BACKGROUND The development of regenerative therapy for human spinal cord injury(SCI)is dramatically restricted by two main challenges:the need for a safe source of functionally active and reproducible neural stem cell...BACKGROUND The development of regenerative therapy for human spinal cord injury(SCI)is dramatically restricted by two main challenges:the need for a safe source of functionally active and reproducible neural stem cells and the need of adequate animal models for preclinical testing.Direct reprogramming of somatic cells into neuronal and glial precursors might be a promising solution to the first challenge.The use of non-human primates for preclinical studies exploring new treatment paradigms in SCI results in data with more translational relevance to human SCI.AIM To investigate the safety and efficacy of intraspinal transplantation of directly reprogrammed neural precursor cells(drNPCs).METHODS Seven non-human primates with verified complete thoracic SCI were divided into two groups:drNPC group(n=4)was subjected to intraspinal transplantation of 5 million drNPCs rostral and caudal to the lesion site 2 wk post injury,and lesion control(n=3)was injected identically with the equivalent volume of vehicle.RESULTS Follow-up for 12 wk revealed that animals in the drNPC group demonstrated a significant recovery of the paralyzed hindlimb as well as recovery of somatosensory evoked potential and motor evoked potential of injured pathways.Magnetic resonance diffusion tensor imaging data confirmed the intraspinal transplantation of drNPCs did not adversely affect the morphology of the central nervous system or cerebrospinal fluid circulation.Subsequent immunohistochemical analysis showed that drNPCs maintained SOX2 expression characteristic of multipotency in the transplanted spinal cord for at least 12 wk,migrating to areas of axon growth cones.CONCLUSION Our data demonstrated that drNPC transplantation was safe and contributed to improvement of spinal cord function after acute SCI,based on neurological status assessment and neurophysiological recovery within 12 wk after transplantation.The functional improvement described was not associated with neuronal differentiation of the allogeneic drNPCs.Instead,directed drNPCs migration to the areas of active growth cone formation may provide exosome and paracrine trophic support,thereby further supporting the regeneration processes.展开更多
Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due...Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models(ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells(CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming(CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid(2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for airliquid interface(ALI) polarized 3 D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.展开更多
Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual pat...Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.展开更多
Cancer is still a major public-health problem that threatens human life worldwide and further study needs to be carried out in the basic and preclinical areas.Although high-throughput sequencing technology and individ...Cancer is still a major public-health problem that threatens human life worldwide and further study needs to be carried out in the basic and preclinical areas.Although high-throughput sequencing technology and individualized precise therapy have made breakthroughs over the years,the high failure rate of clinical translational research has limited the innovation of antitumor drugs and triggered the urgent need for optimal cancer-research models.The development of cancerous cell lines,patient-derived xenograft(PDX)models,and organoid has strongly promoted the development of tumor-biology research,but the prediction values are limited.Conditional reprogramming(CR)is a novel cell-culture method for cancer research combining feeder cells with a Rho-associated coiled-coil kinase(ROCK)inhibitor,which enables the rapid and continuous proliferation of primary epithelial cells.In this review,we summarize the methodology to establish CR model and overview recent functions and applications of CR cell-culture models in cancer research with regard to the study of cancerbiology characterization,the exploration of therapeutic targets,individualized drug screening,the illumination of mechanisms about response to antitumor drugs,and the improvement of patient-derived animal models,and finally discuss in detail the major limitations of this cell-culture system.展开更多
The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into ...The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into induced SwG cells through the ectopic expression of ectodysplasin A.However,the clinical application of this genetic manipulation approach is inherently limited.In this study,we pre-sent findings demonstrating that a combination of six compounds can effectively and speedily reprogram HEKs in culture into fully functional SwG cells.These chemically induced SwG-like cells(ciSGCs)closely resemble the morphology,phenotypes,and functional properties of human primary SwG ductal cells.Furthermore,ciSGCs can be stimulated to differentiate into mature SwG cell types in vitro.In a 3D culture system,they can also generate SwG organoids that exhibit structural and biological features akin to native SwGs.Upon transplantation into scalded mouse paw skin,ciSGCs significantly expedited cuta-neous wound healing and completely restored the structural and functional aspects of the SwGs.In con-clusion,the small molecule cocktail-directed SwG reprogramming offers a non-transgenic and controllable strategy for producing high-quality,clinical-grade SwG cells,showing immense potential for the treatment of burn patients.展开更多
Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individ...Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells （iPSCs） derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.展开更多
Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a coun...Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.展开更多
The direct reprogramming of somatic cells into induced neural progenitor cells(iNPCs)has been envisioned as a promising approach to overcome ethical and clinical issues of pluripotent stem cell transplantation.We prev...The direct reprogramming of somatic cells into induced neural progenitor cells(iNPCs)has been envisioned as a promising approach to overcome ethical and clinical issues of pluripotent stem cell transplantation.We previously reported that astrocyte-derived induced pluripotent stem cells(iPSCs)have more tendencies for neuronal differentiation than fibroblast-derived iPSCs.However,the differences of neurogenic potential between astrocytederived iNPCs(AiNPCs)and iNPCs from non-neural origins,such as fibroblast-derived iNPCs(FiNPCs),and the underlying mechanisms remain unclear.Our results suggested that AiNPCs exhibited higher differentiation efficiency,mobility and survival capacities,compared to FiNPCs.The whole transcriptome analysis revealed higher activities of TGFβsignaling in AiNPCs,versus FiNPCs,following a similar trend between astrocytes and fibroblasts.The higher neurogenic competence,migration ability,and cell death resistance of AiNPCs could be abrogated using TGFβ signaling inhibitor LY2157299.Hence,our study demonstrates the difference between iNPCs generated from neural and non-neural cells,together with the underlying mechanisms,which,provides valuable information for donor cell selection in the reprogramming approach.展开更多
Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness ...Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.展开更多
Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders....Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy...Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.展开更多
Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume respon...Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.展开更多
Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Na...Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.展开更多
Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoti...Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoting susceptibility to lung diseases.The development and progression of lung cancer,as well as the effectiveness of immunotherapy are closely associated with gut flora and metabolites,which influence immunological and inflammatory responses.During abnormal proliferation,non-small cell lung cancer cells acquire more substances and energy by altering their own metabolic pathways.Glucose and amino acid metabolism reprogramming provide tumor cells with abundant ATP,carbon,and nitrogen sources,respectively,providing optimal conditions for tumor cell proliferation,invasion,and immune escape.This article reviews the relationship of immune response with gut flora and metabolic reprogramming in non-small cell lung cancer,and discusses the potential mechanisms by which gut flora and metabolic reprogramming affect the occurrence,development,and immunotherapy of non-small cell lung cancer,in order to provide new ideas for precision treatment of lung cancer patients.展开更多
Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in additio...Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in addition,hydroxy.In addition,hydroxycinnamic acid conjugates as well as flavonoids.The latter is the major class of secondary plant metabolites and comprises various subclasses,including anthocyanidins.Anthocyanins are rarely reported in extracts from C.asiatica and differ structurally due to a flavylium(2-phenylchromenylium)ion that carries a positive charge at the oxygen atom of the C-ring of the basic flavonoid structure.Callus of C.asiatica was initiated and propagated on synthetic media and subjected to different light regimes.White callus resulted from white fluorescent illumination,while purple callus developed in response to white light emitting diode(LED)illumination.To profile the metabolites responsible for the intense purple coloration,methanolic extracts were prepared from the two cell lines.Total phenolic,flavonoid,and anthocyanin content were determined and indicated(i)very low levels of flavonoids and anthocyanins in white callus and(ii)that anthocyanins dominate the flavonoid content of the purple callus.Extracts were subjected to untargeted ultra-high-performance liquid chromatography coupled to high-definition mass spectrometry(UHPLC–MS)to profile newly synthesized anthocyanins.Metabolite annotation was based on accurate mass determination and characteristic fragmentation patterns.Here,the reprogramming of the metabolome of white C.asiatica callus due to LED illumination is reported and the profiles of cryptic anthocyanins as well as putative flavonoid and caffeoylquinic acid co-pigments in purple callus are described.展开更多
Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role ...Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role in embryonic development,tissue regeneration,and wound healing.However,when dysregulated,cell plasticity contributes to cancer initiation,progression,metastasis,and therapeutic resistance.Throughout different stages of tumor development,cancer cells exploit various forms of plasticity to evade normal regulatory mechanisms that govern cell division and homeostasis.Recent evidence highlights the complex interplay between genetic and epigenetic factors,the tumor microenvironment,and epithelial-to-mesenchymal transition in driving cancer cell plasticity.This dynamic reprogramming suggests that“deregulated cell plasticity”could be considered an additional hallmark of cancer.Advancements in next-generation sequencing and single-cell RNA analysis,combined with artificial intelligence technologies such as deep learning,along with Google’s AlphaFold may help predict the trajectories of cancer cells.By predicting protein three-dimensional structures and identifying both active and potential allosteric binding sites,AlphaFold 2 can accelerate the development of new cancer drugs and therapies.For example,allosteric drugs,bind to the allosteric rather than the active sites,can induce conformational changes in proteins,affecting their activities.This can then alter the conformation of an active site that a drug-resistant mutation has created,permitting a blocked orthosteric drug to bind and this enables the design of more effective drugs that can synergize with traditional orthosteric drugs to bind and regain its efficacy.These innovations could provide deeper insights into the intricate mechanisms of cancer progression and resistance,ultimately paving the way for more precise,durable,and personalized oncologic treatments.展开更多
Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the up...Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.展开更多
Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefo...Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.展开更多
Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming hol...Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming holds promise for neurorepair in various disease models,it is not sufficient on its own to achieve significant functional recovery.Methods:A rat SCI model was established using a spinal cord impactor.Seven days postsurgery,adeno-associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin-2(Ngn2)in the spinal cord.The rats were then trained to walk on a weight-supported treadmill for 4 weeks,starting 14 days after modeling.The effects of these interventions on motor and sensory functions,as well as spinal cord tissue repair,were subsequently evaluated.Results:The combination of NeuroD1 and Ngn2 overexpression with weight-supported exercise training significantly improved gait compared to either inter-vention alone.The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments.Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule-associated protein 2-positive neurons in the injury area.These effects were more pronounced than those observed with spinal cord tissue repair alone.Additionally,the combined intervention significantly reduced glial scarring and the size of the injury area.Conclusion:Exercise intervention enhances the reprogramming effects of astrocytes and restores motor function,yielding better results than either intervention alone.展开更多
基金Supported by Russian Science Foundation,No.16-15-10432。
文摘BACKGROUND The development of regenerative therapy for human spinal cord injury(SCI)is dramatically restricted by two main challenges:the need for a safe source of functionally active and reproducible neural stem cells and the need of adequate animal models for preclinical testing.Direct reprogramming of somatic cells into neuronal and glial precursors might be a promising solution to the first challenge.The use of non-human primates for preclinical studies exploring new treatment paradigms in SCI results in data with more translational relevance to human SCI.AIM To investigate the safety and efficacy of intraspinal transplantation of directly reprogrammed neural precursor cells(drNPCs).METHODS Seven non-human primates with verified complete thoracic SCI were divided into two groups:drNPC group(n=4)was subjected to intraspinal transplantation of 5 million drNPCs rostral and caudal to the lesion site 2 wk post injury,and lesion control(n=3)was injected identically with the equivalent volume of vehicle.RESULTS Follow-up for 12 wk revealed that animals in the drNPC group demonstrated a significant recovery of the paralyzed hindlimb as well as recovery of somatosensory evoked potential and motor evoked potential of injured pathways.Magnetic resonance diffusion tensor imaging data confirmed the intraspinal transplantation of drNPCs did not adversely affect the morphology of the central nervous system or cerebrospinal fluid circulation.Subsequent immunohistochemical analysis showed that drNPCs maintained SOX2 expression characteristic of multipotency in the transplanted spinal cord for at least 12 wk,migrating to areas of axon growth cones.CONCLUSION Our data demonstrated that drNPC transplantation was safe and contributed to improvement of spinal cord function after acute SCI,based on neurological status assessment and neurophysiological recovery within 12 wk after transplantation.The functional improvement described was not associated with neuronal differentiation of the allogeneic drNPCs.Instead,directed drNPCs migration to the areas of active growth cone formation may provide exosome and paracrine trophic support,thereby further supporting the regeneration processes.
基金part support by a GUMC COVID-19 grant (to XL)the support from Center for Cell Reprogramming,GUMC。
文摘Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models(ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells(CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming(CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid(2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for airliquid interface(ALI) polarized 3 D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.
基金supported by the Natural Science Foundation of Guangdong Province(No.2021B1515120053)Guangdong Basic and Applied Basic Research Foundation(Grant No.2024A1515140166).
文摘Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.
基金This work was supported by grants from the National Science and Technology Major Project‘Key New Drug Creation and Manufacturing Program’[No.2018ZX09711002,China]Guangzhou Science and Technology Program[No.201707010048,China]the Science and Technology Foundation of Guangdong Province[No.2016A030312014,China].
文摘Cancer is still a major public-health problem that threatens human life worldwide and further study needs to be carried out in the basic and preclinical areas.Although high-throughput sequencing technology and individualized precise therapy have made breakthroughs over the years,the high failure rate of clinical translational research has limited the innovation of antitumor drugs and triggered the urgent need for optimal cancer-research models.The development of cancerous cell lines,patient-derived xenograft(PDX)models,and organoid has strongly promoted the development of tumor-biology research,but the prediction values are limited.Conditional reprogramming(CR)is a novel cell-culture method for cancer research combining feeder cells with a Rho-associated coiled-coil kinase(ROCK)inhibitor,which enables the rapid and continuous proliferation of primary epithelial cells.In this review,we summarize the methodology to establish CR model and overview recent functions and applications of CR cell-culture models in cancer research with regard to the study of cancerbiology characterization,the exploration of therapeutic targets,individualized drug screening,the illumination of mechanisms about response to antitumor drugs,and the improvement of patient-derived animal models,and finally discuss in detail the major limitations of this cell-culture system.
基金supported by the National Nature Science Foundation of China(92268206)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+3 种基金the Military Medical Research Projects(2023-JSKY-SSQG-006)the Independent Research Project of State Key Laboratory of Trauma and Chemical Poisoning,the National Key Research and Development Program of China(2023YFC3011900)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317)the Open Project of the State Key Laboratory of Trauma,Burn and Combined Injury,Third Military Medical University(SKLKF202301).
文摘The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into induced SwG cells through the ectopic expression of ectodysplasin A.However,the clinical application of this genetic manipulation approach is inherently limited.In this study,we pre-sent findings demonstrating that a combination of six compounds can effectively and speedily reprogram HEKs in culture into fully functional SwG cells.These chemically induced SwG-like cells(ciSGCs)closely resemble the morphology,phenotypes,and functional properties of human primary SwG ductal cells.Furthermore,ciSGCs can be stimulated to differentiate into mature SwG cell types in vitro.In a 3D culture system,they can also generate SwG organoids that exhibit structural and biological features akin to native SwGs.Upon transplantation into scalded mouse paw skin,ciSGCs significantly expedited cuta-neous wound healing and completely restored the structural and functional aspects of the SwGs.In con-clusion,the small molecule cocktail-directed SwG reprogramming offers a non-transgenic and controllable strategy for producing high-quality,clinical-grade SwG cells,showing immense potential for the treatment of burn patients.
文摘Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells （iPSCs） derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.
基金The authors declare no competing financial or commercial interests and acknowledge support from the Fritz Thyssen Foundation(grant AZ.10.11.2.160 to A.P.)the European Union(funding/FP7(FP7/2007-2013)/Grant Agreement n°305299/AgedBrainSYSBIO to J.A.).
文摘Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.
基金This work was supported in part by research grants from the State Key Program of the National Natural Science Foundation of China(No.81830037 to J.Z.)the National Basic Research Program of China(973 Program Grant No.2014CB965001 to JZ)+5 种基金Innovative Research Groups of the National Natural Science Foundation of China(No.81221001 to JZ)Joint Research Fund for Overseas Chinese,Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China(No.81329002 to JZ)the National Institutes of Health(No.1R01NS097195–01 to JZ)the National Natural Science Foundation of China(No.81901333 to XX)Shanghai Sailing Program(No.19YF1451700 to XX)China Postdoctoral Science Foundation Grant(No.2018 M642087 to XX).
文摘The direct reprogramming of somatic cells into induced neural progenitor cells(iNPCs)has been envisioned as a promising approach to overcome ethical and clinical issues of pluripotent stem cell transplantation.We previously reported that astrocyte-derived induced pluripotent stem cells(iPSCs)have more tendencies for neuronal differentiation than fibroblast-derived iPSCs.However,the differences of neurogenic potential between astrocytederived iNPCs(AiNPCs)and iNPCs from non-neural origins,such as fibroblast-derived iNPCs(FiNPCs),and the underlying mechanisms remain unclear.Our results suggested that AiNPCs exhibited higher differentiation efficiency,mobility and survival capacities,compared to FiNPCs.The whole transcriptome analysis revealed higher activities of TGFβsignaling in AiNPCs,versus FiNPCs,following a similar trend between astrocytes and fibroblasts.The higher neurogenic competence,migration ability,and cell death resistance of AiNPCs could be abrogated using TGFβ signaling inhibitor LY2157299.Hence,our study demonstrates the difference between iNPCs generated from neural and non-neural cells,together with the underlying mechanisms,which,provides valuable information for donor cell selection in the reprogramming approach.
基金supported by the National Natural Science Foundation of China,No.82202681(to JW)the Natural Science Foundation of Zhejiang Province,Nos.LZ22H090003(to QC),LR23H060001(to CL).
文摘Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.
基金supported by the Key Project of Guangzhou City,No.202206060002Science and Technology Project of Guangdong Province,No.2018B030332001Guangdong Provincial Pearl River Project,No.2021ZT09Y552 (all to GC)。
文摘Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
文摘Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.
基金supported by the National Natural Science Foundation of China,No.31930068National Key Research and Development Program of China,Nos.2018YFA0107302 and 2021YFA1101203(all to HX).
文摘Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.
基金supported by the National Natural Science Foundation of China,No.82101327(to YY)President Foundation of Nanfang Hospital,Southern Medical University,No.2020A001(to WL)+1 种基金Guangdong Basic and Applied Basic Research Foundation,Nos.2019A1515110150,2022A1515012362(both to YY)Guangzhou Science and Technology Project,No.202201020111(to YY).
文摘Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.
基金supported by the Scientific Research Fund Project of Education Department of Yunnan Province,China(No.2024Y386).
文摘Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoting susceptibility to lung diseases.The development and progression of lung cancer,as well as the effectiveness of immunotherapy are closely associated with gut flora and metabolites,which influence immunological and inflammatory responses.During abnormal proliferation,non-small cell lung cancer cells acquire more substances and energy by altering their own metabolic pathways.Glucose and amino acid metabolism reprogramming provide tumor cells with abundant ATP,carbon,and nitrogen sources,respectively,providing optimal conditions for tumor cell proliferation,invasion,and immune escape.This article reviews the relationship of immune response with gut flora and metabolic reprogramming in non-small cell lung cancer,and discusses the potential mechanisms by which gut flora and metabolic reprogramming affect the occurrence,development,and immunotherapy of non-small cell lung cancer,in order to provide new ideas for precision treatment of lung cancer patients.
文摘Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in addition,hydroxy.In addition,hydroxycinnamic acid conjugates as well as flavonoids.The latter is the major class of secondary plant metabolites and comprises various subclasses,including anthocyanidins.Anthocyanins are rarely reported in extracts from C.asiatica and differ structurally due to a flavylium(2-phenylchromenylium)ion that carries a positive charge at the oxygen atom of the C-ring of the basic flavonoid structure.Callus of C.asiatica was initiated and propagated on synthetic media and subjected to different light regimes.White callus resulted from white fluorescent illumination,while purple callus developed in response to white light emitting diode(LED)illumination.To profile the metabolites responsible for the intense purple coloration,methanolic extracts were prepared from the two cell lines.Total phenolic,flavonoid,and anthocyanin content were determined and indicated(i)very low levels of flavonoids and anthocyanins in white callus and(ii)that anthocyanins dominate the flavonoid content of the purple callus.Extracts were subjected to untargeted ultra-high-performance liquid chromatography coupled to high-definition mass spectrometry(UHPLC–MS)to profile newly synthesized anthocyanins.Metabolite annotation was based on accurate mass determination and characteristic fragmentation patterns.Here,the reprogramming of the metabolome of white C.asiatica callus due to LED illumination is reported and the profiles of cryptic anthocyanins as well as putative flavonoid and caffeoylquinic acid co-pigments in purple callus are described.
文摘Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role in embryonic development,tissue regeneration,and wound healing.However,when dysregulated,cell plasticity contributes to cancer initiation,progression,metastasis,and therapeutic resistance.Throughout different stages of tumor development,cancer cells exploit various forms of plasticity to evade normal regulatory mechanisms that govern cell division and homeostasis.Recent evidence highlights the complex interplay between genetic and epigenetic factors,the tumor microenvironment,and epithelial-to-mesenchymal transition in driving cancer cell plasticity.This dynamic reprogramming suggests that“deregulated cell plasticity”could be considered an additional hallmark of cancer.Advancements in next-generation sequencing and single-cell RNA analysis,combined with artificial intelligence technologies such as deep learning,along with Google’s AlphaFold may help predict the trajectories of cancer cells.By predicting protein three-dimensional structures and identifying both active and potential allosteric binding sites,AlphaFold 2 can accelerate the development of new cancer drugs and therapies.For example,allosteric drugs,bind to the allosteric rather than the active sites,can induce conformational changes in proteins,affecting their activities.This can then alter the conformation of an active site that a drug-resistant mutation has created,permitting a blocked orthosteric drug to bind and this enables the design of more effective drugs that can synergize with traditional orthosteric drugs to bind and regain its efficacy.These innovations could provide deeper insights into the intricate mechanisms of cancer progression and resistance,ultimately paving the way for more precise,durable,and personalized oncologic treatments.
基金Supported by the National Natural Science Foundation of China,No.82272719the Natural Science Foundation of Guangdong Province,No.2023A1515012724 and No.2024A1515013249the Science and Technology Projects in Guangzhou,No.2024A04J5205.
文摘Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.
基金supported by the Science and Technology Research Project of Jilin Education Bureau(No.JJKH20230804KJ)。
文摘Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.
文摘Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming holds promise for neurorepair in various disease models,it is not sufficient on its own to achieve significant functional recovery.Methods:A rat SCI model was established using a spinal cord impactor.Seven days postsurgery,adeno-associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin-2(Ngn2)in the spinal cord.The rats were then trained to walk on a weight-supported treadmill for 4 weeks,starting 14 days after modeling.The effects of these interventions on motor and sensory functions,as well as spinal cord tissue repair,were subsequently evaluated.Results:The combination of NeuroD1 and Ngn2 overexpression with weight-supported exercise training significantly improved gait compared to either inter-vention alone.The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments.Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule-associated protein 2-positive neurons in the injury area.These effects were more pronounced than those observed with spinal cord tissue repair alone.Additionally,the combined intervention significantly reduced glial scarring and the size of the injury area.Conclusion:Exercise intervention enhances the reprogramming effects of astrocytes and restores motor function,yielding better results than either intervention alone.
