Biology Direct[JOURNAL]
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200 papers
MEF2A activates the ZDHHC20/NF-κB pathway to inhibit doxorubicin sensitivity and promote the malignant progression of acute myeloid leukemia.
Ming X, Liu W, Wu J … +5 more , Yan S, Su S, Wang Y, Zheng R, Xiao Y
Biol Direct · 2026 Mar · PMID 41882733 · Full text
BACKGROUND: Acute myeloid leukemia (AML) remains challenging due to chemotherapy resistance and disease relapse. Investigating novel regulators of AML pathogenesis and drug sensitivity is crucial for improving outcomes....
BACKGROUND: Acute myeloid leukemia (AML) remains challenging due to chemotherapy resistance and disease relapse. Investigating novel regulators of AML pathogenesis and drug sensitivity is crucial for improving outcomes. Myocyte enhancer factor 2 A (MEF2A) was selected for this study based on its potential role in oncogenic pathways and the unmet need to understand its impact on AML progression and doxorubicin (DOX) chemoresistance. METHODS: Bioinformatics analysis of the GSE245305 dataset was used to identify the differentially expressed genes between AML and normal samples. MEF2A and zDHHC palmitoyltransferase 20 (ZDHHC20) mRNA expression was validated using quantitative real-time PCR (qRT-PCR). Western blotting and immunohistochemistry (IHC) assays were performed to analyze protein expression. Functional assays were performed to analyze cell viability, proliferation, apoptosis, and glucose metabolism. Mechanistic studies involved dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate the association of MEF2A and ZDHHC20. A xenograft mouse model was used to assess the effect of MEF2A knockdown on tumor sensitivity to DOX. RESULTS: MEF2A exhibited upregulated expression in AML samples in comparison with healthy samples. Its knockdown suppressed proliferation, glycolysis (reducing glucose uptake, lactate production, and ATP levels), and tumor growth, while increasing apoptosis and DOX sensitivity in AML cells. Critically, MEF2A transcriptionally activated ZDHHC20 in HL-60 and KG-1 cells. ZDHHC20 overexpression reversed the antitumor effects of MEF2A silencing, promoting malignancy and DOX resistance. Mechanistically, MEF2A depletion inactivated the nuclear factor kappa B (NF-κB) pathway via ZDHHC20 downregulation. In vivo, MEF2A knockdown significantly enhanced the sensitivity of AML xenografts to DOX treatment. CONCLUSION: MEF2A promoted AML progression and DOX resistance by transcriptionally upregulating ZDHHC20, thereby activating the NF-κB pathway. Targeting the MEF2A/ZDHHC20 axis represents a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in AML patients.
In-silico study of machine learning discovers de novo lipogenesis for predicting prognosis and immunotherapy responses in kidney renal clear cell carcinoma.
Liu D, Liu W, Han B … +13 more , Ding T, Nan Y, Zhang Y, Xu H, Pan H, Li Z, Zhang W, Zhao E, Geng B, Jin C, Li X, Wang J, You B
Biol Direct · 2026 Mar · PMID 41882722 · Full text
BACKGROUND: Currently, there is a lack of precise instruments for predicting the prognosis and treatment efficacy of kidney renal clear cell carcinoma (KIRC), often resulting in delayed diagnosis and suboptimal treatment...
BACKGROUND: Currently, there is a lack of precise instruments for predicting the prognosis and treatment efficacy of kidney renal clear cell carcinoma (KIRC), often resulting in delayed diagnosis and suboptimal treatment outcomes. De novo lipogenesis (DNL) has been documented to significantly impact the prognosis and treatment of several cancers and may serve as a biomarker for KIRC treatment and outcomes. METHODS: We utilized TCGA-KIRC as the training cohort and GSE22541, ematb1980, and emtab3267 as validation cohorts to construct prognostic genetic features (DPGS) for DNL using StepCox[backward] + RSF. We confirmed the independent prognostic value of DPGS through multivariate Cox analysis and integrated DPGS with clinical characteristics to construct comprehensive prognostic nomograms. Furthermore, we analyzed the correlations between DPGS and genomic instability, tumor immune microenvironment (TIME), and immunotherapy sensitivity at both the single-cell and RNA-seq levels. These findings were further validated in the GSE78220, IMvigor210, and Checkmate immunotherapy cohorts. Finally, we used immunohistochemistry (IHC), Western blotting (WB), and cell function assays to elucidate SLC19A1’s critical role in KIRC. RESULTS: The composite C-index for DPGS was 0.796, with hazard ratio (HR) values in multivariate Cox regression analyses of 1.06 and 1.01 in the TCGA-KIRC and EMTAB1980 datasets, respectively. These findings suggest that DPGS can function as an independent prognostic risk factor. Furthermore, the area under the curve (AUC) values for DPGS at 2, 3, and 5 years exceeded 0.67 across four cohorts, indicating robust prognostic predictive performance. In addition, DPGS exhibited a significant association with copy number variation (CNV) (R = 0.33, P < 0.001) and tumor mutational burden (TMB) (R = 0.19, P < 0.001). DPGS was found to accumulate in tumor epithelial cells, cancer-associated fibroblasts (CAFs), and macrophages, and acted on effector CD8 T cells via the HLA-E – KLRC1/NKG2A pathway, thereby diminishing immunotherapy sensitivity in the high-risk DPGS group. Furthermore, knockdown of the key gene SLC19A1 further reduced lipid storage in KIRC and mitigated the malignant phenotype. CONCLUSIONS: Our work underscores the critical role of DPGS in modulating TIME, influencing immunotherapy response, and predicting prognosis in KIRC. The integration of DPGS and nomograms based on DNL provides innovated insights into survival prediction and therapy, contributing to the development of DNL-targeted therapeutic strategies.
SIRT1 haploinsufficiency recapitulates age-associated subfertility through sperm α-tubulin hyperacetylation.
Iniesta-Cuerda M, Valentova I, Moravec J … +4 more , Liška F, Králíčková M, Krapf D, Nevoral J
Biol Direct · 2026 Mar · PMID 41882697 · Full text
Advanced paternal age compromises male fertility and correlates to a decline of the deacetylase SIRT1 activity, a central regulator of germline homeostasis and chromatin dynamics. Acetylation imbalance has been pointed o...
Advanced paternal age compromises male fertility and correlates to a decline of the deacetylase SIRT1 activity, a central regulator of germline homeostasis and chromatin dynamics. Acetylation imbalance has been pointed out as a driver of testicular aging. We therefore asked whether SIRT1 insufficiency reproduces aging-associated shifts in the acetylation landscape and how these might propagate to sperm function, fertilization capacity and embryo development. To address this, we combined acetylomic profiling of Sirt1+/− and naturally aged mice with functional assays of sperm quality and in vitro fertilization (IVF). Both Sirt1+/− and aged wild type (WT) testes shared a distinct acetylation signature absent in young WT controls, including nuclear regulators (ZNF638, MORC4), proteins involved in sperm structure and motility (Rootletin, Kinectin, CFAP58), and phosphoinositide signaling mediators such as PLCη1, which regulate intracellular Ca2 + release. Conversely, 22 proteins displayed acetylation exclusively in WT controls but were absent in Sirt1+/− and aged testes, encompassing modules related to flagellar organization (CEP170, CEP350, AKAP13), meiotic control (ANAPC7, PDS5B, ESCO1, CENPE), signaling and metabolism (SHIP1, GAK, ABCD4), chromatin regulation (BRD4, MAGEB4), and testicular architecture (MFAP2). This differential acetylomic profile persisted in mature sperm, with Sirt1+/− males showing elevated acLys levels and, more specifically, midpiece-restricted α-tubulin hyperacetylation, a pattern particularly shared with aged cohorts. Notably, this tubulin hyperacetylation remained after capacitation and correlated with mitochondrial dysfunction, elevated reactive oxygen species, reduced acrosome responsiveness, and diminished fertilization capacity. IVF assays further revealed decreased cleavage and blastocyst developmental rates, indicating defective paternal support of early embryogenesis despite preserved blastocyst quality. Together, these findings indicate that testicular SIRT1 contributes to germline acetylation patterns and that midpiece-restricted α-tubulin hyperacetylation is a shared feature of SIRT1 insufficiency and natural aging, correlating with the mitochondrial dysfunction and impaired sperm performance. Overall, our work broadens current understanding by integrating acetylomic and functional evidence within a model that reflects the physiological, age-related reduction of SIRT1.
FAM83D facilitates EMT and metastasis of cervical cancer via interaction with GSK3β and inactivation of GSK3β/stabilization of Snail signaling.
Li J, Li F, Meng X … +12 more , Yang Z, Li Z, Tang H, Zhu W, Li H, He X, Lin X, Han Z, Chen M, Yang Y, Wang J, Zhang K
Biol Direct · 2026 Mar · PMID 41882663 · Full text
FAM83D plays a crucial role in cervical cancer (CC) metastasis, though its exact mechanism remains unclear. This study found that FAM83D was significantly upregulated in CC tissues, particularly in metastatic cases, and...
FAM83D plays a crucial role in cervical cancer (CC) metastasis, though its exact mechanism remains unclear. This study found that FAM83D was significantly upregulated in CC tissues, particularly in metastatic cases, and correlated with advanced tumor stage and poor prognosis. While it did not affect CC cell proliferation, chemosensitivity, or tumorigenesis, FAM83D overexpression enhanced migration and invasion, whereas its knockdown suppressed these effects. In vivo, silencing FAM83D markedly reduced lung and liver metastases in mice. Mechanistically, FAM83D upregulated EMT-like changes and Snail stability by directly interacting with GSK3β and promoting its Ser9 phosphorylation, thereby activating GSK3β/Snail signaling. Furthermore, AKT and PKA served as key upstream kinases in FAM83D-mediated GSK3β inactivation. Inhibition of GSK3β reversed the anti-metastatic effects of FAM83D knockdown. These results identify FAM83D as a key metastasis driver in CC, functioning through GSK3β/Snail/EMT axis, and suggest its potential as a therapeutic target to inhibit CC progression.
PHGDH mediated serine biosynthesis metabolism suppresses vascular calcification.
Tan L, Liu J, Shi R … +1 more , Liu Y
Biol Direct · 2026 Mar · PMID 41872929 · Full text
BACKGROUND: Vascular calcification is a major pathological process driving cardiovascular morbidity and mortality, yet effective therapies are lacking. This study aims to identify novel causal plasma proteins and therape...
BACKGROUND: Vascular calcification is a major pathological process driving cardiovascular morbidity and mortality, yet effective therapies are lacking. This study aims to identify novel causal plasma proteins and therapeutic targets for vascular calcification through an integrative multi-omics approach and to further explore their functional roles and regulatory mechanisms in vascular calcification. METHODS: We performed a high-throughput Mendelian randomization (MR) analysis using protein quantitative trait loci from two large-scale proteomic studies (deCODE and UKB-PPP) as genetic instruments. Summary-level data for vascular calcification were obtained from genome-wide association studies. Candidate proteins underwent rigorous sensitivity analyses, colocalization, and external replication. Transcriptomic data were analyzed to assess expression changes in calcified vascular smooth muscle cells. Functional validation and mechanism exploration was conducted in high-phosphate-induced human aortic smooth muscle cells (HASMCs) and a 5/6 nephrectomy mouse model of vascular calcification using siRNA, overexpression plasmids, and the pharmacological inhibitor NCT-503. CLINICAL TRIAL NUMBER: Not applicable.
The APC/C subunit APC7 promotes hepatocellular carcinoma progression by mediating ubiquitination and degradation of LATS1 to activate YAP/TAZ.
Sun Y, Zhang R, Guo Y … +12 more , Wu D, Wei H, Tan Z, Huang M, Wang Y, Fang Z, Zhang C, Li C, Li W, Wei D, Bian H, Liu ZK
Biol Direct · 2026 Mar · PMID 41866505 · Full text
BACKGROUND: The anaphase-promoting complex/cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase critically involved in cell cycle regulation. However, the pathological functions of its individual subunits, particular...
BACKGROUND: The anaphase-promoting complex/cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase critically involved in cell cycle regulation. However, the pathological functions of its individual subunits, particularly in hepatocellular carcinoma (HCC), remain largely unexplored. AIM: To systematically analyze the expression and prognosis of APC/C in pan-cancer, and also focus on studying the function and mechanism of APC7 in the progression of HCC. METHODS: Transcriptome data were downloaded from TCGA, ICGC, and GEO databases. The analysis of differential expression genes and clinical characteristics were performed to identify the key APC gene. Moreover, immune subtype analysis was conducted to elucidate potential functions, and immune cell infiltration was assessed using the CIBERSORT algorithm. Then, gain- and loss‐of‐function studies were employed to elucidate the role of APC7 in HCC. Finally, RNA sequencing and ubiquitination assays were employed to elucidate the underlying mechanisms of APC7 in HCC. RESULTS: This study systematically analyzed the expression and prognosis of various subunits of the APC/C complex in pan-cancer samples, and identified APC7 as a key subunit in HCC. APC7 exhibited the most significant upregulation in HCC and was closely associated with poor prognosis in patients. Moreover, the expression profiles of APC7 is closely related to immune checkpoint genes and tumor-infiltrating immune cells. The results of multiplex immunohistochemistry showed that APC7 overexpression markedly increased the infiltration of Foxp3⁺, CD25⁺, and CD4⁺ Treg cells. Functional studies demonstrated that the knockdown of APC7 inhibited HCC cell proliferation, migration, invasion, and G1/S phase transition, whereas overexpression of APC7 promoted these malignant phenotypes in vitro and in vivo. Mechanistically, RNA sequencing and molecular studies revealed that APC7 interacts with CDH1 to mediate ubiquitin-dependent degradation of LATS1 at K860, leading to YAP/TAZ activation. Rescue experiments confirmed that LATS1 ablation reversed the tumor-suppressive effects of APC7 knockdown. CONCLUSIONS: Our findings identify APC7 as a key oncogenic driver in HCC, promoting tumor progression via the Hippo signaling pathway. APC7 may represent a prognostic biomarker and a potential therapeutic target in HCC.
Incomplete radiofrequency ablation may elicit pro-oncogenic effects in thyroid cancer cells in a xenograft mouse model.
Kuo CY, Hsu YC, Li YS … +2 more , Chang SC, Cheng SP
Biol Direct · 2026 Mar · PMID 41845519 · Full text
BACKGROUND: Radiofrequency ablation (RFA) is a safe and effective treatment for benign thyroid nodules and is also considered an alternative option for low-risk papillary cancers. Evaluating the completeness of RFA throu...
BACKGROUND: Radiofrequency ablation (RFA) is a safe and effective treatment for benign thyroid nodules and is also considered an alternative option for low-risk papillary cancers. Evaluating the completeness of RFA through ultrasound and cytology can be challenging, highlighting the need to investigate the thermal effects on any residual viable cancer cells. Our objective was to examine the adaptive responses of thyroid cancer cells that survive transient heat stress. METHODS: Xenograft tumors were established in NOD/SCID mice, and a single session of RFA was administered once the tumors became palpable. For in vitro studies, culture vessels containing papillary thyroid cancer cell lines were briefly submerged in water baths at temperatures of 37, 40, or 42 °C. Functional assays and RNA sequencing were conducted. RESULTS: Following initial volume suppression after RFA, accelerated growth of xenograft tumors was observed. These tumors exhibited higher Ki-67 labeling indices and increased microvessel densities compared to the sham ablation group. Heat treatment at 40–42 °C promoted colony and thyrosphere formation, as well as the migratory and invasive abilities of thyroid cancer cells. The expression levels of HSP90 and HSP70 were upregulated, and treatment with ganetespib, an HSP90 inhibitor, mitigated the promoting effects of heat treatment. Furthermore, heat treatment elevated vascular endothelial growth factor levels and enhanced endothelial cell tube formation. CONCLUSION: Sublethal heat stress may undesirably potentiate tumor growth and angiogenesis. These findings emphasize the importance of achieving complete tumor destruction. Long-term clinical trials are needed to monitor the safety of RFA for thyroid cancer.
Nano gold-loaded Nannochloropsis oculata attenuates fluoride-induced neural and hepatorenal toxicity by modulating the Nrf2/NF-κB axis and aquaporins.
Emam KK, Shanab O, Anajirih N … +13 more , El-Rayes SM, Abdelkader A, Hasan T, Elsayed AM, ELwakeel EE, Kasem EM, Abdelkareem HM, Shukry M, Ibrahim SF, El Nashar EM, Alshehri AM, Rawan AF, Abdeen A
Biol Direct · 2026 Mar · PMID 41840668 · Full text
BACKGROUND: Sodium fluoride (F) is ubiquitously present in the environment and affects animals’ and humans’ health. Nannochloropsis oculata (NO) is a microalga that contains bioactive components with a preferential anti-...
BACKGROUND: Sodium fluoride (F) is ubiquitously present in the environment and affects animals’ and humans’ health. Nannochloropsis oculata (NO) is a microalga that contains bioactive components with a preferential anti-inflammatory and antioxidant action. This study aimed to assess the tenable protective role of NO and nano-gold (AuNO) extracts toward F-evoked toxicity in rats. METHODS: Six groups of male rats were assigned. The CTL (control) group was given distilled water; the NO group, rats were given NO extract (250 mg/kg b.w.), and AuNO group, rats received 500 mg/kg b.w of AuNO extract. Further, F group was given F (30 mg/kg b.w). NO + F group, and AuNO + F rats were administered with a combination of AuNO and F. RESULTS: F exposure caused noteworthy and significant oxidative stress and apoptosis. Additionally, there is a highly significant major regulation of proinflammatory genes and proteins. Furthermore, F significantly downregulated the kidney’s aquaporins, which can be used to identify renal impairment early. F-triggered damage was considerably reduced by pretreatment with both algal extracts. CONCLUSIONS: Our findings support NO supplementation as it exerts alleviating effects against F-prompted toxicity, including the restoration of AQPs expression. The effects were more pronounced with AuNO treatment, suggesting its enhanced protective potential.
Exploring fetal skeletal alterations induced by gold nanoparticles in mice confirmed by laser speckle imaging and LIBS approach.
Alexeree SMI, Youssef D, Galmed AH … +2 more , Elbalshy RM, Abdel-Harith M
Biol Direct · 2026 Mar · PMID 41827003 · Full text
BACKGROUND: The rapid advancement of nanotechnology has expanded the use of nanomaterials across biomedical and industrial applications. Engineered gold nanoparticles (Au NPs) have attracted considerable interest for dia...
BACKGROUND: The rapid advancement of nanotechnology has expanded the use of nanomaterials across biomedical and industrial applications. Engineered gold nanoparticles (Au NPs) have attracted considerable interest for diagnostic and therapeutic applications; however, their ability to cross the placental barrier and the potential for fetotoxic effects remain insufficiently explored. RESULTS: This study aimed to investigate the transplacental transfer and developmental toxicity of biosynthesized Au NPs in a BALB/c mouse model. Pregnant mice were assigned to three groups: a control group (G1) and two treatment groups receiving intravenous doses of 10 µg/g/day (G2) or 20 µg/g/day (G3). Morphological examination of fetal skeletal structures using light microscopy revealed no overt abnormalities. In contrast, comprehensive skeletal assessment using an advanced multimodal complementary laser-based platform demonstrated significant dose-dependent alterations. Laser-Induced Breakdown Spectroscopy (LIBS) detected pronounced dysregulation of calcium and magnesium critical for bone mineralization. Additionally, laser speckle imaging enabled sensitive, nondestructive evaluation of microstructural changes associated with fetal bone ossification and alterations in mineral content. The integrated analysis revealed disrupted ossification centers, abnormal bone density signatures, and subtle skeletal anomalies that were undetectable by conventional microscopy. CONCLUSIONS: The combined application of LIBS and laser speckle imaging proved highly sensitive in identifying early elemental imbalances and microstructural defects in fetal bone development following Au NPs exposure. These findings emphasize the value of advanced photonic and spectroscopic techniques for nanosafety assessment and underscore the necessity for thorough in vivo evaluation of the potential developmental risks associated with biosynthesized gold nanoparticles.
O-GlcNAcylation regulates endometrial decidualization through dual mechanisms: PI3K-AKT axis-mediated phosphorylation and direct modification of FOXO1.
Sun Q, Gao Y, Wang A … +6 more , Chen X, Fan L, Jin S, Guo L, Zhang H, Kong Y
Biol Direct · 2026 Mar · PMID 41821103 · Full text
BACKGROUND: Steroid hormone-driven endometrial decidualization involves the differentiation of endometrial stromal cells into decidual cells, which form the decidua for blastocyst implantation. This process is a prerequi...
BACKGROUND: Steroid hormone-driven endometrial decidualization involves the differentiation of endometrial stromal cells into decidual cells, which form the decidua for blastocyst implantation. This process is a prerequisite for successful embryo implantation. O-GlcNAcylation is a nutrient-sensitive post-translational modification. Our prior work demonstrated that O-GlcNAcylation promotes embryo recognition by enhancing endometrial epithelial cell proliferation, migration and invasion, thereby facilitating embryo implantation. However, its regulatory role in endometrial stromal cell decidualization remains unknown. RESULTS: In this study, we found that O-GlcNAcylation was upregulated during mouse embryo implantation and in vitro decidualization, and its downregulation impaired both embryo implantation efficiency and decidualization. Transcriptome sequencing revealed that the PI3K-AKT pathway was significantly enriched upon OGT inhibition. Mechanistically, O-GlcNAcylation likely promotes decidualization by attenuating PI3K-AKT signaling to reduce phosphorylation of the key decidualization transcription factor FOXO1, while simultaneously increasing direct O-GlcNAcylation of FOXO1, thereby enhancing its stability and nuclear retention to promote decidualization. CONCLUSIONS: This study elucidates how O-GlcNAcylation orchestrates decidualization through FOXO1 regulation, providing important insights into the role of O-GlcNAcylation signaling in normal pregnancy and its dysregulation in decidualization-related disorders.
NCOA4-mediated ferritinophagy modulates colitis-associated ferroptosis in intestinal epithelial cells and mucosal repair.
Huang Q, Liu L, Zhao Y … +7 more , Xiao J, Yang Y, Hong Y, Ji H, Wu H, Ma X, Zhang D
Biol Direct · 2026 Mar · PMID 41821081 · Full text
BACKGROUND: Ferroptosis in intestinal epithelial cells (IECs) acts as a crucial mechanism driving intestinal mucosal injuries and inflammatory reactions in colitis. Nuclear receptor coactivator 4 (NCOA4)-mediated ferriti...
BACKGROUND: Ferroptosis in intestinal epithelial cells (IECs) acts as a crucial mechanism driving intestinal mucosal injuries and inflammatory reactions in colitis. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, a primary pathway for intracellular iron storage, takes part in regulating ferroptosis. Nevertheless, it is yet unknown whether ferritinophagy plays a role in ferroptosis of IECs in colitis. Hence, this experiment used dextran sulfate sodium salt (DSS) to establish an inflammation model with NCM460 cells and an animal model of colitis to discover the role of ferritinophagy in ferroptosis in IECs and colonic mucosal inflammatory damage. RESULTS: DSS induced ferroptosis in IECs, presenting as significantly increased contents of Fe2+, reactive oxygen species (ROS), and malondialdehyde (MDA), decreased protein expression of glutathione peroxidase 4 (GPX4), and increased expression of cyclooxygenase-2 (COX2) (all P<0.05). Moreover, administration of ferroptosis inhibitor liproxstatin-1 and autophagy inhibitor methyladenine (3-MA) ameliorated colonic tissue damage in the animal model of colitis, reducing the disease activity index (DAI), colon macroscopic damage index (CMDI), and pathological score, as well as the serum contents of mucosal permeability markers diamine oxidase (DAO) and D-lactic acid (D-LA) (all P<0.05). Further, knockdown of NCOA4 downregulated the expression of microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 5 (ATG5) proteins, upregulated the expression of ferritin heavy chain 1 (FTH1), inhibited ferritinophagy, and decreased ferroptosis in IECs induced by DSS, thus ameliorating colonic inflammatory damage and mucosal permeability (all P<0.05). On the contrary, overexpression of NCOA4 encouraged ferritinophagy and aggravated ferroptosis in IECs and intestinal damage. CONCLUSIONS: This study provided evidence supporting that NCOA4-mediated ferritinophagy participates in modulating colitis-related ferroptosis in IECs, and suppressing ferritinophagy protects IECs and promotes colonic mucosal repair.
USP19 alleviates LPS-induced acute lung injury via inhibiting TAK1 activation.
Li C, Qin K, Wang Y … +3 more , Huang Y, Zhang J, Chen H
Biol Direct · 2026 Mar · PMID 41821039 · Full text
Acute lung injury (ALI) is a clinically prevalent condition characterized by excessive inflammatory activation leading to tissue damage, with high mortality rates. USP19, a deubiquitinase (DUB) known to play critical rol...
Acute lung injury (ALI) is a clinically prevalent condition characterized by excessive inflammatory activation leading to tissue damage, with high mortality rates. USP19, a deubiquitinase (DUB) known to play critical roles in skeletal muscle atrophy, antiviral responses, and stabilization of transmembrane endoplasmic reticulum-associated degradation (ERAD) substrates, has not been previously investigated in ALI pathogenesis. In this study, we established both in vivo (lipopolysaccharide (LPS)-challenged C57BL/6j mice) and in vitro (LPS-stimulated HULEC-5a cells) to simulate acute lung injury (ALI), demonstrating significant downregulation of USP19 expression during ALI progression. Functional studies revealed that genetic ablation of USP19 in mice exacerbated LPS-induced acute lung injury, manifesting as enhanced pulmonary tissue damage, increased vascular permeability, amplified inflammatory responses, and elevated cellular apoptosis. In HULEC-5a cells, USP19 overexpression attenuated LPS-induced cellular damage, inflammatory activation and apoptosis, while USP19 knockdown exacerbated these effects. These findings were recapitulated in USP19-knockout mouse lung microvascular endothelial cells. Mechanistically, we identified that USP19 exerts its protective effects by suppressing TAK1 phosphorylation, thereby inhibiting activation of the downstream JNK/p38 signaling pathway. These findings not only elucidate USP19 as a novel negative regulator of ALI through modulation of the TAK1-JNK/p38 axis, but also provide potential therapeutic targets and conceptual advances for ALI treatment strategies.
miR-196b inhibits tumor proliferation and metastasis by targeting GATA6 in endometrial cancer.
Guo Z, Liao Y, Yang Y … +6 more , Li X, Wang N, Shang Y, Liu H, Kong Y, Sui L
Biol Direct · 2026 Mar · PMID 41814329 · Full text
BACKGROUND: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence, yet its precise pathogenesis remains unclear. MicroRNAs (miRNAs) have been widely implicated in tumorigenesis. Although...
BACKGROUND: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence, yet its precise pathogenesis remains unclear. MicroRNAs (miRNAs) have been widely implicated in tumorigenesis. Although studies suggest that miR-196b is closely associated with the progression of various malignancies, its specific biological functions and mechanisms in EC remain to be elucidated. RESULTS: In this study, analysis of tissue and serum samples from EC patients revealed that miR-196b is downregulated in EC, whereas GATA6 is upregulated, with a notable negative correlation between their expression levels. In Ishikawa and HEC-1 A EC cell lines, functional assays including CCK-8, colony formation, wound healing, and Transwell experiments revealed that downregulation of miR-196b significantly enhanced cell proliferation, migration, and invasion. A nude mouse xenograft model further confirmed that high miR-196b expression weakened the tumorigenic ability of EC cells. Mechanistically, dual-luciferase reporter assays identified GATA6 as a direct target of miR-196b. Downregulation of miR-196b facilitated the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of EC cells by up-regulating GATA6. The miR-196b/GATA6 axis is involved in regulating the activity of the AKT/ERK signaling pathway. Furthermore, through a series of bioinformatics analyses, we found that miR-196b and GATA6 have potential as diagnostic and prognostic markers for EC. CONCLUSIONS: This study elucidates the molecular mechanism by which miR-196b suppresses EC progression by targeting GATA6. These findings provide novel insights into the pathogenesis of EC and highlight the potential of miR-196b/GATA6 as a diagnostic and prognostic biomarker.
The impact of mesenchymal stromal cells on the proliferation and functional maturation of liver organoids.
Luo S, Mao C, Wu F … +4 more , Huang X, Wu W, Huang T, Liu D
Biol Direct · 2026 Mar · PMID 41808138 · Full text
BACKGROUND: The health burden of end-stage liver disease continues to grow, and orthotopic liver transplantation remains the only curative treatment. Three-dimensional (3D) culture systems support the in vitro culture of...
BACKGROUND: The health burden of end-stage liver disease continues to grow, and orthotopic liver transplantation remains the only curative treatment. Three-dimensional (3D) culture systems support the in vitro culture of primary liver cells, allowing them to recapitulate native tissue architecture. This technology holds considerable potential for regenerative medicine and disease modeling. However, the practical application of liver organoid (LO) technology is hindered by the inherent limitations of LOs derived from single-tissue sources. KEY RESULTS: In this study, we integrated human umbilical cord mesenchymal stromal cells (hUC-MSCs) into single-source LOs and assessed their effects on organoid formation and function. During the expansion phase, co-culture with hUC-MSCs yielded a 2-fold increase in organoid number compared to LOs cultured alone, although no significant changes were observed in the expression of genes related to organoid lifespan. Liver-specific functions of LOs after 7 day incubated with differentiation medium were further investigated. Despite constructing organoids from mature hepatocytes, co-culture with MSCs promoted non-hepatocyte differentiation, as evidenced by the expression of the cholangiocyte organoid marker cytokeratin 19. Furthermore, LOs co-culture with hUC-MSCs demonstrated increased albumin and urea secretion. In contrast, glucose consumption and ammonia clearance rates showed no significant differences. Following in vivo transplantation, serum biochemical markers normalized in both transplanted and control groups. However, histological analysis revealed superior liver tissue repair in the transplanted group. CONCLUSIONS: Our findings indicate that MSCs positively enhance the proliferative capacity of LOs and confer limited functional benefits, and incorporation of MSCs may promote non-hepatic cell differentiation. This effect was particularly evident within the extracellular matrix components of the hydrogel culture system.
VSTM2L mediates the release of extracellular vimentin to drive lymph node metastasis in gastric cancer.
Wu L, Fan H, Sang H … +3 more , Zhao X, Li Y, Xiao J
Biol Direct · 2026 Mar · PMID 41803967 · Full text
BACKGROUND: Lymph node metastasis (LNM), the most common route of gastric cancer (GC) dissemination, remains poorly understood. This study aimed to elucidate the role of V-Set and Transmembrane Domain Containing 2 Like (...
BACKGROUND: Lymph node metastasis (LNM), the most common route of gastric cancer (GC) dissemination, remains poorly understood. This study aimed to elucidate the role of V-Set and Transmembrane Domain Containing 2 Like (VSTM2L) in GC LNM. METHODS: VSTM2L expression was evaluated by immunohistochemistry, qPCR, and western blot. Its effects on cell proliferation, invasion, lymphangiogenesis, and metastasis were examined via colony formation, Transwell, tube formation, and in vivo experiments, respectively. Protein interactions were analyzed by immunoprecipitation and GST-pull down. The role of VSTM2L in promoting vimentin secretion was assessed using Ponceau Red staining and Enzyme-Linked Immunosorbent Assay (ELISA). Rescue experiments were conducted to confirm the functional significance of vimentin. RESULTS: VSTM2L was significantly upregulated in GC cell lines and lymph node-positive tissues, and its high expression correlated with poor survival. Loss- and gain-of-function experiments demonstrated that VSTM2L promotes GC cell proliferation, invasion, and lymphangiogenesis. Mechanistically, VSTM2L interacted with vimentin to enhance its intracellular stability and promote its extracellular secretion. The released vimentin subsequently upregulated focal adhesion complex proteins intracellularly and activated Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) signaling in human lymphatic endothelial cells, leading to cytoskeletal rearrangement and lymphangiogenesis, respectively. Consistent with this mechanism, both in vitro and in vivo evidence confirmed that the secretion of vimentin is essential for the pro-lymphangiogenic effects of VSTM2L. CONCLUSIONS: We identify VSTM2L as a novel and potent driver of LNM. Our findings highlight the therapeutic potential of targeting the VSTM2L-extracellular vimentin axis in GC and elucidate a previously unrecognized mechanism driving vimentin secretion and lymphatic metastasis.
Circadian rhythms and microbiota: molecular crosstalk and its implications for health and disease.
Wu G, Zhang J, Yan S … +15 more , Liu N, Chen W, Wu F, Wang Z, Zhang J, Yang Y, Deng Y, Qiu X, Liu J, Shi L, Cui X, Wan R, Li X, Han Y, Yang G
Biol Direct · 2026 Mar · PMID 41794765 · Full text
Circadian rhythms, evolutionarily conserved 24-hour oscillations, exert precise regulatory control over microbial communities across host niches including the gastrointestinal tract, oral cavity, urinary bladder, and ski...
Circadian rhythms, evolutionarily conserved 24-hour oscillations, exert precise regulatory control over microbial communities across host niches including the gastrointestinal tract, oral cavity, urinary bladder, and skin. This bidirectional interplay is critical to host physiology: host circadian clocks shape the composition and functional rhythms of resident microbiota, while microbiota-derived signals reciprocally modulate circadian entrainment and tissue-specific rhythmicity. Circadian disruption from shift work, irregular feeding, light pollution, or sleep deprivation trigger microbial dysbiosis and circadian misalignment, contributing to metabolic diseases, gastrointestinal disorders, neuropsychiatric conditions, cardiovascular diseases, and dermatological or reproductive disorders. Mechanistically, this crosstalk is mediated by rhythmic hormonal secretion, microbial metabolites, epigenetic regulation, and immune signaling. Therapeutic strategies such as time-restricted feeding, probiotics, melatonin, and polyphenol-rich diets show promise in restoring temporal homeostasis. This review synthesizes current evidence on circadian-microbiota interplay, elucidates its roles in physiology and disease, and highlights translational opportunities for chrono-microbiome-based interventions to optimize host health.
Attenuation of Wnt signaling by miR-27a-5p-GFPT2-HBP axis via metabolic reprogramming in colorectal cancer.
Jiang J, He H, Wang X … +9 more , Jin S, Xiao W, Xie Y, Wei E, Qian C, Fu J, Wang J, Yang C, Lin R
Biol Direct · 2026 Mar · PMID 41772703 · Full text
BACKGROUND: Wnt signaling is a key driver of colorectal cancer (CRC) progression, yet directly inhibiting it remains a major challenge. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gen...
BACKGROUND: Wnt signaling is a key driver of colorectal cancer (CRC) progression, yet directly inhibiting it remains a major challenge. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression, thereby modulating oncogenic pathways. However, the role of miR-27a-5p and its underlying mechanisms in CRC remains largely unknown. METHODS: Bioinformatics analyses and paired clinical CRC specimens were used to evaluate miR-27a-5p expression levels and their association with prognosis. CCK-8, colony formation, wound healing, Transwell invasion, and epithelial–mesenchymal transition (EMT) marker analysis were performed to assess the effects of miR-27a-5p on the malignancy of CRC cells. The potential underlying mechanisms were investigated using dual-luciferase reporter assays, RNA-seq, HPLC-UV, immunoprecipitation/co-immunoprecipitation and immunofluorescence. Xenograft models were used to evaluate the in vivo role of miR-27a-5p in CRC. RESULTS: miR-27a-5p was downregulated in CRC, and its low expression correlated with poorer prognosis. miR-27a-5p directly targeted GFPT2, the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), thereby decreasing intracellular uridine 5′-diphosphate N-acetyl-D-glucosamine (UDP-GlcNAc) levels and global protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation), which in turn reduced β-catenin O-GlcNAcylation, inhibited its nuclear accumulation, and suppressed its transcriptional activity, leading to attenuation of Wnt signaling. Restoring miR-27a-5p expression in CRC cells suppressed proliferation, migration, invasion, and EMT, whereas GFPT2 overexpression or glucosamine supplementation partially reversed the inhibited malignant behaviors. Conversely, β-catenin knockdown attenuated the malignant phenotypes and expression of EMT/Wnt targets induced by miR-27a-5p inhibition, supporting a β-catenin-dependent mechanism. In mouse xenografts, treatment with the O-GlcNAc transferase (OGT) inhibitor OSMI-1 attenuated the accelerated tumor growth driven by miR-27a-5p inhibition, supporting an O-GlcNAcylation-dependent mechanism in vivo. CONCLUSION: These findings reveal a novel miR-27a-5p–GFPT2–HBP axis that links metabolic reprogramming to Wnt signaling in CRC by suppressing β-catenin activity through the reduction of UDP-GlcNAc-dependent O-GlcNAcylation, thereby restraining CRC progression. This suggests that targeting this axis could attenuate Wnt signaling and slow CRC progression.
Integrative bioinformatics approach to the mRNA vaccine development for the human papillomavirus using the capsid protein.
He S, Zubair A, Ahmad F … +3 more , Shahani MY, Zeng L, Afghan N
Biol Direct · 2026 Mar · PMID 41772595 · Full text
Human papillomavirus (HPV) is associated with several serious diseases, consisting of neck-related, lung, oropharyngeal, vaginal, penile, vulvar, and anal tumors. Potential candidates for mRNA vaccination include the cap...
Human papillomavirus (HPV) is associated with several serious diseases, consisting of neck-related, lung, oropharyngeal, vaginal, penile, vulvar, and anal tumors. Potential candidates for mRNA vaccination include the capsid structural peptides L1 and L2, which are prominently recognized by the immune system. This recognition has resulted in the formation of mRNA vaccines targeting these capsid proteins. We employed various bioinformatics methods to predict epitopes for helper CD4 + lymphocytes, CD8 + lymphocytes, and B cells within these proteins, and to evaluate their allergenicity, toxicity, and antigenicity. An orthorhombic TIP3P water box with a buffer region of 10 Å was used for the experiment, and Na⁺/Cl⁻ counter-ions at physiological salt concentration (0.15 M) were included to counteract the system. After equilibration of the NVT and NPT ensembles, a 100 ns production run was conducted at 310 K and 1 atm. Our vaccine construct includes 24 epitopes, comprising both CTLs and HTLs. The vaccine exhibited enhanced hydrophilicity, with an average hydropathicity score of -0.811. The Ramachandran plot indicated remarkable stability, with 94.3% of residues located within the allowed and additionally allowed regions. The vaccine demonstrated significant affinity for the TLR3 receptor, as evidenced by a docking score of -363.44 and a confidence score of 0.9862. Following codon optimization, expression in E. coli vectors showed substantial improvement in vaccine production, reflected by an increased GC content of 58.12%. MM-GBSA analysis revealed a consistent binding affinity for TLR3 at -53.16 kcal/mol. Overall, the designed vaccines against HPV capsid proteins represented favorable outcomes through strong immune responses, supporting their progression to in vitro and in vivo clinical trials.
TDP-43-driven alternative splicing of UQCRC2 modulates mitochondrial bioenergetics.
Xue X, Hou J, Zhang Z … +9 more , Yang Z, Chang L, Yang Z, Liu S, Huang H, Mei L, Mi Y, Zheng P, Sun X
Biol Direct · 2026 Feb · PMID 41761273 · Full text
TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA-binding protein. It has emerged as a key regulator of RNA processing, such as alternative splicing events, which are essential for cellular homeostasis. The mislocaliz...
TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA-binding protein. It has emerged as a key regulator of RNA processing, such as alternative splicing events, which are essential for cellular homeostasis. The mislocalization and aggregation of TDP-43 are closely associated with mitochondrial dysfunction. However, the mechanisms by which the formation TDP-43 contributes to mitochondrial impairment remain poorly understood. In this study, we confirmed that the TDP-43 loss leads to dramatic alterations in mitochondrial morphology and a significant reduction in respiratory capacity. Further analysis of oxidative phosphorylation (OXPHOS) complex assembly revealed a selective disruption of complex III activity. Notably, the core complex III subunit UQCRC2 was significantly decreased as long as TDP-43 was knocked down. The transcript analysis showed that the loss of TDP-43 results in aberrant alternative splicing of the nuclear-encoded UQCRC2 transcript. In parallel, this mis-splicing event was consistently observed in both dividing cells, including HEK293T, and in the neuroblastoma cell line SH-SY5Y, suggesting that TDP-43-mediated regulation of UQCRC2 splicing can be potentially conserved across a wide range of cell types. These findings indicate a novel role for TDP-43 in maintaining mitochondrial integrity via regulation of UQCRC2 expression and splicing, providing mechanistic insight into how dysregulated RNA processing contributes to mitochondrial bioenergetic deficits.
Cepharanthine alleviated chronic prostatitis/chronic pelvic pain syndrome by activating Nrf2 and inhibiting the NF-κB pathway.
Zhang H, Zhang D, Wang Z … +10 more , Liu K, Xu C, Sun H, Yan Z, Li C, Lu B, Yin Y, Zhao C, Niu Y, Li W
Biol Direct · 2026 Feb · PMID 41749289 · Full text
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder impacting the genitourinary system of adult males, primarily driven by pathogenic mechanisms involving immune and inflammatory m...
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder impacting the genitourinary system of adult males, primarily driven by pathogenic mechanisms involving immune and inflammatory mediators, immune cells and molecules, oxidative stress, and apoptosis. Cepharanthine (CEP), a bisbenzylisoquinoline alkaloid, exhibits properties such as immunomodulatory, antioxidant, anti-inflammatory, and antitumor activities. Nevertheless, the effects of CEP on CP/CPPS and its underlying mechanisms remain insufficiently characterized. METHODS: Two experimental models were developed, one utilizing experimental autoimmune prostatitis (EAP) mouse models and the other employing LPS-induced RWPE-1 cells. The pivotal role of Nrf2 was investigated using Nrf2 knockout mice and the Nrf2 inhibitor ML385. RESULTS: Treatment with CEP reduced prostate inflammation scores, alleviated tactile sensitization of the pelvic region in EAP mice, improved pathological damage in prostate tissues, and inhibited the upregulation of systemic and localized pain and pro-inflammatory mediators in the prostate. Furthermore, CEP treatment was shown to inhibit oxidative stress, ameliorate mitochondrial dysfunction, and suppress apoptosis. In vitro studies indicate that CEP treatment stabilizes Nrf2 protein levels by binding to the Nrf2 protein and inhibiting its ubiquitination-mediated degradation. Consequently, CEP treatment activates the Nrf2 signaling pathway, facilitates its nuclear translocation, and upregulates the expression of downstream target proteins, such as HO-1 and NQO1. Concurrently, CEP suppresses the activation of the NF-κB pathway. Notably, the blockade of Nrf2 signaling negates the protective effects mediated by CEP. CONCLUSIONS: CEP inhibits the ubiquitination-mediated degradation of Nrf2 and exhibits potential to activate the Nrf2 pathway while concurrently inhibiting the NF-κB pathway, thereby alleviating CP/CPPS.
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