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BACKGROUND: Dynamic monitoring of the blood-brain barrier (BBB) functional status in septic mice can help to explore the pathological mechanisms. Therefore, we proposed a new method for monitoring BBB permeability and applied it to the detection of sepsis models. METHODS: The new method involves the construction of an optical cranial window and in vivo imaging. We performed dynamic monitoring of BBB permeability and cerebral blood flow (CBF) in cecal ligation puncture (CLP) and endotoxemia (lipopolysaccharide [LPS]) mice. RESULTS: The sensitivity and accuracy of this method were higher than those of Evans blue evaluation. The increase of BBB permeability in the group of CLP mice was relatively mild and correlated with overall survival, and the damage was irreversible. Contrarily, BBB damage in the LPS group was more acute and severe, unrelated to overall survival, but recoverable. The CBF decreased significantly in both model mouse groups 24 h after modeling, but only the CBF proportion decrease in the LPS group was significantly correlated with an increase in BBB permeability. Within 24 h after both models were established, the decrease in blood flow in the digestive organs occurred earlier than in the brain and kidneys, and the decrease in small intestine blood flow in the LPS group progressed faster. CONCLUSIONS: We have successfully demonstrated the feasibility of our novel method to detect BBB permeability in mice. Our results revealed a significant difference in the BBB permeability change trend between the CLP and LPS model mice when survival curves were consistent. Notably, the CLP-model mice demonstrated a closer resemblance to clinical patients. Our findings suggest that early-stage brain tissue hypoperfusion has a greater impact on BBB function damage in endotoxemia mice, which is related to the faster progression of blood flow redistribution.
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Objective: To detect the continuous blood purification (CBP)'s application value in patients with urosepsis caused by ureteral calculi and heart failure after catheterization. Methods: This is a clinical comparative study. Sixty patients with ureteral calculi complicated with heart failure and urosepsis were admitted at Affiliated Hospital of Hebei University from January 2021 to March 2023 randomly split into control and experimental group(n=30). Based on conventional treatment after indwelling the DJ tube, the experimental group was treated with CBP therapy. The control group dealt with conventional anti-inflammatory, oxygen inhalation and other treatments only. Compared and analyzed in terms of alterations in blood inflammatory factors, cardiac function, BNP prior to and after therapy, blood pressure, blood WBC recovery time, and so on. Results: TNF-a, CRP, and PCT levels in the control and experimental groups were substantially more prominent than the average reference value prior to treatment. They decreased considerably at distinct time points after therapy, with substantial distinctions (p< 0.05). A more meaningful decrease was noticed in the experimental group in comparison with the control group (p< 0.05). BNP and cardiac function were improved in both groups prior to and after therapy, and the amelioration of indexes in the experimental group was more substantial than that in the control group after therapy, with statistically considerable distinctions. The improvement time in experimental group was earlier than in the control group, with statistically substantial differences. Conclusion: Patients with urosepsis complicated with heart failure after indwelling DJ tube have their inflammatory factors improved significantly, with more thorough excretion by using conventional treatment combined with CBP therapy.
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Photo-crosslinking polymerization stands as a fundamental pillar in the domains of chemistry, biology, and medicine. Yet, prevailing strategies heavily rely on ultraviolet/visible (UV/Vis) light to elicit in situ crosslinking. The inherent perils associated with UV radiation, namely the potential for DNA damage, coupled with the limited depth of tissue penetration exhibited by UV/Vis light, severely restrict the scope of photo-crosslinking within living organisms. Although near-infrared light has been explored as an external excitation source, enabling partial mitigation of these constraints, its penetration depth remains insufficient, particularly within bone tissues. In this study, we introduce an approach employing X-ray activation for deep-tissue hydrogel formation, surpassing all previous boundaries. Our approach harnesses a low-dose X-ray-activated persistent luminescent phosphor, triggering on demand in situ photo-crosslinking reactions and enabling the formation of hydrogels in male rats. A breakthrough of our method lies in its capability to penetrate deep even within thick bovine bone, demonstrating unmatched potential for bone penetration. By extending the reach of hydrogel formation within such formidable depths, our study represents an advancement in the field. This application of X-ray-activated polymerization enables precise and safe deep-tissue photo-crosslinking hydrogel formation, with profound implications for a multitude of disciplines.
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Hidrogéis , Raios Ultravioleta , Masculino , Animais , Bovinos , Ratos , Hidrogéis/química , Raios X , Polimerização , Raios InfravermelhosRESUMO
Septic cardiomyopathy is associated with high mortality in septic patients, characterized by reversible systolic and diastolic dysfunction. It is essential to monitor cardiac function and hemodynamic changes in septic animals. Here, we present a protocol to monitor cardiac function and hemodynamics in septic rodents. We describe steps for performing cecal ligation and puncture on rodents to induce sepsis, acquiring two-dimensional echocardiographic and M-mode ultrasonic images, and assessing mean arterial pressure in septic animals. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.
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Roedores , Sepse , Animais , Humanos , Hemodinâmica , EcocardiografiaRESUMO
Purpose: The pathogenesis of renal fibrosis (RF) involves intricate interactions between profibrotic processes and immune responses. This study aimed to explore the potential involvement of the pyroptosis signaling pathway in immune microenvironment regulation within the context of RF. Through comprehensive bioinformatics analysis and experimental validation, we investigated the influence of pyroptosis on the immune landscape in RF. Methods: We obtained RNA-seq datasets from Gene Expression Omnibus (GEO) databases and identified Pyroptosis-Associated Regulators (PARs) through literature reviews. Systematic evaluation of alterations in 27 PARs was performed in RF and normal kidney samples, followed by relevant functional analyses. Unsupervised cluster analysis revealed distinct pyroptosis modification patterns. Using single-sample gene set enrichment analysis (ssGSEA), we examined the correlation between pyroptosis and immune infiltration. Hub regulators were identified via weighted gene coexpression network analysis (WGCNA) and further validated in a single-cell RNA-seq dataset. We also established a unilateral ureteral obstruction-induced RF mouse model to verify the expression of key regulators at the mRNA and protein levels. Results: Our comprehensive analysis revealed altered expression of 19 PARs in RF samples compared to normal samples. Five hub regulators, namely PYCARD, CASP1, AIM2, NOD2, and CASP9, exhibited potential as biomarkers for RF. Based on these regulators, a classifier capable of distinguishing normal samples from RF samples was developed. Furthermore, we identified correlations between immune features and PARs expression, with PYCARD positively associated with regulatory T cells abundance in fibrotic tissues. Unsupervised clustering of RF samples yielded two distinct subtypes (Subtype A and Subtype B), with Subtype B characterized by active immune responses against RF. Subsequent WGCNA analysis identified PYCARD, CASP1, and NOD2 as hub PARs in the pyroptosis modification patterns. Single-cell level validation confirmed PYCARD expression in myofibroblasts, implicating its significance in the stress response of myofibroblasts to injury. In vivo experimental validation further demonstrated elevated PYCARD expression in RF, accompanied by infiltration of Foxp3+ regulatory T cells. Conclusions: Our findings suggest that pyroptosis plays a pivotal role in orchestrating the immune microenvironment of RF. This study provides valuable insights into the pathogenesis of RF and highlights potential targets for future therapeutic interventions.
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Biologia Computacional , Piroptose , Animais , Camundongos , Reações Cruzadas , Caspase 1 , Análise por ConglomeradosRESUMO
To assess the correlation between serum fibroblast growth factor 23 (FGF-23)/Klotho levels and end-stage renal disease (ESRD) in middle-aged and elderly patients combined with low bone mineral density (BMD). The BMD of the lumbar vertebrae and femoral neck of 87 patients with ESRD was measured using a dual-energy X-ray bone densitometer during hospitalisation and the patients were divided into a normal bone mass group and a low bone mass group. Haemoglobin, albumin, urea nitrogen, uric acid, creatinine, low-density lipoprotein cholesterol, alkaline phosphatase, blood calcium, blood phosphorus and full parathyroid hormone were detected using an automatic biochemical analyser. The levels of serum FGF-23, Klotho and activated vitamin D in the patients with ESRD were measured via an enzyme-linked immunosorbent assay. Older age and decreased serum creatinine levels and serum Klotho levels were associated with low bone mass. There were significantly more men in normal bone mass group (n=49, 74.24%) than in low bone mass group (n=8, 38.10%). The correlation analysis showed that BMD was negatively correlated with age but positively correlated with serum Klotho. The binary logistic regression analysis indicated that old age and the decrease in serum Klotho level were independent risk factors of a low BMD (all p<0.05). In conclusion, serum Klotho is closely related to BMD changes in middle-aged and elderly patients with ESRD. A high Klotho level is a protective factor and is expected to be a marker in reducing bone mineral metabolism disorders and improving the prognosis of patients with ESRD.
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Doenças Ósseas Metabólicas , Falência Renal Crônica , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Densidade Óssea , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , FemininoRESUMO
In recent years, there has been a significant increase in the prevalence of chronic wounds, such as pressure ulcers, diabetic foot ulcers, and venous ulcers of the lower extremities. The main contributors to chronic wound formation are bacterial infection, prolonged inflammation, and peripheral vascular disease. However, effectively treating these chronic wounds remains a global challenge. Hydrogels have extensively explored as wound healing dressing because of their excellent biocompatibility and structural similarity to extracellular matrix (ECM). Nonetheless, much is still unknown how the hydrogels promote wound repair and regeneration. Signaling pathways play critical roles in wound healing process by controlling and coordinating cells and biomolecules. Hydrogels, along with their therapeutic ingredients that impact signaling pathways, have the potential to significantly enhance the wound healing process and its ultimate outcomes. Understanding this interaction will undoubtedly provide new insights into developing advanced hydrogels for wound repair and regeneration. This paper reviews the latest studies on classical signaling pathways and potential targets influenced by hydrogel scaffolds in chronic wound healing. This work hopes that it will offer a different perspective in developing more efficient hydrogels for treating chronic wounds.
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Pé Diabético , Hidrogéis , Humanos , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Hidrogéis/química , Cicatrização , Bandagens , Pé Diabético/tratamento farmacológico , Transdução de SinaisRESUMO
To study the species of lanthanum (III) nitrate (La[NO3]3) dispersed in cell media and the effect on the osteoblast differentiation of bone marrow stroma cells (BMSCs). Different La-containing precipitations were obtained by adding various concentrations of La(NO3)3 solutions to Dulbecco's modified Eagle medium (DMEM) or DMEM with fetal bovine serum (FBS). A series of characterisation methods, including dynamic light scattering, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, and protein quantification were employed to clarify the species of the different La-containing precipitations. The primary BMSCs were isolated, and the cell viability, alkaline phosphatase activity, and the formation of a mineralised nodule of BMSCs were tested when treated with different La-containing precipitations. The La(NO3)3 solutions in DMEM could form LaPO4, which exits in the particle formation, while the La(NO3)3 solutions in DMEM with FBS could form a La-PO4-protein compound. When treated with La(NO3)3 solutions in DMEM, the cell viability of the BMSCs was inhibited at the concentrations of 1, 10, and 100 µM at 1 day and 3 days. Meanwhile, the supernatant derived from the La(NO3)3 solutions in DMEM did not affect the cell viability of the BMSCs. In addition, the precipitate derived from the La(NO3)3 solutions in DMEM added to the complete medium inhibited the cell viability of the BMSCs at concentrations of 10 µM and 100 µM. When treated with La(NO3)3 solutions in DMEM with FBS, the derived precipitate and supernatant did not affect the cell viability of the BMSCs, except for the concentration of 100 µM La(NO3)3. The La-PO4-protein formed from the La(NO3)3 solutions in DMEM with FBS inhibited the osteoblast differentiation of BMSCs at the concentration of 1 µM La(NO3)3 (P < 0.05) but had no effect on either the osteoblast differentiation at the concentrations of 0.001 and 0.1 µM or on the formation of a mineralised nodule at all tested concentrations of La(NO3)3. Overall, La(NO3)3 solutions in different cell culture media could form different La-containing compounds: La-PO4 particles (in DMEM) and a La-PO4-protein compound (in DMEM with FBS). The different La-containing compounds caused different effects on the cell viability, osteoblast differentiation, and the formation of a mineralised nodule of the BMSCs. The La-containing precipitation inhibited the osteoblast differentiation by inhibiting the expression of osteoblast-related genes and proteins, providing a theoretical basis for clinical doctors to apply phosphorus-lowering drugs such as lanthanum carbon.
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Células-Tronco Mesenquimais , Nitratos , Camundongos , Animais , Nitratos/farmacologia , Nitratos/metabolismo , Lantânio/farmacologia , Lantânio/metabolismo , Osteogênese , Células Cultivadas , Diferenciação Celular , Células da Medula Óssea , Proliferação de Células , Células EstromaisRESUMO
Sepsis-associated encephalopathy (SAE) is a common brain dysfunction, which results in severe cognitive and neurological sequelae and an increased mortality rate in patients with sepsis. Depending on the stimulus, microglia (resident macrophages in the brain that are involved in SAE pathology and physiology) can adopt two polarization states (M1/M2), corresponding to altered microglial morphology, gene expression, and function. We systematically described the pathogenesis, morphology, function, and phenotype of microglial activation in SAE and demonstrated that microglia are closely related to SAE occurrence and development, and concomitant cognitive impairment. Finally, some potential therapeutic approaches that can prime microglia and neuroinflammation toward the beneficial restorative microglial phenotype in SAE were outlined.
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Novel oral therapeutic agents based on inhibition or binding activity without adverse events in CKD patients are urgently needed. Here, 5/6 nephrectomy (NX) rats were used to construct a CKD model. Aminated cellulose (AC711), which is metal-free, non-absorbable, and low-volume expansive, was used as a novel oral therapeutic agent for hyperphosphataemia treatment in rats. The efficacy of AC711 on serum and urinary phosphate levels, the expression of type II sodium-dependent phosphate cotransporter (NPT2b), and type III Na-dependent phosphate cotransporter (PiT-1/2) was examined. Serum fibroblast growth factor-23 (FGF-23) levels, parathyroid hormone (PTH) levels, and the phenotypic transformation of vascular smooth muscle cell markers (smooth muscle 22 (SM22) and Runx2) are considered an adaptive response to elevated serum phosphate levels. A similar efficacy of AC711 was observed on serum and urinary phosphate levels when the same dose of AC711 and sevelamer was administered to 5/6 NX rats. The decreasing expression of NPT2b, PiT-1, and PiT-2 was examined in the AC711 groups in a dose-dependent manner. The sevelamer and AC711-MD groups for FGF-23 and PTH indicated no significant difference. The down-regulation of Runx2 expression and up-regulation of SM22 expression were seen in the AC711 groups in a dose-dependent manner. Two suppression mechanisms (binding and inhibiting activities) were observed in the gastrointestinal (GI) tract in the AC711 groups. A novel oral phosphate binder, AC711, showed both binding and inhibition characteristics. The low-volume expansion of AC711 following exposure to simulated intestinal fluid provides the potential therapeutic benefits with the advantage of moderate GI side effects.
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Celulose , Hiperfosfatemia , Insuficiência Renal Crônica , Animais , Celulose/análogos & derivados , Celulose/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/metabolismo , Hiperfosfatemia/tratamento farmacológico , Hormônio Paratireóideo , Fosfatos/metabolismo , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , SevelamerRESUMO
Indoxyl sulphate (IS) a representative uraemic toxin in the blood of patients with chronic kidney disease (CKD). Its accumulation may be closely related to CKD and the increasing morbidity and mortality of the disease's related complications. Timely and effective detection of the IS level and efficient clearance of IS may effectively prevent the progression of CKD and its related complications. Therefore, this article summarizes the research progress of IS related, including IS in CKD and its associated complications including chronic kidney disease, chronic kidney disease with cardiovascular disease, renal anemia, bone mineral metabolic disease and neuropsychiatric disorders, looking for IS accurate rapid detection methods, and explore the efficient treatment to reduce blood levels of indole phenol sulphate.
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Indicã , Insuficiência Renal Crônica , Humanos , Fenóis , Insuficiência Renal Crônica/terapia , Sulfatos , Toxinas UrêmicasRESUMO
Background and Objectives: Chronic inflammation of bone tissue often results in bone defects and hazards to tissue repair and regeneration. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including anti-inflammatory and osteogenic potential. This study aimed to investigate the efficacy and mechanisms of CBD in the promotion of bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation in the inflammatory microenvironment. Methods and Results: BMSCs isolated from C57BL/6 mice, expressed stem cell characteristic surface markers and presented multidirectional differentiation potential. The CCK-8 assay was applied to evaluate the effects of CBD on BMSCs' vitality, and demonstrating the safety of CBD on BMSCs. Then, BMSCs were stimulated with lipopolysaccharide (LPS) to induce inflammatory microenvironment. We found that CBD intervention down-regulated mRNA expression levels of inflammatory cytokines and promoted cells proliferation in LPS-treated BMSCs, also reversed the protein and mRNA levels downregulation of osteogenic markers caused by LPS treatment. Moreover, CBD intervention activated the cannabinoid receptor 2 (CB2) and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. While AM630, a selective CB2 inhibitor, reduced phosphorylated (p)-p38 levels. In addition, AM630 and SB530689, a selective p38 MAPK inhibitor, attenuated the enhancement of osteogenic markers expression levels by CBD in inflammatory microenvironment, respectively. Conclusions: CBD promoted osteogenic differentiation of BMSCs via the CB2/p38 MAPK signaling pathway in the inflammatory microenvironment.
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Aim: To evaluate the efficiency of tangential flow filtration (TFF) in improving the yield of human umbilical cord mesenchymal stem cell (hucMSC)-derived extracellular vesicles (EVs) while promoting cell regeneration under oxidative stress. Methods: HucMSC-EVs were extracted from supernatants by ultracentrifugation (UC-EVs) and TFF (TFF-EVs), followed by feature characterization and bioactivity assays. Results: The yield of TFF-EVs increased 18-times compared with that of UC-EVs. TFF-EVs displayed proliferation-promoting ability similar to that of UC-EVs in the damaged HaCaT cell model with ultraviolet radiation B (UVB) and H2O2. Furthermore, the antiapoptotic effects of TFF-EVs were improved, whereby the apoptosis rate exhibited a 3.7-fold decrease. Conclusion: HucMSC-EVs extracted by TFF show a higher yield and rejuvenate the damaged HaCaT cells induced by oxidative stress.
Plain language summary The progresses in regenerative medicine will enable a perfect repair of burns. Stem cells release extracellular vesicles around injured tissues to improve its structural and functional repair. But the current methods for vesicles enrichment are not efficient enough to meet the needs of investigation. Here we isolated the vesicles from the stem cells supernatants by either traditional method or ultrafiltration. We found that the vesicles isolated with ultrafiltration method displayed a similar cell proliferation ability of that with the traditional one. The output of the vesicles or its anti-aging capability has increased 18- or 3.7-times respectively. Therefore, the scalable and effective isolation method described here may facilitate the successful medical translation of the vesicles for clinical use.
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Vesículas Extracelulares , Células-Tronco Mesenquimais , Bioensaio , Humanos , Peróxido de Hidrogênio , Raios UltravioletaRESUMO
AIMS: Sepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE. MAIN METHODS: FPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells. KEY FINDINGS: Western blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects both in vivo and in vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosis in vitro. SIGNIFICANCE: This study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.
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Ceramidas/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias/complicações , Encefalopatias/metabolismo , Lesões Encefálicas/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Sepse/complicações , Encefalopatia Associada a Sepse/complicações , Encefalopatia Associada a Sepse/fisiopatologia , Transdução de SinaisRESUMO
A novel polymer poly (6-O-MMAGlc) has been synthesized via free radical polymerization of monomer methyl 6-O-methacryloyl-α-D-glucoside (6-O-MMAGlc) and characterized. The influence of poly(6-O-MMAGlc) on the formation of hen egg white lysozyme (HEWL) amyloid fibril was detailly investigated, indicating that the polymer could effectively inhibit the formation of HEWL amyloid fibril. The formation kinetics of HEWL amyloid fibril with the presence of poly(6-O-MMAGlc) was measured by Thioflavin T (ThT) fluorescence method, demonstrating that poly(6-O-MMAGlc) could significantly inhibit the amyloid fibril formation of HEWL in a dose-dependent manner. The inhibitory result was furtherly illustrated by congo red (CR) binding assay, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence assay, circular dichroism (CD) spectroscopy and transmission electron microscope (TEM).
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Amiloide/química , Proteínas do Ovo/química , Glucosídeos/síntese química , Muramidase/química , Amiloide/metabolismo , Animais , Galinhas , Proteínas do Ovo/metabolismo , Glucosídeos/farmacologia , Metacrilatos/química , Muramidase/metabolismo , Multimerização Proteica/efeitos dos fármacosRESUMO
Neuregulin 4 (Nrg4) is a brown fat-enriched endocrine factor that exerts beneficial metabolic effects on insulin resistance and hepatic steatosis. Autophagy is a mechanism that is essential for preventing hepatic steatosis. The aim of this study was to explore whether Nrg4 ameliorates hepatic steatosis by inducing autophagy. Aged C57BL/6 mice were maintained on a high fat diet with or without Nrg4 intervention for 3 months. Lipid accumulation in the liver was investigated. Autophagy related protein levels along with related signaling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured L-02 cells. Nrg4 decreased high-fat induced intrahepatic lipid content both in vivo and in vitro. Autophagy level in the liver also decreased in obese mice and Nrg4 intervention reactivated autophagy. Further, Nrg4 intervention was found to have activated autophagy via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Moreover, when the AMPK/mTOR pathway was suppressed or autophagy was inhibited, the beneficial effects of Nrg4 intervention on hepatic steatosis were diminished. These results indicated that Nrg4 intervention attenuated hepatic steatosis by promoting autophagy in the liver of aged obese mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signaling pathway.
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Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Neurregulinas/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Serina-Treonina Quinases TOR/metabolismo , Fatores Etários , Animais , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de SinaisRESUMO
Bone metastasis, a clinical complication of patients with advanced breast cancer, seriously reduces the quality of life. To avoid destruction of the bone matrix, current treatments focus on inhibiting the cancer cell growth and the osteoclast activity through combination therapy. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to treat bone metastasis. Here, a bone-targeted nanoplatform was developed using gold nanorods enclosed inside mesoporous silica nanoparticles (Au@MSNs) which were then conjugated with zoledronic acid (ZOL). The nanoparticles (Au@MSNs-ZOL) not only showed bone-targeting ability in vivo but also inhibited the formation of osteoclast-like cells and promoted osteoblast differentiation in vitro. The combination of Au@MSNs-ZOL and photothermal therapy (PTT), triggered by near-infrared irradiation, inhibited tumor growth both in vitro and in vivo and relieved pain and bone resorption in vivo by inducing apoptosis in cancer cells and improving the bone microenvironment. This single nanoplatform combines ZOL and PTT to provide an exciting strategy for treating breast cancer bone metastasis.
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Antineoplásicos/farmacologia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias da Mama/terapia , Nanopartículas/química , Fototerapia , Ácido Zoledrônico/farmacologia , Células 3T3-L1 , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Neoplasias Experimentais/patologia , Neoplasias Experimentais/secundário , Neoplasias Experimentais/terapia , Imagem Óptica , Tamanho da Partícula , Porosidade , Propriedades de Superfície , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Ácido Zoledrônico/administração & dosagemRESUMO
Fragile X syndrome (FXS), the leading cause of inherited forms of mental retardation and autism, is caused by the transcriptional silencing of fmr1 encoding the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is a widely expressed, but primarily in the brain and testis, and associated approximately 4% of transcripts. Macro-orchidism is a common symptom associated with FXS both in humans and mice. Thus, we analyze the pooled samples of cerebral cortex, hippocampus and testis from both the fmr1-KO and wild-type mice by a LC-MS/MS proteomic study. Among the identified proteins, most of those showing significant changes in expression were up- or downregulated in the absence of FMRP. Proteins (FMRP, RPS8, RPL23a and ATPIF1, RPL6, GAP43, MTCH2 and MPZ in brain, and FMRP, CAH3, AKR1B7 and C9 in testis) identified by MS/MS were also verified by Western blotting. The Gene Ontology and WikiPathways analysis revealed that the differentially expressed proteins were clustered in the polyribosome and RNA-binding protein categories in both cerebral cortex and hippocampus, but not in testis. Although this study was limited by the little number of samples, our results provide detailed insights into the ribosomal protein profiles of cerebral cortex, hippocampus and testis in the absence of FMRP. Our studies also provide a better understanding of protein profile changes and the underlying dysregulated pathways arising from fmr1 silencing in FXS.
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Córtex Cerebral/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Hipocampo/metabolismo , Proteoma , Proteínas Ribossômicas/metabolismo , Testículo/metabolismo , Animais , Western Blotting , Cromatografia Líquida , Modelos Animais de Doenças , Masculino , Espectrometria de Massas , Camundongos Knockout , ProteômicaRESUMO
OBJECTIVE: To investigate the differences in imaging quality and radiation dose in CT pulmonary angiography (CTPA) by using fast-kV switching dual energy CT imaging and 3D Smart mA modulation at different body mass indices (BMIs) and at different noise index (NI) values with an adaptive statistical iterative reconstruction (ASIR) algorithm. METHODS: Four hundred patients who underwent CTPA were equally divided into two groups: A (18.5âkg/m2 ⦠BMI <24.9âkg/m2) and B (24.9âkg/m2 ⦠BMI ⦠4.9âkg/m2). The groups were randomly subdivided into four subgroups (nâ=â50): A1-A4 and B1-B4. The patients in subgroups A1 and B1 underwent fast-kV switching dual energy CT imaging. The other patients underwent 3D Smart mA modulation with the ASIR algorithm at NI values 26, 36, and 46 for A2/B2, A3/B3, and A4/B4, respectively. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of all images were calculated after CTPA. Images were then subjectively evaluated using a 5-point scale. The volume CT dose index and dose-length product (DLP) were recorded and their means calculated. The DLP was converted to the effective dose (ED). RESULTS: In group A, the SNR, CNR, and subjective image scores showed no statistical differences (Pâ>â0.05). The ED in subgroup A4 was 67.12% and 31.53% lower than that in A1 and A2, respectively. In group B, the variables showed no significant differences between the subgroups B3, B1, and B2 (Pâ>â0.05). The ED in subgroup B3 was 50.12% and 35.95% lower than that in B1 and B2, respectively. CONCLUSIONS: Setting different NI values according to BMIs and applying the ASIR algorithm can more effectively reduce the radiation dose in CTPA than in fast-kV switching dual energy CT, while maintaining image quality. Imaging may be performed at NIâ=â46 in patients with lower BMI (group A) and at NIâ=â36 in patients with higher BMI (group B).