RESUMO
Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as 'cell polarization.' There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations (microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.
RESUMO
Diabetic wounds are serious clinical complications which manifest wet condition due to the mass exudate, along with disturbed regulation of inflammation, severe oxidative stress and repetitive bacterial infection. Existing treatments for diabetic wounds remain unsatisfactory due to the lack of ideal dressings that encompass mechanical performance, adherence to moist tissue surfaces, quick repair, and diverse therapeutic benefits. Herein, we fabricated a wet adhesive, self-healing, glucose-responsive drug releasing hydrogel with efficient antimicrobial and pro-healing properties for diabetic wound treatment. PAE hydrogel was constructed with poly(acrylic acid-co-acrylamide) (AA-Am) integrated with a dynamic E-F crosslinker, which consisted of epigallocatechin gallate (EGCG) and 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA). Due to the dynamic crosslinking nature of boronate esters, abundant catechol groups and hydrogen bonding, PAE hydrogel demonstrated excellent mechanical properties with about 1000 % elongation, robust adhesion to moist tissues, fast self-healing, and absorption of biofluids of 10 times of its own weight. Importantly, PAE hydrogel exhibited sustained and glucose-responsive release of EGCG. Together, the bioactive PAE hydrogel had effective antibacterial, antioxidative, and anti-inflammatory properties in vitro, and accelerated diabetic wound healing in rats via reducing tissue-inflammatory response, enhancing angiogenesis, and reprogramming of macrophages. Overall, this versatile hydrogel provides a straightforward solution for the treatment of diabetic wound, and shows potential for other wound-related application scenarios.
RESUMO
FVP is a polysaccharide extracted from Flammulina velutipes with immunomodulatory, anti-tumor, and anti-oxidation activities. In this study, we obtained the crude polysaccharide FVP-C from the water extract of Flammulina velutipes, and its main component FVP-S1 was obtained after further purification. Upon structural identification, we found that FVP-C is a neutral polysaccharide, and FVP-S1 was an acidic golden mushroom polysaccharide, consisting of glucuronic acid, xylose, and glucose. Lung adenocarcinoma (A549) was treated with FVP-S1 and FVP-C, respectively, and we found that FVP-S1 and FVP-C inhibited the proliferation and migration ability of tumor cells, as well as changed the morphology of the tumor cells and caused chromosome sheteropythosis, among which FVP-S1 had the best inhibition effect. The results of flow cytometry experiments and mitochondrial membrane potential, RT-qPCR, and Western blot showed that FVP-S1 and FVP-C were able to decrease the mitochondrial membrane potential, increase the expression level of apoptotic proteins Casepase-3 and Casepase-9 proteins, and at the same time, increase the ratio of Bax and Bcl-2, which promoted apoptosis of tumor cells. In conclusion, these data indicated that FVP-S1 and FVP-C were able to induce apoptosis in A549 cells through the mitochondrial pathway, which played an important role in inhibiting tumor cells.
Assuntos
Adenocarcinoma de Pulmão , Apoptose , Proliferação de Células , Flammulina , Neoplasias Pulmonares , Potencial da Membrana Mitocondrial , Mitocôndrias , Humanos , Flammulina/química , Apoptose/efeitos dos fármacos , Células A549 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Polissacarídeos/farmacologia , Polissacarídeos/química , Movimento Celular/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Polissacarídeos Fúngicos/química , Antineoplásicos/farmacologiaRESUMO
Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in epidermal growth factor receptor (EGFR). N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assay showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs. Implications: This study offers more evidences for the involvement of METTL14-mediated m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs.
RESUMO
Mechanisms of cell fate specification remain a central question for developmental biology and regenerative medicine. The pioneer factor ETV2 is a master regulator for the endothelial cell (EC) lineage specification. Here, we studied mechanisms of ETV2-driven fate specification using a highly efficient system in which ETV2 directs human induced pluripotent stem cell-derived mesodermal progenitors to form ECs over two days. By applying CUT&RUN, single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses, we characterized the transcriptomic profiles, chromatin landscapes, dynamic cis-regulatory elements (CREs), and molecular features of EC cell differentiation mediated by ETV2. This defined the scope of ETV2 pioneering activity and identified its direct downstream target genes. Induced ETV2 expression both directed specification of endothelial progenitors and suppressed acquisition of alternative fates. Functional screening and candidate validation revealed cofactors essential for efficient EC specification, including the transcriptional activator GABPA. Surprisingly, the transcriptional repressor REST was also necessary for efficient EC specification. ETV2 recruited REST to occupy and repress non-EC lineage genes. Collectively, our study provides an unparalleled molecular analysis of EC specification at single-cell resolution and identifies the important role of pioneer factors to recruit repressors that suppress commitment to alternative lineages.
RESUMO
Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH.
RESUMO
INTRODUCTION: Interleukin-1 beta (IL-1ß) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1ß in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration. METHODS: First trimester placenta and decidua were collected to study the expression levels of IL-1ß and its receptors by immunohistochemical staining. Primary isolates of first trimester EVT or the HTR-8/SVneo trophoblast like cell line were used to assess migration and invasion. Matrix metalloproteinase levels were assessed by gelatin zymography and ELISA. The phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. Differentially expressed proteins in cells was detected and verified by Western Blot. RESULTS: IL-1ß, its receptors and antagonist are expressed in first trimester placenta and decidua, exogenous IL-1ß stimulates trophoblast cell outgrowth, migration and invasion through the ERK signaling pathway. IL-1ß was significantly increased in the placenta at 6-7 weeks gestation compared with 8-9 weeks gestation (P < 0.0001). Transwell and RTCA assays indicated that IL-1ß stimulates the invasion and migration of EVT. In addition, IL-1ß promoted the phosphorylation of ERK 1/2. It also promoted the expression of MMP2 and MMP9 in EVT as demonstrated by gelatin zymography assay and enzyme linked immunosorbent assay. DISCUSSION: This study demonstrated IL-1ß expression in placenta and decidua, and that it regulates EVT invasion and migration.
Assuntos
Movimento Celular , Interleucina-1beta , Sistema de Sinalização das MAP Quinases , Primeiro Trimestre da Gravidez , Trofoblastos , Humanos , Feminino , Gravidez , Trofoblastos/metabolismo , Movimento Celular/fisiologia , Primeiro Trimestre da Gravidez/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Placenta/metabolismo , Decídua/metabolismo , Metaloproteinase 9 da Matriz/metabolismoRESUMO
Background: No effective therapies exist to prevent degeneration from Mild Cognitive Impairment (MCI) to Alzheimer's disease. Therapies integrating music and/or dance are promising as effective, non-pharmacological options to mitigate cognitive decline. Objective: To deepen our understanding of individuals' relationships (i.e., histories, experiences and attitudes) with music and dance that are not often incorporated into music- and dance-based therapeutic design, yet may affect therapeutic outcomes. Methods: Eleven older adults with MCI and five of their care partners/ spouses participated (4M/12F; Black: n=4, White: n=10, Hispanic/ Latino: n=2; Age: 71.4±9.6). We conducted focus groups and administered questionnaires that captured aspects of participants' music and dance relationships. We extracted emergent themes from four major topics, including: (1) experience and history, (2) enjoyment and preferences, (3) confidence and barriers, and (4) impressions of music and dance as therapeutic tools. Results: Thematic analysis revealed participants' positive impressions of music and dance as potential therapeutic tools, citing perceived neuropsychological, emotional, and physical benefits. Participants viewed music and dance as integral to their lives, histories, and identities within a culture, family, and/ or community. Participants also identified lifelong engagement barriers that, in conjunction with negative feedback, instilled persistent low self-efficacy regarding dancing and active music engagement. Questionnaires verified individuals' moderately-strong music and dance relationships, strongest in passive forms of music engagement (e.g., listening). Conclusions: Our findings support that individuals' music and dance relationships and the associated perceptions toward music and dance therapy may be valuable considerations in enhancing therapy efficacy, participant engagement and satisfaction for individuals with MCI.
RESUMO
Zwitterionic polymers have emerged as an important class of biomaterials to construct wound dressings and antifouling coatings over the past decade due to their excellent hydrophilicity. However, all the reported zwitterionic polymers as wound dressings are nondegradable because of noncleavable carbonâcarbon bonding backbones, and must be removed periodically after treatment to avoid hypoxia in the wound, thus leading to potential secondary injury. In this work, a biodegradable polyzwitterion patch is fabricated for the first time by ring-opening polymerization of carboxybetaine dithiolane (CBDS), which is self-crosslinked via inter-amide hydrogen bonds and zwitterionic dipole-dipole interactions on the side chains. The unprecedented polyCBDS (PCBDS) patch demonstrates enough ductility owing to the intermolecular physical interactions to fully cover irregular wounds, also showing excellent biodegradability and antifouling performance resulted from the existence of disulfide bonds and carboxybetaine groups. Besides, the PCBDS degradation-induced released CBDS owns potent antioxidant and antibacterial activities. This PCBDS patch is used as a diabetic wound dressing, inhibiting bacterial adhesion on the external surface, and its degradation products can exactly kill bacteria and scavenge excessive reactive oxygen species (ROS) at the wound site to regulate local microenvironment, including regulation of cytokine express and macrophage polarization, accelerating infected diabetic wound repair, and also avoiding the potential secondary injury.
Assuntos
Antibacterianos , Cicatrização , Cicatrização/efeitos dos fármacos , Animais , Camundongos , Antibacterianos/química , Antibacterianos/farmacologia , Bandagens , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Polímeros/química , Polímeros/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Betaína/química , Betaína/análogos & derivados , Betaína/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Células RAW 264.7RESUMO
An epidemic of sleep loss currently affects modern societies worldwide and is implicated in numerous physiological disorders, including pain sensitization, although few studies have explored the brain pathways affected by active sleep deprivation (ASD; e.g., due to recreation). Here, we describe a neural circuit responsible for pain sensitization in mice treated with 9-h non-stress ASD. Using a combination of advanced neuroscience methods, we found that ASD stimulates noradrenergic inputs from locus coeruleus (LCNA) to glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HLGlu). Moreover, artificial inhibition of this LCNAâS1HLGlu pathway alleviates ASD-induced pain sensitization in mice, while chemogenetic activation of this pathway recapitulates the pain sensitization observed following ASD. Our study thus implicates activation of the LCNAâS1HLGlu pathway in ASD-induced pain sensitization, expanding our fundamental understanding of the multisystem interplay involved in pain processing.
Assuntos
Locus Cerúleo , Dor , Privação do Sono , Córtex Somatossensorial , Animais , Camundongos , Privação do Sono/fisiopatologia , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiopatologia , Dor/fisiopatologia , Córtex Somatossensorial/fisiopatologia , Masculino , Norepinefrina/metabolismo , Camundongos Endogâmicos C57BL , Neurônios Adrenérgicos/metabolismo , Neurônios Adrenérgicos/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Vias Neurais/fisiopatologiaRESUMO
The advent of covalent adaptable networks (CANs) through the incorporation of dynamic covalent bonds has led to unprecedented properties of macromolecular systems, which can be engineered at the molecular level. Among the various types of stimuli that can be used to trigger chemical changes within polymer networks, light stands out for its remote and spatiotemporal control under ambient conditions. However, most examples of photoactive CANs need to be transparent and they exhibit slow response, side reactions, and limited light penetration. In this vein, it is interesting to understand how molecular engineering of optically active dynamic linkages that offer fast response to visible light can impart "living" characteristics to CANs, especially in opaque systems. Here, the use of carbazole-based thiuram disulfides (CTDs) that offer dual reactivity as photoactivated reshuffling linkages and iniferters under visible light irradiation is reported. The fast response to visible light activation of the CTDs leads to temporal control of shape manipulation, healing, and chain extension in the polymer networks, despite the lack of optical transparency. This strategy charts a promising avenue for manipulating multifunctional photoactivated CANs in a controlled manner.
RESUMO
Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.
RESUMO
The fabrication of stretchable ionic conductors with low hysteresis and anti-freezing properties to enhance the durability and reliability of flexible electronics even at low temperatures remains an unmet challenge. Here, we report a facile strategy to fabricate low hysteresis, high stretchability, self-adhesion and anti-freezing zwitterionic supramolecular polymer ion-conductive elastomers (ICEs) by photoinitiated polymerization of aqueous precursor solutions containing a newly designed zwitterionic monomer carboxybetaine ureido acrylate (CBUIA) followed by solvent evaporation. The resultant poly(carboxybetaine ureido acrylate) (PCBUIA) ICEs are highly stretchable and self-adhesive owing to the presence of strong hydrogen bonds between ureido groups and dipole-dipole interactions of zwitterions. The zwitterion groups on the polymer side chains and loaded-lithium chloride endow PCBUIA ICEs with excellent anti-freezing properties, demonstrating mechanical flexibility and ionic transport properties even at a low temperature (-20 °C). Remarkably, the PCBUIA ICEs demonstrate a low hysteresis (≈10%) during cyclic mechanical loading-unloading (≤500%), and are successfully applied as wearable strain sensors and triboelectric nanogenerators (TENGs) for energy harvesting and human motion monitoring. In addition, the PCBUIA ICE-based TENG was used as a wireless sensing terminal for Internet of Things smart devices to enable wireless sensing of finger motion state detection.
RESUMO
In this paper, a novel laser spot tracking algorithm that incorporates the Kalman filter with the continuously adaptive Meanshift algorithm (Cam-Kalm) is proposed and employed in an underwater optical wireless communication (UOWC) system. Since the Kalman filter has the advantage of predicting the state information of the target spot based on its spatial motion features, the proposed algorithm can improve the accuracy and stability of the moving laser spot tracking. A 2 m optical wireless communication experimental system with auto-tracking based on a green laser diode (LD) is built to evaluate the tracking performance of different algorithms. Experimental results verify that the proposed algorithm outperforms conventional tracking algorithms in aspects of tracking accuracy, interference resistance, and response time. With the proposed Cam-Kalm algorithm, the experimental system can establish an effective communication link, while the maximum tracking speed is 20 mm/s given the forward-error-correction (FEC) threshold.
RESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the onset of symptoms, typically occurring later in life, and significant deficits in cognitive functions including learning, memory, speech, and behavior. Ongoing research endeavors seek to explore methods for preventing and treating AD, as well as delving into the molecular mechanisms underlying existing and novel therapeutic approaches encompassing exercise, diet, and drug regimens for individuals with AD or those at risk of developing AD. Among these interventions, dietary interventions have garnered increasing attention due to their potential in addressing the disease. Eating is among the most fundamental of human daily activities, and controlled dietary practices, such as fasting, have gained prominence as essential clinical methods for disease prevention and treatment. Research findings indicate that fasting holds promise in effectively alleviating and improving the cognitive decline associated with age or as consequence of disease. The clinical efficacy of fasting in addressing AD and related disorders might be grounded in its influence on various molecular mechanisms, including neuroinflammation, glial cell activation, insulin resistance, autophagy regulation, nerve regeneration, the gut microbiome, and accumulations of amyloid-ß and tau proteins. The present study reviews possible molecular mechanisms underpinning the therapeutic effects of fasting in patients with AD, as well as in models of the disorder, to establish a theoretical basis for using fasting as a viable approach to treat AD.
Assuntos
Doença de Alzheimer , Humanos , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Jejum , Proteínas tau , Aprendizagem , Modelos Animais de DoençasRESUMO
BACKGROUND: Cigarette smoking is commonly reported among chronic pain patients in the clinic. Although chronic nicotine exposure is directly linked to nociceptive hypersensitivity in rodents, underlying neurobiological mechanisms remain unknown. METHODS: Multi-tetrode recordings in freely moving mice were used to test the activity of dopaminergic projections from the ventral tegmental area (VTA) to pyramidal neurones in the anterior cingulate cortex (ACC) in chronic nicotine-treated mice. The VTAâACC dopaminergic pathway was inhibited by optogenetic manipulation to detect chronic nicotine-induced allodynia (pain attributable to a stimulus that does not normally provoke pain) assessed by von Frey monofilaments (force units in g). RESULTS: Allodynia developed concurrently with chronic (28-day) nicotine exposure in mice (0.36 g [0.0141] vs 0.05 g [0.0018], P<0.0001). Chronic nicotine activated dopaminergic projections from the VTA to pyramidal neurones in the ACC, and optogenetic inhibition of VTA dopaminergic terminals in the ACC alleviated chronic nicotine-induced allodynia in mice (0.06 g [0.0064] vs 0.28 g [0.0428], P<0.0001). Moreover, optogenetic inhibition of Drd2 dopamine receptor signalling in the ACC attenuated nicotine-induced allodynia (0.07 g [0.0082] vs 0.27 g [0.0211], P<0.0001). CONCLUSIONS: These findings implicate a role of Drd2-mediated dopaminergic VTAâACC pathway signalling in chronic nicotine-elicited allodynia.
Assuntos
Giro do Cíngulo , Nicotina , Humanos , Camundongos , Animais , Nicotina/farmacologia , Hiperalgesia/induzido quimicamente , Dopamina/metabolismo , DorRESUMO
The raccoon dog (Nyctereutes procyonoides) is a typical omnivore possessing wide dietary adaptability and tolerance to rough feeding, which may be attributed to its intestinal microbiota. The study aimed to investigate the effect of dietary alfalfa meal levels on the growth performance, nutrient apparent digestibility, serum parameters, and intestinal microbiota of raccoon dogs. Sixty raccoon dogs were randomly divided into four dietary treatments containing 0% (AM0), 5% (AM5), 10% (AM10), and 15% (AM15) alfalfa meal for a 60-day experiment. The results showed that compared to raccoon dogs fed the AM0 diet, those fed the AM5 and AM10 diets had no significant difference in growth performance, while those fed the AM15 diet experienced a significant decrease. Raccoon dogs fed the AM5 diet had no significant effect on the nutrient apparent digestibility. Dietary supplementation with alfalfa meal significantly decreased serum urea levels and increased the antioxidant capacity of raccoon dogs. The intestinal microbiome analysis showed that the richness and diversity of colonic microbiota significantly increased in the AM15 group. With the increase in dietary alfalfa meal levels, the relative abundance of fiber-degrading bacteria in the colon of raccoon dogs, such as Treponema, Phascolarctobacterium, and Christensenellaceae R-7 group, increased. However, the relative abundance of pathogenic bacteria, including Anaerobiospirillum, decreased. In conclusion, the inclusion of 5% alfalfa meal in the raccoon dogs' diet had no effect on growth performance, but it exhibited the potential to improve serum antioxidant capacity and intestinal microbiota. This indicates that raccoon dogs have a certain tolerance to the addition of alfalfa meal in their diet.
RESUMO
Circular RNAs (circRNAs), a subclass of non-coding RNAs characterized by covalently closed continuous loops, play a key role in tumorigenesis and aggressiveness. However, the potential molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remains largely unknown. Exploring their roles and mechanisms in TNBC progression may help identify new diagnostic markers and therapeutic targets. In this study, we found that circ-FOXO3 was dramatically downregulated in TNBC tissues and blood samples from patients with TNBC. Notably, low circ-FOXO3 expression in TNBC tissues and bloods was associated with lymph node metastasis and unfavorable outcomes in patients with TNBC. Overexpression of circ-FOXO3 significantly inhibited the growth, invasion, and metastasis of TNBC cells both in vitro and in vivo. Moreover, we demonstrated that circ-FOXO3 was predominantly expressed in the cytoplasm and directly interacted with Wolf-Hirschhorn syndrome candidate 1 (WHSC1), thereby inhibiting WHSC1 nuclear localization and activity, resulting in the inhibition of H3K36me2 modifications at the Zeb2 promoter, ultimately inhibiting Zeb2 expression and halting TNBC growth and metastasis. Taken together, these results reveal the tumor-suppressive functions of circ-FOXO3 in inhibiting WHSC1-mediated H3K36me2 modification of Zeb2, suggesting that circ-FOXO3 could serve as a potential novel predictive prognostic biomarker and therapeutic target for TNBC.
Assuntos
MicroRNAs , RNA Circular , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
As the largest transporter family impacting on tumor genesis and development, the prognostic value of solute carrier (SLC) members has not been elucidated in colorectal cancer (CRC). We aimed to identify a prognostic signature from the SLC members and comprehensively analyze their roles in CRC. Firstly, we downloaded transcriptome data and clinical information of CRC samples from GEO (GSE39582) and TCGA as training and testing dataset, respectively. We extracted the expression matrix of SLC genes and established a prognostic model by univariate and multivariate Cox regression. Afterwards, the low-risk and high-risk group were identified. Then, the differences of prognosis traits, transcriptome features, clinical characteristics, immune infiltration and drug sensitivity between the two groups were explored. Furthermore, molecular subtyping was also implemented by non-negative matrix factorization (NMF). Finally, we studied the expression of the screened SLC genes in CRC tumor tissues and normal tissues as well as investigated the role of SLC12A2 by loss of function and gain of function. As a result, we developed a prognostic risk model based on the screened 6-SLC genes (SLC39A8, SLC2A3, SLC39A13, SLC35B1, SLC4A3, SLC12A2). Both in the training and testing sets, CRC patients in the high-risk group had the poorer prognosis and were in the more advanced pathological stage. What's more, the high-risk group were enriched with CRC progression signatures and immune infiltration. Two groups showed different drug sensitivity. On the other hand, two distinct subclasses (C1 and C2) were identified based on the 6 SLC genes. CRC patients in the high-risk group and C1 subtype had a worse prognosis. Furthermore, we found and validated that SLC12A2 was steadily upregulated in CRC. A loss-of-function study showed that knockdown of SLC12A2 expression restrained proliferation and stemness of CRC cells while a gain-of-function study showed the contrary results. Hence, we provided a 6-SLC gene signature for prognosis prediction of CRC patients. At the same time, we identified that SLC12A2 could promote tumor progression in CRC, which may serve as a potential therapeutic target.
Assuntos
Neoplasias Colorretais , Membro 2 da Família 12 de Carreador de Soluto , Humanos , Algoritmos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas de Membrana Transportadoras , Fenótipo , PrognósticoRESUMO
Anxiety-associated symptoms following acute stress usually become extinct gradually within a period of time. However, the mechanisms underlying how individuals cope with stress to achieve the extinction of anxiety are not clear. Here we show that acute restraint stress causes an increase in the activity of GABAergic neurons in the CeA (GABACeA) in male mice, resulting in anxiety-like behaviors within 12 hours; meanwhile, elevated GABACeA neuronal CX3CL1 secretion via MST4 (mammalian sterile-20-like kinase 4)-NF-κB-CX3CL1 signaling consequently activates microglia in the CeA. Activated microglia in turn inhibit GABACeA neuronal activity via the engulfment of their dendritic spines, ultimately leading to the extinction of anxiety-like behaviors induced by restraint stress. These findings reveal a dynamic molecular and cellular mechanism in which microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress.