Biology Direct[JOURNAL]
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200 papers
Obesity-associated lysosomal nitrosative stress promotes retinopathy.
Qian Q, Zhang Z, Li M … +2 more , Sebag SC, Yang L
Biol Direct · 2026 Feb · PMID 41736124 · Full text
BACKGROUND: Obesity and diabetes are major risk factors causing vision loss around the world, yet the molecular mechanisms linking obesity to retinal pathology remain incompletely understood. While chronic inflammation a...
BACKGROUND: Obesity and diabetes are major risk factors causing vision loss around the world, yet the molecular mechanisms linking obesity to retinal pathology remain incompletely understood. While chronic inflammation and dysregulated vascular endothelial growth factor (VEGF) signaling are established contributors to retinopathy, their integration within the context of obesity has not been fully elucidated. METHODS: Retinal transcriptomic RNA sequencing datasets from patients with type 2 diabetes mellitus (T2DM) and obese mouse models were retrieved from the GEO database. Meta-analysis was performed using MetaVolcanoR to identify differentially expressed genes associated with obesity- and diabetes-related retinal alterations. The functional impact of cathepsin B (CTSB) S-nitrosylation on retinal VEGF expression was investigated in diet-induced obese wild-type and transgenic mouse models through molecular and biochemical approaches, including biotin switch assay, ELISA, and quantitative RT-PCR, etc. RESULTS: We conducted a meta-analysis of retinal transcriptomic datasets from T2DM patients and obese mouse models and found that obesity promotes retinal inflammation and vascular endothelial cell proliferation and migration signatures. These transcriptomic profiles were further confirmed by biochemical analysis and gene expression analysis in mice with diet-induced obesity. Moreover, we demonstrated that obesity increased retinal inducible nitric oxide synthase (iNOS) expression but suppressed S-nitrosoglutathione reductase (GSNOR) activity, two essential regulators for nitrosative stress. At the cellular level, we showed that obesity promoted retinal lysosomal nitrosative stress, leading to impaired retinal CTSB activity, a critical lysosomal enzyme. Of note, in the context of obesity, the nitrosative stress-promoted lysosomal impairment is correlated with an accumulation of retinal VEGF. Functionally, suppression of nitrosative stress by iNOS deletion reduced retinal VEGF expression and restored retinal lysosomal function in obese mice. In contrast, elevation of nitrosative stress by GSNOR deletion in obese mice worsened the retinal lysosomal nitrosative stress and lysosomal enzymatic defects. CONCLUSION: Our findings identify lysosomal nitrosative stress as a pivotal mediator that links obesity-driven inflammation to impaired VEGF homeostasis in the retina, thereby advancing our understanding of the molecular underpinnings of obesity-associated retinopathy.
LDN-57444 sensitizes hepatocellular carcinoma cells to sorafenib by promoting ferroptosis through histone deacetylase 2 (HDAC2) inhibition.
Lin JC, Huang TS, Chen YB … +4 more , Chen TY, Wu PS, Liu TP, Yang PM
Biol Direct · 2026 Feb · PMID 41689036 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is still one of the leading causes of cancer-related mortality worldwide. Sorafenib is commonly used as first-line systemic treatment for advanced HCC, but the clinical benefits...
BACKGROUND: Hepatocellular carcinoma (HCC) is still one of the leading causes of cancer-related mortality worldwide. Sorafenib is commonly used as first-line systemic treatment for advanced HCC, but the clinical benefits fall victim to either primary or acquired drug resistance. Modulating ferroptosis, a form of iron-dependent regulated cell death (RCD), has been increasingly explored in order to circumvent this chemoresistance. METHODS: We performed a pharmacogenomic screening analysis using the DepMap database to identify small molecules whose cytotoxicity patterns resemble those of known ferroptosis inducers. Among the candidates, LDN-57444 was selected for further evaluation. Its ability to enhance the anticancer activity of sorafenib was examined in PLC/PRF/5 and Hep3B HCC cell lines using cell viability assays, molecular docking, cellular thermal shift assays (CETSA), and siRNA-mediated gene silencing. RESULTS: In the HCC models tested, sorafenib alone did not induce ferroptosis, unlike some earlier reports. LDN-57444, previously described as an inhibitor of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), emerged as a strong ferroptosis sensitizer. Co-treatment with LDN-57444 and sorafenib led to pronounced synergistic cytotoxicity, and this effect was completely abolished by the ferroptosis inhibitor ferrostatin-1. Mechanistic analyses showed that the synergy is independent of UCH-L1. Structural modeling and target-engagement experiments indicated that histone deacetylase 2 (HDAC2) is the relevant molecular target. Silencing HDAC2, but not HDAC1, reduced sensitivity to the drug combination, supporting the idea that LDN-57444 enhances sorafenib activity by modulating HDAC2. CONCLUSION: Our findings demonstrate that LDN-57444 potentiates sorafenib-induced ferroptosis in HCC cells through an HDAC2-dependent mechanism. These results highlight the therapeutic potential of combining HDAC2 inhibitors with sorafenib to improve treatment responses in advanced HCC.
Comprehensive analysis of the causal risk factor from hypertension associated with prognosis and therapeutic response in renal cell carcinoma by multi-omics analysis and validation.
Chen WJ, Liu ZC, Yang W … +10 more , Zhao WJ, Chen JX, Gan SS, Dong KQ, Lu X, Miao K, Cao J, Pan XW, Luo P, Cui XG
Biol Direct · 2026 Feb · PMID 41680825 · Full text
BACKGROUND: Hypertension is one of the known renal cell carcinoma (RCC)-associated factors. However, the gene expression patterns in hypertension tissues and the mechanisms of hypertension and RCC comorbidity have not be...
BACKGROUND: Hypertension is one of the known renal cell carcinoma (RCC)-associated factors. However, the gene expression patterns in hypertension tissues and the mechanisms of hypertension and RCC comorbidity have not been fully analyzed. This study aims to use single-cell RNA sequencing (scRNA-seq) integrated with multi-omics to explore RCC-associated hypertension gene modules and the causative relationship between key genes and the risk of RCC. METHODS: Heterogenic expression programs in cross-species scRNA-seq tissues were classified by non-negative matrix factorization (NNMF) using scRNA-seq data from aortic tissues of hypertensive patients and spontaneously hypertensive rats (SHR). Molecular subtyping was performed using the bulk-seq and whole exome sequencing (WES) data of pan-cancer and RCC from TCGA. The Lasso-cox machine model was used to explore the predictors of survival and drug response in both TCGA, ICGC, E-MTAB-1980 and IMmotion 151 cohort. A total of 19 tissues were applied to perform scRNA-seq and then test the key gene expression. Finally, summary-data-based Mendelian Randomization (SMR) was used to verify the expression level of genes and traits of hypertension and RCC based on summary-level data from GWAS and expression quantitative trait loci (eQTL) studies. Two independent cohorts of European with GWAS summary statistics were used: hypertension cohort (119,731 cases and 343,202 controls) and RCC cohort (600 cases and 455,676 controls). RESULTS: scRNA-seq analysis revealed that the cross-species HTN-gene module consisted of 48 genes, which could classify the 523 patients into two subgroups with different survival and responses to targeted therapies. The results were then validated in three independent ccRCC cohorts. The core gene-panel scores were significantly different in vascular endothelial cells (P < 0.01), which also distinguished the cells from resistant and hypertensive tumor cells (both P < 0.001). SMR analysis demonstrated that TNXB was a reliable causative factor of hypertension and the RCC risk factor in hypertension (pSMR = 0.0029) and RCC (pSMR = 0.0031). CONCLUSIONS: The results of the present study demonstrated that the HTN key genes were involved in the development of RCC and may represent potential therapeutic targets for the management of this complex disease.
Urea transporter evolution: deep conservation, recent adaptation in mammals, and maintenance of the Jka/Jkb polymorphism in the past ~ 110,000 years.
Cagliani R, Pozzoli U, Forni D … +2 more , Mozzi A, Sironi M
Biol Direct · 2026 Feb · PMID 41673754 · Full text
Urea is a central metabolite and many organisms encode membrane integral urea transporters (UTs). Here, we combined motif homology searches, phylogenetics, and molecular evolution with paleogenomics to investigate the ev...
Urea is a central metabolite and many organisms encode membrane integral urea transporters (UTs). Here, we combined motif homology searches, phylogenetics, and molecular evolution with paleogenomics to investigate the evolutionary dynamics of UTs from prokaryotes to human populations. We discovered previously unknown combinations of UT domains with other functional modules in metazoa, protists, and bacteria, suggesting a wider range of functions and regulatory mechanisms for UTs than previously understood. The early origin of UT domains allowed the identification of specific residues that have remained conserved across billions of years. Contestually, we found evidence that UT-B was a target of positive selection in mammals. In particular, selection targeted UT-B in bats, primates and rodents, possibly as the result of a pressure exerted by blood pathogens. In human populations, a single variant (Asp280Asn) in the UT-B protein is responsible for the common Kidd blood group antigens. Here we provide direct evidence for the temporal stability of the Asp280Asn polymorphism over ~ 110,000 years in Europe and Asia. While we previously proposed this variant to be under balancing selection, this study is the first to use ancient DNA to track its allele frequency through deep time. This novel application of paleogenomics confirms that the polymorphism was maintained at stable frequencies over time, in different European sub-regions, and across continents. Our data show how paleogenomics can provide information on the selective processes in humans, not only limited to directional selection, but also to balancing selection.
Retraction Note: Regulating ferroptosis by non-coding RNAs in hepatocellular carcinoma.
Sun L, Cao H, Wang Y … +1 more , Wang H
Biol Direct · 2026 Feb · PMID 41664212 · Full text
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A dopaminergic projection from the ventral tegmental area to the dorsal raphe nucleus critically regulates propofol anesthesia in mice.
He J, Yao T, Guo H … +5 more , He H, Tian Z, Ma K, Yin J, Li Y
Biol Direct · 2026 Feb · PMID 41656256 · Full text
General anesthesia induces a reversible loss of consciousness, yet the precise neural circuits mediating this state transition remain incompletely understood. The ventral tegmental area (VTA) dopaminergic (DA) neurons an...
General anesthesia induces a reversible loss of consciousness, yet the precise neural circuits mediating this state transition remain incompletely understood. The ventral tegmental area (VTA) dopaminergic (DA) neurons and the dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons are key components of the ascending arousal system. This study investigated the existence and functional role of VTADA→DRN5-HT circuit in regulating propofol anesthesia. Using virus-mediated neural circuit tracing in DAT-Cre and TPH2-CreER transgenic mice, we demonstrated an anatomically connected circuit appositions between VTADA axon terminals and DRN5-HT neurons. In vivo fiber photometry revealed that the activity of both presynaptic VTADA terminals in the DRN and postsynaptic DRN5-HT neurons was significantly suppressed under propofol anesthesia. Chemogenetic activation of either VTADA or DRN5-HT neurons facilitated emergence from propofol anesthesia, whereas their inhibition prolonged the duration of anesthesia. Optogenetic activation of VTADA terminals within the DRN rapidly induced behavioral and electroencephalographic (EEG) arousal from stable propofol anesthesia. Crucially, this pro-arousal effect was abolished by chemogenetic inhibition of DRN5-HT neurons, indicating a functional hierarchy. These findings identify a putative direct pathway VTADA→DRN5-HT circuit that bidirectionally regulates propofol anesthesia, providing a novel neural substrate for conscious state control and a potential target for therapeutic interventions.
CircADAM9 activates autophagy via miR-302b-3p/ULK1 axis to improve depressive-like behaviors.
Liu S, Yu S
Biol Direct · 2026 Feb · PMID 41654935 · Full text
BACKGROUND: Depression is a prevalent mental disorder, and its pathogenesis has not yet been fully elucidated. Circular RNAs (CircRNAs) have exhibit critical regulatory role in depression, while Unc-51-like kinase 1 (ULK...
BACKGROUND: Depression is a prevalent mental disorder, and its pathogenesis has not yet been fully elucidated. Circular RNAs (CircRNAs) have exhibit critical regulatory role in depression, while Unc-51-like kinase 1 (ULK1)-mediated autophagy participates in the pathophysiology of the disorder. Nevertheless, the potential involvement of circRNAs in modulating ULK1-mediated autophagy in depression remains unclear. OBJECTIVES: This study aimed to identify depression-associated circRNAs regulating ULK1-medaited autophagy, and uncover the underlying mechanisms. METHODS: The depression model was established in mice using chronic unpredictable mild stress (CUMS) procedure. RNA sequencing and bioinformatics analysis were carried out to screen signaling pathways, circRNAs and microRNAs (miRNAs) related to depression. Overexpression and knockdown of circRNAs or miRNAs were conducted by lentivirus microinjection and cell transfection. The depression-like phenotypes were assessed through behavioral tests. Western blot, immunofluorescence and transmission electron microscopy (TEM) were employed to evaluated ULK1-mediated autophagy. RNA pull-down and dual-luciferase reporter assay was executed to explore the underlying mechanisms. RESULTS: CircADAM9 exhibited the most significant downregulation in CUMS mice among the differentially expressed circRNAs. Overexpression of circADAM9 relieved depressive-like behaviors, and promoted ULK1-mediated autophagy in vivo and in vitro. Importantly, circADAM9 sponged miR-302b-3p to regulate Ulk1 gene expression, and miR-302b-3p mimics diminished the behavioral improvements and pro-autophagic effect modulated by circADAM9. CONCLUSION: We identified circADAM9 as a novel regulator in depression, which activated autophagy via miR-302b-3p/ULK1 axis to improve depressive-like behaviors. Our findings would provide a new potential therapeutic target for the treatment of depression.
Radix Rehmanniae Preparata polysaccharide promoted zebrafish heart regeneration by activating the IFN-γ/NF-κB signaling axis.
Yan Y, Tao K, Xie H … +7 more , Zhou H, Wu Q, Pu S, Li D, Guo Z, Zhou Z, Xu S
Biol Direct · 2026 Feb · PMID 41630084 · Full text
Radix Rehmanniae Praeparata polysaccharide (RRPP), a primary bioactive component of the traditional Chinese medicine Rehmannia, possesses diverse pharmacological activities including immunomodulatory effects. While its c...
Radix Rehmanniae Praeparata polysaccharide (RRPP), a primary bioactive component of the traditional Chinese medicine Rehmannia, possesses diverse pharmacological activities including immunomodulatory effects. While its cardioprotective potential has been noted, the role of RRPP in promoting cardiac regeneration and the underlying mechanisms remain largely unexplored. Using a zebrafish cardiac cryoinjury model, we demonstrated that RRPP administration significantly enhanced heart regeneration by promoting cardiomyocyte proliferation and dedifferentiation. This regenerative effect was coupled with an accelerated inflammatory response, marked by increased infiltration of L-Plastin+ leukocytes and T cells, and a rapid induction of IFN-γ expression at the injury site. Disruption of IFN-γ signaling, either pharmacologically with the antagonist creatine or genetically in ifng1r+/− heterozygous mutants, severely impaired innate regenerative capacity and abrogated the benefits of RRPP. Transcriptomic profiling revealed that RRPP activates the NOD-like receptor (NLR) signaling pathway, which is associated with the upregulation of NF-κB. Crucially, pharmacological inhibition of NF-κB with aspirin attenuated heart regeneration, and this inhibition was effectively rescued by co-treatment with RRPP. Our findings unveil a novel mechanism whereby RRPP facilitates zebrafish heart regeneration, which is associated with the orchestration of an inflammatory response centered on the IFN-γ/NF-κB signaling axis. This study not only elucidates a pro-regenerative function of RRPP but also highlights the potential of modulating specific inflammatory pathways as a therapeutic strategy for heart repair.
Revealing FPR1 as a potential pathogenic biomarker for aortic dissection based on Mendelian randomization, single-cell transcriptome and clinical data analysis.
Liu Z, Ran H, Tang Y … +6 more , Li L, Gao Z, Li Z, Xie Y, Zeng Q, Yu F
Biol Direct · 2026 Jan · PMID 41620799 · Full text
BACKGROUND: Aortic dissection is characterized by immune cell infiltration and vascular inflammation, yet its molecular mechanisms remain unclear. This study investigates the role of immune-related genes in AD pathogenes...
BACKGROUND: Aortic dissection is characterized by immune cell infiltration and vascular inflammation, yet its molecular mechanisms remain unclear. This study investigates the role of immune-related genes in AD pathogenesis. METHODS: We integrated Mendelian randomization and transcriptomic analyses to identify AD-associated genetic risk genes. Immune infiltration and functional enrichment analyses were applied to explore monocyte and neutrophil involvement. Key genes were validated in human and mouse aortic tissues, and FPR1’s role was assessed using Cyclosporin H treatment. Clinical correlation between FPR1 expression and prognosis was evaluated. RESULTS: Eight highly differentially expressed genes were identified, with FPR1 showing predominant expression in myeloid cells. Single-cell and bulk RNA-seq revealed immune cell accumulation in AD tissues, where FPR1 correlated with monocyte/neutrophil activation and enhanced vascular inflammation. FPR1 upregulation in AD tissues accompanied increased neutrophil activation markers (TNF-α, IL-1β, IL-6, CCL2). FPR1 inhibition suppressed ERK1/2 pathway activation, reduced IL-1β production, and attenuated AD severity in mice. Clinically, elevated FPR1 levels were associated with disease severity and predicted poor postoperative outcomes, with significantly higher expression in 30-day non-survivors. CONCLUSION: FPR1 plays a critical role in AD pathogenesis by promoting myeloid immune cell activation and vascular inflammation, highlighting its potential as a therapeutic target and prognostic biomarker.
Acrylamide disrupts meiotic G2/M transition and SAC activity during oocyte maturation.
Chen S, Wang PX, Wang YT … +5 more , Ke XH, Ou M, Sun SC, Liao BY, Chen X
Biol Direct · 2026 Jan · PMID 41618314 · Full text
Acrylamide is a synthetic material which is widely used in water treatment and paper manufacturing, and it is also generated from food formation, which shows neurological effects, skin irritation, or reproductive toxicit...
Acrylamide is a synthetic material which is widely used in water treatment and paper manufacturing, and it is also generated from food formation, which shows neurological effects, skin irritation, or reproductive toxicity. Several studies focused on the effects of acrylamide on mitochondria and apoptosis in oocytes. In present study, we reported that acrylamide disturbed cell cycle progression of mouse oocyte meiosis. Our data showed that acrylamide caused both germinal vesicle (GV) breakdown and polar body extrusion defects. Further analysis indicated that acrylamide induced DNA damage in the GV oocytes, showing with increased γ-H2A.X expression, which active CHK2 for G2/M transition. This could be confirmed by the altered Cyclin B1 and CDK1 expression in oocytes. Besides, we found kinetochore-microtubule attachment was aberrant in metaphase I (MI) oocytes, which active spindle assembly checkpoint (SAC) for polar body extrusion, and this was confirmed by the consistent presentence of BubR1 and Bub3. This was due to the reduced tubulin acetylation-based microtubule stability, since HDAC6 and NAT10 expression was changed and cold treatment reduced the tubulin polymerization. Taken together, our study reported that acrylamide exposure disrupted cell cycle progression through DNA damage-based MPF activity and tubulin acetylation-based SAC activation in oocytes.
Robust SH2 binding affinity indicates minimal SH3-to-SH2 communication in Grb2.
Ventura ES, Di Felice M, Toso J … +3 more , Pennacchietti V, Toto A, Gianni S
Biol Direct · 2026 Jan · PMID 41578382 · Full text
Growth factor receptor–bound protein 2 (Grb2) is a modular adaptor that links activated receptor tyrosine kinases to downstream signaling pathways through its SH3–SH2–SH3 architecture. Previous studies showed that pertur...
Growth factor receptor–bound protein 2 (Grb2) is a modular adaptor that links activated receptor tyrosine kinases to downstream signaling pathways through its SH3–SH2–SH3 architecture. Previous studies showed that perturbations in the SH2 domain can influence ligand binding at the C-terminal SH3 domain, suggesting directional allosteric communication within the protein. Here, we tested whether the flanking SH3 domains, in turn, modulate SH2-mediated ligand recognition. Using a parallel mutational scan of the isolated SH2 domain and full-length Grb2, combined with stopped-flow kinetics and double-mutant-cycle analysis, we found that SH2 binding energetics remain essentially unchanged in the presence of the SH3 domains. Only three of twenty-one variants displayed measurable coupling, and none exceeded the threshold typically associated with significant allosteric effects. Pre-binding of the C-SH3 domain to a Gab2-derived peptide likewise produced no detectable influence on SH2–ligand binding. These results reveal a marked asymmetry in interdomain communication in Grb2 and show that the SH2 domain functions as a robust, largely autonomous module within the full-length protein.
Catalase inhibits tumor growth by alleviating oxidative stress and promoting the polarization of tumor-associated macrophage from M2 to M1 phenotype in non-small cell lung cancer.
Tian Y, Liu YR, Jin HZ … +9 more , Lin QX, Zhao WY, Song WW, Gong YN, Deng YT, Wang SS, Wang K, Tian L, Gu DN
Biol Direct · 2026 Jan · PMID 41578355 · Full text
BACKGROUND: Catalase (CAT) plays a crucial role in converting hydrogen peroxide (H₂O₂) into water and oxygen, which can help alleviate oxidative stress in body. However, whether CAT is associated with the prognosis and i...
BACKGROUND: Catalase (CAT) plays a crucial role in converting hydrogen peroxide (H₂O₂) into water and oxygen, which can help alleviate oxidative stress in body. However, whether CAT is associated with the prognosis and immunotherapy response in patients with non-small cell lung cancer (NSCLC) requires further investigation. METHODS: This study collected data from over 3,170 NSCLC cases across multiple countries. Thirteen machine learning algorithms were employed to identify the most effective diagnostic model, with performance evaluated based on area under the curve (AUC) values. The prognostic significance of CAT expression was assessed in relation to survival, tumor recurrence, and tumor differentiation in NSCLC patients. Additionally, the effectiveness of immunotherapy in relation to CAT expression was evaluated using an immunotherapy dataset. The GDSC database was utilized to examine the correlation between CAT expression and sensitivity to potential therapeutic agents. A multi-omics approach was then applied to analyze the expression and distribution of CAT in NSCLC. In vitro experiments were conducted to validate CAT expression in lung cancer cell lines, and its impact on cell proliferation and migration was assessed using CCK-8 assays, scratch assays, and colony formation assays following transfection with a CAT overexpression construct. The regulatory role of CAT in oxidative stress was further evaluated by adding hydrogen peroxide. Finally, the xenograft tumor mouse model was established to observe the effect of CAT on macrophage phenotype. RESULTS: We first observed that CAT exhibited the highest AUC value in the machine learning model. Subsequent analyses revealed that NSCLC patients with high CAT expression had prolonged survival, reduced tumor recurrence, and reduced tumor poor differentiation, as confirmed by data from multiple global national databases. Moreover, these patients showed greater responsiveness to immunotherapy and experienced prolonged progression-free survival (PFS). The high CAT expression cohort also exhibited increased sensitivity to Cisplatin, Savolitinib, and Docetaxel. Additionally, we also verified the low expression of CAT in tumor tissues by RT-qPCR and immunohistochemistry. Furthermore, overexpression of CAT inhibited lung cancer cell proliferation and migration, while significantly enhancing its ability to regulate hydrogen peroxide levels. Notably, in the xenograft tumor mouse model, we observed that CAT may suppress tumor growth by alleviating tissue hypoxia and facilitating the polarization of tumor-associated macrophage from the M2 phenotype to M1. CONCLUSION: This study demonstrated the potential of CAT as a prognostic biomarker for NSCLC. Targeting CAT might provide an effective strategy for improving patient survival and the efficacy of immunotherapy.
Polarity protein Par3 deficiency promotes metastasis of bladder cancer via interaction of Ppp1r12c.
Cai J, Jiao C, Xu Y … +4 more , Zhang F, Zhang L, Chen S, Shen B
Biol Direct · 2026 Jan · PMID 41559805 · Full text
BACKGROUND: Bladder cancer (BC) remains the leading global mortality and poor prognosis in genitourinary malignancies, especially in patients with metastasis. RESULTS: In this study, we demonstrate that loss of polarity...
BACKGROUND: Bladder cancer (BC) remains the leading global mortality and poor prognosis in genitourinary malignancies, especially in patients with metastasis. RESULTS: In this study, we demonstrate that loss of polarity protein partitioning defective 3 (Par3, encoded by PARD3) is correlated with stronger metastatic capability and a poorer prognosis in BC. Par3 deletion in high grade BC cells accelerates their invasion and metastasis in vitro and in vivo. Mechanistically, Par3 could directly interact with protein phosphatase 1 regulatory subunit 12 C (Ppp1r12c). Either Par3 or Ppp1r12c over-expression rescues the invasion and metastasis caused by Par3 deficiency in vitro. Moreover, the actin filament-related processions are enriched in the downstream biological function, resulting from the activation of ERK 1/2 and p38 signaling pathways, indicated by proteomics analysis from BC cells and tissue, as well as data mining results from BC public database. CONCLUSION: Together, our study reveals that Par3 deficiency promotes BC metastasis. Par3 directly interacts with Ppp1r12c (390-782aa), activating the Par3/Ppp1r12c/ERK/p38 axis. Par3 could act as a prognostic biomarker and potential therapeutic target for BC.
Synergistic anticancer effects of cabozantinib and cuproptosis induction driven by DHRS2-KAT2A-H3K27ac axis in clear cell renal cell carcinoma.
Cao Y, Xu C, Zhang B … +10 more , Qu C, Liu Y, Shi B, Li X, Li J, Zhang Z, Dai S, Sun Q, Wang Y, Gu J
Biol Direct · 2026 Jan · PMID 41559745 · Full text
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, representing about 70–80% of all renal cell carcinomas. Cuproptosis, a recently identified mode of cell death, has incre...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, representing about 70–80% of all renal cell carcinomas. Cuproptosis, a recently identified mode of cell death, has increasingly been linked to tumor initiation, progression, and drug resistance. Our study provides the first evidence that the histone acetyltransferase KAT2A regulates cuproptosis in ccRCC by modulating histone H3 lysine 27 (H3K27) acetylation. METHODS: Our study commenced by establishing, through in vitro and in vivo experiments including CCK8 assays, angiogenesis assays, and Western Blot analysis, that cabozantinib and cuproptosis inducers exhibit synergistic anticancer effects. Subsequently, whole-transcriptome sequencing identified DHRS2 as a key regulatory gene. A series of functional experiments, including colony formation assays, cell proliferation assays, EdU staining, mitochondrial membrane potential staining, and ROS detection, were then conducted to systematically validate the tumor-suppressive role of DHRS2 and its pro-cuproptosis activity.Further investigation, by analyzing co-expressed genes, led us to identify KAT2A as a downstream effector molecule. We employed RNA immunoprecipitation (RIP) and rescue experiments to confirm the interaction between DHRS2 and KAT2A. To elucidate the molecular mechanism, CHIP-seq (chromatin immunoprecipitation sequencing) revealed that H3K27 acetylation promotes the transcription of GLS, a negative regulator of cuproptosis. This finding was subsequently validated through CHIP-qPCR and luciferase reporter gene assays. RESULTS: Our study reveals that in ccRCC, the combined treatment of cabozantinib and cuproptosis inducers leads to a significant upregulation of DHRS2. Functional experiments demonstrate that DHRS2 exerts a tumor-suppressive effect on ccRCC cells, effectively inhibiting their proliferation and growth. Mechanistically, DHRS2 post-transcriptionally represses KAT2A. Downregulation of KAT2A results in reduced H3K27 acetylation, which, as identified by CHIP-seq, leads to decreased transcriptional activation of its downstream target, GLS. As GLS acts as a negative regulator of cuproptosis, its diminished expression ultimately increases cuproptosis, thereby synergistically suppressing tumor growth. CONCLUSIONS: Our findings demonstrate that DHRS2 suppresses the transcription of KAT2A, leading to reduced H3K27 acetylation levels. This, in turn, diminishes the transcriptional activation of its downstream target, GLS, ultimately inhibiting tumor growth. These results suggest that the combination of cabozantinib and cuproptosis inducers holds promise as a novel therapeutic strategy for ccRCC.
Resilient gut microbiome is linked to immune control in HIV-1 infection.
Silva JMM, Azevedo JLLC, Bezerra KG … +8 more , Guilarde AO, Souza LCS, Guimarães RF, Leite P, Júnior HM, Gardinassi LG, Romão PRT, Fonseca SG
Biol Direct · 2026 Jan · PMID 41559696 · Full text
BACKGROUND: HIV-1 affects millions of people globally, and in rare cases, individuals known as “elite controllers” (EC) maintain undetectable viral load without antiretroviral therapy (ART). Given the crucial role of the...
BACKGROUND: HIV-1 affects millions of people globally, and in rare cases, individuals known as “elite controllers” (EC) maintain undetectable viral load without antiretroviral therapy (ART). Given the crucial role of the gut microbiota in maintaining immune system homeostasis, this study investigated its composition and functionality in people living with HIV (PLHIV) (including viremic individuals, ART-treated individuals, and ECs) and healthy donors (HD). Fecal samples were collected for quantification of short-chain fatty acids (SCFAs), 16S rRNA sequencing, and bioinformatic analysis of taxonomic and functional profiles. RESULTS: ECs and HDs exhibited a similar microbiota, characterized by higher abundance of Bacteroidetes and species associated with anti-inflammatory profiles, such as Bacteroides vulgatus and Bacteroides uniformis, and greater ecological diversity. Viremic individuals (VR) showed predominance of Ruminococcus and Eubacterium hallii, both associated with inflammation and unfavorable clinical progression. SCFAs such as acetate, butyrate, and propionate increased HIV replication in vitro, suggesting a possible role in viral reactivation. Functional analysis revealed differences in bacterial metabolic profiles in PLHIV, primarily in carbohydrate and amino acid metabolism. CONCLUSIONS: This study highlights the potential of the gut microbiota in modulating HIV-1 progression. Therapeutic strategies aimed at restoring an EC-like microbiota composition may contribute to viral control and reduction of inflammation in PLHIV.
Comprehensive pan-cancer analysis reveals SH3GLB1 is a novel prognostic biomarker with immunomodulatory potential.
Sun X, Li R, Liu H … +6 more , Zhang D, Wang S, Zhang Y, Gao W, Li D, Dong G
Biol Direct · 2026 Jan · PMID 41546112 · Full text
BACKGROUND: Cancer continues to represent a significant global health challenge, underscoring the urgent need for novel biomarkers to enhance early diagnosis and prognosis prediction. SH3 domain-containing GRB2-like B1 (...
BACKGROUND: Cancer continues to represent a significant global health challenge, underscoring the urgent need for novel biomarkers to enhance early diagnosis and prognosis prediction. SH3 domain-containing GRB2-like B1 (SH3GLB1), also known as Bax interaction factor 1 (BIF-1), is a key regulator of apoptosis, autophagy, and endocytosis. However, its role across various cancer types remains insufficiently characterized. METHODS: We performed an integrated multi-omics analysi to assess the diagnostic and prognostic potential of SH3GLB1 across 33 cancer types, encompassing expression profiling at both mRNA and protein levels, genomic alterations, interactions with the immune microenvironment, and functional enrichment pathways. The finding was validated in Colorectal Cancer (CRC), both in vitro and in vivo. RESULTS: SH3GLB1 expression was significantly downregulated in the majority of tumor types examined, at both mRNA and protein levels. Low SH3GLB1 expression was associated with poorer overall survival in CRC and several other cancers. Besides, SH3GLB1 was correlated with immune-inflamed tumor microenvironments, characterized by increased infiltration of CD8 + T cells and dendritic cells. Functional analyses revealed that SH3GLB1 loss activated RAS-MAPK and EMT signaling pathways, and experimental models confirmed its role in promoting CRC cell proliferation, migration in vitro, and tumor growth in vivo. CONCLUSION: SH3GLB1 exhibits significant diversity and complexity in its tumor-suppressive functions, highlighting its potential as a promising biomarker and therapeutic target for improving the efficacy of cancer treatments.
S100A4 triggeres the pyroptosis of vsmcs: association with mitochondrial damage, impaired mitophagy, and Ca dysregulation.
Huang J, Zhou B, Wang L … +4 more , Huang Q, Lin X, Zhao H, Xia Y
Biol Direct · 2026 Jan · PMID 41527139 · Full text
BACKGROUND: Atherosclerotic occlusive disease of the lower extremities (ASO-LE) is associated with high rates of disability and mortality, and even after surgery, the rate of long-term lumen patency remains low. Vascular...
BACKGROUND: Atherosclerotic occlusive disease of the lower extremities (ASO-LE) is associated with high rates of disability and mortality, and even after surgery, the rate of long-term lumen patency remains low. Vascular smooth muscle cells (VSMCs) are key players in atherosclerosis. The aim of this study was to investigate the action of S100 calcium-binding protein A4 (S100A4) in regulating VSMCs in ASO-LE. RESULTS: The overexpression of S100A4 in the vessel wall of ASO-LE is detected, and the expression of markers of pyroptosis is high. S100A4 causes mitochondrial damage in VSMCs, increases the intracellular ROS and MDA levels, and decreases the level of SOD, which result in oxidative stress. Moreover, S100A4 disrupts the mitophagy process, manifested by inhibited LC3-II conversion and reduced PE levels, suggesting that the lipidation step of LC3 may be disrupted. These promot the accumulation of a large amount of damaged mitochondria with insufficient clearance and activate intracellular AIM2 inflammatory vesicles, which mediate the occurrence of pyroptosis. We also find that the functions of S100A4 may be associated with disturbances in intracellular calcium ion (Ca2+) signaling, both S100A4 transcription inhibitor (niclosamide) and calcium channel blockers can inhibit the above damaging effects. CONCLUSIONS: S100A4 plays a crucial role in the progression of ASO-LE by driving mitochondrial damage and impairing mitophagy in vascular smooth muscle cells, and it is a potential existing strategies for blocking chronic inflammation that may be used to treat lower extremity atherosclerotic occlusion. CLINICAL TRIAL NUMBER: Not applicable.
Solute carrier family (SLC) amino acid transporters are upregulated in cutaneous squamous cell carcinoma.
Petrilli A, Barnaba D, Mancini M … +6 more , Fania L, Ricci F, Dellambra E, Melino G, Candi E, Smirnov A
Biol Direct · 2026 Jan · PMID 41526979 · Full text
Solute carrier family (SLC) amino acid transporters play key role in maintaining a continuous supply of nutrients to cancer cells. Non melanoma skin tumours, the most common cancer type worldwide, undergo extensive metab...
Solute carrier family (SLC) amino acid transporters play key role in maintaining a continuous supply of nutrients to cancer cells. Non melanoma skin tumours, the most common cancer type worldwide, undergo extensive metabolic rewiring to survive under hostile conditions. To adapt to nutrient-poor microenvironment, tumour cells often boost expression of the key metabolic enzymes. However, the role of the amino acid transporters and their therapeutic potential in non-melanoma skin cancer remain unclear. Here, we analyse publicly available transcriptomics data and identify several amino acid transporters that are strongly upregulated in skin cancer, including neutral amino acid transporter LAT1. LAT1 is overexpressed in proliferating basal-like cells within skin tumours and its level decreases during epidermal differentiation. Furthermore, we show that cutaneous squamous cell carcinoma cells rely on citrulline to survive under arginine scarcity and LAT1 is essential for citrulline import. Pharmacological inhibition of LAT1 by the small compound JPH203 sensitises cells to arginine deprivation. Altogether, we show that amino transporter LAT1 plays an important role in cutaneous squamous cell carcinoma growth in low arginine conditions and highlight its potential as a therapeutic target.
GPR43 alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome activation via β-arrestin 2.
Wang C, Zhang W, Guo Y … +6 more , Liao Y, Li N, Zhang Y, Bo L, Bian J, Wang JF
Biol Direct · 2026 Jan · PMID 41519882 · Full text
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory ailments globally, with the NLRP3 inflammasome playing a crucial role in the progression of ALI. G protein-coupled...
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory ailments globally, with the NLRP3 inflammasome playing a crucial role in the progression of ALI. G protein-coupled receptor 43 (GPR43) plays a role in regulating the immune system and maintaining homeostasis; however, the relationship between this receptor and the NLRP3 inflammasome signaling pathway in ALI is still not well understood. METHODS: Lipopolysaccharide (LPS) in combination with nigericin (Nig) was utilized to stimulate the NLRP3 inflammasome in macrophages from mouse peritoneum in vitro, after which the GPR43 selective agonist 4-CMTB was administered. For the in vivo component, an ALI model was created through intratracheal LPS injection, with the experimental group of mice receiving intraperitoneal administration of 4-CMTB at a dosage of 20 mg/kg. Lung damage was observed as well as the activation of the NLRP3 inflammasome and pyroptosis. RESULTS: According to in vitro studies, 4-CMTB inhibited NLRP3 inflammasome activation, achieved by decreasing the activity of caspase-1. Additionally, it resulted in a reduction of IL-1β and IL-18 secretion, as well as decreased formation of ASC specks under LPS + Nig conditions. It also significantly inhibited the production of GSDMD-N terminus, the released lactate dehydrogenase (LDH), and the comparable ratio of propidium iodide (PI). In vivo studies showed 4-CMTB significantly alleviated the pathological damage caused by LPS in the lungs, including the infiltration of neutrophils, formation of hyaline membranes, and thickening of alveolar septa. It also lowered the lung wet/dry weight ratio and extravasation of Evans blue (EB) dye, as well as protein content of bronchoalveolar lavage fluid (BALF) and levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β). Based on the findings of the mechanistic investigation, β-arrestin 2 binding to NLRP3 was promoted by GPR43, thereby preventing the assembly and activation of the NLRP3 inflammasome. CONCLUSION: GPR43 prevents NLRP3 inflammasome activation and pyroptosis by the β-arrestin 2 pathway in LPS-induced ALI. The results of the research show that we can target GPR43 to treat and cure ALI and other inflammatory diseases. CLINICAL TRIAL NUMBER: Not applicable.
Microvesicles, exosomes and their combinations with cytoplasmic organelles: from their discovery to their innovative roles in clinical medicine.
Meldolesi J
Biol Direct · 2026 Jan · PMID 41514320 · Full text
Extracellular Vesicles (EVs), two types of different size: microvesicles and exosomes, generated by all types of cells. EV interactions with lysosomes and/or autophagosomes, induce establishment of combined forms. EVs ar...
Extracellular Vesicles (EVs), two types of different size: microvesicles and exosomes, generated by all types of cells. EV interactions with lysosomes and/or autophagosomes, induce establishment of combined forms. EVs are composed by a surface membrane of lipid bilayer rich of specific proteins around a cargo with distinct lipids and proteins together with various forms of RNA. This review illustrates the whole life of EVs, from their intracellular generation followed by their release to their extracellular space. The ensuing EV navigations lead to binding/penetration into cells and solid/fluid organs, selected based on specific markers, receptors and metabolism. Modified EVs undergo release with binding to other vesicles accompanied by regeneration of recycling to appropriate cells, at some distance or even far away from their origin/establishments. By action with interactive cells, EVs may induce either health processes or various events of diseases, often employed for diagnosis and interest of patients. By acting especially on stem cells of mesenchymal and cancer nature, EVs induce changes of brain, heart, immunology and other diseases, especially cancer. Upon appropriate engineering various EVs, possibly converted into artificial nanovesicles, undergo loading and traffic of drugs and nanomaterials. These and other factors strengthen the EV therapy by ensuing dynamics in critical cancer conditions. A fraction of EV investigation can be converted into established medical employment by confirmed clinical trials. At present, established conversions are progressed towards direct treatments. Ongoing innovative/promising developments are planned, established for future research and therapies.Clinical trial number Not applicable.
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