Journal of Molecular Medicine-Jmm最新文献

Tumor hypoxia, a hallmark of the tumor microenvironment (TME), profoundly impacts the antitumor functionality of immune cells, particularly natural killer (NK) cells, which play a critical role in cancer immunosurveillance and immunotherapy success. This review provides a comprehensive analysis of the mechanisms by which hypoxia impairs NK cell-mediated cytotoxicity and antitumor activities, emphasizing the molecular pathways and cellular adaptations that enable cancer cell to evade NK cell attack. Key factors that participate in this phenomenon include the stabilization of hypoxia-inducible factors, metabolic reprogramming, angiogenesis, cancer stemness, autophagy, and the secretion of immunosuppressive molecules. Moreover, hypoxia induces phenotypic and functional changes in both cancer and NK cells, promoting tumor progression and resistance to immunotherapy. Emerging strategies to counteract hypoxia-induced immunosuppression are being explored, including nanotechnology-based approaches, cytokine-mediated NK cell preconditioning, and vascular normalization techniques. These interventions highlight promising avenues for enhancing NK cell functionality and synergizing with existing cancer therapies. By addressing the immunosuppressive challenges of the hypoxic TME, in this review, we underscore the potential of innovative strategies to improve therapeutic outcomes in cancer treatment.

Relative cerebral blood flow (rCBF), assessed using pulsed arterial spin labeling (pASL) MRI, and the standardized uptake value ratio (SUVr) in early-phase amyloid-PET (ePET) are used as proxies for brain perfusion. These methods have the potential to streamline clinical workflows and reduce the burden on patients by eliminating the need for additional procedures. While both techniques have shown good agreement with the gold standard for glucose metabolism assessment, F-fluorodeoxyglucose-PET, a direct comparison between them has yet to be fully clarified. This retrospective study aimed to compare perfusion-like data from pASL (rCBF) and ePET (SUVr) in a memory clinic cohort. We included 46 subjects (69 ± 8 years; 37 women) from the Geneva Memory Center (cognitively impaired-CI n = 29; cognitively unimpaired-CU n = 17), with available pASL and ePET. We evaluated the association between rCBF and SUVr values across 18 cortical and subcortical regions using linear regression and the within-subject coefficient of variation (wsCV). Regional differences between CU and CI groups were assessed using linear regression model corrected for age. We observed significant association between rCBF and SUVr in precuneus (β = 0.69, wsCV = 16.9), angular gyrus (β = 0.64, wsCV = 19.4), and hippocampus (β = 0.23, wsCV = 16.1). Additionally, significant differences in rCBF between CU and CI were also observed in the posterior cingulate, precuneus, calcarine, hippocampus, and composite (p < 0.05), while SUVr showed significant differences only in the hippocampus. Our findings indicate weak to moderate local correlations between the two techniques. However, both exhibited differing regional perfusion levels in CU and CI groups, with rCBF showing more regional differences between cognitive stages in comparison with SUVr. KEY MESSAGES: rCBF is assessed through pASL MRI and SUVr through ePET, both serving as proxies of brain perfusion. Weak to moderate associations between rCBF and SUVr were found in a number of brain regions. rCBF and SUVr differences between cognitive stages were observed mostly in cortical and subcortical regions respectively. Both techniques were able to identify AD perfusion-like differences expected in cognitively impaired vs unimpaired.

The development of therapeutics that enhances the regeneration of myelin sheaths following demyelination is predicted to prevent neurodegeneration. A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNFα) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis. KEY MESSAGES: Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by: Leading to a lower percentage of unmyelinated axons at early stages. Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages. Covering large calibre axons with thinner myelin sheaths at later stages.

Myeloid differentiation protein 2 (MD2), a co-receptor of toll-like receptor 4 (TLR4) in the innate immune system, has emerged as a promising target for anti-inflammatory therapies. Rheumatoid arthritis (RA), a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction, remains a therapeutic challenge due to the lack of effective treatment options. In this study, we investigated the role of MD2 in the pathogenesis and progression of RA. Our findings show that MD2 is overexpressed in both the whole blood and synovial tissues of RA patients. Furthermore, MD2 expression was upregulated in collagen-induced RA mouse models. MD2 knockout significantly alleviated key symptoms of RA, including improved body weight, reduced paw swelling, and decreased bone destruction and cartilage erosion. Additionally, MD2 deficiency led to a significant reduction in serum levels of inflammatory cytokines and a decrease in the expression of inflammatory protein within synovial tissue. Notably, animal models revealed that genetic ablation of MD2 exerts potent anti-ferroptosis effects in arthritic pathophysiology. This protective effect was recapitulated at the cellular level through pharmacological interventions, where MD2-targeting inhibitors effectively attenuated lipopolysaccharide-induced ferroptotic cell death in murine macrophages, as evidenced by characteristic biomarkers including glutathione depletion and lipid peroxidation. Mechanistically, the reduction in ferroptosis and inflammation following MD2 knockout was associated with the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the synovial tissue. These results suggest that MD2 plays a critical role in both the inflammatory response and ferroptosis, in the context of RA. Consequently, MD2 represents a key mediator of RA pathogenesis and an innovative therapeutic target for the treatment of this debilitating disease. KEY MESSAGES: MD2 expression is upregulated in synovial tissue following the onset of rheumatoid arthritis. MD2 knockout alleviates bone destruction, cartilage erosion, and inflammation in rheumatoid arthritis mice. MD2 deficiency mitigates rheumatoid arthritis in mice by inhibiting ferroptosis induced by the MAPK and NF-κB signaling pathways. MD2 may serve as a potential therapeutic target for rheumatoid arthritis.

Innate immunity is the immune system that organisms possess from birth. It is primarily responsible for the rapid, nonspecific recognition of pathogens when they invade, activating the host's immune response to eliminate. Cervical cancer is one of the most well-known tumors caused by human papillomavirus (HPV) infection. As the first line of defense against pathogens, innate immunity plays a crucial role in the response to HPV invasion, and there has been significant research in this area in recent years. The findings suggest that innate immune responses not only contribute to the clearance of HPV but may also facilitate the spread of the virus and the carcinogenic transformation of cervical epithelial cells. In this review, we comprehensively examine the activation of innate immune responses during HPV infection, the mechanisms by which HPV evades these immune defenses, and the role of innate immunity in promoting cervical intraepithelial neoplasia. Additionally, we explore the characteristics of innate immune responses within the tumor microenvironment of cervical cancer. Furthermore, we summarize recent advances in understanding the various mechanisms by which innate immune responses can be activated, with a focus on potential therapeutic implications. By reviewing the latest research, this article aims to provide valuable insights and stimulate further investigation into the role of innate immunity in HPV-associated cervical lesions, potentially leading to more effective strategies for prevention and treatment in the future.

The TNF family member LIGHT (TNFSF14) binds to two receptors, HVEM (TNFSFR14) and LTβR (TNFSFR3). HVEM functions as a costimulatory molecule, whereas LTβR is involved in the development of lymph nodes and ectopic tertiary lymphoid structures at chronic inflammation sites. The classical approach of fusing soluble recombinant proteins to the Fc fragment of IgG resulted in a functionally inactive Ig.mouse (m) LIGHT protein. However, in line with the fact that TNF family members cluster receptors as trimers, addition of a small homotrimeric domain (foldon) N-terminal of mLIGHT produced an Ig.Foldon-mLIGHT protein able to bind and engage HVEM and LTβR in a cell-based reporter bioassay. In the tumor model of B16.F10 melanoma cells implanted into syngeneic recipients, cells transduced with membrane-bound mLIGHT grew as aggressively as mock-transduced cells, but growth of tumors of B16.F10 cells expressing Ig.Foldon-mLIGHT was delayed and characterized by significant immune infiltration of dendritic cells and cytotoxic cells. This work unveils the potential of active soluble LIGHT, as a single agent, to recruit cytotoxic cells and dendritic cells at the tumor site to inhibit tumor growth. This effect may be further enhanced with immune checkpoint blockade therapies. KEY MESSAGES: The classical approach of fusing soluble recombinant proteins to the Fc fragment of IgG resulted in a functionally inactive Ig.mouse (m) LIGHT (TNFSF14) protein. The addition of a small homotrimeric domain (foldon) N-terminal of mouse LIGHT produces a proper folded bioactive mouse LIGHT recombinant protein. Constitutive intratumor expression of secreted Ig-Foldon-LIGHT, but not membrane LIGHT, delays tumor growth. Tumors secreting LIGHT, as a single agent, promote beneficial anti-tumor responses through the recruitment and infiltration of cytotoxic cells and dendritic cells.

Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). Recent studies examining the use of metformin for the treatment of children with metabolic dysfunction-associated steatotic liver disease (MASLD) showed controversial results. To evaluate the patient-specific impact of metformin on hepatic glucose, lipid, amino acid, and energy metabolism in a cohort of 70 paediatric patients with biopsy-proven MASH. We parametrized our mathematical model HEPATOKIN1 of liver metabolism with patient-specific proteomics data of liver enzyme abundances and simulated metformin-induced diurnal changes of a large panel of metabolic functions. On average, a single dose (250 mg) of metformin reduced diurnal HGP by 19%. Based on a Z-score of 1, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels within four after metformin ingestion, energy metabolism, cytosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 h, these metabolic side effects were not significant. In particular, there was no significant impact of metformin on hepatic fat storage. Baseline lactate and insulin activity at 90 min after glucose challenge (OGTT) correlated significantly with the reduction in HGP and may serve as predictors of effective therapy. On a daily average, metformin selectively affects hepatic glucose production, glycogen storage and lactate uptake, while numerous other metabolic functions are significantly altered only for several hours after administration of the drug. Our method provides a patient-specific analysis of the potential effects of metformin therapy on central hepatic metabolism and may therefore help guide the physician's therapeutic decision.

Ferroptosis has been closely linked to the pathological processes of various diseases, making it a promising target for therapeutic intervention. Understanding the regulatory mechanisms underlying ferroptosis and developing effective pharmacological strategies is essential. Nanomedicine, particularly the use of nanozymes, offers a potential approach for regulating ferroptosis. In this study, we investigated the inhibitory activity of ultra-small, biocompatible cerium oxide nanoparticles (CeO₂ NPs) on ferroptosis and explored the underlying molecular mechanisms. CeO₂ NPs exhibited potent superoxide dismutase (SOD) and catalase (CAT) activities, efficiently scavenging multiple free radicals and lipid peroxidation products both intracellularly and extracellularly. These activities effectively prevented or alleviated ferroptosis in RSL3-induced cells. Proteomic analysis revealed that CeO₂ NPs significantly altered the expression of numerous proteins, including a reduction in pro-inflammatory cytokines. Mechanistically, CeO₂ NPs specifically regulated the expression of key proteins involved in ferroptosis-related metabolic processes, reducing iron accumulation and lipid peroxidation, and thereby decreasing cellular susceptibility to ferroptosis. Our findings demonstrate that CeO₂ NPs synergistically inhibit ferroptosis by both scavenging reactive oxygen species (ROS) and modulating the expression of ferroptosis-regulating proteins. In conclusion, this study highlights the potential of CeO₂ NPs as a promising nanozymes for ferroptosis inhibition, offering novel insights into the design of CeO₂ NPs-based therapies for ferroptosis-related diseases.

Diabetic retinopathy (DR) is a chronic disease that severely impairs the vision of working individuals and is closely linked to blood-retinal barrier (BRB) dysfunction. Flotillin- 1 (FLOT1), a protein located in membrane lipid rafts, is essential for various intracellular biological processes. However, its role in the pathogenesis of DR remains unclear. Ferroptosis in high-glucose was assessed using Cell counting kit- 8 (CCK- 8), Malondialdehyde (MDA), Glutathione (GSH), Fe²⁺ assays, and transferrin expression. BRB disruption was evaluated with Evans blue staining. The interaction between FLOT1 and NF-E2-related factor 2 (Nrf2) was confirmed by immunoprecipitation and ferroptosis mechanisms were explored by inhibiting Nrf2 with ML385. In db/db mice (a type 2 diabetes model) was intravitreal injection of an adeno-associated virus (AAV) overexpressing FLOT1. Expression levels of Nrf2, solute carrier family 7 member 11 (SLC7 A11), and glutathione peroxidase 4 (GPX4) were evaluated in retina. Our study indicated that FLOT1 significantly alleviated BRB damage in DR, reversing high-glucose induced reductions in GPX4 and GSH, and inhibited the elevation of MDA and Fe²⁺. FLOT1 also suppressed ROS accumulation. Mechanistically, FLOT1 activates the Nrf2 pathway by enhancing its expression and promoting its nuclear translocation, thereby stimulating the SLC7 A11/GPX4 pathway to inhibiting lipid peroxidation and ferroptosis. We have identified ferroptosis is a key mechanism driving BRB damage in DR.

Melanoma poses a significant health concern due to its propensity to metastasize and its high mortality rate. Immunotherapy has emerged as a promising treatment strategy for harnessing the patient's immune system to fight tumor cells. However, not all patients respond equally to immunotherapy, highlighting the need for predictive biomarkers to identify potential responders and optimize treatment strategies. Using data from 579 immunology-related genes evaluated by the NanoString nCounter Human Immunology v2 Panel, we integrated transcriptomic data with the clinical characteristics of 35 individuals to develop a predictive signature for immunotherapy response in melanoma patients. Through comprehensive analysis, we identified 18 genes upregulated in non-responder patients and three upregulated in responder patients. In multivariate analysis, CD24, NFIL3, FN1, and KLRK1 were identified as key predictors with significant potential for forecasting treatment outcomes. We then calculated a score incorporating the expression levels of these genes. The score achieved high accuracy in discriminating responders from non-responders, with an area under the curve of 0.935 (p < 0.001). The signature was also significantly associated with progression-free survival, overall survival, and survival following immunotherapy (p < 0.001). The validation of the signature in two independent cohorts confirmed its robustness and applicability, with areas under the curve of 0.758 (p = 0.036) and 0.833 (p = 0.004), respectively. This study represents a significant advance in precision medicine for melanoma. By identifying patients unlikely to benefit from immunotherapy, our approach could help optimize treatment allocation and improve patient outcomes. KEY MESSAGES: Novel 4-gene signature predicts immunotherapy failure in melanoma. High accuracy for personalized treatment decisions. Signature associated with decreased survival for non-responders. Signature validated in independent cohorts, enhancing generalizability. Potential to tailor treatment strategies and avoid unnecessary burden to patients.