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An outbreak of SARS-CoV-2 coronavirus (COVID-19) first detected in Wuhan, China, has created a public health emergency all over the world. The pandemic has caused more than 340 million confirmed cases and 5.57 million deaths as of 23 January 2022. Although carbohydrates have been found to play a role in coronavirus binding and infection, the role of cell surface glycans in SARS-CoV-2 infection and pathogenesis is still not understood. Herein, we report that the SARS-CoV-2 spike protein S1 subunit binds specifically to blood group A and B antigens, and that the spike protein S2 subunit has a binding preference for Lea antigens. Further examination of the binding preference for different types of red blood cells (RBCs) indicated that the spike protein S1 subunit preferentially binds with blood group A RBCs, whereas the spike protein S2 subunit prefers to interact with blood group Lea RBCs. Angiotensin converting enzyme 2 (ACE2), a known target of SARS-CoV-2 spike proteins, was identified to be a blood group A antigen-containing glycoprotein. Additionally, 6-sulfo N-acetyllactosamine was found to inhibit the binding of the spike protein S1 subunit with blood group A RBCs and reduce the interaction between the spike protein S1 subunit and ACE2.

Multidrug resistance (MDR), an unfavorable factor compromising the treatment efficacy of anticancer drugs, involves the upregulation of ATP binding cassette (ABC) transporters and induction of galectin-3 signaling. Galectin-3 plays an anti-apoptotic role in many cancer cells and regulates various pathways to activate MDR. Thus, the inhibition of galectin-3 has the potential to enhance the efficacy of the anticancer drug epirubicin. In this study, we examined the effects and mechanisms of silencing galectin-3 via RNA interference (RNAi) on the β-catenin/GSK-3β pathway in human colon adenocarcinoma Caco-2 cells. Galectin-3 knockdown increased the intracellular accumulation of epirubicin in Caco-2 cells; suppressed the mRNA expression of galectin-3, β-catenin, cyclin D1, c-myc, P-glycoprotein (P-gp), MDR-associated protein (MRP) 1, and MRP2; and downregulated the protein expression of P-gp, cyclin D1, galectin-3, β-catenin, c-Myc, and Bcl-2. Moreover, galectin-3 RNAi treatment significantly increased the mRNA level of GSK-3β, Bax, caspase-3, and caspase-9; remarkably increased the Bax-to-Bcl-2 ratio; and upregulated the GSK-3β and Bax protein expressions. Apoptosis was induced by galectin-3 RNAi and/or epirubicin as demonstrated by chromatin condensation, a higher sub-G1 phase proportion, and increased caspase-3 and caspase-9 activity, indicating an intrinsic/mitochondrial apoptosis pathway. Epirubicin-mediated resistance was effectively inhibited via galectin-3 RNAi treatment. However, these phenomena could be rescued after galectin-3 overexpression. We show for the first time that the silencing of galectin-3 sensitizes MDR cells to epirubicin by inhibiting ABC transporters and activating the mitochondrial pathway of apoptosis through modulation of the β-catenin/GSK-3β pathway in human colon cancer cells.

Triple-negative breast cancer (TNBC) remains a significant therapeutic challenge due to its unresponsiveness to hormone and HER2-targeted treatments. This study investigated the potential of acetylated globotetraose (Ac-Gb4) as a novel therapeutic approach targeting glycolipid-mediated signaling in breast cancer cells. We synthesized acetylated globotetraose (Gb4) to enhance its membrane permeability while preserving its biological recognition properties. Flow cytometry analysis revealed that Ac-Gb4 treatment significantly decreased SSEA3 and SSEA4 expression in MDA-MB-231 breast cancer cells, which are Globo-H-negative cells. Notably, Ac-Gb4 demonstrated selective cytotoxicity against cancer cells by significantly reducing proliferation and inducing apoptosis in MDA-MB-231 cells while sparing hTERT-HME1 normal breast epithelial cells. Mechanistic studies through Western blot analysis revealed that Ac-Gb4 simultaneously modulated multiple signaling pathways, including FAK cleavage, reduced AKT expression, and increased caspase-3 activation, particularly at the 4 mM concentration. These molecular changes correlated with decreased cancer cell invasion capability in a dose-dependent manner. Our findings demonstrated that Ac-Gb4 effectively targeted breast cancer cells through the modulation of critical signaling pathways involved in cell survival and invasion while maintaining a minimal impact on normal cells. This anti-cancer activity suggests that Ac-Gb4 represents a promising therapeutic candidate for breast cancer treatment, particularly for aggressive subtypes such as TNBC.

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin’s antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin’s antidepressant effects, indicating the involvement of BDNF–TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H2O2 production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF–TrkB signaling, leading to reduced ROS/H2O2 accumulation and alleviation of CRS-induced depression-like behaviors.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, characterized by high incidence and poor survival rates. Glycosylation, a fundamental post-translational modification, influences protein stability, signaling, and tumor progression, with aberrations implicated in immune evasion and metastasis. This study investigates the role of glycosylation-related genes (Glycosylation-RGs) in CRC using machine learning and bioinformatics. Data from The Cancer Genome Atlas (TCGA) and the Molecular Signatures Database (MSigDB) were analyzed to identify 67 differentially expressed Glycosylation-RGs. These genes were used to classify CRC patients into two subgroups with distinct survival outcomes, highlighting their prognostic value. Weighted gene coexpression network analysis (WGCNA) revealed key modules associated with CRC traits, including pathways like glycan biosynthesis and PI3K–Akt signaling. A machine-learning-based prognostic model demonstrated strong predictive performance, stratifying patients into high- and low-risk groups with significant survival differences. Additionally, the model revealed correlations between risk scores and immune cell infiltration, providing insights into the tumor immune microenvironment. Drug sensitivity analysis identified potential therapeutic agents, including Trametinib, SCH772984, and Oxaliplatin, showing differential efficacy between risk groups. These findings enhance our understanding of glycosylation in CRC, identifying it as a critical factor in disease progression and a promising target for future therapeutic strategies.

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Key Clinical Message Temporal percutaneous transhepatic duodenum drainage (PTDD) seems to be effective in the treatment of postoperative afferent loop syndrome (ALS) following transverse loop colostomy for obstructive colorectal cancer. Management of obstructive colorectal cancer still remains a challenge. There are various options with different risks of mortality and mobility for obstructive colorectal cancer. A rare unexpected postoperative ALS following a low anterior resection and transverse loop colostomy for obstructive colorectal cancer is presented in this report. A 64‐year‐old man had the acute ALS had been noted 10 days after transverse loop colostomy. An option was temporal PTDD treatment in the patient with history of Billroth's operation II for upper gastrointestinal bleeding 30 years ago. Acute ALS was treated by temporal PTDD. The drainage tube for PTDD was not removed until closure of the transverse colostomy 2 months later. The patient recovered uneventfully. Acute ALS after transverse loop colostomy for obstructive colorectal cancer is rare and has never been reported in the literature. The mechanism of acute ALS after construction of a loop colostomy and the treatment strategy of PTDD for acute ALS is presented.

Cytokines are central regulators of inflammation and immune responses within the tumor microenvironment and have been implicated in cancer progression and prognosis. However, the prognostic value of coordinated cytokine-related transcriptional programs across cancer types has not been systematically explored. Pan-cancer transcriptomic and clinical data were analyzed to construct a cytokine-related prognostic signature using least absolute shrinkage and selection operator (LASSO) Cox regression. Patients were stratified into high-risk and low-risk groups based on the derived risk score. Prognostic performance was evaluated in training and test cohorts, and biological relevance was assessed through survival analyses and pathway-level investigations. A 16-gene cytokine-related signature was established that consistently stratified patients into distinct prognostic groups across multiple cancer types. High cytokine-related risk scores were significantly associated with unfavorable survival outcomes and were linked to enhanced cell cycle activity, epithelial-mesenchymal transition, and extracellular matrix remodeling. Integration of the risk score with clinical variables improved individualized survival prediction. Immunohistochemical analyses further confirmed increased protein expression of representative risk-associated genes, including pannexin 1 (PANX1) and FERM domain containing 8 (FRMD8), in multiple tumor tissues compared with corresponding normal tissues. The cytokine-related prognostic signature captures key inflammatory and immune-related programs underlying tumor aggressiveness and provides a robust tool for pan-cancer risk stratification with potential clinical utility.

Background Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in cancer progression and therapeutic resistance. Concurrently, glycosylation, as a key post-translational modification, plays a critical role in regulating cell signaling, immune evasion, and metastasis. Although both processes are independently implicated in tumor biology, the intersection between ferroptosis and glycosylation remains largely unexplored. Methods We performed a comprehensive pan-cancer multi-omics analysis, integrating bulk transcriptomics, epigenomics, and single-cell RNA sequencing datasets. Ferroptosis and glycosylation-related genes were curated from The Molecular Signatures Database (MSigDB), leading to the identification of the metal ion transporter, SLC39A14 (solute carrier family 39 member 14), as a key intersecting gene. A ferroptosis-related gene signature was constructed using machine learning and Cox regression models, followed by survival analyses, immune microenvironment profiling, and a pathway enrichment analysis across The Cancer Genome Atlas (TCGA) cohort. Results SLC39A14 was found to be significantly upregulated across multiple tumor types and associated with a poor prognosis, immune-stromal infiltration, and ferroptosis resistance. Among all cancer types analyzed, glioblastoma multiforme (GBM) and kidney renal cell carcinoma (KIRC) exhibited the significantly prognostic associations and the most pronounced differential expression of SLC39A14. Single-cell analysis revealed that SLC39A14 expression was enriched between stromal and immune populations, hypoxic perivascular niches, confirming its microenvironment-specific functions. These findings were corroborated by DNA methylation data showing promoter hypomethylation of SLC39A14 in tumors compared to normal tissues. Functionally, SLC39A14 was highly enriched in pathways related to angiogenesis, the epithelial-to-mesenchymal transition, cytokine signaling, and oxidative stress adaptation including vascular endothelial growth factor (VEGF) and cell metabolism-related signaling. A nomogram integrating SLC39A14 expression with clinical parameters improved overall survival predictions. Conclusions In this study, we identified SLC39A14 as a dual regulator at the interface of ferroptosis and glycosylation, with significant impacts on tumor microenvironmental remodeling and therapeutic resistance. By leveraging multi-omics and single-cell transcriptomic data, we establish SLC39A14 as a promising prognostic biomarker and therapeutic target, particularly in brain and kidney cancers where ferroptosis modulation could offer novel clinical strategies.

Background Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive progression, pronounced stromal desmoplasia, and a limited response to targeted therapies. Although epidermal growth factor receptor (EGFR) inhibitors have shown promise in preclinical studies, their clinical efficacy has been modest, suggesting the existence of compensatory signaling networks. Methods An integrated analytical framework was employed, combining bulk transcriptomic analyses of TCGA-PDAC and GTEx datasets, DNA methylation profiling, protein–protein interaction (PPI) network analysis, immune infiltration estimation, and single-cell RNA sequencing. Expression patterns and clinical associations of integrin αvβ3 were evaluated using TCGA, GEPIA, UALCAN, and the Human Protein Atlas. Functional validation was performed using in vitro assays in pancreatic cancer cell lines to assess the effects of DL-N2, a tetrac-conjugated nanoparticle targeting integrin αvβ3, alone or in combination with gefitinib. Results Integrin αvβ3 (ITGAV/ITGB3) was upregulated in PDAC tissues compared with normal pancreatic tissue and was associated with poor prognosis. Single-cell transcriptomic profiling localized αvβ3 expression to malignant ductal cells and stromal fibroblasts. Computational analyses predicted strong associations of αvβ3 with EGFR, MMP2, and MMP9, implicating it in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune regulation. In vitro, experiments showed that DL-N2 suppressed basal and EGF-induced proliferation, decreased the expression of EGFR , PCNA , and CCND1 , and reduced angiogenic and invasive mediators, including VEGF-α , bFGF2 , and MMP9 . Notably, DL-N2 inhibited PD-L1 expression, linking αvβ3 signaling to immune evasion. In addition, both DL-N2 and gefitinib inhibited cell migration, and their combined treatment exerted an additive effect on the suppression of pancreatic cancer cell migration. Conclusion Our findings establish integrin αvβ3 as a multifunctional regulator of pancreatic cancer progression, integrating growth-associated signaling, extracellular matrix regulation, and immune-associated pathways. Targeting αvβ3 with DL-N2 remodels both tumor-intrinsic and microenvironmental pathways, potentially enhancing EGFR inhibition and restoring chemosensitivity. Dual blockade of αvβ3 and EGFR represents a rational therapeutic strategy to overcome drug resistance and improve outcomes in PDAC. Highlights Mechanistic Crosstalk Clarity : Ensure the introduction (which you've drafted well) leads directly to results that prove how integrin αvβ3 and EGFR interact. Mentioning FAK (Focal Adhesion Kinase) as the bridge is a common 2026 reviewer expectation for this pathway. Clinical Relevance : JTM editors look for \"human-centric\" data. If your paper relies on cell lines, ensure you have validated the expression of αvβ3 and EGFR in human PDAC tissue samples or publicly available databases (like TCGA or GTEx) to prove clinical significance. Address “Thyroid Hormone” Implications : Since you mentioned thyroid hormones (T3/T4) binding to αvβ3, reviewers may ask if patients on thyroid medication show different PDAC outcomes. Briefly addressing this \"translational\" clinical potential in your discussion can significantly strengthen your case