RESUMEN
Gliomas are primary tumors that originate in the central nervous system. The conventional treatment options for gliomas typically encompass surgical resection and temozolomide (TMZ) chemotherapy. However, despite aggressive interventions, the median survival for glioma patients is merely about 14.6 months. Consequently, there is an urgent necessity to explore innovative therapeutic strategies for treating glioma. The foundational study of regulated cell death (RCD) can be traced back to Karl Vogt's seminal observations of cellular demise in toads, which were documented in 1842. In the past decade, the Nomenclature Committee on Cell Death (NCCD) has systematically classified and delineated various forms and mechanisms of cell death, synthesizing morphological, biochemical, and functional characteristics. Cell death primarily manifests in two forms: accidental cell death (ACD), which is caused by external factors such as physical, chemical, or mechanical disruptions; and RCD, a gene-directed intrinsic process that coordinates an orderly cellular demise in response to both physiological and pathological cues. Advancements in our understanding of RCD have shed light on the manipulation of cell death modulation - either through induction or suppression - as a potentially groundbreaking approach in oncology, holding significant promise. However, obstacles persist at the interface of research and clinical application, with significant impediments encountered in translating to therapeutic modalities. It is increasingly apparent that an integrative examination of the molecular underpinnings of cell death is imperative for advancing the field, particularly within the framework of inter-pathway functional synergy. In this review, we provide an overview of various forms of RCD, including autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis and immunogenic cell death. We summarize the latest advancements in understanding the molecular mechanisms that regulate RCD in glioma and explore the interconnections between different cell death processes. By comprehending these connections and developing targeted strategies, we have the potential to enhance glioma therapy through manipulation of RCD.
RESUMEN
SCOPE: Depression, a prevalent mental disorder, has significantly impacted the lives of 350 million people, yet it holds promise for amelioration through food-derived phenolics. Raspberries, renowned globally for their delectable flavor, harbor a phenolic compound known as raspberry ketone (RK). However, the impact of RK on depressive symptoms remains ambiguous. This study aims to investigate the impact of RK on lipopolysaccharide (LPS)-induced depressed mice and elucidates its potential mechanisms, focusing on the gut-brain axis. METHODS AND RESULTS: Through behavioral tests, RK exerts a notable preventive effect on LPS-induced depression-like behaviors in mice. RK proves capable of attenuating gut inflammation, repairing gut barrier impairment, modulating the composition of the gut microbiome (Muribaculaceae, Streptococcus, Lachnospiraceae, and Akkermansia), and promoting the production of short-chain fatty acids. Furthermore, RK alleviates neuroinflammation by suppressing the TLR-4/NF-κB pathway and bolsters synaptic function by elevating levels of neurotrophic factors and synapse-associated proteins. CONCLUSION: The current study provides compelling evidence that RK effectively inhibits the TLR-4/NF-κB pathway via the gut-brain axis, leading to the improvement of LPS-induced depression-like behaviors in mice. This study addresses the research gap in understanding the antidepressant effects of RK and illuminates the potential of utilizing RK as a functional food for preventing depression.
Asunto(s)
Eje Cerebro-Intestino , Depresión , Microbioma Gastrointestinal , Lipopolisacáridos , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Depresión/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Eje Cerebro-Intestino/efectos de los fármacos , Eje Cerebro-Intestino/fisiología , Butanonas/farmacología , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos , Antidepresivos/farmacologíaRESUMEN
The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.
RESUMEN
Glioma is a frequently occurring type of cancer that affects the central nervous system. Despite the availability of standardized treatment options including surgical resection, concurrent radiotherapy, and adjuvant temozolomide (TMZ) therapy, the prognosis for glioma patients is often unfavorable. Exosomes act as vehicles for intercellular communication, contributing to tissue repair, immune modulation, and the transfer of metabolic cargo to recipient cells. However, the transmission of abnormal substances can also contribute to pathologic states such as cancer, metabolic diseases, and neurodegenerative disorders. The field of exosome research in oncology has seen significant advancements, with exosomes identified as dynamic modulators of tumor cell proliferation, migration, and invasion, as well as angiogenesis and drug resistance. Exosomes have negligible cytotoxicity, low immunogenicity, and small size, rendering them an ideal therapeutic candidate for glioma. This comprehensive review discusses the dual effects of exosomes in glioma, with an emphasis on their role in facilitating drug resistance. Furthermore, the clinical applications and current limitations of exosomes in glioma therapy are also discussed in detail.
RESUMEN
MicroRNAs (miRNAs) are endogenous short non-encoding RNAs which play a critical role on the output of the proteins, and influence multiple biological characteristics of the cells and physiological processes in the body. Mesenchymal stem/stromal cells (MSCs) are adult multipotent stem cells and characterized by self-renewal and multidifferentiation and have been widely used for disease treatment and regenerative medicine. Meanwhile, MSCs play a critical role in maintaining homeostasis in the body, and dysfunction of MSC differentiation leads to many diseases. The differentiation of MSCs is a complex physiological process and is the result of programmed expression of a series of genes. It has been extensively proven that the differentiation process or programmed gene expression is also regulated accurately by miRNAs. The differentiation of MSCs regulated by miRNAs is also a complex, interdependent, and dynamic process, and a full understanding of the role of miRNAs will provide clues on the appropriate upregulation or downregulation of corresponding miRNAs to mediate the differentiation efficiency. This review summarizes the roles and associated signaling pathways of miRNAs in adipogenesis, chondrogenesis, and osteogenesis of MSCs, which may provide new hints on MSCs or miRNAs as therapeutic strategies for regenerative medicine and biotherapy for related diseases.
RESUMEN
The autoimmune diseases are characterized by overactivation of immune cells, chronic inflammation, and immune response to self-antigens, leading to the damage and dysfunction of multiple organs. Patients still do not receive desired clinical outcomes while suffer from various adverse effects imparted by current therapies. The therapeutic strategies based on mesenchymal stromal cell (MSC) transplantation have become the promising approach for the treatment of autoimmune diseases due to the immunomodulation property of MSCs. MSCs derived from perinatal tissues are collectively known as perinatal MSCs (PMSCs), which can be obtained via painless procedures from donors with lower risk of being contaminated by viruses than those MSCs from adult tissue sources. Therefore, PMSCs may be the ideal cell source for the treatment of autoimmune diseases. This article summarizes recent progress and possible mechanisms of PMSCs in treating autoimmune diseases in animal experiments and clinical studies. This review also presents existing challenges and proposes solutions, which may provide new hints on PMSC transplantation as a therapeutic strategy for the treatment of autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Adulto , Animales , Enfermedades Autoinmunes/terapia , Femenino , Humanos , Inmunomodulación , EmbarazoRESUMEN
Mesenchymal stem cells (MSCs) have proven powerful potential for cell-based therapy both in regenerative medicine and disease treatment. Human umbilical cords and exfoliated deciduous teeth are the main sources of MSCs with no donor injury or ethical issues. The goal of this study was to investigate the differences in the biological characteristics of human umbilical cord mesenchymal stem cells (UCMSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). UCMSCs and SHEDs were identified by flow cytometry. The proliferation, differentiation, migration, chemotaxis, paracrine, immunomodulatory, neurite growth-promoting capabilities, and acetaldehyde dehydrogenase (ALDH) activity were comparatively studied between these two MSCs in vitro. The results showed that both SHEDs and UCMSCs expressed cell surface markers characteristic of MSCs. Furthermore, SHEDs exhibited better capacity for proliferation, migration, promotion of neurite growth, and chondrogenic differentiation. Meanwhile, UCMSCs showed more outstanding adipogenic differentiation and chemotaxy. Additionally, there were no significant differences in osteogenic differentiation, immunomodulatory capacity, and the proportion of ALDHBright compartment. Our findings indicate that although both UCMSCs and SHEDs are mesenchymal stem cells and presented some similar biological characteristics, they also have differences in many aspects, which might be helpful for developing future clinical cellular therapies.
Asunto(s)
Células Madre Mesenquimatosas/citología , Diente Primario/citología , Cordón Umbilical/citología , Adipogénesis , Aldehído Oxidorreductasas/metabolismo , Animales , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Quimiotaxis , Condrogénesis , Humanos , Ratones , Células 3T3 NIH , Neuritas/metabolismo , OsteogénesisRESUMEN
BACKGROUND: The umbilical cord blood (UCB) has been widely accepted as an alternative source of hematopoietic stem/progenitor cells (HSPCs) for transplantation, and its use in adults is still restricted because of low absolute numbers. To overcome this obstacle, expansion of UCB-HSPCs under feeder cell-based coculture is a promising possibility. In this study, we explored UCB-CD34+ cells ex vivo expansion using Wharton's jelly mesenchymal stem cells (WJ-MSCs) or umbilical vein endothelial cells (UVECs) as feeder layer-based serum-free coculture system with a cocktail of cytokines. METHODS: UCB-CD34+ cells were cultured in five different coculture conditions composed of umbilical cord stromal cells (WJ-MSCs or UVECs) with or without a cocktail of cytokines (SCF, FLT3L, and TPO). The cultured cells were harvested at day 10 and analyzed for phenotypes and functionalities, including total nuclear cells (TNCs), CD34+ cells, CD34+CD38- cells, colony-forming unit (CFU) for committed progenitors, and long-term culture initiating cells (LTC-ICs) for HSPCs. RESULTS: Our work showed the numbers of TNC cells, CD34+ cells, and CD34+CD38- cells were expanded under five coculture conditions, and the feeder layer-based cocultures further promoted the expansion. The numbers of colonies of CFU-GM, CFU-E/BFU-E, and CFU-GEMM in the cocultures with cytokines were significantly higher than their counterparts at day 0 (p < 0.05), while no significant difference (p > 0.05) in those without the addition of cytokines. The numbers of LTC-ICs were increased both under the WJ-MSCs and UVECs with cytokine cocultures, but only in the UVECs group showed a significant difference (p < 0.05), and were decreased under conditions without cytokine (p < 0.05). CONCLUSION: Our data demonstrate that both WJ-MSCs and UVECs as feeder layer could efficiently support the expansion of UCB-CD34+ cells in synergy with SCF, FLT3L, and TPO under serum-free culture condition. The UVECs combined with the 3GF cytokine cocktail could maintain the growth of LTC-ICs derived from UCB-CD34+ cells and even expand to some extent.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Medio de Cultivo Libre de Suero/farmacología , Citocinas/farmacología , Células Endoteliales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Antígenos CD34/metabolismo , Técnicas de Cocultivo , Medio de Cultivo Libre de Suero/química , Células Endoteliales/citología , Sangre Fetal/citología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Células Madre Mesenquimatosas/citología , Venas Umbilicales/citología , Gelatina de Wharton/citologíaRESUMEN
Current treatment options for hypoxic-ischemic encephalopathy (HIE) are limited. Human umbilical cord mesenchymal stem cells (UC-MSCs) and cord blood mononuclear cells (CB-MNCs) offer great potential for the treatment of many neurological diseases. The aim of the present study was to identify which cell type is more effective for the treatment of HIE. PKH26-labeled UC-MSCs and CB-MNCs were transplanted into rats with hypoxia-ischemia (HI)-induced brain damage. Apoptotic cell numbers in the brain, as labeled by TUNEL, were assessed. Myelination and gliosis were investigated using myelin basic protein and glial fibrillary acidic protein immunohistochemistry, respectively. The Morris water maze was used to assess animal learning abilities. Our data show that transplantation of UC-MSCs or CB-MNCs after HI reduced astrogliosis, prevented neuronal loss in the striatum, and markedly improved functional brain outcomes after a 28-day recovery period. Moreover, treatment with CB-MNCs increased the proportion of mature oligodendrocytes and improved myelination in cortical areas. Both UC-MSCs and CB-MNCs may result in the recovery of neurological function in HI rats. Based on our data, UC-MSCs and UCB-MNCs may be particularly effective stem cell subsets for treatment of neonatal HIE.
Asunto(s)
Hipoxia-Isquemia Encefálica/terapia , Memoria/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Cordón Umbilical/citología , Animales , Animales Recién Nacidos , Diferenciación Celular/fisiología , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas/métodos , RatasRESUMEN
BACKGROUND: The physiological approach suggests that an environment associating mesenchymal stromal cells with low O2 concentration would be most favorable for the maintenance of hematopoietic stem/progenitor cells (HSPCs). To test this hypothesis, we performed a coculture of cord blood CD34+ cells with Wharton's jelly mesenchymal stem cells (WJ-MSCs) under different O2 concentration to simulate the growth of HSPCs in vivo, and assessed the impacts on stemness maintenance and proliferation of cord blood HSPCs in vitro. METHODS: CD34+ cells derived from cord blood were isolated and cocultured under 1%, 3%, or 20% O2 concentrations with irradiated WJ-MSCs without adding exogenous cytokines for 7 days. The cultured cells were harvested and analyzed for phenotype and functionality, including total nuclear cells (TNC), CD34+Lin- cells, colony forming unit (CFU) for committed progenitors, and long-term culture initiating cells (LTC-ICs) for HSPCs. The cytokine levels in the medium were detected with Luminex liquid chips, and the mRNA expression of hypoxia inducible factor (HIF) genes and stem cell signal pathway (Notch, Hedgehog, and Wnt/ß-catenin) downstream genes in cord blood HSPCs were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our results showed that the number of TNC cells, CD34+Lin- cells, and CFU were higher or similar with 20% O2 (normoxia) in coculture and compared with 1% O2 (hypoxia). Interestingly, a 1% O2 concentration ensured better percentages of CD34+Lin- cells and LTC-IC cells. The hypoxia tension (1% O2) significantly increased vascular endothelial growth factor (VEGF) secretion and decreased interleukin (IL)-6, IL-7, stem cell factor (SCF), and thrombopoietin (TPO) secretion of WJ-MSCs, and selectively activated the Notch, Wnt/ß-catenin, and Hedgehog signaling pathway of cord blood HSPCs by HIF-related factors, which may play an important role in stemness preservation and for sustaining HSPC quiescence. CONCLUSIONS: Our data demonstrate that cord blood HSPCs maintain stemness better under hypoxia than normoxia with WJ-MSC coculture, partially due to the increased secretion of VEGF, decreased secretion of IL-6 by WJ-MSCs, and selective activation of stem cell signal pathways in HSPCs. This suggests that the oxygenation may not only be a physiological regulatory factor but also a cell engineering tool in HSPC research, and this may have important translational and clinical implications.
Asunto(s)
Antígenos CD34/metabolismo , Hipoxia de la Célula/fisiología , Técnicas de Cocultivo/métodos , Sangre Fetal/metabolismo , Células Madre Mesenquimatosas/metabolismo , Gelatina de Wharton/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , HumanosRESUMEN
mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f,Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f,Nes-cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability.