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Quantifying metal bioaccumulation in a sedimentary environment is a valuable line of evidence when evaluating the ecological risks associated with metal-contaminated sediments. However, the precision of bioaccumulation predictions has been hindered by the challenges in accurately modeling metal influx processes. This study focuses on nickel bioaccumulation from sediment and introduces an innovative approach using the isotopically modified bioassay to directly measure nickel assimilation rates in sediment. Tested in sediments spiked with two distinct nickel concentrations, the measured Ni assimilation rates ranged from 35 to 78 ng g-1 h-1 in the Low-Ni treatment and from 96 to 320 ng g-1 h-1 in the High-Ni treatment. Integrating these rates into a biodynamic model yielded predictions of nickel bioaccumulation closely matching the measured results, demonstrating high accuracy with predictions within a factor of 3 for the Low-Ni treatment and within a factor of 1 for the High-Ni treatment. By eliminating the need to model metal uptake from various sources, this streamlined approach provides a reliable method for predicting nickel bioaccumulation in contaminated sediments. This advancement holds promise for linking bioaccumulation with metal toxicity risks in sedimentary environments, enhancing our understanding of metal-contaminated sediment risks and providing valuable insights to support informed decision-making in ecological risk assessment and management.
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Níquel , Poluentes Químicos da Água , Sedimentos Geológicos , Bioacumulação , Metais , Bioensaio , Poluentes Químicos da Água/análiseRESUMO
Acacetin, a natural flavonoid, possesses broad spectrum of pharmacological and biochemical activities, such as neuroprotection, antinociception and inhibition of monoamine oxidase. The current work aimed to investigate the antidepressant-like activity of acacetin in mice and explore the underlying mechanism(s). Chronic, but not acute, acacetin treatment (5, 15 or 45â¯mg/kg, p.o., once per day for three weeks) exerted in mice dose-dependently antidepressant-like activity, assessed by forced swim test (FST) and tail suspension test (TST). Although acacetin-treated mice showed normal circadian hypothalamo-pituitary-adrenal (HPA) axis activity, their endocrine responsivity to both acute restraint stress and intracerebroventricular injection of corticotropin-releasing factor (CRF) was buffered. The acacetin-triggered antidepressant-like activities are serotonergically dependent, since its impacts on behavior and stress responsivity were totally abolished by chemical depletion of brain serotonin by PCPA. Consistently, acacetin-treated mice showed escalated levels of brain monoamines especially serotonin and depressed activity of monoamine oxidase. Moreover, the acacetin-evoked anti-depression was preferentially counteracted by co-administration of 5-HT1A receptor antagonist WAY-100635, but potentiated by 5-HT1A receptor agonist 8-OH-DPAT and sub-effective dose of serotonergic antidepressant fluoxetine, suggesting a pivotal engagement of 5-HT1A related serotonergic system. In vitro, acacetin (1-100â¯nM) increased the Emax of 8-OH-DPAT. Collectively, these findings confirm that chronic acatetin administration to mice engenders antidepressant-like efficacy on both behavior and stress axis responsivity, with serotonergic system that preferentially couples with 5-HT1A receptors being critically involved.
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Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Flavonas/farmacologia , Serotonina/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Animais , Depressão/metabolismo , Fluoxetina/farmacologia , Elevação dos Membros Posteriores/fisiologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Natação/fisiologiaRESUMO
Glucagon-like peptide-1 (GLP-1) expression is shared by both intestinal cells and neurons of brainstem, which plays anorexigenic role on food intake. However, the exact source of physiological GLP-1 influencing food intake and pertinent mechanism of GLP-1 receptor agonists (GLP-1RA) remain unelucidated. In this study, the immediate early gene product c-Fos was chosen as the specific antigen for immunohistochemistry to show the certain areas of central nervous system (CNS) activation by the GLP-1RA. Thirty normal SD rats were randomly assigned to 3 groups, which were single intraperitoneally injected with Liraglutide (200 µg/kg), Exenatide (10 µg/kg) and saline, respectively. After injection, the amount of food intake and acute glycemic variation were assessed for comparison. The results showed that acute pharmacological dosage of GLP-1RA (Liraglutide or Exenatide) could significantly influence food intake. However, glycemic change indicated that the anorexic effect was dissociated with change in blood glucose in normal rats. Moreover, c-Fos was expressed significantly higher in major critical nuclei related to food intake in GLP-1RA groups when compared with the control group, and its expression was also found in spinal cord. The results suggested that acute administration of pharmacological doses of GLP-1 influences CNS via circulation and vagal pathways, especially on the arcuate nucleus (ARC) and the nucleus of solitary tract (NTS), and GLP-1 modulates autonomic nervous activities.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Liraglutida/farmacologia , Animais , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Traumatic vertebral artery injury (TVAI) is associated with craniocervical trauma that can lead to potentially fatal posterior circulation stroke. It presents a clinical challenge since it is hard to detect and there are no widely accepted guidelines on diagnosis and management. High-grade TVAI is more difficult to treat and no consensus has been reached yet. METHODS: We performed a single-center, long-term, therapeutic study involving 272 patients with craniocervical injury, eleven of which were diagnosed with high-grade TVAI. Individualized endovascular treatments were performed on these patients based upon the hemodynamic and morphological characteristics of the injured vertebral artery. Postoperative angiography was conducted at 2 weeks, 3 months and 6 months, and then annually after intervention. RESULTS: Ten vertebral pseudoaneurysms and one arteriovenous fistula (AVF) were confirmed by postoperative angiography. All the participants' neurological deficit symptoms disappeared or were significantly alleviated gradually, and no new symptoms were found after endovascular treatment. Follow-up angiography of the patients with pseudoaneurysms showed a normally shaped vertebral artery with no stenosis or aneurysms; the angiographic result of the patient with the AVF presented successful embolization in the proximal vertebral artery fistula with no progression or new stenosis. Their modified Rankin Scale (mRS) scores were also satisfactory. CONCLUSIONS: Application of individualized endovascular therapy in high-grade TVAI is safe, technically feasible and clinically effective, but there is no comparison between endovascular management and other management approaches because randomized trials cannot be carried out currently.
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Falso Aneurisma/terapia , Fístula Arteriovenosa/terapia , Embolização Terapêutica , Medicina de Precisão , Traumatismos do Sistema Nervoso/terapia , Artéria Vertebral/lesões , Adolescente , Adulto , Idoso , Falso Aneurisma/diagnóstico , Fístula Arteriovenosa/diagnóstico , Angiografia Cerebral , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Traumatismos do Sistema Nervoso/diagnóstico , Insuficiência Vertebrobasilar/diagnóstico , Insuficiência Vertebrobasilar/terapiaRESUMO
Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.
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Vacinas Anticâncer , Nanopartículas , Neoplasias , Humanos , Nanovacinas , Antígenos de Neoplasias , Imunoterapia , Células DendríticasRESUMO
ABSTRACT: Iron is indispensable for the viablility of nearly all living organisms, and it is imperative for cells, tissues, and organisms to acquire this essential metal sufficiently and maintain its metabolic stability for survival. Disruption of iron homeostasis can lead to the development of various diseases. There is a robust connection between iron metabolism and infection, immunity, inflammation, and aging, suggesting that disorders in iron metabolism may contribute to the pathogenesis of arthritis. Numerous studies have focused on the significant role of iron metabolism in the development of arthritis and its potential for targeted drug therapy. Targeting iron metabolism offers a promising approach for individualized treatment of arthritis. Therefore, this review aimed to investigate the mechanisms by which the body maintains iron metabolism and the impacts of iron and iron metabolism disorders on arthritis. Furthermore, this review aimed to identify potential therapeutic targets and active substances related to iron metabolism, which could provide promising research directions in this field.
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Artrite , Ferro , Humanos , Ferro/metabolismo , Artrite/metabolismo , Artrite/tratamento farmacológico , Homeostase , AnimaisRESUMO
BACKGROUND: The causal relationship between visceral adipose tissue (VAT) and gout is still unclear. We aimed to examine the potential association between them using observational and Mendelian randomization (MR) analyses. METHODS: In the observational analyses, a total of 11,967 participants (aged 39.5 ± 11.5 years) were included from the National Health and Nutrition Examination Survey. Logistic regression models were used to investigate the association between VAT mass and the risk of gout. In two-sample MR analyses, 211 VAT mass-related independent genetic variants (derived from genome-wide association studies in 325,153 UK biobank participants) were used as instrumental variables. The random-effects inverse-variance weighted (IVW) method was used as the primary analysis. Additional sensitivity analyses were also performed to validate our results. RESULTS: Observational analyses found that an increase in VAT mass (per standard deviation) was associated with a higher risk of gout after controlling for confounding factors (odds ratio [OR] = 1.27, 95% confidence intervals [CI] = 1.11-1.45). The two-sample MR analyses demonstrated a causal relationship between increased VAT mass and the risk of gout in primary analyses (OR = 1.78, 95% CI = 1.57-2.03). Sensitivity analyses also showed similar findings, including MR-Egger, weighted median, simple mode, weighted mode, and leave-one-out analyses. CONCLUSIONS: Observational analyses showed a robust association of VAT mass with the risk of gout. Meanwhile, MR analyses also provided evidence of a causal relationship between them. In summary, our findings suggested that targeted interventions for VAT mass may be beneficial to prevent gout.
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OBJECTIVE: Evidence from prospective studies on the consumption of tea and risk of gout is conflicting and limited. We aimed to investigate the potential causal effects of tea intake on gout using Mendelian randomization (MR). METHODS: Genome-wide association studies in UK Biobank included 349 376 individuals and successfully discovered single-nucleotide polymorphisms linked to consumption of one cup of tea per day. Summary statistics from the Chronic Kidney Disease Genetics consortium included 13 179 cases and 750 634 controls for gout. Two-sample MR analyses were used to evaluate the relationship between tea consumption and gout risk. The inverse-variance weighted (IVW) method was used for primary analysis, and sensitivity analyses were also conducted to validate the potential causal effect. RESULTS: In this study, the genetically predicted increase in tea consumption per cup was associated with a lower risk of gout in the IVW method (OR: 0.90; 95% CI: 0.82-0.98). Similar results were found in weighted median methods (OR: 0.88; 95% CI: 0.78-1.00), while no significant associations were found in MR-Egger (OR: 0.89; 95% CI: 0.71-1.11), weighted mode (OR: 0.80; 95% CI: 0.65-0.99), and simple mode (OR: 1.01; 95% CI: 0.75-1.36). In addition, no evidence of pleiotropy was detected by MR-Egger regression (P=0.95) or MR-PRESSO analysis (P=0.07). CONCLUSION: This study provides evidence for the daily consumption of an extra cup of tea to reduce the risk of gout.
Assuntos
Estudo de Associação Genômica Ampla , Gota , Humanos , Análise da Randomização Mendeliana , Estudos Prospectivos , Gota/epidemiologia , Gota/genética , CháRESUMO
In clinical chemotherapy, albumin-bound paclitaxel (Abraxane) can improve the tumor targeting property and therapeutic efficacy of paclitaxel (PTX) against orthotopic malignancies. However, patients with metastatic cancer have a poor prognosis, probably due to the instability, chemoresistance, and inability of albumin-bound paclitaxel to alter the tumor microenvironment. Here we propose a new biguanide-modified albumin-based nanoplatform that encapsulates paclitaxel for the effective treatment of metastatic cancer. The PTX is encapsulated in poly (lactic-co-glycolic acid) cores coated with biguanide-modified albumin (HSA-NH). The functionalized nanoparticles (HSA-NH NPs) exhibit a remarkable stable profile with low drug release (P < 0.05 versus Abraxane), target tumor tissues, suppress epithelial-mesenchymal transition (EMT) events for anti-metastatic effects, and reduce the phenotype of cancer stem cells. As a result, HSA-NH NPs effectively prolong animal survival (55 days) by inhibiting not only primary tumor growth but also metastasis. This study provides proof of concept that the biguanide-anchored albumin-based nanoplatform encapsulating PTX is a powerful, safe, and clinically translational strategy for the treatment of metastatic cancer. STATEMENT OF SIGNIFICANCE: Albumin-bound paclitaxel (Abraxane) can increase paclitaxel's tumor targeting and therapeutic efficacy in clinical cancer treatments such as breast cancer. However, the instability, chemoresistance, and lack of tumor microenvironment modulation of albumin-bound paclitaxel may lead to poor therapeutic efficacy in metastatic cancer patients. Here we develop biguanide-anchored albumin-based nanoplatforms that encapsulate paclitaxel (HSA-NH NPs) for metastatic cancer treatment. Poly(lactic-co-glycolic acid) (PLGA) cores encapsulating paclitaxel improve the stability of HSA-NH NPs. Based on the activities of metformin, biguanide-anchored albumin adsorbed on PLGA cores improves paclitaxel efficacy, inhibits various aberrant changes during epithelial-mesenchymal transition, and reduces tumor cell stemness. The biguanide-anchored albumin-based nanoplatform encapsulating PTX can serve as a potent, safe, and clinically translational approach for metastatic cancer therapies.
Assuntos
Nanopartículas , Neoplasias , Animais , Humanos , Paclitaxel Ligado a Albumina , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Albuminas/farmacologia , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joint and spine. However, the real mechanisms of immune cells acting on syndesmophyte formation in AS are not well identified. We aimed to find the key AS-associated cytokine and assess its pathogenic role in AS. METHODS: A protein array with 1000 cytokines was performed in five AS patients with the first diagnosis and five age- and gender-matched healthy controls to discover the differentially expressed cytokines. The candidate differentially expressed cytokines were further quantified by multiplex protein quantitation (3 AS-associated cytokines and 3 PDGF-pathway cytokines) and ELISA (PDGFB) in independent samples (a total of 140 AS patients vs 140 healthy controls). The effects of PDGFB, the candidate cytokine, were examined by using adipose-derived stem cells (ADSCs) and human fetal osteoblast cell line (hFOB1.19) as in vitro mesenchymal cell and preosteoblast models, respectively. Furthermore, whole-transcriptome sequencing and enrichment of phosphorylated peptides were performed by using cell models to explore the underlying mechanisms of PDGFB. The xCELLigence system was applied to examine the proliferation, chemotaxis, and migration abilities of PDGFB-stimulated or PDGFB-unstimulated cells. RESULTS: The PDGF pathway was observed to have abnormal expression in the protein array, and PDGFB expression was further found to be up-regulated in 140 Chinese AS patients. Importantly, PDGFB expression was significantly correlated with BASFI (Pearson coefficient/p value = 0.62/6.70E - 8) and with the variance of the mSASSS score (mSASSS 2 years - baseline, Pearson coefficient/p value = 0.76/8.75E - 10). In AS patients, preosteoclasts secreted more PDGFB than the healthy controls (p value = 1.16E - 2), which could promote ADSCs osteogenesis and enhance collagen synthesis (COLI and COLIII) of osteoblasts (hFOB 1.19). In addition, PDGFB promoted the proliferation, chemotaxis, and migration of ADSCs. Mechanismly, in ADSCs, PDGFB stimulated ERK phosphorylation by upregulating GRB2 expression and then increased the expression of RUNX2 to promote osteoblastogenesis of ADSCs. CONCLUSION: PDGFB stimulates the GRB2/ERK/RUNX2 pathway in ADSCs, promotes osteoblastogenesis of ADSCs, and enhances the extracellular matrix of osteoblasts, which may contribute to pathological bone formation in AS.
Assuntos
Proteínas Proto-Oncogênicas c-sis , Espondilite Anquilosante , Humanos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Citocinas/metabolismo , Proteína Adaptadora GRB2/metabolismo , Osteogênese/fisiologia , Proteínas Proto-Oncogênicas c-sis/genética , Proteínas Proto-Oncogênicas c-sis/metabolismo , Coluna Vertebral/metabolismo , Espondilite Anquilosante/genética , Espondilite Anquilosante/metabolismoRESUMO
Mesenchymal stem cells (MSCs) exhibited remarkable therapeutic potential in ischemic stroke due to their exceptional immunomodulatory ability and paracrine effect; they have also been regarded as excellent neuroprotectant delivery vehicles with inflammatory tropism. However, the presence of high levels of reactive oxygen species (ROS) and an oxidative stress environment at the lesion site inhibits cell survival and further therapeutic effects. Using bioorthogonal click chemistry, ROS-responsive luteolin-loaded micelles were tethered to the surface of MSCs. As MSCs migrated to the ischemic brain, the micelles would achieve ROS-responsive release of luteolin to protect MSCs from excessive oxidative damage while inhibiting neuroinflammation and scavenging ROS to ameliorate ischemic stroke. This study provided an effective and prospective therapeutic strategy for ischemic stroke and a framework for a stem cell-based therapeutic system to treat inflammatory cerebral diseases.
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Apoptotic vesicles (ApoVs) hold great promise for inflammatory regulation and tissue repair. However, little effort has been dedicated to developing ApoV-based drug delivery platforms, while the insufficient targeting capability of ApoVs also limits their clinical applications. This work presents a platform architecture that integrates apoptosis induction, drug loading, and functionalized proteome regulation, followed by targeting modification, enabling the creation of an apoptotic vesicle delivery system to treat ischemic stroke. Briefly, α-mangostin (α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory agent for cerebral ischemia/reperfusion injury. Matrix metalloproteinase activatable cell-penetrating peptide (MAP), a microenvironment-responsive targeting peptide, was modified on the surface of ApoVs to obtain the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs targeted the injured ischemic brain after systemic injection and achieved an enhanced neuroprotective activity due to the synergistic effect of ApoVs and α-M. The internal protein payloads of ApoVs, upon α-M activation, were found engaged in regulating immunological response, angiogenesis, and cell proliferation, all of which contributed to the therapeutic effects of ApoVs. The findings provide a universal framework for creating ApoV-based therapeutic drug delivery systems for the amelioration of inflammatory diseases and demonstrate the potential of MSC-derived ApoVs to treat neural injury.
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AVC Isquêmico , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/tratamento farmacológico , Encéfalo , Isquemia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
The aim of this study was to identify the effects of melatonin on acute gouty inflammation and to investigate the underlying mechanisms. We found significantly lower serum melatonin levels in gout patients in the acute phase than in those in the remission phase or in normal individuals. The mRNA expression of melatonin receptor 2 (MT2) was also lower in gout patients than in normal individuals. To verify the in-vivo role of melatonin, a gouty arthritis model was established by intraarticular injection of monosodium urate (MSU, 1 mg) crystals into the paws of C57BL/6 mice. Joint inflammation in the mouse model was evaluated by measuring the thickness of the right paw/left paw, and the inflammation index was determined by examining infiltrating neutrophils with haematoxylin and eosin (H&E) staining. Melatonin was found to reduce both paw thickness and the inflammation index in the mouse model, and melatonin also reduced the mRNA levels of interleukin-1 beta (IL-1ß), IL-6 and NLR family pyrin domain containing 3 (NLRP3) inflammasome. To mimic gouty inflammation in vitro, mouse peritoneal macrophages were stimulated with lipopolysaccharides (LPS) plus MSU. Melatonin was revealed to reduce IL-1ß secretion by stimulated macrophages. The mRNA expression levels of IL-1ß and IL-6 were also inhibited by melatonin. Western blot analysis showed that the expression of NLRP3, caspase-1 and pro-IL-1ß was also inhibited by melatonin. In conclusion, our study demonstrated that melatonin alleviated gouty inflammation in vivo and in vitro, and the underlying mechanism may involve inhibiting the assembly of the NLRP3 inflammasome.
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Artrite Gotosa/tratamento farmacológico , Gota/tratamento farmacológico , Inflamação/tratamento farmacológico , Melatonina/farmacologia , Receptor MT2 de Melatonina/sangue , Doença Aguda/epidemiologia , Animais , Artrite Gotosa/sangue , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/genética , Modelos Animais de Doenças , Gota/metabolismo , Gota/patologia , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Interleucina-1beta/genética , Interleucina-6/genética , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Melatonina/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , RNA Mensageiro/sangue , Ácido Úrico/toxicidadeRESUMO
PURPOSE: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. METHODS: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. RESULTS: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. CONCLUSION: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ambroxol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
BACKGROUND: Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation. The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently. In the present study, the potential roles of AdipoRon, an adiponectin receptor agonist, in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored. METHODS: BALB/c mice (nâ=â144, male) were divided into three sets. In set 1, 32 mice were randomized into four groups: the control group, the AdipoRon group, the LPS/D-Gal group, and the AdipoRon + LPS/D-Gal group. The mice in set 1 were sacrificed after LPS/D-Gal treatment, and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α). In set 2, the 32 mice were also divided into four groups similar to that of set 1. The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected. In set 3, 80 mice (divided into four groups, nâ=â20) were used for survival observation. The survival rate, plasma aminotransferases, histopathological damage were measured and compared between these four groups. RESULTS: AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3â±â781.9 to 286.8â±â133.1 U/L for alanine aminotransferase, Pâ<â0.01; from 566.5â±â243.4 to 180.1â±â153.3 U/L for aspartate aminotransferase, Pâ<â0.01), attenuated histopathological damage and improved the survival rate (from 10% to 60%) in mice with LPS/D-Gal-induced acute hepatitis. Additionally, AdipoRon down-regulated the production of TNF-α (from 328.6â±â121.2 to 213.4â±â52.2 pg/mL, Pâ<â0.01), inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control), caspase-8 (from 2.03-fold to 1.31-fold of the control), and caspase-9 (from 2.14-fold to 1.43-fold of the control), and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group). The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced. CONCLUSIONS: These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon, implying that AdipoRon might become a new reagent for treatment of acute hepatitis.
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Hepatite/tratamento farmacológico , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Modelos Animais de Doenças , Galactosamina , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador alfa/sangueRESUMO
CD4(+)CD25(+) regulatory T cells (Tregs) and the expression of their molecular markers (GITR, Foxp3) in peripheral blood of the patients with systemic lupus erythematosus (SLE) were investigated in order to reveal the pathogenesis of SLE on the cellular and molecular levels. The level of Tregs in peripheral blood was detected by flow cytometry. The expression levels of GITR and Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs) were assayed by reverse transcriptase-polymerase chain reaction (RT-PCR). The level of IL-6 in the plasma was measured by ELISA. Comparisons were made among 3 groups: the active SLE group, the inactive SLE group, and normal control group. The level of Tregs in the active SLE group and the inactive SLE group was significantly lower than in the normal control group (P<0.01). The level of Tregs in the active group was lower than in the inactive group with the difference being not significant (P>0.05). The level of Tregs in SLE patients was significantly negatively correlated with the disease active index in SLE (SLEDAI) (r=-0.81, P<0.01). The expression levels of GITR mRNA in PBMCs of the active SLE group and the inactive SLE group were significantly higher than in the normal control group (P<0.05), and those of Foxp3 mRNA in SLE patients of both active and inactive SLE groups were significantly lower than in the normal control group (P<0.05). There was no significant difference in the expression of GITR and Foxp3 mRNA between the active SLE group and inactive SLE group (P>0.05). The plasma levels of IL-6 in both the inactive SLE group and active SLE group were significantly higher than in the normal control group (P<0.01). The plasma level of IL-6 in the active SLE group was significantly increased as compared with that in the inactive SLE group (P<0.05), and the plasma level of IL-6 in SLE was significantly positively correlated with SLEDAI scores (r=0.58, P<0.01) and significantly negatively correlated with the ratio of CD4(+)CD25(+) cells/CD4(+) cells (r=-0.389, P<0.05). It was concluded that the levels of Tregs and Foxp3 mRNA in peripheral blood of SLE patients were decreased and the levels of GITR mRNA and plasma IL-6 were increased. The Tregs and their molecular markers GITR, Foxp3 as well as the plasma IL-6 might play an important role in the pathogenesis of SLE.
Assuntos
Fatores de Transcrição Forkhead/sangue , Interleucina-6/sangue , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Fator de Crescimento Neural/sangue , Receptores do Fator de Necrose Tumoral/sangue , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Feminino , Fatores de Transcrição Forkhead/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/etiologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue , RNA Mensageiro/genética , Receptores de Fator de Crescimento Neural/genética , Receptores do Fator de Necrose Tumoral/genética , Adulto JovemRESUMO
Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan-PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC-0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC-0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers.
RESUMO
To explore the expression and clinical significance of molecular chaperone heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMC) and plasma level of interleukin-6 (IL-6) in patients with systemic lupus erythematosus (SLE), HSP90 was detected in PBMC by Western blot assay and the plasma level of IL-6 was measured by ELISA in 38 SLE patients and 20 normal controls. The correlation analysis was performed between the SLE disease activity index (SLE-DAI) and the expression of HSP90 and IL-6. The results showed that there was increased expression of HSP90 in the SLE patients. The active SLE group exhibited higher HSP90 levels (0.82+/-0.10) than the inactive SLE group (0.54+/-0.09) (P<0.01). The expression of HSP90 in normal control group (0.37+/-0.11) showed significant statistical difference as compared to both the inactive and active SLE groups (P<0.01, P<0.01, respectively). The plasma level of IL-6 exhibited a significant increase in both the inactive and active SLE groups (28.99+/-1.74 pg/mL, 44.58+/-9.15 pg/mL, respectively) compared with normal control group (P<0.01, P<0.01, respectively). The expression of HSP90 and IL-6 in SLE patients showed significant positive correlation with SLEDAI scoring (r=0.80, P<0.01: r= 0.74, P<0.01, respectively). In addition, there was a positive correlation between the level of IL-6 and HSP90 in SLE patients (r=0.86, P<0.01). The increased expression of molecular chaperone HSP90 and IL-6 may play an important role in the pathogenesis of SLE by regulating autoimmunity.
Assuntos
Proteínas de Choque Térmico HSP90/sangue , Interleucina-6/sangue , Lúpus Eritematoso Sistêmico/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Treatment of refractory idiopathic intracranial hypertension (IIH) is a challenging problem. We reported a refractory IIH patient who manifested with typical intracranial hypertensive symptoms successfully treated with endovascular stent implantation. Pre-operative cerebrospinal fluid (CSF) opening pressure is 36 cmH2O. Cerebral angiography demonstrated a stenotic lesion located at the right transverse sinus (TS). The stenotic TS returned to its normal caliber and the pressure gradient deceased from 36 mmHg to 4 mmHg after the stent placement. The intracranial hypertensive symptoms resolved and one month later, the CSF opening pressure decreased to 14 cmH2O.