RESUMO
Plant parasitic nematodes (PPNs) pose a significant threat to global crop productivity, causing an estimated annual loss of US $157 billion in the agriculture industry. While synthetic chemical nematicides can effectively control PPNs, their overuse has detrimental effects on human health and the environment. Biocontrol agents (BCAs), such as bacteria and fungi in the rhizosphere, are safe and promising alternatives for PPNs control. These BCAs interact with plant roots and produce extracellular enzymes, secondary metabolites, toxins, and volatile organic compounds (VOCs) to suppress nematodes. Plant root exudates also play a crucial role in attracting beneficial microbes toward infested roots. The complex interaction between plants and microbes in the rhizosphere against PPNs is mostly untapped which opens new avenues for discovering novel nematicides through multi-omics techniques. Advanced omics approaches, including metagenomics, transcriptomics, proteomics, and metabolomics, have led to the discovery of nematicidal compounds. This review summarizes the status of bacterial and fungal biocontrol strategies and their mechanisms for PPNs control. The importance of omics-based approaches for the exploration of novel nematicides and future directions in the biocontrol of PPNs are also addressed. The review highlighted the potential significance of multi-omics techniques in biocontrol of PPNs to ensure sustainable agriculture.
RESUMO
Over the last decade, accumulating evidence has suggested that tumor-associated macrophages (TAMs) play a significant role in the tumor development. This commentary wishes to highlight the findings by You, et al. that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma (OSCC) via the IL6/Stat3/THBS1 feedback loop. These unprecedented findings identified M1-like TAMs-regulated processes as potentially tumor-promotion in the context of OSCC immunomicroenvironment.
Assuntos
Macrófagos , Neoplasias Bucais , Humanos , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Carcinogênese/imunologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/imunologia , AnimaisRESUMO
MicroRNA-33b (miR-33b) affected various biological pathways in regulating cholesterol homeostasis which may link to the pathogenesis of atherosclerotic lesions. However, whether this marker is associated with the presence and severity of coronary heart disease (CHD) is undetermined. We aim to explore the diagnostic value of circulating miR-33b level in the presence and severity of CHD. Altogether 320 patients were enrolled, including 240 patients diagnosed with CHD while 80 were classified as controls after CAG examination. Circulating miR-33b level was analyzed in all subjects, the Gensini score was calculated to assess the severity of stenotic lesions. The association between miR-33b and the presence and severity of CHD was analyzed, and the diagnostic potential of miR-33b of CHD was performed by the receiver operating characteristic (ROC) analysis. The CHD group had higher miR-33b levels (p < 0.001), and the miR-33b content significantly elevated following an increasing Gensini score (p for trend < 0.001). After adjustments for potential risk factors, such as several blood lipid markers, miR-33b remained a significant determinant for CHD (p < 0.001). ROC analysis disclosed that the AUC was 0.931. The optimal cutoff value of miR-33b was with a sensitivity of 81.3% and a specificity of 98.7% in differentiating CHD. It can prognosticate that the higher level of miR-33b was linked to increased severity of disease in CHD patients. Thus, the application of this marker might assist in the diagnosis and classification of CHD patients. Nevertheless, additional studies with larger sample sizes will be required to verify these results.
Assuntos
Biomarcadores , Doença das Coronárias , MicroRNAs , Curva ROC , Índice de Gravidade de Doença , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Doença das Coronárias/sangue , Doença das Coronárias/genética , Doença das Coronárias/diagnóstico , MicroRNAs/sangue , Fatores de RiscoRESUMO
A series of ß-carboline derivatives were designed and synthesized by introducing the chalcone moiety into the harmine. The synthesized derivatives were evaluated their anti-proliferative activities against six human cancer cell lines (MCF-7, MDA-MB-231, HepG2, HT29, A549, and PC-3) and one normal cell line (L02). Among them, compound G11 exhibited the potent anti-proliferative activity against MCF-7 cell line, with an IC50 value of 0.34 µM. Further biological studies revealed that compound G11 inhibited colony formation of MCF-7 cells, suppressed MCF-7 cell migration by downregulating migration-associated protein MMP-2. In addition, it could induce apoptosis of MCF-7 cells by downregulating Bcl-2 and upregulating Cleaved-PARP, Bax, and phosphorylated Bim proteins. Furthermore, compound G11 can act as a Topo I inhibitor, affecting DNA synthesis and transcription, thereby inhibiting cancer cell proliferation. Moreover, compound G11 inhibited tumor growth in 4T1 syngeneic transplant mice with an inhibition rate of 43.19 % at a dose of 10 mg/kg, and 63.87 % at 20 mg/kg, without causing significant toxicity to the mice or their organs, achieving the goal of reduced toxicity and increased efficacy. All these results indicate of G11 has enormous potential as an anti-tumor agent and merits further investigation.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Harmina/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Antineoplásicos/farmacologia , Células MCF-7 , Proliferação de Células , Apoptose , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
Plants are constantly exposed to various phytopathogens such as fungi, Oomycetes, nematodes, bacteria, and viruses. These pathogens can significantly reduce the productivity of important crops worldwide, with annual crop yield losses ranging from 20% to 40% caused by various pathogenic diseases. While the use of chemical pesticides has been effective at controlling multiple diseases in major crops, excessive use of synthetic chemicals has detrimental effects on the environment and human health, which discourages pesticide application in the agriculture sector. As a result, researchers worldwide have shifted their focus towards alternative eco-friendly strategies to prevent plant diseases. Biocontrol of phytopathogens is a less toxic and safer method that reduces the severity of various crop diseases. A variety of biological control agents (BCAs) are available for use, but further research is needed to identify potential microbes and their natural products with a broad-spectrum antagonistic activity to control crop diseases. This review aims to highlight the importance of biocontrol strategies for managing crop diseases. Furthermore, the role of beneficial microbes in controlling plant diseases and the current status of their biocontrol mechanisms will be summarized. The review will also cover the challenges and the need for the future development of biocontrol methods to ensure efficient crop disease management for sustainable agriculture.
Assuntos
Nematoides , Praguicidas , Animais , Humanos , Produtos Agrícolas , Bactérias , Agricultura , Doenças das Plantas/prevenção & controle , Doenças das Plantas/microbiologiaRESUMO
OBJECTIVE: To investigate the influencing factors of ultrasound-guided HIFU (USgHIFU) ablation for adenomyosis with a non-perfused volume ratio (NPVR)≥50%. METHODS: A total of 299 patients with adenomyosis who underwent USgHIFU ablation were enrolled. Quantitative signal intensity (SI) analysis was performed on T2WI and dynamic enhancement type. The energy efficiency factor (EEF) was defined as the ultrasound energy delivered for ablating 1 mm3 of tissue. NPVR ≥ 50% was used as the criterion for technical success. Adverse effects and complications were recorded. Logistic regression analyses of variables were conducted to identify the factors affecting NPVR ≥ 50%. RESULTS: The median NPVR was 53.5% (34.7%). There were 159 cases in the NPVR ≥ 50% group and 140 cases in the NPVR < 50% group. The EEF in NPVR < 50.0% group was significantly higher than that in NPVR ≥ 50% group (p < 0.05). The incidence of intraoperative adverse effects and postoperative adverse events in the NPVR < 50% group were higher than those in the NPVR ≥ 50% group (p < 0.05 for both). Logistic regression analysis showed that abdominal wall thickness, SI difference on T2WI between adenomyosis and rectus abdominis, and enhancement type on T1WI were protective factors for NPVR ≥ 50% (p < 0.05), while the history of childbirth was an independent risk factor (p < 0.001). CONCLUSIONS: Compared with NPVR < 50%, NPVR ≥ 50% did not increase the intraprocedural and postprocedural adverse reactions. The possibility of NPVR ≥ 50% was higher in patients with thinner abdominal walls, showed slight enhancement of adenomyosis on T1WI, with a history of childbirth, or in whom the SI difference on T2WI between adenomyosis and rectus abdominis was more minor.
Assuntos
Adenomiose , Ablação por Ultrassom Focalizado de Alta Intensidade , Feminino , Gravidez , Humanos , Adenomiose/diagnóstico por imagem , Adenomiose/cirurgia , Ablação por Ultrassom Focalizado de Alta Intensidade/efeitos adversos , Ultrassonografia , Fatores de Risco , Parto Obstétrico , Resultado do Tratamento , Imageamento por Ressonância Magnética , Estudos RetrospectivosRESUMO
The Rho kinase inhibitor fasudil exerts neuroprotective effects. We previously showed that fasudil can regulate M1/M2 microglia polarization and inhibit neuroinflammation. Here, the therapeutic effect of fasudil on cerebral ischemiareperfusion (I/R) injury was investigated using the middle cerebral artery occlusion and reperfusion (MCAO/R) model in SpragueDawley rats. The effect of fasudil on the phenotype of microglia and neurotrophic factors in the I/R brain and its potential molecular mechanism was also explored. It was found that fasudil ameliorated neurological deficits, neuronal apoptosis, and inflammatory response in rats with cerebral I/R injury. Fasudil also promoted the polarization of microglia into the M2 phenotype, in turn promoting the secretion of neurotrophic factors. Furthermore, fasudil significantly inhibited the expression of TLR4 and NFκB. These findings suggest that fasudil could inhibit the neuroinflammatory response and reduce brain injury after I/R injury by regulating the shift of microglia from an inflammatory M1 phenotype to an antiinflammatory M2 phenotype, which may be related to the regulation of the TLR4/ NFκB signal pathway.
Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Ratos , Animais , Ratos Sprague-Dawley , NF-kappa B/metabolismo , NF-kappa B/farmacologia , NF-kappa B/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fatores de Crescimento Neural/farmacologia , Microglia/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
The distribution range of root-knot nematode Meloidogyne graminicola is rapidly expanding, posing a severe threat to rice production. In this study, the sequences of cytochrome oxidase subunit I (COI) genes of rice M. graminicola populations from all reported provinces in China were amplified and sequenced by PCR. The distribution pattern and phylogenetic tree showed that all 54 M. graminicola populations in China have distinct geographical distribution characteristics; specifically, cluster 1 (southern China), cluster 2 (central south and southwest China), and cluster 3 (central and eastern China). The high haplotype diversity (Hd = 0.646) and low nucleotide diversity (π = 0.00682), combined with the negative value of Tajima's D (-1.252) and Fu's Fs (-3.06764), suggested that all nematode populations were expanding. The existence of high genetic differentiation (Fst = 0.5933) and low gene flow (Nm = 0.3333) indicated that there was a block of gene exchange between most populations. Mutation accumulation with population expansion might be directly responsible for the high genetic differentiation; therefore, the tested nematode population showed high within-group genetic variation (96.30%). The haplotype Hap8 was located at the bottom of the network topology, with the widest distribution and the highest frequency (59.26%), indicating that it was the ancestral haplotype. The populations in cluster 3 were newly invasive according to the lowest frequency of occurrence of Hap8, the highest number of endemic haplotypes, and the highest total haplotype frequency (60%). In contrast, cluster 1 having the highest genetic diversity (Hd = 0.772, π = 0.01127) indicated that it was the most primitive. Interestingly, the highest gene flow (Nm > 1), lowest genetic differentiation (Fst ≤ 0.33), and closest genetic distance (0.000) only occurred between the Guangdong/Hainan population and others, which suggested that there might be channels for gene exchange between them and that long-distance dispersal occurred. This suggestion is further confirmed by the weak correlation between genetic distance and geographical distance. Based on these data, a hypothesis can be drawn that M. graminicola populations in China were spreading from south to north, specifically from Guangdong and Hainan Provinces to other regions. Natural selection (including anthropogenic) and genetic drift were the main drivers of their evolution. Coincidentally, this hypothesis was consistent with the gradual warming trend and the chronological order of reporting these populations. The main factors influencing current M. graminicola population expansion and distribution patterns might be geography, climate, long-distance seedling transport, interregional operations of agricultural machinery, and rotation mode. It reminds human beings of the necessity to be vigilant about preventing nematode disease according to local conditions all year round.
Assuntos
Oryza , Tylenchoidea , Animais , Humanos , Filogenia , Tylenchoidea/genética , Geografia , Deriva Genética , ChinaRESUMO
OBJECTIVE: To observe the effect of acupuncture on microglia polarization and inflammatory reaction in rats with cerebral ischemia-reperfusion injury (CIRI), so as to explore its mechanisms underlying improvement of CIRI. METHODS: Thirty male SD rats were randomly divided into sham operation, model, and acupuncture groups, with 10 rats in each group. The CIRI model was established by occlusion of the middle cerebral artery (MCAO) for 1 h, followed by reperfusion. After modeling, rats in the acupuncture group received manual acupuncture stimulation of "Dazhui" (GV14), "Baihui"(GV20), "Shuigou" (GV26), bilateral "Zusanli" (ST36) and "Fengchi" (GB20) by twirling the needles rapidly for 10 s/acupoint every 10 min, with the needles retained for 20 min. The treatment was conducted once daily for successive 7 days. The neurological function was evaluated according to Longa's method. The state of CIRI was observed after Nissl staining, and the expression levels of Iba-1, iNOS, Arg1, BDNF, GDNF and NeuN in the ischemic cortex tissue were detected by immunofluorescence staining. The contents of TNF-α, IL-6 and IL-10 in the ischemic tissue were assayed by ELISA. The protein expression levels of BDNF, GDNF, TLR4, MyD88 and NF-κB in the ischemic tissues were detected by Western blot. RESULTS: The neurological deficit score on the 24 h and 7th day was considerably higher in the model group than in the sham operation group (P<0.01), and evidently lower on the 7th day in the acupuncture group than in the model group (P<0.01). The number of NeuN positive cellsï¼the area of immunofluorescence dual labelling of Arg1, BDNF and GDNF positive staining, IL-10 content, BDNF and GDNF protein expressions were significantly decreased (P<0.01), and the immunofluorescence dual labelling area of Iba-1 and iNOS, TNF-α and IL-6 contents, the pretein expression levels of TLR4, MyD88 and NF-κB considerably increased (P<0.01) in the model group relevant to the sham operation group. In contrast to the model group, the acupuncture group had a significant increase in the number of NeuN positive cells, the immunofluorescence dual labelling area of Arg1, BDNF and GDNF positive staining, IL-10 content, and BDNF and GDNF protein expressions (P<0.05, P<0.01), and an evident decrease in Iba-1 and iNOS positive staining, contents of TNF-α and IL-6, and the protein expression levels of TLR4, MyD88 and NF-κB (P<0.01, P<0.05). Nissl staining showed a marked reduction in the number of neurons, the nucleus pyknosis and nissl bodies and loose arrangement of the neuronal cells in the model group, which was relatively milder in the acupuncture group. CONCLUSION: Acupuncture intervention can improve neurological function in CIRI rats, which may be related to its effects in regulating the polarization of microglia, reducing inflammatory reaction and increasing the secretion of neurotrophic factors in the brain, inhibiting TLR4/MyD88/NF-κB signaling pathway.
Assuntos
Terapia por Acupuntura , Traumatismo por Reperfusão , Masculino , Animais , Ratos , Ratos Sprague-Dawley , Interleucina-10/genética , Microglia , NF-kappa B/genética , Fator de Necrose Tumoral alfa , Fator Neurotrófico Derivado do Encéfalo , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Interleucina-6 , Fator 88 de Diferenciação Mieloide/genética , Receptor 4 Toll-Like/genética , Infarto Cerebral , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/terapiaRESUMO
Objective: To explore the influencing factors of decision-making in patients with adenomyosis, who are receiving high-intensity focused ultrasound (HIFU) treatment. Methods: A total of 776 patients with adenomyosis were enrolled into HIFU group (241 cases) and hysterectomy group (535 cases) according to the treatment methods. The general data, clinical symptoms, marital and childbearing history, and economic status were compared between the two groups, and factors with P < 0.05 were introduced into multivariate logistic regression analysis to determine the determinants of patients choosing HIFU. Results: The average age of the patients in the HIFU group was 39.1 ± 5.2 years, which was lower than that in the hysterectomy group, which was 45.1 ± 3.9 years (P < 0.05). The basic medical insurance for urban workers in the HIFU group was more than the hysterectomy group (P < 0.05). 95.9% of the hysterectomy group had no desire to have children, compared to 60.6% of the HIFU group, the difference was significant (P < 0.05). The treatment costs of HIFU group were significantly lower than that of hysterectomy group (P < 0.05). The main symptoms of the two groups were dysmenorrhea, menorrhagia, and secondary anemia. The results of multivariate logistic regression analysis showed that 31-40 years old, fertility desire, dysmenorrhea, menorrhagia, anemia and dizziness and fatigue were the influencing factors for the decision-making of HIFU for patients with adenomyosis. Conclusion: 31-40 years old, fertility desire, dysmenorrhea, menorrhagia, anemia and dizziness and fatigue were the influencing factors for patients to choose HIFU treatment. HIFU therapy has emerged as a new option for patients with adenomyosis as an alternative to hysterectomy.
RESUMO
Objective: To compare the therapeutic effect of high-intensity focused ultrasound (HIFU) ablation and HIFU pretreated with gonadotropin-releasing hormone analogue (GnRH-a) in the treatment of hyperintense uterine fibroids on T2-weighted magnetic resonance imaging (T2WI) by using propensity score matching. Materials and methods: 339 women with 368 hyperintense uterine fibroids on T2WI who underwent single-session HIFU ablation were enrolled, including 283 patients with 303 fibroids in the single-session HIFU (sHIFU) group and 56 patients with 65 fibroids in the HIFU pretreated with GnRH-a (Gn-HIFU) group. The signal intensity (SI) value and standard deviation (SD) value were measured based on T2WI, and the fibroids were further subdivided into heterogeneous hyperintense fibroids, slightly homogeneous hyperintense fibroids and markedly homogeneous hyperintense fibroids as 3 subgroups (HHF, sHHF and mHHF group respectively). Treatment time, sonication time, dose, non-perfused volume (NPV), NPV per sonication time, non-perfused volume ratio (NPVR), energy effect ratio (EEF) and adverse events were recorded. Results: Out of 339 patients, the median NPVR was 75.2% (interquartile range,31.5%). After propensity score matching, the matched cohort included 91 (64.5%) patients in the sHIFU group and 48 (34.5%) patients in the Gn-HIFU group. The NPVR of sHHF in the Gn-HIFU group had significantly smaller than that in the sHIFU group (60.2% versus 74.9%, p = 0.005), and the NPVR of HHF in the Gn-HIFU group was higher than those in the sHIFU group (87.4% versus 72.9%, p = 0.002). Conclusions: Compared with HIFU alone, the therapeutic efficacy of the heterogeneous hyperintense fibroids may be enhanced by GnRH-a pretreated with HIFU, however it is important to rule out the slightly homogeneous hyperintense fibroids.
RESUMO
Tumor metastasis is an important cause of tumor treatment failure. Its molecular mechanism is closely related to tumor cells remodeling immune cells and immunosuppressive microenvironment, so as to create a suitable soil for tumor cell invasion and growth. "Huoxue Huayu" is one of the important therapeutic principles in cancer treatment, but the influence of Huoxue drugs on tumor metastasis has been controversial in clinical application. In this paper, we systematically summarized the comparative study of Huoxue drugs and Yiqi Huoxue drugs in tumor metastasis in recent years, and discussed the differences of molecular mechanisms of Huoxue drugs and Yiqi Huoxue drugs in anti-tumor metastasis from the perspective of immune remodeling, so as to provide scientific basis for clinical rational application of Huoxue drugs and Yiqi Huoxue drugs.
RESUMO
Incompatibility group C (IncC) plasmids have received attention due to their broad host range and because they harbor key antibiotic resistance genes. Because these resistance genes can spread from food-producing animals to human, the proliferation of these plasmids represents a public health risk. In this study, a total of 20 IncC plasmids were collected from food-producing animals in China, and characterized by Oxford Nanopore Technologies long-read sequencing. Based on four key differences of the IncC backbone, 4 IncC plasmids were classified as type 1, 15 were classified as type 1/2 hybrid, and one was classified as type 2. The 15 type 1/2 hybrids were further divided into 13 type 1/2a and 2 type 1/2b, based on sequence differences arising from different homologous recombination events between type 1 and type 2 IncC backbones. Genome comparison of accessory resistance modules showed that different IncC plasmids exhibited various phenotypes via loss and gain of diverse modules, mainly within the bla CMY -carrying region, and two antibiotic resistance islands designated ARI-A and ARI-B. Interestingly, in addition to insertion and deletion events, IS26 or IS1294-mediated large sequence inversions were found in the IncC genome of the 4 type1/2a plasmids, suggesting that insertion sequence-mediated rearrangements also promote the diversity of the IncC genome. This study provides insight into the structural diversification and multidrug resistance of IncC plasmids identified from food-producing animals in China.
RESUMO
Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.
Assuntos
Ciclopentanos/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/uso terapêutico , Ginkgolídeos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Feminino , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Regeneração Nervosa/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The cuprizone (CPZ)-induced demyelination is a relatively reproducible animal model and has been extremely useful for identifying the specific cellular and molecular signals that regulate oligodendrocyte survival and efficiency of oligodendrogenesis and remyelination. Here, we reported the temporal and spatial dynamics of astroglial reaction and immune response in CPZ-induced demyelinating model. CPZ did not induce significant microglia and astrocyte reaction after 2 weeks of feeding. After 4-6 weeks of CPZ feeding, microglia and astrocytes were markedly migrated and accumulated in myelin sheath. Simultaneously, the expression of tight junction protein ZO-1 was declined and the infiltration of CD4+IFNγ+ and CD4+IL-17+ T cells was increased in the brain, accompanied by increased production of IFN-γ and IL-17 in the extract of brain. However, the levels of IFN-γ and IL-17 were reduced, while IL-6 and TNF-α were elevated in the supernatant of splenocytes. At the 4th and 6th weeks of feeding, CPZ caused astrocyte activation and upregulated the expression of BDNF, CNTF, and IGF-II, providing a neurotrophic microenvironment in the brain. At this stage, NG2+ and PDGF-Rα+ oligodendroglia progenitor cells were enhanced in the corpus callosum, but the myelin sheath is still severely lost. Therefore, targeting microglia to improve the inflammatory microenvironment should contribute to the remyelination.
Assuntos
Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Animais , Astrócitos/imunologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/imunologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/efeitos dos fármacos , Linfócitos T/efeitos dos fármacosRESUMO
AIM: Multiple sclerosis (MS) is a relapsing-remitting inflammatory demyelinating disease that requires long-term treatment. Although Rho kinase inhibitor Fasudil shows good therapeutic effect in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, certain side effects may limit its clinical use. This study aimed at observing the therapeutic potential of Fasudil-modified encephalitogenic mononuclear cells (MNCs) via nasal delivery in EAE and exploring possible mechanisms of action. METHODS: Experimental autoimmune encephalomyelitis was induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice, and encephalitogenic MNCs were treated with Fasudil in vitro. Mice received 3 × 106 cells/10 µL per nasal cavity on day 3 and 11 postimmunization, respectively. RESULTS: Fasudil-modified MNCs reduced clinical severity of EAE, improved demyelination, and decreased inflammatory cells in spinal cords. Immunohistochemical results indicated that CD4+ T cells and CD68+ macrophages were barely detected in Fasudil-MNCs group. Fasudil-modified MNCs decreased CD4+ IFN-γ+ and CD4+ IL-17+ T cells, increased CD4+ IL-10+ T cells, restrained M1 markers CD16/32, CCR7, IL-12, CD8a, enhanced M2 markers CD206, CD200, CD14 in spleen. Fasudil-modified MNCs inhibited the activation of inflammatory signaling p-NF-kB/P38, accompanied by the decrease of COX-2 and the increase of Arg-1 in spinal cord, as well as the reduction of IL-17, TNF-α, IL-6 and the elevation of IL-10 in cultured supernatant of splenocytes. Fasudil-modified MNCs enhanced the levels of neurotrophic factors BDNF and NT-3 in spinal cord. CONCLUSION: Our results indicate that intranasal delivery of Fasudil-modified MNCs have therapeutic potential in EAE, providing a safe and effective cell therapeutic strategy to MS and/or other related disorders.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Encefalomielite Autoimune Experimental/terapia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Administração Intranasal , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/transplante , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Inibidores de Proteínas Quinases/farmacologia , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination, neuroinflammation and oligodendrocyte loss. The cuprizone (CPZ) model is characterized by primary and reversible demyelination, accompanied by oligodendrocyte loss and neuroinflammation. In the current study, we explored the efficiency of Bilobalide in the demyelination and remyelination. The results demonstrate that Bilobalide improved behavioral abnormality and promoted remyelination in the corpus callosum by using Luxol Fast Blue, Black Gold II and myelin basic protein (MBP) staining. We for the first time found that CPZ caused the splenic atrophy and induced the formation of myelin oligodendrocyte glycoprotein (MOG) antibody, which was attenuated by Bilobalide. Thus, Bilobalide decreased the loss of O4+ oligodendrocytes possibly through MOG antibody-dependent cell cytotoxicity. Bilobalide also prevented the infiltration of CD4+ T cells, CD68+ macrophages and B220+ B cells within the brain, and reduced the inflammatory microenvironment mediated with Iba1+iNOS+ and Iba1+NF-kB+ microglia after CPZ challenge, accompanied by the inhibition of IL-1ß and IL-6 in the brain. These results identify a potent therapeutic efficiency for Bilobalide and highlight clear pleiotropic effects of the compound beyond specific autoantibody and inflammatory microenvironment in CPZ-mediated demyelination.
Assuntos
Corpo Caloso/efeitos dos fármacos , Ciclopentanos/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Furanos/uso terapêutico , Ginkgolídeos/uso terapêutico , Inflamação/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oligodendroglia/efeitos dos fármacos , Animais , Autoanticorpos/sangue , Comportamento Animal , Corpo Caloso/fisiologia , Cuprizona , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Humoral/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Oligodendroglia/fisiologiaRESUMO
The synthesis of ultrathin metal nanosheets (NSs) attracts broad scientific and technological interest, and it still remains a challenge for non-noble metals like nickel due to their intrinsic cubic symmetry and high surface energy. Herein, we report a NiO intermediated solvothermal method towards the synthesis of ultrathin Ni NSs (thickness < 3 nm) using N,N-dimethylformamide as the solvent and n-butylamine as the shape controlling reagent. The growth of the ultrathin Ni NSs follows an intermediate mechanism which was proved by the results obtained by means of transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray absorption spectra (XAS) and X-ray photoelectron spectroscopy (XPS). Under solvothermal conditions, the nickel acetylacetonate precursor was first reduced to a NiO NS intermediate, then reduction occurred and NiO NSs were reduced to Ni NSs. The synthesized ultrathin Ni NSs predominately in a metallic state showed high selectivity (88.0-92.0%) towards styrene (ST) in the phenylacetylene (PA) semihydrogenation reaction under mild conditions (323 K, 1 atm of hydrogen) in a broad PA conversion range (2.0-98.0%). The low coverage of oxygen atoms on the Ni NS surface is proposed to account for the high ST selectivity, as indicated by density functional theory (DFT) calculations.