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Patients with neuropsychiatric disorders often exhibit a combination of clinical symptoms such as autism, epilepsy, or schizophrenia, complicating diagnosis and development of therapeutic strategies. Functional studies of novel genes associated with co-morbidities can provide clues to understand the pathogenic mechanisms and interventions. NOMO1 is one of the candidate genes located at 16p13.11, a hotspot of neuropsychiatric diseases. Here, we generate nomo1-/- zebrafish to get further insight into the function of NOMO1. Nomo1 mutants show abnormal brain and neuronal development and activation of apoptosis and inflammation-related pathways in the brain. Adult Nomo1-deficient zebrafish exhibit multiple neuropsychiatric behaviors such as hyperactive locomotor activity, social deficits, and repetitive stereotypic behaviors. The Habenular nucleus and the pineal gland in the telencephalon are affected, and the melatonin level of nomo1-/- is reduced. Melatonin treatment restores locomotor activity, reduces repetitive stereotypic behaviors, and rescues the noninfectious brain inflammatory responses caused by nomo1 deficiency. These results suggest melatonin supplementation as a potential therapeutic regimen for neuropsychiatric disorders caused by NOMO1 deficiency.
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Transtorno Autístico , Melatonina , Animais , Adulto , Humanos , Peixe-Zebra/genética , Transtorno Autístico/genética , EncéfaloRESUMO
MicroRNA (miRNA), functioning as a post-transcriptional regulatory element, plays a significant role in numerous regulatory mechanisms and serves as a crucial intrinsic factor influencing axon regeneration. Prior investigations have elucidated the involvement of miRNA-9 in various processes, however, its specific contribution to axon regeneration in the central nervous system (CNS) remains uncertain. Hence, the zebrafish Mauthner axon regeneration model was employed to manipulate the expression of miRNA-9 in single cells, revealing that upregulation of miRNA-9 facilitated axon regeneration. Additionally, her6, a downstream target gene of miRNA-9, was identified as a novel gene associated with axon regeneration. Suppression of her6 resulted in enhanced Mauthner axon regeneration, as evidenced by the significantly improved regenerative capacity observed in her6 knockout zebrafish. In addition, modulation of her6 expression affects intracellular calcium levels in neurons and promoting her6 expression leads to a decrease in calcium levels in vivo using the new NEMOf calcium indicator. Moreover, the administration of the neural activity activator, pentylenetetrazol (PTZ) partially compensated for the inhibitory effect of her6 overexpression on the calcium level and promoted axon regeneration. Taken together, our study revealed a role for miRNA-9 in the process of axon regeneration in the CNS, which improved intracellular calcium activity and promoted axon regeneration by inhibiting the expression of downstream target gene her6. In our study, miRNA-9 emerged as a novel and intriguing target in the intricate regulation of axon regeneration and offered compelling evidence for the intricate relationship between calcium activity and the facilitation of axon regeneration.
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Cálcio , MicroRNAs , Animais , Peixe-Zebra/genética , Axônios , Regeneração Nervosa/genética , MicroRNAs/genéticaRESUMO
Malus baccata (L.) var. gracilis (Rehd.) has high ornamental value and breeding significance, and comparative chloroplast genome analysis was applied to facilitate genetic breeding for desired traits and resistance and provide insight into the phylogeny of this genus. Using data from whole-genome sequencing, a tetrameric chloroplast genome with a length of 159,992 bp and a total GC content of 36.56% was constructed. The M. baccata var. gracilis chloroplast genome consists of a large single-copy sequence (88,100 bp), a short single-copy region (19,186 bp), and two inverted repeat regions, IRa (26,353 bp) and IRb (26,353 bp). This chloroplast genome contains 112 annotated genes, including 79 protein-coding genes (nine multicopy), 29 tRNA genes (eight multicopy), and four rRNA genes (all multicopy). Calculating the relative synonymous codon usage revealed a total of 32 high-frequency codons, and the codons exhibited a biased usage pattern towards A/U as the ending nucleotide. Interspecific sequence comparison and boundary analysis revealed significant sequence variation in the vast single-copy region, as well as generally similar expansion and contraction of the SSC and IR regions for 10 analyzed Malus species. M. baccata var. gracilis and Malus hupehensis were grouped together into one branch based on phylogenetic analysis of chloroplast genome sequences. The chloroplast genome of Malus species provides an important foundation for species identification, genetic diversity analysis, and Malus chloroplast genetic engineering. Additionally, the results can facilitate the use of pendant traits to improve apple tree shape.
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Genoma de Cloroplastos , Malus , Filogenia , Melhoramento Vegetal , Códon/genéticaRESUMO
3-phosphoinositide-dependent protein kinase 1 (PDK1) exhibits a substantial influence on immune cell development by establishing a vital connection between PI3K and downstream mTOR signaling cascades. However, it remains unclear whether PDK1 signaling affects the homeostasis and functionality of immune cells. To explore the impact of PDK1 on different immune cells within immune organs, transgenic mouse strains with lymphocyte-specific PDK1 knockout (PDK1fl/fl CD2-Cre) were generated. Unlike wild-type (WT) mice, lymphocyte-specific PDK1 knockout (KO) mice exhibited thymic atrophy, elevated percentages of CD8+ T cells and neutrophils, and reduced proportions of γδ T cells, B cells, and NK cells in the spleen. Functional analysis revealed elevated release of IFN-γ and IL-17A by T cells in PDK1 KO mice, contrasting with diminished levels observed in γδ T cells and Treg cells. Furthermore, the activation, cytotoxicity, and migratory potential of γδ T cells in PDK1 KO mice are heightened, indicating a potential association with the regulation of the mTOR signaling pathway. To conclude, the findings of this research demonstrated that specific knockout of PDK1 in lymphocytes hindered T cell development in the thymus and exhibited a substantial influence on immune cell homeostasis in the spleen and lymph nodes.
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Camundongos Knockout , Timo , Animais , Camundongos , Timo/imunologia , Baço/imunologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Transdução de Sinais , Camundongos Endogâmicos C57BL , Serina-Treonina Quinases TOR/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Interleucina-17/metabolismo , Interleucina-17/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by normocytic normochromic anemia with severe reticulocytopenia and absence of erythroid precursors in the bone marrow. For refractory PRCA patients, the low response rate and high toxicity of alternative therapies pose a great challenge. T-cell large granular lymphocyte (T-LGL) leukemia is one of the most common conditions in secondary PRCA and also the most difficult form to manage with an inferior treatment response to other secondary PRCA forms. T-LGL leukemia exhibits sustained activation of the intracellular JAK-STAT signaling pathway. We herein report a case of PRCA associated with T-LGL leukemia that had been refractory to multiple lines of therapies and was successfully treated by ruxolitinib. The patient achieved complete remission and tolerated ruxolitinib well without occurrence of neutropenia or thrombocytopenia. This preliminary finding favors ruxolitinib as a potential salvage therapy for refractory PRCA associated with T-LGL leukemia.
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Leucemia Linfocítica Granular Grande , Nitrilas , Pirazóis , Pirimidinas , Aplasia Pura de Série Vermelha , Humanos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/complicações , Masculino , Pessoa de Meia-Idade , Idoso , Indução de Remissão , Terapia de SalvaçãoRESUMO
BACKGROUND: Reticuloendotheliosis virus (REV), a member of the family Retroviridae, is a hot area of research, and a previous study showed that exosomes purified from REV-positive semen were not blocked by REV-specific neutralizing antibodies and established productive infections. METHODS: To further verify the infectivity of exosomes from REV-infected cells, we isolated and purified exosomes from REV-infected DF-1 cells and identified them using Western blot and a transmission electron microscope. We then inoculated 7-day-old embryonated eggs, 1-day-old chicks and 23-week-old hens with and without antibody treatment. REV was administered simultaneously as a control. RESULTS: In the absence of antibodies, the results indicated that REV-exosomes and REV could infect chicks, resulting in viremia and viral shedding, compared with the infection caused by REV, REV-exosomes reduced the hatching rate and increased mortality after hatching, causing severe growth inhibition and immune organ damage in 1-day-old chicks; both REV and REV-exosomes also could infect hens, however, lead to transient infection. In the presence of antibodies, REV-exosomes were not blocked by REV-specific neutralizing antibodies and infected 7-day-old embryonated eggs. However, REV could not infect 1-day-old chicks and 23-week-old hens. CONCLUSION: In this study, we compared the infectious ability of REV-exosomes and REV, REV-exosomes could escape from REV-specific neutralizing antibodies in embryonated eggs, providing new insights into the immune escape mechanism of REV.
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Anticorpos Antivirais , Galinhas , Exossomos , Doenças das Aves Domésticas , Vírus da Reticuloendoteliose , Infecções por Retroviridae , Eliminação de Partículas Virais , Animais , Exossomos/virologia , Exossomos/imunologia , Anticorpos Antivirais/imunologia , Galinhas/virologia , Vírus da Reticuloendoteliose/imunologia , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/transmissão , Doenças das Aves Domésticas/imunologia , Infecções por Retroviridae/virologia , Infecções por Retroviridae/transmissão , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/veterinária , Anticorpos Neutralizantes/imunologia , Linhagem Celular , Viremia/virologia , FemininoRESUMO
Malus sieversii is a precious apple germplasm resource. Browning of explants is one of the most important factors limiting the survival rate of plant tissue culture. In order to explore the molecular mechanism of the browning degree of different strains of Malus sieversii, we compared the dynamic changes of Malus sieversii and Malus robusta Rehd. during the whole browning process using a multi-group method. A total of 44 048 differentially expressed genes (DEGs) were identified by transcriptome analysis on the DNBSEQ-T7 sequencing platform. KEGG enrichment analysis showed that the DEGs were significantly enriched in the flavonoid biosynthesis pathway. In addition, metabonomic analysis showed that (-)-epicatechin, astragalin, chrysin, irigenin, isoquercitrin, naringenin, neobavaisoflavone and prunin exhibited different degrees of free radical scavenging ability in the tissue culture browning process, and their accumulation in different varieties led to differences in the browning degree among varieties. Comprehensive transcriptome and metabonomics analysis of the data related to flavonoid biosynthesis showed that PAL, 4CL, F3H, CYP73A, CHS, CHI, ANS, DFR and PGT1 were the key genes for flavonoid accumulation during browning. In addition, WGCNA analysis revealed a strong correlation between the known flavonoid structure genes and the selected transcriptional genes. Protein interaction predictions demonstrated that 19 transcription factors (7 MYBs and 12 bHLHs) and 8 flavonoid structural genes had targeted relationships. The results show that the interspecific differential expression of flavonoid genes is the key influencing factor of the difference in browning degree between Malus sieversii and Malus robusta Rehd., providing a theoretical basis for further study on the regulation of flavonoid biosynthesis.
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Malus , Malus/genética , Malus/metabolismo , Multiômica , Flavonoides/metabolismo , Perfilação da Expressão Gênica , Transcriptoma , Regulação da Expressão Gênica de PlantasRESUMO
Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKß phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases.
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Lesão Pulmonar Aguda , Quinases Semelhantes a Duplacortina , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos/farmacologia , Proteínas Serina-Treonina Quinases , Inflamação/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológicoRESUMO
Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.
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Autoimunidade , Benzofuranos , Interleucina-2 , Fator de Transcrição STAT5 , Transdução de Sinais , Linfócitos T Reguladores , Animais , Fator de Transcrição STAT5/metabolismo , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Benzofuranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Interleucina-2/metabolismo , Autoimunidade/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Masculino , Doenças Genéticas Ligadas ao Cromossomo X , Diabetes Mellitus Tipo 1/congênito , Diarreia , Doenças do Sistema Imunitário/congênito , DepsídeosRESUMO
The AT-hook motif nuclear-localized (AHL) family is pivotal for the abiotic stress response in plants. However, the function of the cassava AHL genes has not been elucidated. Promoters, as important regulatory elements of gene expression, play a crucial role in stress resistance. In this study, the promoter of the cassava MeAHL31 gene was cloned. The MeAHL31 protein was localized to the cytoplasm and the nucleus. qRT-PCR analysis revealed that the MeAHL31 gene was expressed in almost all tissues tested, and the expression in tuber roots was 321.3 times higher than that in petioles. Promoter analysis showed that the MeAHL31 promoter contains drought, methyl jasmonate (MeJA), abscisic acid (ABA), and gibberellin (GA) cis-acting elements. Expression analysis indicated that the MeAHL31 gene is dramatically affected by treatments with salt, drought, MeJA, ABA, and GA3. Histochemical staining in the proMeAHL31-GUS transgenic Arabidopsis corroborated that the GUS staining was found in most tissues and organs, excluding seeds. Beta-glucuronidase (GUS) activity assays showed that the activities in the proMeAHL31-GUS transgenic Arabidopsis were enhanced by different concentrations of NaCl, mannitol (for simulating drought), and MeJA treatments. The integrated findings suggest that the MeAHL31 promoter responds to the abiotic stresses of salt and drought, and its activity is regulated by the MeJA hormone signal.
Assuntos
Arabidopsis , Regulação da Expressão Gênica de Plantas , Manihot , Reguladores de Crescimento de Plantas , Proteínas de Plantas , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Estresse Fisiológico , Arabidopsis/genética , Arabidopsis/metabolismo , Plantas Geneticamente Modificadas/genética , Estresse Fisiológico/genética , Manihot/genética , Manihot/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Secas , Ciclopentanos/farmacologia , Ciclopentanos/metabolismo , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Oxilipinas/farmacologia , Oxilipinas/metabolismo , Acetatos/farmacologiaRESUMO
The 2,7-fluorenone-linked bis(6-imidazo[1,5-a]pyridinium) salt H2-1(PF6)2 reacts with Ag2O in CH3CN to yield the [2]catenane [Ag4(1)4](PF6)4. The [2]catenane rearranges in DMF to yield two metallamacrocycles [Ag2(1)2](PF6)2. 2,7-Fluorenone-bridged bis-(imidazolium) salts H2-L(PF6)2 (L=2 a, 2 b) react with Ag2O in CH3CN to yield metallamacrocycles [Ag2(L)2](PF6)2 with interplanar distances between the fluorenone rings too small for [2]catenane formation. Intra- and intermolecular πâ â â π interactions between the fluorenone groups were observed by X-ray crystallography. The strongly kinked 2,7-fluorenone bridged bis(5-imidazo[1,5-a]pyridinium) salt H2-4(PF6)2 reacts with Ag2O to yield [Ag2(4)(CN)](PF6), while the tetranuclear assembly [Ag4(4)2(CO3)](PF6)2 was obtained in the presence of K2CO3.
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Precise regulation of the active site structure is an important means to enhance the activity and selectivity of catalysts in CO2 electroreduction. Here, we creatively introduce anionic groups, which can not only stabilize metal sites with strong coordination ability but also have rich interactions with protons at active sites to modify the electronic structure and proton transfer process of catalysts. This strategy helps to convert CO2 into fuel chemicals at low overpotentials. As a typical example, a composite catalyst, CuO/Cu-NSO4/CN, with highly dispersed Cu(II)-SO4 sites has been reported, in which CO2 electroreduction to formate occurs at a low overpotential with a high Faradaic efficiency (-0.5â V vs. RHE, FEformate=87.4 %). Pure HCOOH is produced with an energy conversion efficiency of 44.3 % at a cell voltage of 2.8â V. Theoretical modeling demonstrates that sulfate promotes CO2 transformation into a carboxyl intermediate followed by HCOOH generation, whose mechanism is significantly different from that of the traditional process via a formate intermediate for HCOOH production.
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Lightweight porous hydrogels provide a worldwide scope for functional soft mateirals. However, most porous hydrogels have weak mechanical strength, high density (>1 g cm-3 ), and high heat absorption due to weak interfacial interactions and high solvent fill rates, which severely limit their application in wearable soft-electronic devices. Herein, an effective hybrid hydrogel-aerogel strategy to assemble ultralight, heat-insulated, and tough polyvinyl alcohol (PVA)/SiO2 @cellulose nanoclaws (CNCWs) hydrogels (PSCG) via strong interfacial interactions with hydrogen bonding and hydrophobic interaction is demonstrated. The resultant PSCG has an interesting hierarchical porous structure from bubble template (≈100 µm), PVA hydrogels networks introduced by ice crystals (≈10 µm), and hybrid SiO2 aerogels (<50 nm), respectively. PSCG shows unprecedented low density (0.27 g cm-3 ), high tensile strength (1.6 MPa) & compressive strength (1.5 MPa), excellent heat-insulated ability, and strain-sensitive conductivity. This lightweight porous and tough hydrogel with an ingenious design provides a new way for wearable soft-electronic devices.
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Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.
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Efeito Espectador/efeitos dos fármacos , Dano ao DNA , Raios gama/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Estresse Oxidativo/efeitos da radiação , Lesões Experimentais por Radiação/metabolismo , Animais , Feminino , Células-Tronco Hematopoéticas/patologia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Lesões Experimentais por Radiação/patologiaRESUMO
Multiple triggered-release strategies are widely utilized to control the release of caged target molecules. Among them, photocages with conditional triggers provide extra layers of control in photorelease. In this work, a series of pH-responsive photocages was designed that could be triggered under irradiation and specific intracellular pH values. pH-sensitive phenolic groups were conjugated with o-nitrobenzyl (oNB) to form azo-phenolic NPX photocages with tunable pKa. These azo-phenol-based oNB photocages showed differentiable photoreleasing profiles at pHâ 5.0, 7.2 and 9.0. By attaching fluorogenic cargos, it was shown that one of the photocages, NPdiCl, could be used to differentiate between acidic pHâ 5.0 and neutral pHâ 7.2 in cells under artificial pH conditions. Finally, NPdiCl was identified as a promising pH-responsive photocage for photoreleasing cargo inside acidic tumor cells.
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Fenol , Fenóis , Concentração de Íons de Hidrogênio , Compostos Azo/químicaRESUMO
Proton pump inhibitors (PPIs) are the mainstay of therapy for gastroesophageal reflux disease (GERD) but up to 60% of patients have inadequate response to therapy. Acid sensing ion channels (ASICs) play important roles in nociception. This study aimed to investigate whether the increased expression of ASICs results in neuronal hyperexcitability in GERD. Esophageal biopsies were taken from GERD patients and healthy subjects to compare expression of ASIC1 and 3. Next, gene and protein expression of ASIC1 and 3 from esophageal mucosa and dorsal root ganglia (DRG) neurons were measured by qPCR, Western-blot and immunofluorescence in rodent models of reflux esophagitis (RE), non-erosive reflux disease (NERD), and sham operated groups. Excitability of DRG neurons in the GERD and sham groups were also tested by whole-cell patch-clamp recordings. We demonstrated that ASIC1 and 3 expression were significantly increased in patients with RE compared with healthy controls. This correlated positively with symptom severity of heartburn and regurgitation (p < .001). Next, ASIC1 and 3 gene and protein expression in rodent models of RE and NERD were similarly increased in esophageal mucosa as well as T3-T5 DRG neurons compared with sham operation. DRG neurons from RE animals showed hyperexcitability compared with sham group. However, intrathecal injection of ASIC specific inhibitors, PcTx1 and APTEx-2, as well as silencing ASIC1 and 3 genes with specific siRNAs prevented visceral hypersensitivity. Overall, upregulation of ASIC1 and 3 may lead to visceral hypersensitivity in RE and NERD and may be a potential therapeutic target for PPI non-responsive patients.
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Canais Iônicos Sensíveis a Ácido/biossíntese , Esôfago/metabolismo , Refluxo Gastroesofágico/metabolismo , Azia/metabolismo , Regulação para Cima , Canais Iônicos Sensíveis a Ácido/genética , Animais , Refluxo Gastroesofágico/genética , Azia/genética , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Fruquintinib is an oral small-molecule angiogenesis inhibitor, markedly specifically inhibited vascular endothelial growth factor 2 (VEGFR2). This retrospective study aimed to evaluate the safety and efficacy of fruquintinib, or in combination with immunotherapy or chemotherapy in patients with bone and soft tissue sarcoma (STS), who have failed at least secondary-line treatment. PATIENTS AND METHODS: We performed a retrospective analysis of advanced bone and STS patients who received fruquintinib containing third- or further-line therapy in Shanghai Jiao Tong University Affiliated Sixth People's and the Affiliated Hospital of Jiangxi University of Traditional Chiese Medicine from September 2019 to February 2022. All of them had accepted at least anthracyclines-based chemotherapy. For the experimental group, 25 cases, the patients took a basic dose of fruquintinib 3-5 mg once a day for 21 days per 4 weeks as a cycle until the disease progression or intolerable toxicity. The other 20 patients in the control group received the best supportive care. The patients were evaluated by computed tomography (CT) or MRI once 2 months or symptoms worse. The DCR, progression-free survival (PFS), and adverse reactions of the drug were recorded and reviewed. RESULTS: The DCR in patients receiving fruquintinib therapy was 80.0%. The median PFS (mPFS) in the fruquintinib-containing therapy group was significantly longer than that in the control group (4.8 vs. 1.4 months; P < 0.001). The mPFS in the fruquintinib group, the fruquintinib-OI group and the fruquintinib-chemotherapy group were 3.2 months [95% confidence interval (CI), 2.0-7.9], 4.9 months (95% CI, 3.0-9.9) and 4.2 months (95% CI, 2.6-6.6) respectively, all of them were longer than the mPFS of 1.4 months (95% CI, 0.3-2.5) in the control group ( P < 0.001). CONCLUSION: Fruquintinib was reported for the first time to have favorable efficacy and safety as an optional treatment for patients with advanced bone and STS who failed in multi-line therapies.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular , China , Sarcoma/tratamento farmacológicoRESUMO
BACKGROUND: Acute lung injury (ALI) is a critical inflammatory response syndrome that rapidly develops into acute respiratory distress syndrome (ARDS). Currently, no effective therapeutic modalities are available for patients with ALI/ARDS. According to recent studies, inhibiting both the release of pro-inflammatory cytokines and the formation of reactive oxygen species (ROS) as early as possible may be a promising therapy for ALI. RESULTS: In this study, a ROS-responsive nano-delivery system based on oxidation-sensitive chitosan (Ox-CS) was fabricated for the simultaneous delivery of Ce NPs and RT. The in vitro experiments have shown that the Ox-CS/Ceria-Resatorvid nanoparticles (Ox-CS/CeRT NPs) were rapidly and efficiently internalised by inflammatory endothelial cells. Biological evaluations validated the significant attenuation of ROS-induced oxidative stress and cell apoptosis by Ox-CS/CeRT NPs, while maintaining mitochondrial function. Additionally, Ox-CS/CeRT NPs effectively inhibited the release of pro-inflammatory factors. After intraperitoneal (i.p.) administration, Ox-CS/CeRT NPs passively targeted the lungs of LPS-induced inflamed mice and released the drug activated by the high ROS levels in inflammatory tissues. Finally, Ox-CS/CeRT NPs significantly alleviated LPS-induced lung injury through inhibiting both oxidative stress and pro-inflammatory cytokine expression. CONCLUSIONS: The created Ox-CS/CeRT NPs could act as a prospective nano-delivery system for a combination of anti-inflammatory and anti-oxidant therapy of ALI.
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Lesão Pulmonar Aguda , Nanopartículas , Síndrome do Desconforto Respiratório , Humanos , Camundongos , Animais , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/farmacologia , Células Endoteliais , Lipopolissacarídeos/farmacologia , Estudos Prospectivos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Pulmão , Nanopartículas/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
Two oxygenated ergostane-type steroids including one new compound, 3ß-hydroxy-5α,6ß-methoxyergosta-7,22-dien-15-one (1) along with a known analogue ergosta-6,22-dien-3ß,5α,8α-triol (2) were isolated from the crude extracts of the marine sponge-derived fungus Aspergillus sp. Their structures were elucidated on the basis of combined NMR and MS spectroscopic methods. Compound 1 was a marine ergostane-type steroid with two methoxy groups at C-5 and C-6, respectively. These oxygenated ergostane-type steroids were evaluated for their antibacterial activities against human or aquatic pathogens. Among them, compound 1 exhibited antibacterial activity against Staphylococcus aureus.
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A series of [2]catenanes has been prepared from di-NHC building blocks by utilizing solvophobic effects and/or πâ â â π stacking interactions. The dinickel naphthobiscarbene complex syn-[1] and the kinked biphenyl-bridged bipyridyl ligand L2 yield the [2]catenane [2-IL](OTf)4 by self-assembly. Solvophobic effects are pivotal for the formation of the interlocked species. Substitution of the biphenyl-linker in L2 for a pyromellitic diimide group gave ligand L3 , which yielded in combination with syn-[1] the [2]catenane [3-IL](OTf)4 . This assembly exhibits enhanced stability in diluted solution, aided by additional πâ â â π stacking interactions. The πâ â â π stacking was augmented by the introduction of a pyrene bridge between two NHC donors in ligand L4 . Di-NHC precursor H2 -L4 (PF6 )2 reacts with Ag2 O to give the [Ag2 L4 2 ]2 [2]catenane [4-IL](PF6 )4 , which shows strong πâ â â π stacking interactions between the pyrene groups. This assembly was readily converted into the [Au2 L4 2 ]2 gold species [5-IL](PF6 )4 , which exhibits exceptional stability based on the strong πâ â â π stacking interactions and the enhanced stability of the Au-CNHC bonds.