RESUMO
Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that carries a significant global economic burden. Elevated levels of reactive oxygen species (ROS) have been recognized as contributing to AD exacerbation, making them a potential therapeutic target for AD treatment. Here, we introduce a dual-site biomimetic copper/zinc metal-organic framework (Cu/Zn-MOF) featuring four types of enzyme-like activities for AD treatment via suppressing the Fcγ receptor (FcγR)-mediated phagocytosis signal by mimicking the bimetallic sites of natural copper-zinc superoxide dismutase (CuZn-SOD). Interestingly, the neighboring Cu and Zn sites in both Cu/Zn-MOF and CuZn-SOD are at similar distances of â¼5.98 and â¼6.3 Å from each other, respectively, and additionally, both Cu and Zn sites are coordinated to nitrogen atoms in both structures, and the coordinating ligands to Cu and Zn are both imidazole rings. Cu/Zn-MOF exhibits remarkable SOD-like activity as well as its glutathione peroxidase (GPx)-, thiol peroxidase (TPx)-, and ascorbate peroxidase (APx)-like activities to continuously consume ROS and mitigate oxidative stress in keratinocytes. Animal experiments show that Cu/Zn-MOF outperforms halcinonide solution (a potent steroid medication) in terms of preventing mechanical injuries, reducing cutaneous water loss, and inhibiting inflammatory responses while presenting favorable biosafety. Mechanistically, Cu/Zn-MOF functions through an FcγR-mediated phagocytosis signal pathway, decreasing the continuous accumulation of ROS in AD and ultimately suppressing disease progression. These findings will provide an effective paradigm for AD therapy and contribute to the development of two-site bionics (TSB).
Assuntos
Dermatite Atópica , Estruturas Metalorgânicas , Humanos , Animais , Superóxido Dismutase/metabolismo , Cobre , Receptores de IgG , Zinco/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Biomimética , Glutationa Peroxidase/metabolismoRESUMO
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
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Cobre , Imunoterapia , Indóis , Nanoestruturas , Polímeros , Cobre/química , Polímeros/química , Animais , Imunoterapia/métodos , Indóis/química , Indóis/farmacologia , Camundongos , Nanoestruturas/química , Linhagem Celular Tumoral , Humanos , Catálise , Feminino , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.
Assuntos
Biofilmes , Insulina , Macrófagos , Agulhas , Transdução de Sinais , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Insulina/metabolismo , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Masculino , Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental , Nanopartículas/química , Células RAW 264.7 , Camundongos Endogâmicos C57BLRESUMO
Objective: This study aims to investigate the impact of patient-centered health education on individuals with type 2 diabetes coexisting with hyperlipidemia. Methods: A cohort of 80 patients with type 2 diabetes and hyperlipidemia attending our hospital from February 2022 to August 2022 were randomly assigned to either the health education group or the control group. While the control group received routine health education, the health education group received additional patient-centered health education. Subsequently, we compared blood glucose and lipid levels, negative emotions, quality of life, and the incidence of unhealthy eating or overweight between the two groups post-education. Results: Following the health education intervention, the health education group exhibited superior improvements in blood glucose and lipid levels compared to the control group. Moreover, there was a significant decrease in SAS and SDS scores and a notable increase in quality of life compared to the control group. The health education group also demonstrated a lower incidence of unhealthy eating or overweight. Conclusions: Patient-centered health education for individuals with type 2 diabetes and hyperlipidemia proves effective in enhancing glucose and lipid metabolism, mitigating negative emotions, improving quality of life, and reducing unhealthy habits.
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Long noncoding RNA DNAJC3-AS1 (lncRNA DNAJC3-AS1) has been probed in many studies, while the regulatory mechanism of DNAJC3-AS1 on papillary thyroid carcinoma (PTC) via regulating microRNA (miR)-27a-3p remains inadequate. This research aims to depict the role of DNAJC3-AS1, miR-27a-3p, collagen, and calcium-binding EGF domain-containing protein 1 (CCBE1) on PTC development. DNAJC3-AS1, miR-27a-3p, and CCBE1 expression levels in PTC tissues and adjacent normal tissues were tested. The relation of DNAJC3-AS1, miR-27a-3p, and CCBE1 was analyzed. DNAJC3-AS1 and miR-27a-3p and CCBE1-related oligonucleotides were transfected into IHH-4 cells to investigate their role in PTC development. Cell tumorigenicity was detected by in vivo assay. DNAJC3-AS1 and CCBE1 expressed highly and miR-27a-3p expressed lowly in PTC. Downregulation of DNAJC3-AS1, upregulating miR-27a-3p or downregulating CCBE1 impaired the malignant behaviors of IHH-4 cells. Depletion of miR-27a-3p reversed the DNAJC3-AS1 suppression-induced phenotypic inhibition of IHH-4 cells. DNAJC3-AS1 bound to miR-27a-3p and CCBE1 as a target of miR-27a-3p. Our study highlights that DNAJC3-AS1 inhibits miR-27a-3p to promote CCBE1 expression, thereby facilitating PTC development. This study affords distinguished therapeutic strategies and novel research directions for PTC treatment.
Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Myocardial infarction (MI) resulting from coronary artery occlusion is the leading global cause of cardiovascular disability and mortality. Anti-inflammatory treatment plays an important role in MI treatment. Triptolide (TPL), as a Chinese medicine monomer, has a variety of biological functions, including anti-inflammatory, anti-tumor, and immunoregulation. However, it has been proved that TPL is poorly water soluble, and has clear hepatotoxicity and nephrotoxicity, which seriously limits its clinical application. Herein, we designed a long-acting hydrogel platform (TPL@PLGA@F127) for MI treatment by intramyocardial injection. First, we found that the inflammatory response and immune regulation might be the main mechanisms of TPL against MI by network pharmacology. Subsequently, we prepared the hydrogel platform (TPL@PLGA@F127) and tested its effects and toxicity on normal organs in the early stage of MI (3 days after MI-operation). The results showed that TPL@PLGA@F127 could not only promote "repair" macrophages polarization (to M2 macrophage) by day 3 after MI, but also has a long-lasting anti-inflammatory effect in the later stage of MI (28 days after MI-operation). Additionally, we proved that TPL@PLGA@F127 could attenuate the toxicity of TPL by releasing it more slowly and stably. Finally, we observed the long-term effects of TPL@PLGA@F127 on MI and found that it could improve cardiac function, depress the myocardial fibrosis and protect the cardiomyocytes. In summary, this study indicated that TPL@PLGA@F127 could not only enhance the therapeutic effects of TPL on MI, but also attenuate the hepatotoxicity and nephrotoxicity, which established a strong foundation for the clinical application of TPL for MI.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Infarto do Miocárdio , Humanos , Hidrogéis/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miócitos CardíacosRESUMO
Intestinal epithelia impairment of inflammatory bowel disease (IBD) leads to the leakage of bacteria and antigens and the consequent persistent immune imbalance. Restoring the epithelial barrier is a promising therapeutic target but lacks effective and safe clinical interventions. By identifying the catalase (CAT) presence in the IBD pathological environment, we herein develop a CAT-catalyzed pathologically coating on the damaged epithelial barrier to inhibit intestinal leakage for IBD therapy. With the codelivery of CaO2 (a CAT substrate) and dopamine, the nanosystem can enable CAT-catalyzed oxygen (O2) production and in-situ polymerization of dopamine and then yield a thin and integrative polydopamine (PDA) coating on the intestinal barrier due to the highly adhesive property of PDA. In vivo study demonstrates that PDA coating provides not only a protective barrier by restricting intestinal leakage but also a favorable anti-inflammation effect. Beyond drug management, this work provides a physical repair strategy via catalyzed coating for IBD therapy.
Assuntos
Dopamina , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal , CatáliseRESUMO
Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of "antigen multi-copy display" and "calcium carbonate (CaCO3) biomineralization" to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4+ T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.
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Vacinas Anticâncer , Neoplasias , Humanos , Pós , Linfócitos T CD8-Positivos , Biomineralização , Células Apresentadoras de Antígenos , Neoplasias/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Microambiente TumoralRESUMO
The hyperexcitability of the anterior cingulate cortex (ACC) has been implicated in the development of chronic pain. As one of the key causes of ACC hyperexcitation, disinhibition of the ACC may be closely related to the dysfunction of inhibitory parvalbumin (PV)-expressing interneurons (PV-INs). However, the molecular mechanism underlying the ACC PV-INs injury remains unclear. The present study demonstrates that spared sciatic nerve injury (SNI) induces an imbalance in the excitation and inhibition (E/I) of the ACC. To test whether tumor necrosis factor-α (TNF-α) upregulation in the ACC after SNI activates necroptosis and participates in PV-INs damage, we performed a differential analysis of transcriptome sequencing using data from neuropathic pain models and found that the expression of genes key to the TNF-α-necroptosis pathway were upregulated. TNF-α immunoreactivity (IR) signals in the ACCs of SNI rats were co-located with p-RIP3- and PV-IR, or p-MLKL- and PV-IR signals. We then systematically detected the expression and cell localization of necroptosis-related proteins, including kinase RIP1, RIP3, MLKL, and their phosphorylated states, in the ACC of SNI rats. Except for RIP1 and MLKL, the levels of these proteins were significantly elevated in the contralateral ACC and mainly expressed in PV-INs. Blocking the ACC TNF-α-necroptosis pathway by microinjecting TNF-α neutralizing antibody or using an siRNA knockdown to block expression of MLKL in the ACC alleviated SNI-induced pain hypersensitivity and inhibited the upregulation of TNF-α and p-MLKL. Targeting TNF-α-triggered necroptosis within ACC PV-INs may help to correct PV-INs injury and E/I imbalance in the ACC in neuropathic pain.
Assuntos
Neuralgia , Fator de Necrose Tumoral alfa , Ratos , Animais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Parvalbuminas/metabolismo , Giro do Cíngulo/metabolismo , Necroptose , Interneurônios/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Biochar was derived from Eucheuma (EBC) at a temperature of 500 °C and the resulting biochar was modified using NaOH, KOH, NaOH + KOH and HNO3 + HCl. This study investigated the impact of these modifications on the characteristics of the biochar and its effectiveness in adsorbing phenanthrene (Phe) from an aqueous solution. The results indicated that the surface roughness increased, leading to an increase in the specific surface area, and the development of complex pore structure, leading to a decrease in the polarity and increase in hydrophobicity of biochar modified by a mixture of KOH and HNO3 + HCl (EBC-K and EBC-H). The EBC-K and EBC-H samples exhibited superior surface areas (272.76 and 289.60 m2 g-1) and adsorption capabilities for Phe (removal rates of 99.8% and 99.4%). The pseudo-first order, pseudo-second order and intraparticle diffusion Kinetic model demonstrated that the adsorption process is determined by both physicochemical and intra-particle diffusion. The adsorption process was well described by the Langmuir model. The maximum adsorption capacity of EBC-K and EBC-H was increased by approximately 2.4 times compared with the original biochar. Batch adsorption experiments indicated that the removal rate increases with the increase of dosage. Additionally, EBC-H regenerated from n-hexane removed 85.52% of the Phe solution.
Assuntos
Fenantrenos , Poluentes Químicos da Água , Adsorção , Hidróxido de Sódio , Poluentes Químicos da Água/análise , Carvão Vegetal/química , Cinética , ÁguaRESUMO
The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal pathogen is Candida albicans. Fluconazole (FLC) is the common drug for treating C. albicans infections, but increasing drug resistance has limited its clinical use. Currently, combination therapy is being investigated as a treatment to overcome the resistance of C. albicans. This report investigated the synergistic properties of deferoxamine (DFO) and FLC combination therapy in vitro and in vivo against drug-resistant C. albicans. The results showed that the combination of DFO and FLC had a great synergistic antifungal effect against C. albicans, an FLC-resistant strain, with a fractional inhibition concentration index (FICI) of 0.25 by the broth microdilution checkerboard assay. Furthermore, the combination of DFO and FLC significantly inhibited the activity of C. glabrata cells (approximately 30% of C. glabrata cells are azole-resistant). The time-growth curves confirmed that the combination of DFO and FLC have a potent synergistic antifungal effect. Hyphal formation assays confirmed that DFO inhibited the hyphal induction of C. albicans. In addition, the combination of DFO and FLC significantly inhibited the expression of the adhesion gene (ALS1). In vivo experiments showed that the combination of DFO and FLC significantly reduced pustules, CFU counts and inflammatory cell infiltration in skin tissue. These results suggest that the combination of DFO and FLC inhibits yeast-hyphae transformation, reduces C. albicans infectivity and resistance in vitro and in vivo, and affects Cek1 MAPK signaling. This may offer a new option for the treatment of cutaneous candidiasis.
Assuntos
Candida , Fluconazol , Humanos , Fluconazol/farmacologia , Antifúngicos/farmacologia , Desferroxamina/farmacologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Candida albicans , Candida glabrataRESUMO
BACKGROUND: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus result in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first-order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. METHODS: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC glutamatergic neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling. RESULTS: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC glutamatergic neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. CONCLUSIONS: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.
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Hiperalgesia , Neuralgia , Animais , Gânglios Espinais/metabolismo , Giro do Cíngulo/metabolismo , Hiperalgesia/metabolismo , Interleucina-6/metabolismo , Mamíferos/metabolismo , Neuralgia/metabolismo , Doenças Neuroinflamatórias , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of "one stone kill two birds", i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.
Assuntos
Nanopartículas , Microambiente Tumoral , Humanos , Linhagem Celular Tumoral , Hipóxia , Nanopartículas/química , Ácido Láctico/metabolismoRESUMO
The anterior cingulate cortex (ACC) is particularly critical for pain information processing. Peripheral nerve injury triggers neuronal hyper-excitability in the ACC and mediates descending facilitation to the spinal dorsal horn. The mechanically gated ion channel Piezo1 is involved in the transmission of pain information in the peripheral nervous system. However, the pain-processing role of Piezo1 in the brain is unknown. In this work, we found that spared (sciatic) nerve injury (SNI) increased Piezo1 protein levels in inhibitory parvalbumin (PV)-expressing interneurons (PV-INs) but not in glutaminergic CaMKâ ¡+ neurons, in the bilateral ACC. A reduction in the number of PV-INs but not in the number of CaMKâ ¡+ neurons and a significant reduction in inhibitory synaptic terminals was observed in the SNI chronic pain model. Further, observation of morphological changes in the microglia in the ACC showed their activated amoeba-like transformation, with a reduction in process length and an increase in cell body area. Combined with the encapsulation of Piezo1-positive neurons by Iba1+ microglia, the loss of PV-INs after SNI might result from phagocytosis by the microglia. In cellular experiments, administration of recombinant rat TNF-α (rrTNF) to the BV2 cell culture or ACC neuron primary culture elevated the protein levels of Piezo1 and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3). The administration of the NLRP3 inhibitor MCC950 in these cells blocked the rrTNF-induced expression of caspase-1 and interleukin-1ß (key downstream factors of the activated NLRP3 inflammasome) in vitro and reversed the SNI-induced Piezo1 overexpression in the ACC and alleviated SNI-induced allodynia in vivo. These results suggest that NLRP3 may be the key factor in causing Piezo1 upregulation in SNI, promoting an imbalance between ACC excitation and inhibition by inducing the microglial phagocytosis of PV-INs and, thereby, facilitating spinal pain transmission.
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Neuralgia , Traumatismos dos Nervos Periféricos , Ratos , Animais , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/metabolismo , Parvalbuminas/metabolismo , Giro do Cíngulo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuralgia/metabolismo , Regulação para Cima , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ratos Sprague-Dawley , Interneurônios/metabolismoRESUMO
As the star sensor works under high dynamic conditions, the spot formed by the star on the imaging plane will become a tail, which directly reduces the accuracy of centroid positioning. In addition, the imaging quality of the star sensor is seriously hit by the rolling shutter effect in the rolling shutter exposure mode, which further increases positioning error. Considering the diffusion radius and the dynamic tailing of the star spot, the imaging trajectory and the energy distribution models of the star spot under the rolling shutter exposure mode are established in this paper. Furthermore, based on the purposed models, the influence of the starting positions of stars and the dispersion of star spots to the centroid positioning error are analyzed by numerical simulation respectively, from which the variation laws of the two kinds of errors are obtained. Then, the laboratory experiments are implemented to evaluate the latter error; it indicates from the experimental results that the variation of the latter error is consistent with the simulation results, which is simultaneously proved that it cannot be ignored in practical engineering application. These results can be a valuable reference for developing a high precision star sensor. The models proposed in this paper can describe the star imaging process and evaluate the centroid positioning accuracy under the roller shutter exposure mode effectively, which lays a foundation for further eliminating the rolling shutter effect in the following research and improving the dynamic performance of star sensors.
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Ubiquitin/ISG15-conjugating enzyme E2 L6 (UBE2L6/Ube2l6) catalyzes protein ISGylation and ubiquitylation, post-translational modifications which regulate protein stability. Ube2l6 plays a role in promoting in vitro adipogenesis; however, its mechanism(s) of action and in vivo effects remain unknown. Here, we discovered that UBE2L6 levels were upregulated, and UBE2L6 and adipose triglyceride lipase (ATGL/Atgl) levels were negatively correlated, in white adipose tissue (WAT) from obese humans and obese mice. Therefore, we employed adipose-specific Ube2l6 knockout (Ube2l6AKO) mice and age-matched Ube2l6ï¬ox/ï¬ox controls to assess adipocyte Ube2l6's role in high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis. HFD-fed Ube2l6AKO mice displayed lower subcutaneous and visceral WAT mass levels relative to controls. HFD-fed Ube2l6AKO mice also showed WAT adipocyte hypoplasia and hypotrophy as well as enhanced whole-body metabolic activity relative to controls. Furthermore, glucose intolerance, insulin resistance, compensatory hyperinsulinemia, hypercholesterolemia, and hepatic steatosis were lower in HFD-fed Ube2l6AKO mice as compared to controls. Mechanistically, we found that Atgl protein expression and Atgl-mediated lipolysis were negatively regulated by Ube2l6's promotion of Atgl protein ubiquitylation. Collectively, adipocyte Ube2l6 functions as a negative regulator of Atgl protein stability and, consequently, promotes HFD-induced obesity, insulin resistance, and hepatic steatosis.
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Adipócitos/metabolismo , Adipogenia/genética , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , Técnicas de Inativação de Genes , Resistência à Insulina/genética , Obesidade/etiologia , Obesidade/genética , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/fisiologia , Animais , Humanos , Lipase/genética , Lipase/metabolismo , Lipase/fisiologia , Camundongos , Ubiquitinação/efeitos dos fármacosRESUMO
The receptor tyrosine kinase MET plays a vital role in skeletal muscle development and in postnatal muscle regeneration. However, the effect of MET on myogenesis of myoblasts has not yet been fully understood. This study aimed to investigate the effects of MET on myogenesis in vivo and in vitro. Decreased myonuclei and down-regulated expression of myogenesis-related markers were observed in Met p.Y1232C mutant heterozygous mice. To explore the effects of MET on myoblast proliferation and differentiation, Met was overexpressed or interfered in C2C12 myoblast cells through the lentiviral transfection. The Met overexpression cells exhibited promotion in myoblast proliferation, while the Met deficiency cells showed impediment in proliferation. Moreover, myoblast differentiation was enhanced by the stable Met overexpression, but was impaired by Met deficiency. Furthermore, this study demonstrated that SU11274, an inhibitor of MET kinase activity, suppressed myoblast differentiation, suggesting that MET regulated the expression of myogenic regulatory factors (MRFs) and of desmin through the classical tyrosine kinase pathway. On the basis of the above findings, our work confirmed that MET promoted the proliferation and differentiation of myoblasts, deepening our understanding of the molecular mechanisms underlying muscle development.
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Diferenciação Celular , Proliferação de Células , Desenvolvimento Muscular , Mioblastos/citologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Células Cultivadas , Camundongos , Mioblastos/metabolismoRESUMO
Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.
Assuntos
Radical Hidroxila/metabolismo , Ácido Láctico/metabolismo , Nanopartículas/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/química , Morte Celular Imunogênica/efeitos dos fármacos , Ácido Láctico/química , Camundongos , Oxigenases de Função Mista/química , Oxigenases de Função Mista/metabolismo , Nanopartículas/uso terapêutico , Nanopartículas/toxicidade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polietilenoimina/química , Microambiente TumoralRESUMO
PURPOSE: Preaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown. METHODS: A rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model. RESULTS: A novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression. CONCLUSION: Our results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms.
Assuntos
Proteínas Hedgehog/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Botões de Extremidades/crescimento & desenvolvimento , Proteínas de Membrana/genética , Polidactilia/genética , Polimorfismo de Nucleotídeo Único , Polegar/anormalidades , Regulação para Cima , Animais , Células CACO-2 , Modelos Animais de Doenças , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Íntrons , Botões de Extremidades/metabolismo , Botões de Extremidades/patologia , Masculino , Camundongos , Camundongos Transgênicos , Linhagem , Polidactilia/metabolismoRESUMO
Infection resulting from carbapenem-resistant Klebsiella pneumoniae (CRKP) is an intractable clinical problem. Outer membrane vesicles (OMVs) from CRKP are believed to be potential vaccine candidates. However, their immune response remains elusive due to low structural stability and poor size homogeneity. In this study, hollow OMVs were reinforced internally by size-controlled BSA nanoparticles to obtain uniform and stable vaccines through hydrophobic interaction. The result showed that the BSA-OMV nanoparticles (BN-OMVs) were homogenous with a size around 100 nm and exhibited a core-shell structure. Remarkably, subcutaneous BN-OMVs vaccination mediated significantly higher CRKP specific antibody titers. The survival rate of the mice infected with a lethal dose of CRKP was increased significantly after BN-OMV immunization. The adoptive transfer experiment demonstrated that the protective effect of BN-OMVs was dependent on humoral and cellular immunity. This study demonstrated that the structure optimization improved the immune efficacy of OMVs for vaccine development against CRKP.