Achieving industrial-level electrochemical CO_(2)reduction to formate remains a significant challenge due to limitations in catalyst selectivity and interfacial proton management at high current densities.In a recent ...Achieving industrial-level electrochemical CO_(2)reduction to formate remains a significant challenge due to limitations in catalyst selectivity and interfacial proton management at high current densities.In a recent study,Prof.Guo and colleagues report the development of Turingstructured electrocatalysts,which incorporate reaction-diffusion-inspired topologies to engineer mesoscale surface patterns.This design enables precise modulation of the interfacial microenvironment,enhancing CO_(2)activation and suppressing competing hydrogen evolution.The resulting catalysts achieve efficient and stable CO_(2)-to-formate conversion under industrially relevant conditions,offering a promising strategy for scalable carbon-neutral chemical production.展开更多
Ferroptosis is a novel form of cell death driven by oxidative damage,and is implicated in various pathological conditions,including neurodegenerative diseases,retinal damage,and ischemia-reperfusion injury of organs.I...Ferroptosis is a novel form of cell death driven by oxidative damage,and is implicated in various pathological conditions,including neurodegenerative diseases,retinal damage,and ischemia-reperfusion injury of organs.Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases,underscoring the urgent need to develop effective ferroptosis inhibitors.Although Ferrostatin-1(Fer-1)is a potent ferroptosis inhibitor,its susceptibility to oxidation and metabolic inactivation limits its clinical utility.In this study,the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin-1 prodrugs with reactive oxygen species-responsive features.This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas,allowing for targeted release and improved stability.The novel compounds demonstrated significant inhibitory effects and selectivity against RSL-3-induced ferroptosis in HK-2 cells,with compound a1 exhibiting an EC50 of 15.4�0.7μM,outperforming Fer-1.These compounds effectively identify the oxidative microenvironment associated with ferroptosis,enabling the targeted release of Fer-1,which prevents lipid peroxide accumulation and inhibits ferroptosis.This strategy holds promise for treating diseases related to ferroptosis,offering a targeted and intelligent therapeutic approach.展开更多
The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanic...The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments.展开更多
Epidemiological studies show that long-term exposure to PM is associated with an increased risk of cancer. The EuroLifeNet study measured the personal exposure to PM2.5 in 90 pupils attending three schools in Milan, u...Epidemiological studies show that long-term exposure to PM is associated with an increased risk of cancer. The EuroLifeNet study measured the personal exposure to PM2.5 in 90 pupils attending three schools in Milan, using a portable nephelometer, over a three-week period spanning November and December 2006. Background levels explained 40% of the variability of the exposure. Methods: As a second part of that study we analyzed the role of different microenvironments as determinants of personal exposure to PM2.5. Results: Exposure was influenced by the time of day, zone of the city and different microenvironments. Exposure was higher indoors than out, and indoors it was higher in the kitchen, particularly during cooking. In outdoor environments exposure was higher at bus stops where road traffic was heavy. Conclusions: Even though background concentration can be a good predictor of personal exposure to PM, students’ personal exposure is strongly influenced by different microenvironments and should be considered in population studies. The EuroLifeNet experience gives a contribution to personal exposure measure methodology.展开更多
Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed ...Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed to various levels of PAEs. In the present study, four typical occupational groups were chosen, including doctors, college teachers, college students, and drivers who worked in public traffic system. In order to understand the exposure levels to PAEs via inhalation, air samples were collected from multiple microenvironments including indoor and outdoor in Hangzhou to measure the gas and particle concentrations of six PAEs, together with time spent in different microenvironments of these four groups. A comprehensive PAEs exposure model was built to estimate the daily PAEs exposure through inhalation, oral and dermal pathways. The Monte Carlo simulation results show that doctors were exposed to the highest level of PAEs, and consequently had the highest health risk among these four occupational groups. In contrast, college students had the lowest health risk. By setting the exposure level of staying in residences as the baseline, doctors and drivers were two occupations exposed to high PAEs health risk. Di-（2-ethylhexyl） phthalate（DEHP） was the largest contributor among the six phthalates, posing moderate health risk（10-5–10-6） to every occupation. For traffic microenvironments alone, the total exposure levels for different transportation modes were in the descending order of busses, cars, cabs, tubes, motor bikes, and walking.展开更多
BACKGROUND Despite significant advances in multimodality treatments,hepatocellular carcinoma(HCC)remains one of the most common malignant tumors.Identification of novel prognostic biomarkers and molecular targets is u...BACKGROUND Despite significant advances in multimodality treatments,hepatocellular carcinoma(HCC)remains one of the most common malignant tumors.Identification of novel prognostic biomarkers and molecular targets is urgently needed.AIM To identify potential key genes associated with tumor microenvironments and the prognosis of HCC.METHODS The infiltration levels of immune cells and stromal cells were calculated and quantified based on the ESTIMATE algorithm.Differentially expressed genes(DEGs)between high and low groups according to immune or stromal scores were screened using the gene expression profile of HCC patients in The Cancer Genome Atlas and were further linked to the prognosis of HCC.These genes were validated in four independent HCC cohorts.Survival-related key genes were identified by a LASSO Cox regression model.RESULTS HCC patients with a high immune/stromal score had better survival benefits than patients with a low score.A total of 899 DEGs were identified and found to be involved in immune responses and extracellular matrices,147 of which were associated with overall survival.Subsequently,52 of 147 survival-related DEGs were validated in additional cohorts.Finally,ten key genes(STSL2,TMC5,DOK5,RASGRP2,NLRC3,KLRB1,CD5L,CFHR3,ADH1C,and UGT2B15)were selected and used to construct a prognostic gene signature,which presented a good performance in predicting overall survival.CONCLUSION This study extracted a list of genes associated with tumor microenvironments and the prognosis of HCC,thereby providing several valuable directions for the prognostic prediction and molecular targeted therapy of HCC in the future.展开更多
Effective detection of cellular microenvironments and understanding of physiological activities in living cells remain a considerable challenge.In recent years,fluore scence(or Forster)resonance energy trans fe r(FRET...Effective detection of cellular microenvironments and understanding of physiological activities in living cells remain a considerable challenge.In recent years,fluore scence(or Forster)resonance energy trans fe r(FRET)technology has emerged as a valuable method for real-time imaging of intracellular environment with high sensitivity,specificity and spatial resolution.Particularly,polymer-based imaging systems show enhanced stability,improved biodistribution,increased dye payloads,and amplified signal/noise ratio compared with small molecular sensors.This review summarizes the recent progress in FRET-based polymeric systems for probing the physiological environments in cells.展开更多
Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem c...Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering,mesenchymal stem cells(MSCs)are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use.The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs,indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration.Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues,MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years.This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions,giving additional insight into the current clinical application of these cells.展开更多
Increasing data indicate that cancer cell migration is regulated by extracellular matrixes and their surrounding biochemical microenvironment,playing a crucial role in pathological processes such as tumor invasion and...Increasing data indicate that cancer cell migration is regulated by extracellular matrixes and their surrounding biochemical microenvironment,playing a crucial role in pathological processes such as tumor invasion and metastasis.However,conventional two-dimensional cell culture and animal models have limitations in studying the influence of tumor microenvironment on cancer cell migration.Fortunately,the further development of microfluidic technology has provided solutions for the study of such questions.We utilize microfluidic chip to build a random collagen fiber microenvironment(RFM)model and an oriented collagen fiber microenvironment(OFM)model that resemble early stage and late stage breast cancer microenvironments,respectively.By combining cell culture,biochemical concentration gradient construction,and microscopic imaging techniques,we investigate the impact of different collagen fiber biochemical microenvironments on the migration of breast cancer MDA-MB-231-RFP cells.The results show that MDA-MB-231-RFP cells migrate further in the OFM model compared to the RFM model,with significant differences observed.Furthermore,we establish concentration gradients of the anticancer drug paclitaxel in both the RFM and OFM models and find that paclitaxel significantly inhibits the migration of MDA-MB-231-RFP cells in the RFM model,with stronger inhibition on the high concentration side compared to the low concentration side.However,the inhibitory effect of paclitaxel on the migration of MDA-MB-231-RFP cells in the OFM model is weak.These findings suggest that the oriented collagen fiber microenvironment resembling the late-stage tumor microenvironment is more favorable for cancer cell migration and that the effectiveness of anticancer drugs is diminished.The RFM and OFM models constructed in this study not only provide a platform for studying the mechanism of cancer development,but also serve as a tool for the initial measurement of drug screening.展开更多
Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment.In recent years,immune therapeutics targeting T lymphocytes,such as immune checkpoint blockade(ICB)and CAR-T,have made...Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment.In recent years,immune therapeutics targeting T lymphocytes,such as immune checkpoint blockade(ICB)and CAR-T,have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers.However,responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients.As major components of most solid tumors,myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity,thus determining tumor progression as well as therapeutic responses.In this review,we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells.We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells,and discuss recent progress in revealing different mechanisms—chemotaxis,proliferation,survival,and alternative sources—involved in the infiltration and accumulation of myeloid cells within tumors.Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.展开更多
Automated parallel manipulation of multiple micro-objects with optoelectronic tweezers(OET)has brought significant research interests recently.However,the parallel manipulation of multiple objects in complex obstacle-...Automated parallel manipulation of multiple micro-objects with optoelectronic tweezers(OET)has brought significant research interests recently.However,the parallel manipulation of multiple objects in complex obstacle-dense microenvironment using OET technology based on negative dielectrophoresis(nDEP)remain a big technical challenge.In this work,we proposed an adaptive light pattern design strategy to achieve automated parallel OET manipulation of multiple micro-objects and navigate them through obstacles to target positions with high precision and no collision.We first developed a multi-micro-object parallel manipulation OET system,capable of simultaneous image processing and microparticles path planning.To overcome microparticle collisions caused by overlapping light patterns,we employed a novel adaptive light pattern design that can dynamically adjust the layout of overlapping light patterns according to surrounding environment,ensuring enough space for each microparticle and preventing unintended escapes from the OET trap.The efficacy of this approach has been verified through systematic simulations and experiments.Utilizing this strategy,multiple polystyrene microparticles were autonomously navigated through obstacles and microchannels to their intended destinations,demonstrating the strategy’s effectiveness and potential for automated parallel micromanipulation of multiple microparticles in complex and confined microenvironments.展开更多
Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of t...Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of the tumor microenvironment(TME).Functionally polarized into distinct subtypes,TAMs play dual roles:proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12(IL-12)and tumor necrosis factor alpha(TNF-α)and direct tumor cell cytotoxicity,whereas M2-type TAMs promote tumor progression by facilitating angiogenesis,metastasis,and immunosuppression.This polarization is dynamically regulated by different cytokines,various signaling pathways,and metabolic cues within the TME.Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions,where they secrete factors such as vascular endothelial growth factor(VEGF),transforming growth factor beta(TGF-β),and matrix metalloproteinases(MMPs)to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1(PD-L1)and arginase-1 upregulation.Crucially,TAMs interact extensively with immune cells;M2-TAMs secrete interleukin-10(IL-10)and TGF-βto inhibit cytotoxic T lymphocytes while expanding regulatory T(Treg)cells and impairing natural killer(NK)cell function via altered antigen presentation.Conversely,M1-TAMs synergize with dendritic cells to enhance T-cell priming.Therapeutically,targeting TAMs offers promising strategies,including colony-stimulating factor-1 receptor(CSF-1R)inhibitors,CCL2 antagonists,and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype.Emerging genetic approaches,such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9(CRISPR-Cas9)editing,aim to disrupt protumorigenic pathways in TAMs.Additionally,TAM-related biomarkers(e.g.,CD206 and CD163)are being evaluated for their prognostic and predictive utility in immunotherapies.Despite progress,challenges persist owing to TAM plasticity and TME heterogeneity across cancers.This review synthesizes TAM biology,immune crosstalk,and therapeutic advancements,providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.展开更多
Wound healing in chronic diabetic patients remains challenging due to the multiple types of cellular dysfunction and the impairment of multidimensional microenvironments.The physical signals of structural anisotropy o...Wound healing in chronic diabetic patients remains challenging due to the multiple types of cellular dysfunction and the impairment of multidimensional microenvironments.The physical signals of structural anisotropy offer significant potential for orchestrating multicellular regulation through physical contact and cellular mechano-sensing pathways,irrespective of cell type.In this study,we developed a highly oriented anisotropic nanofiber hydrogel designed to provide directional guidance for cellular extension and cytoskeletal organization,thereby achieving pronounced multicellular modulation,including shape-induced polarization of macrophages,morphogenetic maturation of Schwann cells,oriented extracellular matrix(ECM)deposition by fibroblasts,and enhanced vascularization by endothelial cells.Additionally,we incorporated a VEGF-mimicking peptide to further reinforce angiogenesis,a pivotal phase that interlocks with immune regulation,neurogenesis,and tissue regeneration,ultimately contributing to optimized inter-microenvironmental crosstalk.In vivo studies validated that the anisotropic bioactive nanofiber hydrogel effectively accelerated diabetic wound healing by harnessing the triadic synergy of the immune-angiogenic-neurogenic microenvironments.Our findings highlight the promising potential of combining physical and bioactive signals for the modulation of various cell types and the refinement of the multidimensional microenvironment,offering a novel strategy for diabetic wound healing.展开更多
Background:Penile squamous cell carcinoma(PSCC)is a rare yet potentially lethal malignancy,often resulting in devastating disfigurement,with a 5-year survival rate of only -50%.Human papillomavirus(HPV)infection is im...Background:Penile squamous cell carcinoma(PSCC)is a rare yet potentially lethal malignancy,often resulting in devastating disfigurement,with a 5-year survival rate of only -50%.Human papillomavirus(HPV)infection is implicated in approximately half of PSCCcases and is associated with improved clinical outcomes;however,the underlying mechanisms remain poorly understood.Methods:To elucidate HPV-associated differences in the tumor microenvironment,we performed single-cell RNA sequencing ontumors from 11 treatment-naive PSCC patients,analyzing a total of 52980 single cells.Unsupervised clustering identified 49 distinctcellular clusters across immune and stromal compartments.Results:HPV-positive tumors exhibited an increased abundance of mast cells and a reduction in the proliferative macrophages subpopulation compared to HPV-negative tumors.Notably,CD8^(+)T cells in HPV-positive PSCC expressed lower levels of immune checkpoint molecules,suggesting a less exhausted immune state.Conversely,TIGIT and its ligands were significantly enriched in HPV-negative tumors,potentially fostering an immunosuppressive niche.Conclusion:Collectively,our study delineates the single-cell landscape of PSCC and highlights distinct tumor microenvironmentremodeling associated with HPV status,suggesting that the reduced immunosuppression in HPV-positive tumors may underlie theirmore favorable prognosis.展开更多
Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing int...Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione(GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4(GPX4).However,the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported.Herein,novel tumor microenvironments(TME)-activated metal-organic frameworks involving Fe&Cu ions bridged by disulfide bonds with PEGylation(FCSP MOFs)were developed,which would be degraded specifically under the redox TME,simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction,therefore causing ferroptosis.More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs.The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy.Better tumor therapeutic efficiency could be achieved by doxorubicin(DOX)loading since it can not only cause apoptosis,but also indirectly produce H2O2 to amplify Fenton reaction.Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.展开更多
We read with great interest the investigation of Kang et al related the applications of the multiparametric magnetic resonance imaging-based predictive model for assessing chemotherapy efficacy in colorectal cancer pa...We read with great interest the investigation of Kang et al related the applications of the multiparametric magnetic resonance imaging-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.The authors focused on decision-making based on the integration of tumor differentiation,signal intensity ratio,margin distance,and magnetic resonance imaging-detected lymph node metastasis.Indeed,these multiparameter predictive models could also be used for diagnosis as an alternative to invasive tissue examination methods.However,progress in this field enables us to shift the paradigm to radiology biopsies,particularly given the nonlinear effects of various radiation sources.展开更多
We read with the great interest the study by Ababneh et al in which inducedmesenchymal stem cell-derived exosomes were shown to exhibit a stronger andmore sustained anti-proliferative effect by inducing a senescence-l...We read with the great interest the study by Ababneh et al in which inducedmesenchymal stem cell-derived exosomes were shown to exhibit a stronger andmore sustained anti-proliferative effect by inducing a senescence-like state withoutapoptosis.The results obtained by the authors highlight the features of theeffects of senescent drift induction in surrounding tissues.In the light of thesefindings,the role of the properties of extracellular matrix and cellular glycocalyxin responses of human tumors to therapy remain uninvestigated.These extracellularbarriers appear to be significant obstacles to effective cancer therapy,especiallyin relation to the use of unique properties of tumor microenvironment forthe immunotherapy-resistant cancer treatment.展开更多
Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent...Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent,and metastatic malignancies.Mechanistically,ferroptosis induction not only directly eliminates tumor cells but also promotes immunogenic cell death(ICD),eliciting damage-associated molecular patterns(DAMPs)release to activate partial antitumor immunity.However,standalone ferroptosis therapy fails to initiate robust systemic antitumor immune responses due to inherent limitations:low tumor immunogenicity,immunosuppressive microenvironment constraints,and tumor microenvironment(TME)-associated physiological barriers(e.g.,hypoxia,dense extracellular matrix).To address these challenges,synergistic approaches have been developed to enhance immune cell infiltration and reestablish immunosurveillance,encompassing(1)direct amplification of antitumor immunity,(2)disruption of immunosuppressive tumor niches,and(3)biophysical hallmark remodeling in TME.Rational nanocarrier design has emerged as a critical enabler for overcoming biological delivery barriers and optimizing therapeutic efficacy.Unlike prior studies solely addressing ferroptosis or nanotechnology in tumor therapy,this work first systematically outlines the synergistic potential of nanoparticles in combined ferroptosis-immunotherapy strategies.It advances multidimensional nanoplatform design principles for material selection,structural configuration,physicochemical modulation,multifunctional integration,and artificial intelligence-enabled design,providing a scientific basis for efficacy optimization.Moreover,it examines translational challenges of ferroptosis-immunotherapy nanoplatforms across preclinical and clinical stages,proposing actionable solutions while envisioning future onco-immunotherapy directions.Collectively,it provides systematic insights into advanced nanomaterial design principles and therapeutic optimization strategies,offering a roadmap for accelerating clinical translation in onco-immunotherapy research.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemot...Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.展开更多
基金financially supported by the National Natural Science Foundation of China(No.22209024)Tongcheng R&D Foundation(No.CPCIF-RA-0102)the State Key Laboratory of Advanced Fiber Materials,Donghua University
文摘Achieving industrial-level electrochemical CO_(2)reduction to formate remains a significant challenge due to limitations in catalyst selectivity and interfacial proton management at high current densities.In a recent study,Prof.Guo and colleagues report the development of Turingstructured electrocatalysts,which incorporate reaction-diffusion-inspired topologies to engineer mesoscale surface patterns.This design enables precise modulation of the interfacial microenvironment,enhancing CO_(2)activation and suppressing competing hydrogen evolution.The resulting catalysts achieve efficient and stable CO_(2)-to-formate conversion under industrially relevant conditions,offering a promising strategy for scalable carbon-neutral chemical production.
基金supported by the Natural Science Foundation of Liaoning Province(2023-MSBA-020)the Fundamental Research Funds for Central Universities(DUT24MS020)Science and Technology Innovation Fund of Dalian(2022JJ13SN073).
文摘Ferroptosis is a novel form of cell death driven by oxidative damage,and is implicated in various pathological conditions,including neurodegenerative diseases,retinal damage,and ischemia-reperfusion injury of organs.Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases,underscoring the urgent need to develop effective ferroptosis inhibitors.Although Ferrostatin-1(Fer-1)is a potent ferroptosis inhibitor,its susceptibility to oxidation and metabolic inactivation limits its clinical utility.In this study,the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin-1 prodrugs with reactive oxygen species-responsive features.This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas,allowing for targeted release and improved stability.The novel compounds demonstrated significant inhibitory effects and selectivity against RSL-3-induced ferroptosis in HK-2 cells,with compound a1 exhibiting an EC50 of 15.4�0.7μM,outperforming Fer-1.These compounds effectively identify the oxidative microenvironment associated with ferroptosis,enabling the targeted release of Fer-1,which prevents lipid peroxide accumulation and inhibits ferroptosis.This strategy holds promise for treating diseases related to ferroptosis,offering a targeted and intelligent therapeutic approach.
文摘The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments.
文摘Epidemiological studies show that long-term exposure to PM is associated with an increased risk of cancer. The EuroLifeNet study measured the personal exposure to PM2.5 in 90 pupils attending three schools in Milan, using a portable nephelometer, over a three-week period spanning November and December 2006. Background levels explained 40% of the variability of the exposure. Methods: As a second part of that study we analyzed the role of different microenvironments as determinants of personal exposure to PM2.5. Results: Exposure was influenced by the time of day, zone of the city and different microenvironments. Exposure was higher indoors than out, and indoors it was higher in the kitchen, particularly during cooking. In outdoor environments exposure was higher at bus stops where road traffic was heavy. Conclusions: Even though background concentration can be a good predictor of personal exposure to PM, students’ personal exposure is strongly influenced by different microenvironments and should be considered in population studies. The EuroLifeNet experience gives a contribution to personal exposure measure methodology.
基金supported by the National Key Research and Development Program of China(No.2016YFC0207103)the National Natural Science Foundation of China(No.21607127)Koninklijke Philips N.V.(No.BB3-2016-01)
文摘Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed to various levels of PAEs. In the present study, four typical occupational groups were chosen, including doctors, college teachers, college students, and drivers who worked in public traffic system. In order to understand the exposure levels to PAEs via inhalation, air samples were collected from multiple microenvironments including indoor and outdoor in Hangzhou to measure the gas and particle concentrations of six PAEs, together with time spent in different microenvironments of these four groups. A comprehensive PAEs exposure model was built to estimate the daily PAEs exposure through inhalation, oral and dermal pathways. The Monte Carlo simulation results show that doctors were exposed to the highest level of PAEs, and consequently had the highest health risk among these four occupational groups. In contrast, college students had the lowest health risk. By setting the exposure level of staying in residences as the baseline, doctors and drivers were two occupations exposed to high PAEs health risk. Di-（2-ethylhexyl） phthalate（DEHP） was the largest contributor among the six phthalates, posing moderate health risk（10-5–10-6） to every occupation. For traffic microenvironments alone, the total exposure levels for different transportation modes were in the descending order of busses, cars, cabs, tubes, motor bikes, and walking.
文摘BACKGROUND Despite significant advances in multimodality treatments,hepatocellular carcinoma(HCC)remains one of the most common malignant tumors.Identification of novel prognostic biomarkers and molecular targets is urgently needed.AIM To identify potential key genes associated with tumor microenvironments and the prognosis of HCC.METHODS The infiltration levels of immune cells and stromal cells were calculated and quantified based on the ESTIMATE algorithm.Differentially expressed genes(DEGs)between high and low groups according to immune or stromal scores were screened using the gene expression profile of HCC patients in The Cancer Genome Atlas and were further linked to the prognosis of HCC.These genes were validated in four independent HCC cohorts.Survival-related key genes were identified by a LASSO Cox regression model.RESULTS HCC patients with a high immune/stromal score had better survival benefits than patients with a low score.A total of 899 DEGs were identified and found to be involved in immune responses and extracellular matrices,147 of which were associated with overall survival.Subsequently,52 of 147 survival-related DEGs were validated in additional cohorts.Finally,ten key genes(STSL2,TMC5,DOK5,RASGRP2,NLRC3,KLRB1,CD5L,CFHR3,ADH1C,and UGT2B15)were selected and used to construct a prognostic gene signature,which presented a good performance in predicting overall survival.CONCLUSION This study extracted a list of genes associated with tumor microenvironments and the prognosis of HCC,thereby providing several valuable directions for the prognostic prediction and molecular targeted therapy of HCC in the future.
基金supported by the National Natural Science Foundation of China(Nos.51873118,21474064,51203101)the National Science Fund for Distinguished Young Scholars of China(No.51425305)the Project of State Key Laboratory of Polymer Materials Engineering。
文摘Effective detection of cellular microenvironments and understanding of physiological activities in living cells remain a considerable challenge.In recent years,fluore scence(or Forster)resonance energy trans fe r(FRET)technology has emerged as a valuable method for real-time imaging of intracellular environment with high sensitivity,specificity and spatial resolution.Particularly,polymer-based imaging systems show enhanced stability,improved biodistribution,increased dye payloads,and amplified signal/noise ratio compared with small molecular sensors.This review summarizes the recent progress in FRET-based polymeric systems for probing the physiological environments in cells.
基金the Ministry of Education,Science and Technological Development,Republic of Serbia,No.451-03-9/2021-14/200015.
文摘Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering,mesenchymal stem cells(MSCs)are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use.The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs,indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration.Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues,MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years.This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions,giving additional insight into the current clinical application of these cells.
基金support from the National Natural Science Foundation of China(Grant Nos.11974066,12174041,12104134,T2350007,and 12347178)the Fundamental and Advanced Research Program of Chongqing(Grant No.cstc2019jcyj-msxm X0477)+3 种基金the Natural Science Foundation of Chongqing(Grant No.CSTB2022NSCQMSX1260)the Science and Technology Research Program of Chongqing Municipal Education Commission(Grant No.KJQN202301333)the Scientific Research Fund of Chongqing University of Arts and Sciences(Grant Nos.R2023HH03 and P2022HH05)College Students’Innovation and Entrepreneurship Training Program of Chongqing Municipal(Grant No.S202310642002)。
文摘Increasing data indicate that cancer cell migration is regulated by extracellular matrixes and their surrounding biochemical microenvironment,playing a crucial role in pathological processes such as tumor invasion and metastasis.However,conventional two-dimensional cell culture and animal models have limitations in studying the influence of tumor microenvironment on cancer cell migration.Fortunately,the further development of microfluidic technology has provided solutions for the study of such questions.We utilize microfluidic chip to build a random collagen fiber microenvironment(RFM)model and an oriented collagen fiber microenvironment(OFM)model that resemble early stage and late stage breast cancer microenvironments,respectively.By combining cell culture,biochemical concentration gradient construction,and microscopic imaging techniques,we investigate the impact of different collagen fiber biochemical microenvironments on the migration of breast cancer MDA-MB-231-RFP cells.The results show that MDA-MB-231-RFP cells migrate further in the OFM model compared to the RFM model,with significant differences observed.Furthermore,we establish concentration gradients of the anticancer drug paclitaxel in both the RFM and OFM models and find that paclitaxel significantly inhibits the migration of MDA-MB-231-RFP cells in the RFM model,with stronger inhibition on the high concentration side compared to the low concentration side.However,the inhibitory effect of paclitaxel on the migration of MDA-MB-231-RFP cells in the OFM model is weak.These findings suggest that the oriented collagen fiber microenvironment resembling the late-stage tumor microenvironment is more favorable for cancer cell migration and that the effectiveness of anticancer drugs is diminished.The RFM and OFM models constructed in this study not only provide a platform for studying the mechanism of cancer development,but also serve as a tool for the initial measurement of drug screening.
基金supported by project grants from the National Key R&D Program of China(No.2023YFA0915703)the National Natural Science Foundation of China(Nos.82372877,82071743 and 32230034)+2 种基金the Fundamental Research Funds for the Central Universities(No.23yxqntd001)Guangdong Science and Technology Department(No.2023B1212060028)the Guangdong Key-Area R&D Program(No.2023B1111020005).
文摘Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment.In recent years,immune therapeutics targeting T lymphocytes,such as immune checkpoint blockade(ICB)and CAR-T,have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers.However,responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients.As major components of most solid tumors,myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity,thus determining tumor progression as well as therapeutic responses.In this review,we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells.We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells,and discuss recent progress in revealing different mechanisms—chemotaxis,proliferation,survival,and alternative sources—involved in the infiltration and accumulation of myeloid cells within tumors.Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.
基金the support from Optoseeker Biotechnology(Shenzhen)Co.,Ltd.to help build the OET system and provide Optobot 500 to carry out the experiment shown in supplementary Movie S4.National Key R&D Program of China(2023YFE0112400,2022YFA1207100,2024YFC3406900)National Natural Science Foundation of China(62103050,62473245,61933008)+6 种基金Beijing Municipal Natural Science Foundation(4242060,L246030)the Chongqing Municipal Natural Science Foundation(Grant No.2024NSCQJQX0192,CSTB2024NSCQ-JQX0034)the BIT Research and Innovation Promoting Project(Grant No.2023CX01002)Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-09-E0013)Shanghai Science and Technology plan project(23ZR1422300)Shenzhen Science and Technology Program(KJZD20240903101359020)Open Research Fund of Guangdong Provincial Key Laboratory of Advanced Biomaterials(Southern University of Science and Technology,Grant No.KLAB202404002).
文摘Automated parallel manipulation of multiple micro-objects with optoelectronic tweezers(OET)has brought significant research interests recently.However,the parallel manipulation of multiple objects in complex obstacle-dense microenvironment using OET technology based on negative dielectrophoresis(nDEP)remain a big technical challenge.In this work,we proposed an adaptive light pattern design strategy to achieve automated parallel OET manipulation of multiple micro-objects and navigate them through obstacles to target positions with high precision and no collision.We first developed a multi-micro-object parallel manipulation OET system,capable of simultaneous image processing and microparticles path planning.To overcome microparticle collisions caused by overlapping light patterns,we employed a novel adaptive light pattern design that can dynamically adjust the layout of overlapping light patterns according to surrounding environment,ensuring enough space for each microparticle and preventing unintended escapes from the OET trap.The efficacy of this approach has been verified through systematic simulations and experiments.Utilizing this strategy,multiple polystyrene microparticles were autonomously navigated through obstacles and microchannels to their intended destinations,demonstrating the strategy’s effectiveness and potential for automated parallel micromanipulation of multiple microparticles in complex and confined microenvironments.
基金supported by the National Natural Science Foundation of China(11932017 to X.X.K.,82072624 to K.F.D.)China Postdoctoral Science Foundation General Program under No.2024M762922 to J.S.X.+7 种基金Zhejiang Provincial Health Department General Project under No.2025KY872 to J.S.X.2024 Zhejiang Provincial Postdoctoral Research Project Special Funding under No.2024-00004 to J.S.X.Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2024ZD0520100 to K.F.D.,No.2023ZD0512500 to J.S.X.)Research Program of Zhejiang University Binjiang Institute Research Center for Life Science and Human Health under No.ZY202501SMKY002-4 to J.S.X.Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No.LHDMY22C060002 to X.X.K.the Fundamental Research Funds for the Central Universities(No.226-2022-00009,No.226-2024-00062,No.226-2024-00176)to K.F.D.the Program for Zhejiang Provincial Clinical Research Center for CANCER under No.2022E50008 to K.F.D.Key R&D Program of Zhejiang under 2024C03170 to K.F.D.
文摘Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of the tumor microenvironment(TME).Functionally polarized into distinct subtypes,TAMs play dual roles:proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12(IL-12)and tumor necrosis factor alpha(TNF-α)and direct tumor cell cytotoxicity,whereas M2-type TAMs promote tumor progression by facilitating angiogenesis,metastasis,and immunosuppression.This polarization is dynamically regulated by different cytokines,various signaling pathways,and metabolic cues within the TME.Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions,where they secrete factors such as vascular endothelial growth factor(VEGF),transforming growth factor beta(TGF-β),and matrix metalloproteinases(MMPs)to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1(PD-L1)and arginase-1 upregulation.Crucially,TAMs interact extensively with immune cells;M2-TAMs secrete interleukin-10(IL-10)and TGF-βto inhibit cytotoxic T lymphocytes while expanding regulatory T(Treg)cells and impairing natural killer(NK)cell function via altered antigen presentation.Conversely,M1-TAMs synergize with dendritic cells to enhance T-cell priming.Therapeutically,targeting TAMs offers promising strategies,including colony-stimulating factor-1 receptor(CSF-1R)inhibitors,CCL2 antagonists,and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype.Emerging genetic approaches,such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9(CRISPR-Cas9)editing,aim to disrupt protumorigenic pathways in TAMs.Additionally,TAM-related biomarkers(e.g.,CD206 and CD163)are being evaluated for their prognostic and predictive utility in immunotherapies.Despite progress,challenges persist owing to TAM plasticity and TME heterogeneity across cancers.This review synthesizes TAM biology,immune crosstalk,and therapeutic advancements,providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.
基金financial support from the Beijing Natural Science Foundation of China(Grant No.QY23102,2254091,and L234075)the National Natural Science Foundation of China(Grant No.32271414,32401140,and 82301560).
文摘Wound healing in chronic diabetic patients remains challenging due to the multiple types of cellular dysfunction and the impairment of multidimensional microenvironments.The physical signals of structural anisotropy offer significant potential for orchestrating multicellular regulation through physical contact and cellular mechano-sensing pathways,irrespective of cell type.In this study,we developed a highly oriented anisotropic nanofiber hydrogel designed to provide directional guidance for cellular extension and cytoskeletal organization,thereby achieving pronounced multicellular modulation,including shape-induced polarization of macrophages,morphogenetic maturation of Schwann cells,oriented extracellular matrix(ECM)deposition by fibroblasts,and enhanced vascularization by endothelial cells.Additionally,we incorporated a VEGF-mimicking peptide to further reinforce angiogenesis,a pivotal phase that interlocks with immune regulation,neurogenesis,and tissue regeneration,ultimately contributing to optimized inter-microenvironmental crosstalk.In vivo studies validated that the anisotropic bioactive nanofiber hydrogel effectively accelerated diabetic wound healing by harnessing the triadic synergy of the immune-angiogenic-neurogenic microenvironments.Our findings highlight the promising potential of combining physical and bioactive signals for the modulation of various cell types and the refinement of the multidimensional microenvironment,offering a novel strategy for diabetic wound healing.
基金supported by the Key Research and DevelopmentProgram of Anhui Province(grant No.202204295107020003 toT.T.)the Distinguished Young Scholars Fund of Anhui Province(grant No.2022AH020078 to T.T.)+1 种基金Major Joint Project of NewMedicine of USTC(grant No.YD9110002018 to T.T.)Anhui Provincial Cancer Hospital Project(grant No.QLGC 2024003to T.T.).
文摘Background:Penile squamous cell carcinoma(PSCC)is a rare yet potentially lethal malignancy,often resulting in devastating disfigurement,with a 5-year survival rate of only -50%.Human papillomavirus(HPV)infection is implicated in approximately half of PSCCcases and is associated with improved clinical outcomes;however,the underlying mechanisms remain poorly understood.Methods:To elucidate HPV-associated differences in the tumor microenvironment,we performed single-cell RNA sequencing ontumors from 11 treatment-naive PSCC patients,analyzing a total of 52980 single cells.Unsupervised clustering identified 49 distinctcellular clusters across immune and stromal compartments.Results:HPV-positive tumors exhibited an increased abundance of mast cells and a reduction in the proliferative macrophages subpopulation compared to HPV-negative tumors.Notably,CD8^(+)T cells in HPV-positive PSCC expressed lower levels of immune checkpoint molecules,suggesting a less exhausted immune state.Conversely,TIGIT and its ligands were significantly enriched in HPV-negative tumors,potentially fostering an immunosuppressive niche.Conclusion:Collectively,our study delineates the single-cell landscape of PSCC and highlights distinct tumor microenvironmentremodeling associated with HPV status,suggesting that the reduced immunosuppression in HPV-positive tumors may underlie theirmore favorable prognosis.
基金supported by the National Natural Science Foundation of China(Grant Nos.81371559,81671709,81601550,81871371,81701711,and 82072056)Guangzhou Municipal Science and Technology Project(No.201804010106,China)National College Students Innovation and Entrepreneurship Training Program(No.201812121007,China)。
文摘Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione(GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4(GPX4).However,the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported.Herein,novel tumor microenvironments(TME)-activated metal-organic frameworks involving Fe&Cu ions bridged by disulfide bonds with PEGylation(FCSP MOFs)were developed,which would be degraded specifically under the redox TME,simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction,therefore causing ferroptosis.More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs.The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy.Better tumor therapeutic efficiency could be achieved by doxorubicin(DOX)loading since it can not only cause apoptosis,but also indirectly produce H2O2 to amplify Fenton reaction.Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.
基金Supported by Russian Science Foundation,No.24-64-00028.
文摘We read with great interest the investigation of Kang et al related the applications of the multiparametric magnetic resonance imaging-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.The authors focused on decision-making based on the integration of tumor differentiation,signal intensity ratio,margin distance,and magnetic resonance imaging-detected lymph node metastasis.Indeed,these multiparameter predictive models could also be used for diagnosis as an alternative to invasive tissue examination methods.However,progress in this field enables us to shift the paradigm to radiology biopsies,particularly given the nonlinear effects of various radiation sources.
文摘We read with the great interest the study by Ababneh et al in which inducedmesenchymal stem cell-derived exosomes were shown to exhibit a stronger andmore sustained anti-proliferative effect by inducing a senescence-like state withoutapoptosis.The results obtained by the authors highlight the features of theeffects of senescent drift induction in surrounding tissues.In the light of thesefindings,the role of the properties of extracellular matrix and cellular glycocalyxin responses of human tumors to therapy remain uninvestigated.These extracellularbarriers appear to be significant obstacles to effective cancer therapy,especiallyin relation to the use of unique properties of tumor microenvironment forthe immunotherapy-resistant cancer treatment.
基金supported by the National Natural Science Foundation of China(Nos.82302373,81903846)Natural Science Foundation of Sichuan Province(No.2022NSFSC1925)+1 种基金Chengdu Technology Innovation Research and Development Project(No.2022-YF05-01546-SN)the Introduction of Talents Research Project of Chengdu University(No.2081921049)。
文摘Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent,and metastatic malignancies.Mechanistically,ferroptosis induction not only directly eliminates tumor cells but also promotes immunogenic cell death(ICD),eliciting damage-associated molecular patterns(DAMPs)release to activate partial antitumor immunity.However,standalone ferroptosis therapy fails to initiate robust systemic antitumor immune responses due to inherent limitations:low tumor immunogenicity,immunosuppressive microenvironment constraints,and tumor microenvironment(TME)-associated physiological barriers(e.g.,hypoxia,dense extracellular matrix).To address these challenges,synergistic approaches have been developed to enhance immune cell infiltration and reestablish immunosurveillance,encompassing(1)direct amplification of antitumor immunity,(2)disruption of immunosuppressive tumor niches,and(3)biophysical hallmark remodeling in TME.Rational nanocarrier design has emerged as a critical enabler for overcoming biological delivery barriers and optimizing therapeutic efficacy.Unlike prior studies solely addressing ferroptosis or nanotechnology in tumor therapy,this work first systematically outlines the synergistic potential of nanoparticles in combined ferroptosis-immunotherapy strategies.It advances multidimensional nanoplatform design principles for material selection,structural configuration,physicochemical modulation,multifunctional integration,and artificial intelligence-enabled design,providing a scientific basis for efficacy optimization.Moreover,it examines translational challenges of ferroptosis-immunotherapy nanoplatforms across preclinical and clinical stages,proposing actionable solutions while envisioning future onco-immunotherapy directions.Collectively,it provides systematic insights into advanced nanomaterial design principles and therapeutic optimization strategies,offering a roadmap for accelerating clinical translation in onco-immunotherapy research.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
文摘Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.
