abundance of this new kind of organic material in the environment would have provided novel nutrient opportunities for microbes, as part of the beginnings of animal-microbial coevolution. Indeed, a diverse ensemble of extant microbial groups appear to possess the enzymatic ability to cleave collagen, the most abundant animal-specific protein, through the use of matrix metalloproteinases (MMPs). In animals, MMPs serve to reshape the extracellular matrix in the course of development, but their prevalence in the microbial world has been largely overlooked. RESULTS: MMPs have extensive diversity in Bacteria, Eumetazoa, and Streptophyta. We show that in marine metagenomes, MMP abundance is highly correlated with chitinase abundance, implying that even microbial MMPs are associated with animal-derived substrates. Reconstructing the phylogeny of MMP proteins reveals a history of rapid diversification, as well as multiple interkingdom and interdomain horizontal gene transfers. Included among these is a transfer to the ancestral lineage of the archaeal family Methanosarcinaceae, constraining this group to postdate the evolution of collagen, and therefore animal diversification. CONCLUSIONS: MMPs have an unusual genetic history, marked by multiple instances of gene transfer between bacteria and multicellular eukaryotes, a smoking gun for some of the earliest coevolution between prokaryotes and metazoans. By calculating an end-Permian divergence of Methanosarcina, we demonstrate that the phylogenies of substrate-specific enzymes can provide valuable older-bound age calibrations for improving molecular clock age estimates across the Tree of Life.
Galectin-3 directs mitophagy in response to Parkin-/proteasome-dependent rupture of mitochondrial outer membrane.
Liu PH, Lin YS, Chu WH … +4 more , Sun WT, Huang PY, Huang JR, Chiang WC
Biol Direct · 2025 Nov · PMID 41194217 · Full text
PINK1/Parkin-dependent mitophagy is an intracellular process that selectively removes damaged, depolarized mitochondria. In this form of mitophagy, the mitochondrial outer membrane (OMM) undergoes focal rupture through a...
PINK1/Parkin-dependent mitophagy is an intracellular process that selectively removes damaged, depolarized mitochondria. In this form of mitophagy, the mitochondrial outer membrane (OMM) undergoes focal rupture through a Parkin- and proteasome-dependent mechanism, which consequently results in the exposure of mitochondrial inner membrane (IMM) mitophagy receptors. The OMM rupture marks the damaged mitochondria and ensures their proper disposal. However, our understanding of the molecular events triggered by OMM rupture remains limited. Here, our proteomic study revealed that Galectin-3, a member of the β-galactoside-binding protein family, is significantly enriched in the ruptured OMM of damaged mitochondria. Galectin-3 is necessary for mitophagy, and it relocalizes from the cytosol to enclose the damaged mitochondria in response to mitophagy induction. The mitochondrial recruitment of Galectin-3 is Parkin- and proteasome-dependent, suggesting that the enclosure of mitochondria by Galectin-3 is a consequence of OMM rupture during PINK1/Parkin-mediated mitophagy. Functionally, Galectin-3 interacts with IMM protein PHB2 and recruits autophagy initiation factors ULK1 on the damaged mitochondria. Importantly, mutations in key residues that confer the liquid-liquid phase separation (LLPS) properties of Galectin-3 abrogates its mitochondrial relocalization, ULK1 recruitment, and mitophagy, suggesting that the capacity to form biomolecular condensates around the damaged mitochondria is crucial for the mitophagy function of Galectin-3. While much of the prior research on Galectin-3 focused on its extracellular functions, our findings shed light on its previously underexplored intracellular functions on the mitochondria and illuminated a novel mechanism by which Galectin-3 senses the damaged mitochondria and maintains organellar quality control.
Comparative preclinical drug response analyses of T-prolymphocytic leukemia reveal no differences between known gene expression subgroups.
Mikhaylenko N, Braun T, Timonen S … +3 more , Mustjoki S, Herling M, Seifert M
Biol Direct · 2025 Oct · PMID 41146244 · Full text
BACKGROUND: T-prolymphocytic leukemia (T-PLL) is a rare mature T-cell neoplasm with poor prognosis that mainly affects elderly people. Alemtuzumab is widely considered as first-line therapy, but almost all patients relap...
BACKGROUND: T-prolymphocytic leukemia (T-PLL) is a rare mature T-cell neoplasm with poor prognosis that mainly affects elderly people. Alemtuzumab is widely considered as first-line therapy, but almost all patients relapse within one year, if not consolidated by an allogeneic stem cell transplantation. The improved understanding of T-PLL-specific molecular pathomechanisms gained over the last years suggested new potential therapeutic targets (epigenetic dysregulation, defective DNA damage response, aberrant cell cycle regulation, dysregulated prosurvival pathways), which were recently evaluated in a preclinical drug response study. In addition, existing genomewide T-PLL gene expression profiles enabled the identification of three robust T-PLL gene expression subgroups differing in cellular processes like immune response, cellular respiration, cell proliferation, apoptosis, or migration. So far, these T-PLL gene expression subgroups were not considered in preclinical drug response analyses, but recently published drug response screens and corresponding already publicly available gene expression profiles offer the great opportunity to integrate both data types. Therefore, we computationally analyzed samples from 34 T-PLL patients of two comparable cohorts for their response to in total 11 drugs. RESULTS: No T-PLL subgroup-specific differences or sex differences in response to the tested drugs were found. With respect to the underlying drug dosage schemes, venetoclax and cladribine were most effective in erasing T-PLL cancer cells among both cohorts. Also dinaciclib, idasanutlin, romidepsin, and KRT-232, which were only tested in one of both cohorts, were very effective for all or most of the T-PLL patient samples. For the three drugs bendamustine, cladribine, and fludarabine, which were only effective in a subset of the T-PLL samples, an exploratory differential gene expression analysis predicted drug-specific genes that distinguished between strongly and not strongly responding samples. In-depth annotation and literature analyses showed that many of these genes are known to play a role in leukemias or other types of cancer. Many of these genes were also confirmed by a direct correlation analysis between gene expression levels and drug responses. CONCLUSIONS: The absence of T-PLL gene expression subgroup-specific drug responses across the tested drugs can be important for the design of future drug screens and may ease potential clinical trials. Genes associated with drug-specific responses could be useful for improved patient stratification and may help to characterize molecular settings associated with effective responses. CLINICAL TRIAL NUMBER: Not applicable.
RGS16-driven cancer-associated fibroblasts promote esophageal squamous cell carcinoma progression via the MDK-SDC1 axis-mediated intercellular crosstalk.
Wu D, Cao M, Yang C … +5 more , Li W, Zhang D, Yao S, Yu H, Jiang G
Biol Direct · 2025 Oct · PMID 41094576 · Full text
BACKGROUND: Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME) and have important roles in carcinogenesis and metastasis by facilitating cancer cell proliferation, angiogenes...
BACKGROUND: Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME) and have important roles in carcinogenesis and metastasis by facilitating cancer cell proliferation, angiogenesis, extracellular matrix (ECM) remodeling, and drug resistance. The purpose of this study is to extensively describe CAFs in esophageal cancer (ESCA) and develop a CAF-based prognostic risk score to predict clinical outcomes in patients with ESCA. METHODS: Data for single-cell RNA sequencing (scRNA-seq) were collected from the GEO database. The GEO and TCGA databases provided the bulk RNA-seq data and microarray data for esophageal squamous cell carcinoma (ESCC), respectively. The Seurat R program was used to identify CAF clusters from scRNA-seq data. Univariate Cox regression analysis was then used to identify prognosis-related genes linked to CAFs. Using 65 machine learning algorithms, a risk signature was created using CAF-related prognosis genes. We investigated the relationships between the CAF-related gene risk score and clinical features, mutation landscape, immunotherapy response, and medication sensitivity. RESULTS: Using scRNA-seq analysis in ESCC, 4856 genes associated with CAF clusters were identified, 14 of which were selected to construct a prognostic risk signature. Functional validation revealed that overexpression of the regulator of G-protein signaling 16-nuclear factor (RGS16) in CAFs co-cultured with the ESCC cell line KYSE520 significantly increased cancer cell proliferation, invasion, and migration. The secreted midkine (MDK) coupled to its receptor syndecan1 (SDC1) on ESCC cells, further helping their malignant tendencies. CONCLUSIONS: Comprehensive assessment of CAF heterogeneity in ESCC sheds light into the mechanisms of immunotherapy resistance and suggests prospective options for creating novel treatment therapies. Furthermore, we demonstrate that RGS16+ CAFs promote ESCC progression through the nuclear factor kappa B(NF-κB)-MDK-SDC1 axis, highlighting their crucial involvement in tumor-stromal interaction. These findings emphasize the therapeutic potential of targeting RGS16+ CAFs, which presents a promising method for disrupting the tumor-promoting microenvironment and improving clinical outcomes in ESCC patients. CLINICAL TRIAL NUMBER: Not applicable.
Indispensable role of AcrEF in modulating Salmonella virulence and disrupting host tight junctions to facilitate paracellular entry and invasion.
Kirthika P, Senevirathne A, Jawalagatti V … +3 more , Park S, Kwon J, Lee JH
Biol Direct · 2025 Oct · PMID 41094502 · Full text
BACKGROUND: The Salmonella stress response regulator CpxR controls the AcrEF drug efflux pump, which is crucial for key virulence traits such as invasiveness and disruption of the host paracellular pathway. Understanding...
BACKGROUND: The Salmonella stress response regulator CpxR controls the AcrEF drug efflux pump, which is crucial for key virulence traits such as invasiveness and disruption of the host paracellular pathway. Understanding the role of acrEF and its regulation by CpxR can provide new insights into Salmonella pathogenesis and future therapeutic development. METHODS: We performed differential gene expression analysis using Salmonella enterica serovar Typhimurium (ST) wild-type and cpxR mutants to identify virulence-associated genes affected by the stress response system. The candidate genes acrE and acrF were deleted and used to evaluate virulence-related phenotypes, including adhesion, invasion, and epithelial barrier disruption both in vitro and in vivo, in wild-type and mutant strains. RESULTS: Deletion of acrEF in both ST wild-type and cpxR mutants significantly reduced Salmonella adhesion, invasion of multiple epithelial cell lines, and expression of virulence genes. It also led to enhanced tight junction integrity in epithelial cells, potentially via upregulation of genes like ZO-1, suggesting a novel invasion mechanism. The loss of acrEF function impaired the bacteria’s ability to breach host cell tight junctions, which directly correlated with attenuated invasion and survival in vivo. These effects were similarly observed in both wild-type and cpxR mutants, indicating a central role for acrEF in Salmonella virulence. CONCLUSION: The AcrEF efflux pump plays a key role in regulating Salmonella virulence, particularly in modulating tight junction disruption and epithelial invasion. Although CpxR may regulate acrEF expression, the loss of acrEF function independently results in significant attenuation of virulence. These findings reveal a critical pathway of Salmonella epithelial invasion mediated by the AcrEF system and regulated, in part, by the CpxR stress response regulator. CLINICAL TRIAL NUMBER: Not applicable.
Measles and public health: an integrative approach.
Branda F, Giovanetti M, Petrosillo N … +7 more , Ahmed MM, Perra M, Sanna D, Ceccarelli G, Ciccozzi M, Bucci E, Scarpa F
Biol Direct · 2025 Oct · PMID 41088248 · Full text
BACKGROUND: Measles, once considered under control in many high-income countries, has experienced a notable resurgence in recent years due to declining vaccination rates, increased vaccine hesitancy, and gaps in public h...
BACKGROUND: Measles, once considered under control in many high-income countries, has experienced a notable resurgence in recent years due to declining vaccination rates, increased vaccine hesitancy, and gaps in public health preparedness. This study provides an overview of the current measles outbreaks in two socio-culturally distinct realities, both facing a challenging epidemiological situation, i.e., the Region of the Americas and Italy, the European country most impacted after Romania. The aim is to understand transmission dynamics and identify factors contributing to outbreak severity. RESULTS: Epidemiological data show that Canada experienced an unprecedented increase in measles incidence, particularly in Ontario and Alberta, where spatial modelling revealed relative risks greater than 30 in high burden areas (i.e., the estimated likelihood of measles occurrence in these areas was more than 30 times higher than the national average, based on Bayesian spatial modeling). In Mexico, the epidemic was highly localised, with over 90% of cases and all but one death concentrated in the state of Chihuahua. In the United States, 89% of cases were linked to epidemic outbreaks, with Texas showing significant spatial clustering and daily growth rates of over 4% in high-risk counties. In Italy, the 2024 outbreak marked a significant increase in measles cases compared to previous years, primarily affecting unvaccinated individuals. Over 50% of those affected required hospitalization, and major urban regions such as Lazio and Lombardy experienced sustained transmission. An initial phase of exponential growth (66% monthly) was followed by a plateau, with no significant decline observed, underlining delays in containment and persistent immune deficiencies. From genetic point of view, the study revealed the predominance of genotype D8, known for sustained global circulation, suggesting a single transmission chain behind the recent outbreaks. Phylogenetic analysis showed no significant intra-genotypic diversification, suggesting that the outbreak likely originated from a single introduction event followed by rapid, localized transmission. This limited genetic variation is consistent with a short transmission window and the absence of strong evolutionary pressure. CONCLUSION: The outbreaks in the United States and Italy, despite differences in healthcare systems and sociopolitical contexts, reveal common underlying issues. In the U.S., the epidemic was characterized by clusters of unvaccinated individuals in certain communities, while Italy faced challenges due to gaps in routine immunization programs and delays in responding to the outbreak. Both outbreaks illustrate the devastating impact of under-vaccination, inadequate surveillance, and the spread of misinformation on public health. Our results contribute to a deeper understanding of the dynamics of measles recurrence, providing a solid basis for science-based prevention and control measures. Furthermore, the study emphasises the importance of continuous and integrated surveillance to detect emerging or divergent strains at an early stage. CLINICAL TRIAL NUMBER: Not applicable.
Structural and functional insights into Ubl domain-mediated regulation of SARS-CoV-2 PLpro.
Arya R, Ganesh J, Prashar V … +1 more , Kumar M
Biol Direct · 2025 Oct · PMID 41044763 · Full text
BACKGROUND: SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and immune evasion. It contains an N-terminal ubiquitin-like (Ubl) domain, whose involvement in enzymatic function remains poorly und...
BACKGROUND: SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and immune evasion. It contains an N-terminal ubiquitin-like (Ubl) domain, whose involvement in enzymatic function remains poorly understood. RESULTS: In this study, we investigated the role of the Ubl domain in modulating the structural dynamics and catalytic efficiency of PLpro. Using molecular dynamics (MD) simulations, inhibitor binding assays, and steady-state kinetic analyses, we found that the Ubl domain stabilizes critical structural elements, notably the ridge helix in the thumb subdomain. Removal of the Ubl domain altered substrate processing, reducing catalytic efficiency of the enzyme. Interestingly, free ubiquitin enhanced enzymatic activity, likely via non-canonical binding sites distinct from the SUb1 and SUb2 sites. CONCLUSION: These findings uncover a regulatory role for the Ubl domain in allosteric modulation of PLpro activity and reveal additional layers of enzymatic plasticity. Understanding these mechanisms could guide the design of future antiviral therapeutics targeting PLpro's regulatory or allosteric sites.
HMGA1 promotes the progression of lung adenocarcinoma through the STAT1-mediated transcriptional activation of DDAH1.
Hu T, Shi R, Yin S … +4 more , Xu T, Xu Y, Xu D, Shu Y
Biol Direct · 2025 Oct · PMID 41035072 · Full text
BACKGROUND: Advancements in precision oncology have generated increased interest in the prognostic and therapeutic capabilities of transcription factors, among which HMGA1 is significantly correlated with LUAD prognosis....
BACKGROUND: Advancements in precision oncology have generated increased interest in the prognostic and therapeutic capabilities of transcription factors, among which HMGA1 is significantly correlated with LUAD prognosis. However, our understanding of HMGA1 remains insufficient. This study seeks to elucidate the biological functions of HMGA1 and to investigate the underlying mechanisms. METHODS: The prognostic value of HMGA1 was validated across multiple independent patient cohorts with LUAD, and its impact on tumor proliferation was verified by both in vitro and in vivo models. A series of experiments were performed to investigate the underlying molecular mechanism, including RNA sequencing, co-immunoprecipitation and chromatin immunoprecipitation. RESULTS: HMGA1 plays a crucial role in promoting the proliferation of LUAD. The underlying mechanism involves the recruitment of STAT1 to the promoter region of DDAH1, which synergistically increases its transcription and subsequently activates the ADMA/NO signaling pathway. Notably, the STAT1 inhibitor fludarabine has been shown to effectively impede the progression of LUAD models characterized by high levels of HMGA1. CONCLUSION: Our research reveals a previously unrecognized mechanism through which the HMGA1/STAT1 complex facilitates LUAD proliferation by transcriptionally activating DDAH1. Moreover, we propose that fludarabine could serve as a promising therapeutic option for LUAD patients exhibiting elevated levels of HMGA1.
MINPP1 promotes ferroptosis in HBV-related hepatocellular carcinoma by regulating CTSB K33-linked deubiquitination via ZRANB1.
Chen W, Song Y, Wang L … +2 more , Xiong F, Zhang S
Biol Direct · 2025 Oct · PMID 41035046 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is significantly influenced by hepatitis B virus (HBV) infection. However, the roles of ferroptosis and ubiquitination modifications in this context remain poorly understood. ME...
BACKGROUND: Hepatocellular carcinoma (HCC) is significantly influenced by hepatitis B virus (HBV) infection. However, the roles of ferroptosis and ubiquitination modifications in this context remain poorly understood. METHODS: In this study, we utilized immunoprecipitation, immunofluorescence, and analysis of ubiquitin modifications to explore the regulatory mechanisms of MINPP1 in ferroptosis and its effects on tumor progression. Further mechanistic studies revealed that ZRANB1 regulates the K33-linked ubiquitination of CTSB. Ultimately, the contribution of the MINPP1-CTSB axis to tumor progression was validated using in vivo experiments. RESULTS: Our study demonstrates that MINPP1 regulates ferroptosis in HBV-positive HCC cells via a glycolytic bypass mechanism. Bioinformatics analysis indicates that MINPP1 stabilizes CTSB, thereby participating in the regulation of ferroptosis. Specifically, MINPP1 modulates K33-linked deubiquitination of CTSB through ZRANB1, which stabilizes CTSB expression and identifies its deubiquitination site. In contrast, the MINPP1-ZRANB1-CTSB axis does not regulate ferroptosis in HBV-negative HCC cells. However, upon the introduction of HBV into these cells, the MINPP1-ZRANB1-CTSB axis becomes active and promotes ferroptosis. Finally, in vivo assays showed that MINPP1 regulates tumor progression by regulating K33-linked ubiquitination of CTSB, thereby affecting ferroptosis levels. CONCLUSION: Our research showed outcomes suggest that the MINPP1-ZRANB1-CTSB axis promotes ferroptosis in HBV-positive HCC cells through glycolysis, emphasizing the function of MINPP1 in mediating ferroptosis in HBV-related HCC cells via CTSB deubiquitination modification. This provides valuable insights and a foundation for the treatment of HBV-associated HCC.
Phage-encoded protein PavP modulates Pseudomonas aeruginosa virulence by dual inhibition of growth and pathogenic traits.
Yang Y, Yan W, Zhao Y … +11 more , Gao T, Yang Y, Cao L, Tao R, Liu N, Yang Y, Liu Y, Li M, Liu L, Zhang Y, Wang T
Biol Direct · 2025 Sep · PMID 41029464 · Full text
Pseudomonas aeruginosa, one of the most prevalent pathogens, is notorious for its multidrug resistance, necessitating novel therapeutic strategies. Phage therapy has emerged as a promising alternative treatment strategy,...
Pseudomonas aeruginosa, one of the most prevalent pathogens, is notorious for its multidrug resistance, necessitating novel therapeutic strategies. Phage therapy has emerged as a promising alternative treatment strategy, which offers a dual advantage by directly killing bacteria and modulating host-pathogen interactions. Here, we identify PavP (PaoP5_160), a small protein encoded by bacteriophage PaoP5, which exhibits bacteriostatic activity on P. aeruginosa while altering virulence pathways at sub-inhibitory concentrations. Specifically, PavP impairs bacterial motility, enhances biofilm formation, and upregulates type 3 secretion system expression. The global transcriptome analysis shows that PavP modulates multiple pathways which participate in the pathogenicity and cell vitality of host bacteria. Crucially, in vivo virulence assays confirm that PavP attenuates P. aeruginosa pathogenicity. Our results reveal PavP as a multifunctional virulence modulator in P. aeruginosa, which highlights its potential as a dual-target antimicrobial agent capable of simultaneously restricting bacterial proliferation and disrupting virulence networks.
Necroptosis-driven T cell activation promotes IL-6-mediated PD-L1 upregulation in cholangiocarcinoma cells: IL-6 gene signature as a biomarker for chemo-immunotherapy response.
Lomphithak T, Duangthim N, Sonkaew S … +1 more , Jitkaew S
Biol Direct · 2025 Sep · PMID 40983928 · Full text
BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options. Despite the approval of chemotherapy and immune checkpoint inhibitors (ICIs) in clinical practice, treatment outcomes remai...
BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options. Despite the approval of chemotherapy and immune checkpoint inhibitors (ICIs) in clinical practice, treatment outcomes remain poor, largely due to the poorly immunogenic tumor microenvironment associated with this type of carcinoma. Necroptosis, an inflammatory form of programmed cell death, has emerged as a promising therapeutic target for stimulating antitumor immunity. Our previous study linked necroptosis to increased CD8 + T cell infiltration and T cell-induced PD-L1 expression in CCA cells, suggesting its role in enhancing ICI efficacy. However, the underlying mechanisms by which necroptosis-activated T cells induce PD-L1 expression remain unclear. Here, we investigate how necroptosis in CCA cells influences T cell response, which subsequently promotes PD-L1 expression, thus providing insights for optimizing necroptosis-based therapies in combination with ICIs. RESULTS: Conditioned medium from gemcitabine-induced necroptotic CCA cells triggers PBMC-derived T cell activation by upregulating the surface activation marker CD69 and promoting cytokine release, primarily IL-6 and IL-1β. This cytokine release subsequently induces PD-L1 expression in CCA cells via IL-6, as confirmed by IL-6 neutralizing antibodies. Furthermore, T cell killing assays demonstrated that pembrolizumab, an anti-PD-1 inhibitor, enhances T cell cytotoxicity against PD-L1-upregulated CCA cells. Additionally, bioinformatics analysis identified an IL-6 signaling-related gene signature associated with ICI responsiveness, suggesting potential biomarkers for personalized treatment strategies. CONCLUSION: This study highlights that necroptosis shapes the tumor immune microenvironment by promoting T cell activation and IL-6-mediated PD-L1 upregulation in CCA cells. These findings support the integration of necroptosis-based therapies with ICIs as a sequential chemo-immunotherapy strategy. Additionally, the identified IL-6 signaling-related gene signature may serve as a biomarker for patient stratification and personalized treatment in CCA.
Single-cell transcriptome analysis suggests cells of the tumor microenvironment as a major discriminator between brain and extracranial melanoma metastases.
Grützmann K, Seifert M
Biol Direct · 2025 Sep · PMID 40954493 · Full text
BACKGROUND: Despite therapeutic advances, metastatic melanoma, and particularly brain metastasis (MBM), remains a lethal burden for patients. Existing single-cell studies offer a more detailed view of melanoma and its mi...
BACKGROUND: Despite therapeutic advances, metastatic melanoma, and particularly brain metastasis (MBM), remains a lethal burden for patients. Existing single-cell studies offer a more detailed view of melanoma and its microenvironment, which is crucial to improve diagnosis and treatment. RESULTS: We here present a computational reanalysis of single-nucleus data comparing 15 MBM and 10 extracranial melanoma metastases (ECM), considering recent best practice recommendations. We used cell type-specific pseudobulking and omit imputation during patient integration to gain complementary insights. Interestingly, our analysis revealed high homogeneity in tumor cell expression profiles within and between MBM and ECM. However, MBM displayed even higher homogeneity but a more flexible energy metabolism, suggesting a specific metastatic adaptation to the putatively more restricted brain microenvironment. While tumor cells were homogeneous, the metastasis microenvironment, especially lymphocytes and related immune-tumor interaction pathways, exhibited greater divergence between MBM and ECM. Overall, this suggests that major differences between MBM and ECM are potentially driven by variations in their microenvironment. Finally, a comparison of single-cell data to previous bulk studies, including their deconvoluted putative cell types, showed significant differences, potentially causing divergent conclusions. CONCLUSION: Our study contributed to refine the understanding of differences between MBM and ECM, suggesting these are potentially more influenced by their local microenvironments. Future research and therapies could possibly focus on the metabolic flexibility of melanoma brain metastases and patient-specific immune pathway alterations.
Spleen granulopoiesis in psoriasis immune microenvironment aggravates psoriasis via IL-6/P-STAT3 signaling.
Shi F, Gong P, Huang S … +5 more , Zhu W, Shi C, Qi C, Lei Z, Ding Y
Biol Direct · 2025 Sep · PMID 40890773 · Full text
BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory condition characterized by significant neutrophil infiltration in the skin. Given that the spleen is the largest peripheral immune organ in the body, it is...
BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory condition characterized by significant neutrophil infiltration in the skin. Given that the spleen is the largest peripheral immune organ in the body, it is important to investigate whether it has any impact on skin inflammation in psoriasis. METHODS: To investigate this mechanism, a psoriatic mouse model was established by IMQ application. Flow cytometry and immunohistochemistry analyses were performed to determine the percentage of various immune cells in the spleen. The role of neutrophils was specifically assessed using the anti-Gr-1 antibody. Splenic granulopoiesis was evaluated using EdU labeling. To understand the spleen's role in skin inflammation, splenectomy was performed on the experimental mice. IL-6 levels were measured by ELISA, and P-STAT3 in neutrophils was detected via immunofluorescence. Further examination of IL-6's effects on neutrophil formation involved treating mice with IL-6 antibody. The severity of psoriasis was evaluated through histological staining and PASI scoring. RESULTS: Our study revealed that the spleens of psoriatic mice were enlarged compared to those of vehicle mice. Among immune cell populations, neutrophils showed the most significant changes, with marked increases in both spleen and skin of psoriatic mice and patients, contributing to disease progression. Post-splenectomy, neutrophil infiltration in the skin was reduced by approximately 60% in psoriatic mice. This indicates that the neutrophils in the skin were primarily derived from the spleen. Additionally, the spleen showed a notable capacity for granulopoiesis with elevated neutrophils. Moreover, we found elevated IL-6 levels in the skin, blood, and spleen in the model, which was decreased after splenectomy. Treatment with an IL-6 antibody reduced neutrophil formation in both the spleen and skin, which alleviated skin inflammation in psoriatic mice. Additionally, P-STAT3 signaling was decreased following IL-6 antibody treatment. The neutrophil infiltration in spleen and skin was decreased after injection with the inhibitor of P-STAT3, which also alleviated the inflammation of psoriatic model. Thus, IL-6 served as the dominant regulator of spleen granulopoiesis, a process potentially mediated by P-STAT3 signaling. CONCLUSIONS: The spleen plays a crucial role in the immune microenvironment of psoriasis as a major site of granulopoiesis, influencing neutrophil infiltration in the skin of psoriatic mice. Additionally, IL-6 is a key regulator of neutrophil formation in the spleen of psoriatic mice, likely through P-STAT3-dependent mechanisms.
Evolution of cell therapies derived from adipose tissue: historical perspectives, current development trends and future directions.
Gandolfi S, Lupon E, Varin A … +5 more , Coste A, Sallerin B, Boyer C, Berkane Y, Chaput B
Biol Direct · 2025 Aug · PMID 40866969 · Full text
Over the last few decades, adipose tissue has attracted increasing attention in the field of regenerative medicine, thanks to discoveries related to its regenerative, anti-inflammatory, and pro-angiogenic properties. Ove...
Over the last few decades, adipose tissue has attracted increasing attention in the field of regenerative medicine, thanks to discoveries related to its regenerative, anti-inflammatory, and pro-angiogenic properties. Over the years, with the advancement of sophisticated research around adipose tissue, there has been a shift from tissue transfer to cell transfer, and then to the application of cell-free derivatives and bioengineering. Understanding the evolution of this scientific revolution around adipose tissue not only helps clarify potential therapeutic products and indications but also allows us to discuss its limitations and future directions.
Inhibition of PRC1 elicits immunogenic cell death by triggering ROS-dependent ER stress in colorectal cancer via the Wnt/β-catenin signaling pathway.
Wang W, Zhou L, Zhang X … +1 more , Li Z
Biol Direct · 2025 Aug · PMID 40847353 · Full text
Due to the low response rate and severe side effects, the clinical efficacy of current immunotherapy for patients with colorectal cancer (CRC) remains unsatisfactory. Induction of immunogenic cell death (ICD) has been ev...
Due to the low response rate and severe side effects, the clinical efficacy of current immunotherapy for patients with colorectal cancer (CRC) remains unsatisfactory. Induction of immunogenic cell death (ICD) has been evidenced to be conducive to enhancing the survival benefit of immune checkpoint blockade (ICB) therapy. Protein regulator of cytokinesis 1 (PRC1) has been proven to be a tumor promoter in CRC and an immune marker. However, whether and how PRC1 is involved in the ICD regulation in CRC remains undiscovered. The current study identified the upregulation of PRC1 in CRC tissues and its prognostic value via bioinformatics analyses. Similarly, we determined the close correlation between PRC1 and ICD. In addition, knockdown of PRC1 induced ICD and downregulated PD-L1 expression in CRC cells, which was attenuated by ER stress inhibitor 4-PBA. PRC1 silencing elicited ER stress, but this effect was partially rescued by the ROS scavenger N-acetylcysteine. Mechanism investigation revealed that PRC1 could stimulate Wnt/β-catenin activation in CRC cells. According to results of rescue assays, activation of Wnt/β-catenin by BML-284 could partially reverse the effects of PRC1 knockdown on ER stress and ICD in CRC cells. Finally, the in vivo experiments demonstrated that silencing of PRC1 restrained tumor growth in CRC animal models. In conclusion, this study verified that inhibition of PRC1 expression could induce ICD in CRC by triggering ER stress via the Wnt/β-catenin signaling pathway. These findings highlight a novel molecular pathway whereby PRC1 exerts carcinogenic role in tumor immune microenvironment through ICD in CRC.
Matrix stiffness induced gallbladder fibroblasts activation and paracrine SEMA7A promotes gallbladder cancer cell epithelial-mesenchymal transition and cancer stem cell-like properties by modulating AKT/p300 signalling.
Sun L, Wang H, Li H … +8 more , Yang R, Dong X, Dong D, Fan Y, Li E, Wang H, Wu Y, Shi Y
Biol Direct · 2025 Aug · PMID 40830485 · Full text
BACKGROUND & AIMS: Gallbladder cancer (GBC) is characterised by a desmoplastic microenvironment rich in collagen fibres and extracellular matrix, contributing to increased matrix stiffness. SEMAs are overexpressed in var...
BACKGROUND & AIMS: Gallbladder cancer (GBC) is characterised by a desmoplastic microenvironment rich in collagen fibres and extracellular matrix, contributing to increased matrix stiffness. SEMAs are overexpressed in various cancers but their expression and role in the crosstalk between activated gallbladder fibroblasts (GFs) and GBC cells within a stiff microenvironment remain unclear. Herein, we aimed to elucidate the expression patterns and tumour-promoting effects of SEMAs in activated GFs under the matrix stiffness microenvironment. METHODS: Masson staining assessed collagen deposition in GBC stroma. GFs were isolated from gallbladder tissues and cultured on silicon or polyacrylamide hydrogels. SEMA expression in GFs under different stiffness conditions was determined via RNA-seq and RT-qPCR. Transwell assays, tumorsphere-formation and Western blot assays were used to investigate the effects of GFs-derived SEMA7A on GBC epithelial-mesenchymal transition (EMT) and cancer stem-like traits. Subcutaneous tumour models were established by co-injecting GFs and GBC cells to assess SEMA7A's role in vivo. Co-immunoprecipitation, WB, Elisa and mutation assays were employed to elucidate the mechanism of SEMA7A involvement in GFs-GBC cell crosstalk. RESULTS: This study revealed a high-stiffness microenvironment in GBC, inducing GFs activation and SEMA7A paracrine through YAP/TAZ signalling. GFs-secreted SEMA7A under matrix stiffness microenvironment promoted GBC EMT and cancer stem-like traits. Mechanistically, GFs-secreted SEMA7A bound to its receptor integrin β1 instead of plexinC1 on GBC cells to induce the phosphorylation of p300 at S1834 and maintain the malignant phenotypes of GBC cells. Moreover, the SEMA7A/integrin β1 axis-induced p300 phosphorylation at S1834 was mediated by Akt activation (p-Akt at S473) in GBC cells. CONCLUSIONS: Our findings demonstrate a complex stiffness/SEMA7A/integrin β1/AKT/p300 cascade mediating reciprocal interactions between GFs and GBC cells, offering a potential therapeutic target for patients with GBC.
High oxidative phosphorylation represented by UQCRFS1 marks CD8 + tumor-infiltrating lymphocytes exhaustion in diffuse large B-cell lymphoma.
Yang Y, Shu Y, Qin Z … +5 more , Zeng Y, Chen K, Liu X, Jian S, Zhu Q
Biol Direct · 2025 Aug · PMID 40804681 · Full text
BACKGROUND: Metabolic alterations are closely associated with the exhaustion and immune deficiency of CD8 tumor-infiltrating lymphocytes (TILs), while little is known about diffuse large B-cell lymphoma (DLBCL). This stu...
BACKGROUND: Metabolic alterations are closely associated with the exhaustion and immune deficiency of CD8 tumor-infiltrating lymphocytes (TILs), while little is known about diffuse large B-cell lymphoma (DLBCL). This study aimed to elucidate the significance of the metabolic alterations in exhausted CD8TILs and its underlying regulatory mechanism in DLBCL. METHODS: The metabolic alterations in exhausted CD8TILs in DLBCL were evaluated through single-cell RNA sequencing (scRNA-seq). The crucial metabolic pathway and its significance in the biological function of exhausted CD8TILs were investigated by scRNA-seq and RNA sequencing. The marker gene in crucial metabolic pathway, and its correlations between exhaustion status, the tumor microenvironment (TME) composition, clinicopathological characteristics, prognosis, and immune checkpoint blockade (ICB) therapy efficacy were evaluated by scRNA-seq, RNA sequencing, immunohistochemistry, and RT-qPCR. Furthermore, the underlying regulatory mechanism involved in the metabolic alteration related to CD8TILs exhaustion was explored through scRNA-seq, RNA sequencing, and somatic mutation analysis. RESULTS: Our study illustrated the metabolic heterogeneity in CD8TILs, and demonstrated that oxidative phosphorylation (OXPHOS) was the crucial pathway in CD8TILs exhaustion. The high OXPHOS activity indicated the immune deficiency in exhausted CD8TILs, and UQCRFS1 was identified as a marker gene. High UQCRFS1 indicated the immunosuppressive TME, severe clinicopathological characteristics, including activated B-cell-like subtype, high IPI and PS score, advanced stage, dismal prognosis, and resistance to ICB therapy. Furthermore, MYC-related signaling and P2RY8 mutation in DLBCL may regulate the UQCRFS1 expression in exhausted CD8TILs. CONCLUSIONS: Our study highlights the importance of OXPHOS activity in CD8TILs exhaustion and suggests its possible regulatory mechanism, which is feasible in clinical evaluation and beneficial for novel immunotherapeutic approaches in DLBCL.
mA methylation-mediated lncRNA RNF144A-AS1 promotes hepatocellular carcinoma progression through the miR-1301-3p/RNF38 pathway.
Kong M, Li W, Li H … +4 more , Jing Y, Xu M, He Y, Guo W
Biol Direct · 2025 Jul · PMID 40734179 · Full text
BACKGROUND: Globally, HCC is still one of the most common cancers. N6-methyladenosine (mA) modifications and long-stranded noncoding RNAs (lncRNAs) play key roles in regulating HCC progression. The role of the lncRNA RNF...
BACKGROUND: Globally, HCC is still one of the most common cancers. N6-methyladenosine (mA) modifications and long-stranded noncoding RNAs (lncRNAs) play key roles in regulating HCC progression. The role of the lncRNA RNF144A-AS1, a newly identified lncRNA, in HCC is unclear. METHODS: In HCC, RNF144A-AS1 expression level and its effect on prognosis were investigated by bioinformatics. CCK-8, EdU, scratch assay, and Transwell assays were used to detect the impact of RNF144A-AS1 on hepatocellular carcinoma malignancy. Assays using MeRIP-qPCR, RIP, and Actinomycin D were used to study the effects of mA methylation on hepatocellular carcinoma malignant phenotypes. Revealing the potential mechanism of action of RNF144A-AS1 by luciferase reporter gene assay, PCR, and Western blot assays, and Nude mice subcutaneous load cell and lung metastasis models were used to verify the effect of RNF144A-AS1 on the malignant phenotype of tumors in vivo. RESULTS: The lncRNA RNF144A-AS1 was significantly upregulated in HCC, and it was significantly associated with poor prognosis. Functionally, HCC cells with RNF144A-AS1 knockdown were inhibited in terms of proliferation, migration, and invasion. Further studies in vivo confirmed that RNF144A-AS1 knockdown inhibited tumor cell growth and metastasis. Mechanistically, METTL3 increased the mA modification and stability of RNF144A-AS1 in an IGF2BP1-associated manner. In addition, RNF144A-AS1 was inhibited by sponge-like miR-1301-3p to inhibit RNF38 degradation, thereby promoting the HCC malignant phenotype. CONCLUSION: The RNF144A-AS1 gene is affected by METTL3/IGF2BP1 methylation and encourages liver cancer proliferation and metastasis by increasing expression of RNF38 through sponge-like miR-1301-3p. RNF144-AS1 promises to be a therapeutic target for HCC.
The genus Akkermansia is populated by a multitude of biological species with a wide distribution in the animal kingdom.
Molteni C, Forni D, Cagliani R … +1 more , Sironi M
Biol Direct · 2025 Jul · PMID 40707972 · Full text
BACKGROUND: The mucin-degrading bacterium Akkermansia muciniphila has attracted enormous interest for its beneficial effects on human health. However, growing evidence suggests that the Akkermansia genus is populated by...
BACKGROUND: The mucin-degrading bacterium Akkermansia muciniphila has attracted enormous interest for its beneficial effects on human health. However, growing evidence suggests that the Akkermansia genus is populated by several species that differ in phenotypic characteristics and association with human traits. RESULTS: We present the most comprehensive phylotaxonomic analysis of Akkermansia genomes in terms of sample size and host representation. By applying approaches based on average nucleotide identities and on the biological species concept, we show that the Akkermansia genus comprises at least 31 species, 13 of which can be detected in humans. The largest species diversity is contributed by non-human and non-mouse animals, and limited evidence of species-specificity is evident, with several Akkermansia species detected in phylogenetically distant animals. Analysis of accessory gene content among species also failed to reveal species-specific or diet-specific associations, but rather reflected genome size. Thus, A. muciniphila and A. ignis have, on average, small genomes and retain a part of genes that characterize either A. massiliensis or A. sp004167605/A. biwaensis. Finally, investigation of the population structure of A. muciniphila, the species that has been more intensely investigated due to its effects on human health, clearly distinguished two phylogroups corresponding to AmIa and AmIb. However, analysis of laboratory mouse-derived genomes revealed that additional populations, specific to these animals, exist. Such populations show limited evidence of admixture, suggesting bottleneck or competition effects. CONCLUSIONS: Our data support the concept that the genetic diversity of Akkermansia should be taken into account in experimental settings. They also call for sequencing efforts to characterize the wider genetic diversity of Akkermansia bacteria.
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