Molecular Medicine最新文献

The galactoside-binding galectin-3 is a multi-mode promoter in a broad range of cancers, as well as in the pathogenesis of inflammation and fibrosis-associated diseases. It is currently a hotly pursued therapeutic target in those disease areas. Several carbohydrate-based galectin-3 inhibitors have recently demonstrated encouraging results in early phase clinical trials. This study reports the discovery of two synthetic, non-carbohydrate, small molecule compounds (named K2 an L2) as potent galectin-3 inhibitors. K2 and L2 share the same molecular composition with difference of one -NH2 group located at para (K2) or meta (L2) position at one of its aromatic rings. These novel compound inhibitors were shown to bind to galectin-3 on the canonical S-face of galectin-3 carbohydrate-recognition domain. Their binding was shown to alter galectin-3 conformation and significantly inhibit galectin-3-mediated activities in cancer cell adhesion, invasion, angiogenesis and macrophage secretion of pro-inflammatory cytokines min vitro, and markedly reduce galectin-3-mediated tumour growth and metastasis in vivo in mice as well as in chick embryos. Moreover, these novel galectin-3 inhibitors showed no detectable cytotoxicity and no genotoxicity. K2 and L2 therefore represent a unique class of novel galectin-3 inhibitors that can effectively inhibit galectin-3-mediated activities in vitro and in vivo. The discovery of these non-carbohydrate galectin-3 inhibitors offers significant promises to the development of galectin-3-targeted therapeutic drugs for the treatment of cancer and other galectin-3-mediated pathologies such as inflammation and fibrosis-associated diseases.

Background: Lithium is a first-line treatment for bipolar disorder (BD), but only 30% of patients respond satisfactorily to monotherapy, and the biological basis for this variability remains unclear. This study aimed to identify potential biomarkers and therapeutic targets by analyzing olfactory neuroepithelium (ONE) cells from BD lithium non-responders (BDNR), responders (BDR), and control subjects.

Methods: Immunofluorescence and proteomic analyses of ONE cells were conducted. Blood samples were examined to improve accessibility for clinical applications.

Results: Immunofluorescence and proteomic analyses of ONE cells revealed that BDNR cells exhibited impaired adhesion capacity, which was restored by lithium treatment in vitro. However, BDNR cells also showed significant alterations in cell morphology and cytoskeletal organization that were unaffected by lithium. Proteomic analysis identified significant changes in pathways associated with "cell morphology," with CDN2A highlighted as a key protein. In BDR cells, lithium treatment restored adhesion capacity but failed to reverse migration deficits. Proteomic analysis of BDR ONE cells identified differentially expressed proteins linked to neurotransmitter release, synaptic function, and mitochondrial activity, many of which were significantly modulated by lithium. Additionally, peripheral blood mononuclear cells from BDR patients displayed lower levels of RHOC protein, mirroring reductions seen in ONE BDR cells treated with lithium.

Conclusions: This study underscores cellular and proteomic differences between BDNR and BDR cells, with lithium exerting pronounced effects on BDR cells while having limited impact on BDNR cells. These findings advance our understanding of lithium responsiveness in BD and point to potential biomarkers and therapeutic targets for personalized treatment approaches.

Purpose: Osteoarthritis (OA) is a debilitating joint disease with no effective cure. This study investigates the role of Insulin Receptor Substrate 2 (IRS2) in OA and its potential as a therapeutic target.

Methods: Transcriptomic analysis of OA-related datasets (GSE178557, GSE169077, GSE64394, GSE57218) was conducted to identify differentially expressed genes (DEGs), with KEGG pathway analysis highlighting the PI3K/AKT pathway. In vivo, the destabilization of the medial meniscus (DMM) OA mouse model was used to assess IRS2 expression through histology, qPCR, and Western blot. IRS2 was overexpressed in primary mouse chondrocytes via adenoviral transfection, with proliferation, apoptosis, and autophagy assessed by EdU, Annexin V/PI staining, and autophagy-related protein analysis. Adenovirus expressing Irs2 was injected intra-articularly into DMM mice, and cartilage integrity was assessed using histology and micro-CT.

Results: IRS2 expression was significantly reduced in OA cartilage, correlating with PI3K/AKT pathway inhibition. IRS2 overexpression restored AKT activation, FOXO1 phosphorylation, and mitochondrial autophagy. Intra-articular IRS2 injection improved cartilage matrix integrity, reduced MMP13, and alleviated subchondral bone changes in DMM mice.

Conclusion: IRS2 plays a key role in OA pathogenesis and targeting it may provide a promising therapeutic approach for OA.

Background: Through evolutionary genomics analysis, we identified Yulink (MIOS, Entrez Gene: 54,468), a highly conserved gene encoding an 875 amino acid protein with diverse functions in humans. Given the importance of accelerated glycolysis in hepatocellular carcinoma (HCC), we explored the expression and function of Yulink in HCC cells and analyzed clinicopathological data to unveil its impact on patient survival.

Methods: Clinicopathological data from 184 patients with resectable HCC were mined to establish a correlation between Yulink expression and patient survival. We employed reverse transcription quantitative polymerase chain reaction (RT-qPCR) to assess Yulink expression in the tumor tissues. Various assays, including Western blotting, migration, MTT, cell cycle, immunofluorescence, oxidative stress, tumorigenesis, glucose uptake, glycolytic function, proximity ligation, and immunoprecipitation, were conducted on Huh7 cells to identify the regulatory mechanisms under glucose restriction.

Results: Comparative evolutionary genomics analysis revealed that patients with high Yulink expression had significantly shorter relapse-free survival (RFS) and overall survival (OS) (P < 0.0001 and = 0.0015, respectively). Multivariable Cox regression analysis identified Yulink expression as an independent unfavorable predictor of RFS (HR, 2.63; 95% CI, 1.58-4.38; P < 0.001) in HCC. Furthermore, Yulink expression positively correlated with Huh7 migration and survival, especially in response to glucose restriction. Yulink deficiency enhanced glucose restriction-induced cell death, likely due to increased reactive oxygen species (ROS) and DNA damage, with a failure of ATM-CHK2 activation. Huh7 xenografts with Yulink suppression exhibited delayed tumorigenesis in immunocompromised nude mice. Importantly, proximity Ligation assays and immunoprecipitation demonstrated that Yulink colocalized and interacted with glucose transporter 1 (GLUT1). Knockdown of Yulink not only suppressed GLUT1 expression, but also disrupted GLUT1 translocation from the cytosol to the cell membrane, resulting in downregulated glucose uptake and glycolysis.

Conclusions: Our results underscore the protective role of Yulink in HCC survival under glucose restriction and its pivotal function in glucose metabolism, suggesting a mechanistic link between lower Yulink expression and higher survival in patients with HCC.

Background: Anti-ribosomal P protein autoantibodies (anti-P) are associated with psychosis and cognitive dysfunction in patients with systemic lupus erythematosus (SLE), yet the underlying mechanisms remain undefined, hindering targeted therapies. Anti-P cross-react with a neuronal surface protein (NSPA), alter glutamatergic synaptic transmission and plasticity in hippocampal slices, and impair spatial memory in a short-term passive transfer mouse model. NSPA knockout mice display spatial memory deficit linked to reduced NMDAR activity and postsynaptic density (PSD) levels, along with an increased membrane-associated tyrosine phosphatase PTPMEG, suggesting disrupted glutamatergic receptor trafficking. Here, we investigated the acute effects of anti-P on receptor cell surface expression and trafficking in cultured hippocampal neurons and their long-term impact on hippocampal components and spatial memory in anti-P( +) immunized mice.

Methods: NMDAR and AMPAR surface expression and NMDAR recycling were assessed in 21-24 DIV primary hippocampal neurons by immunofluorescence and FRAP using SEP-tagged receptors under the effects of rabbit anti-P IgG fractions. In vivo, female C57BL/6 mice were immunized with recombinant P0 ribosomal protein to induce anti-P, followed by lipopolysaccharide (LPS) intraperitoneal administration to breach the blood-brain-barrier (BBB). Spatial memory was evaluated with a water maze memory flexibility test. Hippocampal synaptosomal membranes and PSD-enriched fractions were analyzed by immunoblotting. Neuronal density, microglia and dendritic architecture were evaluated using Cresyl Violet, Iba1 and Golgi staining, respectively.

Results: Anti-P treatment of cultured neurons reduced GluN2A and GluA1 surface levels and impaired SEP-GluN2A and SEP-GluN2B recycling. Anti-P( +) mice showed spatial memory deficits persisting up to 24 days post-LPS, along with hippocampal alterations that include reduced levels of NMDAR, AMPAR, and PSD-95 in PSD fractions; increased membrane-associated PTPMEG; ~ 7% neuronal loss; higher number of microglia with reduced ramifications, and diminished dendritic width and spine density. Notably, increased PTPMEG levels were already detectable by day 10 post-LPS.

Conclusions: Anti-P antibodies acutely impair glutamatergic receptor recycling and surface expression, while their long-term effects lead to sustained memory impairment associated with altered neuronal and microglial architecture, and PTPMEG increased levels preceding PSD protein loss. These findings provide mechanistic insight into anti-P-mediated cognitive dysfunction and may inform therapeutic strategies for neuropsychiatric SLE.

During pregnancy, profound immunological, hormonal, and metabolic adaptations occur to support fetal development. The impact of pregnancy on vaccine-induced immunity remains incompletely characterized, as previous studies have primarily focused on serological antibody levels but not immune memory. Immune memory is critical for vaccine effectiveness, but effect of pregnancy on immune memory remain unknown. In addition, the memory B cell response profile induced by inactivated coronavirus disease 2019 (COVID-19) vaccines in pregnant women remains unclear. This study comprehensively investigated the serological responses and memory B cell response induced by an inactivated COVID-19 vaccine in pregnant women. The results demonstrated that while pregnant women and non-pregnant women of childbearing age showed comparable serological antibody levels, vaccine-induced monoclonal antibodies (mAbs) from pregnant women exhibited significantly lower binding potency to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and its segments and weaker neutralizing potency and breadth than those from non-pregnant women. Vaccine-induced mAbs from pregnant women were derived predominantly from IGHV3-30, whereas those from non-pregnant women were derived diverse germline genes. Most of mAbs from pregnant women targeted the receptor-binding domain (RBD) (40.9%) and S2 domain (31.8%), whereas most of mAbs from non-pregnant women targeted the RBD (51.3%) and N-terminal domain (30.8%). These findings suggested that pregnancy may impair the potency of vaccine-induced memory B cells. These insights may be valuable for the development of vaccination strategies for pregnant women.