RESUMO
Background: Microangiogenesis and lymphangiogenesis are essential for tumor growth in the tumor microenvironment, contributing to tumor invasion and metastasis. Limited literature exists on these processes in esophageal squamous cell carcinoma (ESCC). Therefore, the purpose of this study is to explore the impacts of microangiogenesis and lymphangiogenesis on the occurrence, progression, and prognosis assessment of ESCC. Methods: Surgical specimens and paraffin-embedded human tissues were procured from ESCC patients, encompassing 100 ESCC tissues and 100 cancer-adjacent normal (CAN) tissues. CD34 and D2-40 were utilized as markers for microvessel endothelial cells and lymphatic vessel endothelial cells, respectively. Microvascular density (MVD) and lymphatic vessel density (LVD) were evaluated through immunohistochemical quantification. Results: We found that tumor tissues in ESCC patients had significantly higher MVD and LVD than cancer-adjacent normal (CAN) tissues. High MVD and LVD were associated with lymph node metastasis and advanced tumor clinical stages. Additionally, both high MVD and high LVD were strongly linked to poorer prognosis among cancer patients. Furthermore, a positive correlation was found between high MVD and high LVD (p < 0.05). The presence of these markers individually indicated a worse prognosis, with their combined assessment showcasing enhanced prognostic value. Conclusions: Overall, the increased MVD and LVD indicates higher invasion and metastasis of ESCC, closely correlating with unfavorablefor poor prognosis of ESCC patients.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Vasos Linfáticos , Densidade Microvascular , Humanos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/irrigação sanguínea , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Vasos Linfáticos/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/irrigação sanguínea , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/irrigação sanguínea , Metástase Linfática/patologia , Linfangiogênese/fisiologia , Idoso , Neovascularização Patológica/patologia , Microvasos/patologia , Antígenos CD34/metabolismo , Imuno-HistoquímicaRESUMO
Congenital Quadricuspid Aortic Valve (QAV) malformation is a relatively rare cardiac valve malformation, especially with abnormal coronary opening and severe stenosis of Coronary Artery Disease (CAD). The patient underwent "one-stop" interventional treatment with transcatheter aortic valve replacement and percutaneous coronary stent implantation. Follow up for 12-month with good outcomes.
Assuntos
Valva Aórtica , Doença da Artéria Coronariana , Substituição da Valva Aórtica Transcateter , Humanos , Valva Aórtica/cirurgia , Valva Aórtica/anormalidades , Valva Aórtica/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/complicações , Substituição da Valva Aórtica Transcateter/métodos , Masculino , Stents , Intervenção Coronária Percutânea/métodos , Angiografia Coronária , IdosoRESUMO
This study aims to investigate the mechanism of Xuanbai Chengqi Decoction in treating acute lung injury(ALI) based on network pharmacology and animal experiments. The potential targets and signaling pathways of Xuanbai Chengqi Decoction in regulating ALI were predicted by network pharmacology. The rat model of ALI was constructed and administrated with different doses of Xuanbai Chengqi Decoction. The pathological changes in the lung tissue of rats were observed by hematoxylin-eosin(HE) staining. The levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α) in the peripheral blood were measured by enzyme-linked immunosorbent assay(ELISA). The mRNA and protein levels of factors in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway were determined by quantitative real-time PCR(qPCR) and Western blot, respectively. A total of 52 compounds from Xuanbai Chengqi Decoction were predicted to be involved in the treatment of ALI, including ß-sitosterol, emodin, stigmasterol, glabridin, and aloe-emodin, which corresponded to 112 targets,and 4 723 targets of ALI were predicted. The compounds and ALI shared 94 common targets. The key targets included TNF, IL-1ß,prostaglandin-endoperoxide synthase 2(PTGS2), and tumor protein 53(TP53). Lipids and atherosclerosis, p53 signaling pathway,IL-17 signaling pathway, and PI3K/Akt signaling pathway were mainly involved in the treatment. Animal experiments showed that compared with the model group, Xuanbai Chengqi Decoction alleviated the pathological changes in the lung tissue, lowered the serum levels of IL-6, IL-1ß, and TNF-α, down-regulated the mRNA and protein levels of PI3K, Akt, and mTOR, and reduced the p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR ratios in ALI rats. The results showed that Xuanbai Chengqi Decoction exerted its therapeutic effects on ALI via multiple components, targets, and pathways. Meanwhile, Xuanbai Chengqi Decoction may reduce the inflammation and attenuate the lung injuries of ALI rats by inhibiting the PI3K/Akt/mTOR signaling pathway.
Assuntos
Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Interleucina-1beta , Farmacologia em Rede , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Masculino , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismoRESUMO
OBJECTIVE: Multiple myeloma (MM) is a plasma cell malignancy characterized by abnormal plasma cell proliferation in the bone marrow. Circulating exosomal miRNA-451 is associated with the progression of many tumors, but the relationship between its expression and MM has not been reported. In this study, we aimed to investigate the clinical value of miRNA-451 as a biomarker for diagnosis and prognosis of multiple myeloma. METHODS: A total of 120 patients with multiple myeloma and 120 healthy control people were recruited in this study. The miRNA-451 expression in serum exosomes of participants was measured by quantitative real-time polymerase chain reaction, and the diagnostic value of miRNA-451 for multiple myeloma was assessed by receiver operating characteristic (ROC) curve. The correlation between miRNA-451 expression and plasma cells ratio and M protein content was analyzed by Pearson correlation coefficient. The prognosis of different miRNA-451 expression was evaluated by survival curves. RESULTS: Results suggested that serum exosomal miRNA-451 expression was significantly decreased in patients with multiple myeloma rather than in the healthy controls. The ROC curve showed that area under the curve value of miRNA-451 was 0.888, suggesting that miRNA-451 had diagnostic value to multiple myeloma. Moreover, there was a negative correlation between miRNA-451 expression and plasma cells ratio or M protein content. Survival curves showed that patients with high miRNA-451 expression had a longer survival time, suggesting the value of miRNA-451 as a prognostic indicator of multiple myeloma. CONCLUSION: We demonstrated the relationship between miRNA-451 expression and multiple myeloma, indicating that miRNA-451 in circulating exosomes may be an effective diagnostic biomarker and prognostic indicator for multiple myeloma.
RESUMO
Background: The extensive community of gut microbiota significantly influences various biological functions throughout the body, making its characterization a focal point in biomedicine research. Over the past few decades, studies have revealed a potential link between specific gut bacteria, their associated metabolic pathways, and influenza. Bacterial metabolites can communicate directly or indirectly with organs beyond the gut via the intestinal barrier, thereby impacting the physiological functions of the host. As the microbiota increasingly emerges as a 'gut signature' in influenza, gaining a deeper understanding of its role may offer new insights into its pathophysiological relevance and open avenues for novel therapeutic targets. In this Review, we explore the differences in gut microbiota between healthy individuals and those with influenza, the relationship between gut microbiota metabolites and influenza, and potential strategies for preventing and treating influenza through the regulation of gut microbiota and its metabolites, including fecal microbiota transplantation and microecological preparations. Methods: We utilized PubMed and Web of Science as our search databases, employing keywords such as "influenza," "gut microbiota," "traditional Chinese medicine," "metabolites," "prebiotics," "probiotics," and "machine learning" to retrieve studies examining the potential therapeutic connections between the modulation of gut microbiota and its metabolites in the treatment of influenza. The search encompassed literature from the inception of the databases up to December 2023. Results: Fecal microbiota transplantation (FMT), microbial preparations (probiotics and prebiotics), and traditional Chinese medicine have unique advantages in regulating intestinal microbiota and its metabolites to improve influenza outcomes. The primary mechanism involves increasing beneficial intestinal bacteria such as Bacteroidetes and Bifidobacterium while reducing harmful bacteria such as Proteobacteria. These interventions act directly or indirectly on metabolites such as short-chain fatty acids (SCFAs), amino acids (AAs), bile acids, and monoamines to alleviate lung inflammation, reduce viral load, and exert anti-influenza virus effects. Conclusion: The gut microbiota and its metabolites have direct or indirect therapeutic effects on influenza, presenting broad research potential for providing new directions in influenza research and offering references for clinical prevention and treatment. Future research should focus on identifying key strains, specific metabolites, and immune regulation mechanisms within the gut microbiota to accurately target microbiota interventions and prevent respiratory viral infections such as influenza.
RESUMO
Efforts to synergize hydrogen sulfide (H2S) with NSAIDs have faced challenges due to complex structural entities and independent release kinetics. This study presents a highly atom-efficient approach of using a thiocarboxylic acid (thioacid) as a novel H2S releasing precursor and successfully employs it to modify NSAIDs, which offers several critical advantages. First, thioacid-modified NSAID is active in inhibiting cyclooxygenase, sometimes with improved potency. Second, this prodrug approach avoids introducing extra structural moieties, allowing for the release of only the intended active principals. Third, the release of H2S and NSAID is concomitant, thus optimally synchronizing the concentration profiles of the two active principals. The design is based on our discovery that esterases can directly and efficiently hydrolyze thiocarboxylic acids, enabling controlled release H2S. This study demonstrates the proof of principle through synthesizing analogs, assesses release kinetics, enzyme inhibition, and pharmacological efficacy, and evaluates toxicity and gut microbiota regulation in animal models.
RESUMO
OBJECTIVE: To investigate the expression of long non-coding RNA lncSNHG16 in hepatocellular carcinoma (HCC), associations between its expression and patient survival, and its potential role in regulating autophagy in the disease. METHODS: Expression of lncSNHG16 was measured using quantitative real-time PCR in HCC cells in culture and HCC tissues from patients. Effects of lncSNHG16 overexpression were examined in HCC cultures using assays of cell proliferation, wound healing, and migration or invasion in Transwell dishes. Effects of lncSNHG16 overexpression were also examined in subcutaneous tumor in mice. Relationships of lncSNHG16 expression to autophagy and apoptosis in HCC cultures were explored using western blotting and flow cytometry. RESULTS: Higher lncSNHG16 expression in HCC tissues was associated with significantly worse overall and recurrence-free survival of patients. Overexpressing lncSNHG16 in HCC cell culture promoted cell proliferation, migration, and invasion while suppressing apoptosis. lncSNHG16 was associated with upregulation of STAT3 as well as inhibition of autophagy and associated apoptosis. Overexpressing lncSNHG16 accelerated tumor growth and weight in mice. CONCLUSION: The non-coding RNA lncSNHG16 suppresses autophagy and associated apoptosis in HCC, making it a potential therapeutic target.
RESUMO
This technical note outlines a minimalist arthroscopic approach to anterior cruciate ligament avulsion fracture fixation using a bioabsorbable knotless suture anchor. This method represents a less invasive alternative to traditional techniques, catering specifically to fractures classified as Meyers and McKeever type II or III. The procedure is performed through standard anterolateral and anteromedial portals without the need for additional incisions or bone tunnel drilling, making it particularly suitable for children and adolescent patients with open physes. The technique involves the use of a suture hook to pass a double-stranded suture through the anterior cruciate ligament, anchored eccentrically to the anterior tibial incline with a knotless suture anchor. This approach allows for anatomic reduction with adjustable tension and without the potential risk of iatrogenic osteochondral injury. Nonetheless, it should be acknowledged that prospective biomechanical studies and larger patient samples are necessary to validate this technique compared with existing fixation methods.
RESUMO
In speech perception, low-frequency cortical activity tracks hierarchical linguistic units (e.g., syllables, phrases, and sentences) on top of acoustic features (e.g., speech envelope). Since the fluctuation of speech envelope typically corresponds to the syllabic boundaries, one common interpretation is that the acoustic envelope underlies the extraction of discrete syllables from continuous speech for subsequent linguistic processing. However, it remains unclear whether and how cortical activity encodes linguistic information when the speech envelope does not provide acoustic correlates of syllables. To address the issue, we introduced a frequency-tagging speech stream where the syllabic rhythm was obscured by echoic envelopes and investigated neural encoding of hierarchical linguistic information using electroencephalography (EEG). When listeners attended to the echoic speech, cortical activity showed reliable tracking of syllable, phrase, and sentence levels, among which the higher-level linguistic units elicited more robust neural responses. When attention was diverted from the echoic speech, reliable neural tracking of the syllable level was also observed in contrast to deteriorated neural tracking of the phrase and sentence levels. Further analyses revealed that the envelope aligned with the syllabic rhythm could be recovered from the echoic speech through a neural adaptation model, and the reconstructed envelope yielded higher predictive power for the neural tracking responses than either the original echoic envelope or anechoic envelope. Taken together, these results suggest that neural adaptation and attentional modulation jointly contribute to neural encoding of linguistic information in distorted speech where the syllabic rhythm is obscured by echoes.
RESUMO
Normal aging is accompanied by changes in brain structure and function associated with cognitive decline. Structural and functional abnormalities, particularly the prefrontal cortex (PFC) and subcortical regions, contributed to cognitive aging. However, it remains unclear how the synchronized changes in structure and function of individual brain regions affect the cognition in aging. Using 3D T1-weighted structural data and movie watching functional magnetic resonance imaging data in a sample of 422 healthy individuals (ages from 18 to 87 years), we constructed regional structure-function coupling (SFC) of cortical and subcortical regions by quantifying the distribution similarity of gray matter volume (GMV) and amplitude of low-frequency fluctuation (ALFF). Further, we investigated age-related changes in SFC and its relationship with cognition. With aging, increased SFC localized in PFC, thalamus and caudate nucleus, decreased SFC in temporal cortex, lateral occipital cortex and putamen. Moreover, the SFC in the PFC was associated with executive function and thalamus was associated with the fluid intelligence, and partially mediated age-related cognitive decline. Collectively, our results highlight that tighter structure-function synchron of the PFC and thalamus might contribute to age-related cognitive decline, and provide insight into the substrate of the thalamo-prefrontal pathway with cognitive aging.
RESUMO
Objective: Given the limited evidence on the relationship between the triglyceride-glucose (TyG) index and the risk of prediabetes among young adults, our study aimed to investigate the potential impact of the TyG index on the future development of prediabetes in young individuals. Methods: This retrospective cohort study included 125,327 healthy adults aged 20 to 45 years. We utilized Cox proportional hazards regression models, combined with cubic spline functions and smooth curve fitting, to assess the relationship between baseline TyG index and the risk of prediabetes among young adults, exploring its non-linear association. A series of sensitivity analyses and subgroup analyses were conducted to ensure the robustness of our findings. Results: After adjusting for covariates, the study found a positive correlation between the TyG index and the risk of prediabetes (HR=1.81, 95%CI: 1.54-2.13, p<0.0001). The risk of prediabetes increased progressively across quartiles of the TyG index (Q1 to Q4), with Q4 showing a significantly higher risk compared to Q1 (adjusted HR=2.33, 95% CI=1.72-3.16). Moreover, a non-linear relationship was identified between the TyG index and the risk of prediabetes, with an inflection point at 9.39. To the left of the inflection point, the HR was 2.04 (95% CI: 1.69 to 2.46), while to the right, the HR was 0.89 (95% CI: 0.48 to 1.65). Conclusion: Our study reveals a non-linear relationship and a saturation effect between the TyG index and the development of prediabetes among young individuals in China, with an inflection point at 9.39. Understanding this non-linear relationship can assist clinicians in identifying young individuals at high risk and implementing targeted interventions to reduce their risk of progressing to diabetes.
Assuntos
Glicemia , Estado Pré-Diabético , Triglicerídeos , Humanos , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/diagnóstico , Estudos Retrospectivos , Adulto , Feminino , Masculino , Adulto Jovem , Glicemia/análise , China/epidemiologia , Triglicerídeos/sangue , Fatores de Risco , Pessoa de Meia-Idade , Estudos de Coortes , Seguimentos , População do Leste AsiáticoRESUMO
RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from cancer patients, but not in other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
RESUMO
The herbaceous peony (Paeonia lactiflora Pall.) plant is world-renowned for its ornamental, medicinal, edible, and oil values. As global warming intensifies, its growth and development are often affected by high-temperature stress, especially in low-latitude regions. Superoxide dismutase (SOD) is an important enzyme in the plant antioxidant systems and plays vital roles in stress response by maintaining the dynamic balance of reactive oxygen species (ROS) concentrations. To reveal the members of then SOD gene family and their potential roles under high-temperature stress, we performed a comprehensive identification of the SOD gene family in the low-latitude cultivar 'Hang Baishao' and analyzed the expression patterns of SOD family genes (PlSODs) in response to high-temperature stress and exogenous hormones. The present study identified ten potential PlSOD genes, encoding 145-261 amino acids, and their molecular weights varied from 15.319 to 29.973 kDa. Phylogenetic analysis indicated that PlSOD genes were categorized into three sub-families, and members within each sub-family exhibited similar conserved motifs. Gene expression analysis suggested that SOD genes were highly expressed in leaves, stems, and dormancy buds. Moreover, RNA-seq data revealed that PlCSD1-1, PlCSD3, and PlFSD1 may be related to high-temperature stress response. Finally, based on the Quantitative Real-time PCR (qRT-PCR) results, seven SOD genes were significantly upregulated in response to high-temperature stress, and exogenous EBR and ABA treatments can enhance high-temperature tolerance in P. lactiflora. Overall, these discoveries lay the foundation for elucidating the function of PlSOD genes for the thermotolerance of herbaceous peony and facilitating the genetic breeding of herbaceous peony cultivars with strong high-temperature resistance.
RESUMO
Constructing van der Waals (vdW) heterostructures is a prospective approach that is essential for developing a new generation of functional two-dimensional (2D) materials and designing new conceptual nanodevices. Using density-functional theory combined with a nonequilibrium Green's function approach allows for the theoretical and systematic exploration of the electronic structure, transport properties, and sensitivity of organic small molecules adsorbed on 2D C3B/graphene (Gra) and C3N/Gra vdW heterojunctions. Calculations show the metallic properties of C3B/Gra and C3N/Gra after the formation of heterojunctions. Interestingly, the heterojunctions C3B/Gra (C3N/Gra) for the adsorption of small organic molecules (C2H2, C2H4, CH3OH, CH4, and HCHO) at the C3B (C3N) side are sensitive to the chemisorption of C2H2 and C2H4. Similarly, the Gra/C3B is chemisorbed for both C2H2 and C2H4 when adsorbed on Gra side, while it is only chemisorbed for C2H2 in Gra/C3N. Interestingly, all heterojunctions on different sides are physisorbed for CH3OH, CH4, and HCHO. Furthermore, the calculated I-V curves demonstrate that the devices based on the adsorption of C2H2 and C2H4 at each side of the heterojunction have remarkable anisotropy, in with the current being considerably greater in the zigzag direction than in the armchair direction. More specifically, with C2H2 adsorbed on the Gra side, the sensitivity along the armchair direction is up to 85.0% for Gra/C3B and close to 100% for Gra/C3N. This study reveals that C3B/Gra (C3N/Gra) heterojunctions with high selectivity, high anisotropy, and excellent sensitivity are highly prospective 2D materials for applications, which further contributes new insights into the development of future electronic nanodevices.
Assuntos
Grafite , Grafite/química , Adsorção , Teoria da Densidade Funcional , Gases/química , Gases/análise , Compostos Orgânicos/química , Nitrilas/químicaRESUMO
OBJECTIVE: Dystonic posturing (DP) is a common semiology in temporal lobe epilepsy (TLE). We aimed to explore cerebellar gradient alterations in functional connectivity in TLE patients with and without DP. METHODS: Resting-state functional MRI data were obtained in 60 TLE patients and 32 matched healthy controls. Patients were further divided into two groups: TLE with DP (TLE + DP, 31 patients) and TLE without DP (TLP-DP, 29 patients). We explored functional gradient alterations in the cerebellum based on cerebellar-cerebral functional connectivity and combined with independent component analysis to evaluate cerebellar-cerebral functional integration and reveal the contribution of the motor components to the gradient. RESULTS: There were no obvious differences in clinical features and postoperative seizure outcomes between TLE + DP and TLE-DP patients. Patients and controls all showed a clear unimodal-to-transmodal gradient transition in the cerebellum, while TLE patients demonstrated an extended principal gradient in functional connectivity compared to healthy controls, which was more limited in TLE + DP patients. Gradient alterations were more widespread in TLE-DP patients, involving bilateral cerebellum, while gradient alterations in TLE + DP patients were limited in the cerebellum ipsilateral to the seizure focus. In addition, more cerebellar motor components contributed to the gradient alterations in TLE + DP patients, mainly in ipsilateral cerebellum. SIGNIFICANCE: Extended cerebellar principal gradients in functional connectivity revealed excessive functional segregation between unimodal and transmodal systems in TLE. The functional connectivity gradients were more limited in TLE + DP patients. Functional connectivity in TLE patients with dystonic posturing involved more contribution of cerebellar motor function to ipsilateral cerebellar gradient. PLAIN LANGUAGE SUMMARY: Dystonic posturing contralateral to epileptic focus is a common symptom in temporal lobe epilepsy, and the cerebellum may be involved in its generation. In this study, we found cerebellar gradients alterations in functional connectivity in temporal lobe epilepsy patients with and without contralateral dystonic posturing. In particular, we found that TLE patients with dystonic posturing may have more limited cerebellar gradient in functional connectivity, involving more contribution of cerebellar motor function to ipsilateral cerebellar gradient. Our study suggests a close relationship between ipsilateral cerebellum and contralateral dystonic posturing.
RESUMO
Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
Assuntos
Antineoplásicos , DNA (Citosina-5-)-Metiltransferase 1 , Inibidores de Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/síntese química , Animais , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , FemininoRESUMO
BACKGROUND: Spinal cord injury (SCI) is considered a central nervous system (CNS) disorder. Nuclear factor kappa B (NF-κB) regulates inflammatory responses in the CNS and is implicated in SCI pathogenesis. The mechanism(s) through which NF-κB contributes to the neuroinflammation observed during SCI however remains unclear. METHODS: SCI rat models were created using the weight drop method and separated into Sham, SCI and SCI+NF-κB inhibitor groups (n = 6 rats per-group). We used Hematoxylin-Eosin Staining (H&E) and Nissl staining for detecting histological changes in the spinal cord. Basso-Beattie-Bresnahan (BBB) behavioral scores were utilized for assessing functional locomotion recovery. Mouse BV2 microglia were exposed to lipopolysaccharide (LPS) to mimic SCI-induced microglial inflammation in vitro. RESULTS: Inhibition of NF-κB using JSH-23 alleviated inflammation and neuronal injury in SCI rats' spinal cords, leading to improved locomotion recovery (p < 0.05). NF-κB inhibition reduced expression levels of CD86, interleukin-6 (IL-6), IL-1ß, and inducible Nitric Oxide Synthase (iNOS), and improved expression levels of CD206, IL-4, and tissue growth factor-beta (TGF-ß) in both LPS-treated microglia and SCI rats' spinal cords (p < 0.05). Inhibition of NF-κB also effectively suppressed mitochondrial fission, evidenced by the reduced phosphorylation of dynamin-related protein 1 (DRP1) at Ser616 (p < 0.001). CONCLUSION: We show that inhibition of the NF-κB/DRP1 axis prevents mitochondrial fission and suppresses pro-inflammatory microglia polarization, promoting neurological recovery in SCI. Targeting the NF-κB/DRP1 axis therefore represents a novel approach for SCI.
Assuntos
Dinaminas , Microglia , NF-kappa B , Traumatismos da Medula Espinal , Animais , Masculino , Camundongos , Ratos , Linhagem Celular , Polaridade Celular/efeitos dos fármacos , Modelos Animais de Doenças , Dinaminas/metabolismo , Dinaminas/genética , Inflamação/metabolismo , Lipopolissacarídeos , Locomoção/efeitos dos fármacos , Microglia/metabolismo , Microglia/efeitos dos fármacos , Neuroproteção , NF-kappa B/metabolismo , Quinazolinonas , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologiaRESUMO
Sexual motivation refers to the intensity of willingness to have sex with or near a potential partner and is important for sexual health. At present, low sexual desire has become an increasingly prominent social problem, and there are no unified standards for its detection and evaluation. In this paper, we systematically sorted out the commonly used methods for detecting sexual motivation in male rats, including the three major categories of male-female mating, competitive selection and task acquisition, and discussed the relevant evaluation indexes and the advantages and disadvantages of various methods. We also explored the nature of sexual motivation, elaborated sexual contact behavior as a direct manifestation of sexual motivation, and proposed focusing relevant studies on contact behaviors and differentiating sexual proximity from social proximity.
Assuntos
Motivação , Comportamento Sexual Animal , Animais , Ratos , Masculino , FemininoRESUMO
The study elucidates that the pH shifting treatment unfolds the conformation of soybean protein isolate (SPI), enabling it to intertwine with bacterial cellulose (BC) and form SPI/BC co-assemblies. Results from intrinsic fluorescence spectroscopy and surface hydrophobicity indicate that the SPI with pH shifting treatment shows a notable blue shift in maximum emission wavelength and increased surface hydrophobicity. It demonstrates that pH shifting treatment facilitates the unfolding of SPI's molecular conformation, promoting its entanglement with high aspect ratio BC. Particle size distribution and microstructural analysis further demonstrate that the pH shifting treatment facilitates the formation of SPI/BC co-assemblies. Evaluation of processing properties reveals that the SPI/BC co-assemblies exhibited exceptional gel and emulsification properties, with gel strength and emulsifying activity respectively six and two times higher than natural SPI. This enhancement is attributed to the thickening properties of BC with a high aspect ratio and the superior hydrophobicity of SPI in its molten globule state.
Assuntos
Celulose , Glycine max , Interações Hidrofóbicas e Hidrofílicas , Proteínas de Soja , Proteínas de Soja/química , Celulose/química , Concentração de Íons de Hidrogênio , Glycine max/química , Tamanho da Partícula , Emulsões/químicaRESUMO
BACKGROUND: Osteoarthritis (OA) is a chronic and degenerative joint disease that remains a great challenge in treatment due to the lack of effective therapies. 4-octyl itaconate (4-OI) is a novel and potent modulator of inflammation for the treatment of inflammatory disease. However, the clinical usage of 4-OI is limited due to its poor solubility and low bioavailability. As a promising drug delivery strategy, injectable hydrogels offers an effective approach to address these limitations of 4-OI. OBJECTIVE: The aim of the study was to verify that the composite 4-OI/SA hydrogels could achieve a controlled release of 4-OI and reduce damage to articular cartilage in the group of osteoarthritic rats treated with the system. METHODS: In this study, an injectable composite hydrogel containing sodium alginate (SA) and 4-octyl itaconate (4-OI) has been developed for continuous intra-articular administration in the treatment of OA. RESULTS: After intra-articular injection in arthritic rats, the as-prepared 4-OI/SA hydrogel containing of 62.5 µM 4-OI effectively significantly reduced the expression of TNF-α, IL-1ß, IL-6 and MMP3 in the ankle fluid. Most importantly, the as-prepared 4-OI/SA hydrogel system restored the morphological parameters of the ankle joints close to normal. CONCLUSION: 4-OI/SA hydrogel shows a good anti-inflammatory activity and reverse cartilage disruption, which provide a new strategy for the clinical treatment of OA.