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1.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892173

RESUMO

A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The Unc80 gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of Unc80 and its editing, however, are still largely undefined. In this study, we first demonstrated that Unc80 editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate Unc80 knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant (Unc80G/G) exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" (Unc80S/S) counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of Unc80G/G mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both Unc80 deficient (Unc80+/-) and Unc80S/S mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of Unc80 editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of Unc80's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.


Assuntos
Adenosina Desaminase , Percepção Olfatória , Edição de RNA , Animais , Camundongos , Percepção Olfatória/fisiologia , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Bulbo Olfatório/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Neurônios/metabolismo , Sistemas CRISPR-Cas , Masculino , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
2.
Diabetologia ; 66(5): 913-930, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36692509

RESUMO

AIMS/HYPOTHESIS: The mitochondrial chaperonin heat shock protein (HSP) 60 is indispensable in protein folding and the mitochondrial stress response; however, its role in nutrient metabolism remains uncertain. This study investigated the role of HSP60 in diet-induced non-alcoholic fatty liver disease (NAFLD). METHODS: We studied human biopsies from individuals with NAFLD, murine high-fat-diet (HFD; a diet with 60% energy from fat)-induced obesity (DIO), transgenic (Tg) mice overexpressing Hsp60 (Hsp60-Tg), and human HepG2 cells transfected with HSP60 cDNA or with HSP60 siRNA. Histomorphometry was used to assess hepatic steatosis, biochemistry kits were used to measure insulin resistance and glucose tolerance, and an automated home cage phenotyping system was used to assess energy expenditure. Body fat was assessed using MRI. Macrophage infiltration, the lipid oxidation marker 4-hydroxy-2-nonenal (4-HNE) and the oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were detected using immunohistochemistry. Intracellular lipid droplets were evaluated by Nile red staining. Expression of HSP60, and markers of lipogenesis and fatty acid oxidation were quantified using RT-PCR and immunoblotting. Investigations were analysed using the two-way ANOVA test. RESULTS: Decreased HSP60 expression correlated with severe steatosis in human NAFLD biopsies and murine DIO. Hsp60-Tg mice developed less body fat, had reduced serum triglyceride levels, lower levels of insulin resistance and higher serum adiponectin levels than wild-type mice upon HFD feeding. Respiratory quotient profile indicated that fat in Hsp60-Tg mice may be metabolised to meet energy demands. Hsp60-Tg mice showed amelioration of HFD-mediated hepatic steatosis, M1/M2 macrophage dysregulation, and 4-HNE and 8-OHdG overproduction. Forced HSP60 expression reduced the mitochondrial unfolded protein response, while preserving mitochondrial respiratory complex activity and enhancing fatty acid oxidation. Furthermore, HSP60 knockdown enhanced intracellular lipid formation and loss of sirtuin 3 (SIRT3) signalling in HepG2 cells upon incubation with palmitic acid (PA). Forced HSP60 expression improved SIRT3 signalling and repressed PA-mediated intracellular lipid formation. SIRT3 inhibition compromised HSP60-induced promotion of AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferator-activated receptor α (PPARα levels), while also decreasing levels of fatty acid oxidation markers. CONCLUSION/INTERPRETATION: Mitochondrial HSP60 promotes fatty acid oxidation while repressing mitochondrial stress and inflammation to ameliorate the development of NAFLD by preserving SIRT3 signalling. This study reveals the hepatoprotective effects of HSP60 and indicates that HSP60 could play a fundamental role in the development of therapeutics for NAFLD or type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Sirtuína 3 , Animais , Humanos , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Resistência à Insulina/genética , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo
3.
J Nanobiotechnology ; 20(1): 157, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35337331

RESUMO

BACKGROUND: Late diagnosis of lung cancer is one of the leading causes of higher mortality in lung cancer patients worldwide. Significant research attention has focused on the use of magnetic resonance imaging (MRI) based nano contrast agents to efficiently locate cancer tumors for surgical removal or disease diagnostics. Although contrast agents offer significant advantages, further clinical applications require improvements in biocompatibility, biosafety and efficacy. RESULTS: To address these challenges, we fabricated ultra-fine Iron Carbonate Nanoparticles (FeCO3 NPs) for the first time via modified literature method. Synthesized NPs exhibit ultra-fine size (~ 17 nm), good dispersibility and excellent stability in both aqueous and biological media. We evaluated the MR contrast abilities of FeCO3 NPs and observed remarkable T2 weighted MRI contrast in a concentration dependent manner, with a transverse relaxivity (r2) value of 730.9 ± 4.8 mM-1 S-1at 9.4 T. Moreover, the r2 values of present FeCO3 NPs are respectively 1.95 and 2.3 times higher than the clinically approved contrast agents Resovist® and Friedx at same 9.4 T MR scanner. FeCO3 NPs demonstrate an enhanced T2 weighted contrast for in vivo lung tumors within 5 h of post intravenous administration with no apparent systemic toxicity or induction of inflammation observed in in vivo mice models. CONCLUSION: The excellent biocompatibility and T2 weighted contrast abilities of FeCO3 NPs suggest potential for future clinical use in early diagnosis of lung tumors.


Assuntos
Neoplasias Pulmonares , Imageamento por Ressonância Magnética , Animais , Meios de Contraste , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Magnetismo , Camundongos , Fenômenos Físicos
4.
Int J Mol Sci ; 23(9)2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35563108

RESUMO

Neurogenic inflammation and central sensitization play a role in chronic prostatitis/chronic pelvic pain syndrome. We explore the molecular effects of low-intensity shock wave therapy (Li-ESWT) on central sensitization in a capsaicin-induced prostatitis rat model. Male Sprague-Dawley rats underwent intraprostatic capsaicin (10 mM, 0.1 cm3) injections. After injection, the prostate received Li-ESWT twice, one day apart. The L6 dorsal root ganglion (DRG)/spinal cord was harvested for histology and Western blotting on days 3 and 7. The brain blood oxygenation level-dependent (BOLD) functional images were evaluated using 9.4 T fMRI before the Li-ESWT and one day after. Intraprostatic capsaicin injection induced increased NGF-, BDNF-, and COX-2-positive neurons in the L6 DRG and increased COX-2, NGF, BDNF, receptor Trk-A, and TRPV1 protein expression in the L6 DRG and the dorsal horn of the L6 spinal cord, whose effects were significantly downregulated after Li-ESWT on the prostate. Intraprostatic capsaicin injection increased activity of BOLD fMRI responses in brain regions associated with pain-related responses, such as the caudate putamen, periaqueductal gray, and thalamus, whose BOLD signals were reduced after Li-ESWT. These findings suggest a potential mechanism of Li-ESWT on modulation of peripheral and central sensitization for treating CP/CPPS.


Assuntos
Tratamento por Ondas de Choque Extracorpóreas , Prostatite , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Capsaicina , Ciclo-Oxigenase 2/metabolismo , Gânglios Espinais/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Fator de Crescimento Neural/metabolismo , Prostatite/induzido quimicamente , Prostatite/diagnóstico por imagem , Prostatite/terapia , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
5.
FASEB J ; 34(2): 3267-3288, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908036

RESUMO

TIAM2S, the short form of human T-cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non-neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1-derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S-TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well-differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole-transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S-knockdown (TIAM2S-KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin-related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S-KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the non-oncogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior.


Assuntos
Encéfalo/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Locomoção , Serotonina/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Crescimento Neuronal , Plasticidade Neuronal
6.
Neurourol Urodyn ; 38(8): 2159-2169, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31541501

RESUMO

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.


Assuntos
Cistite/induzido quimicamente , Medicamentos de Ervas Chinesas/farmacologia , Ketamina/efeitos adversos , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Animais , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Cistite/metabolismo , Cistite/patologia , Cistite/fisiopatologia , Feminino , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Neuroimagem Funcional , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Imageamento por Ressonância Magnética , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Células Receptoras Sensoriais , Substância P/efeitos dos fármacos , Substância P/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária Hiperativa/fisiopatologia , Urotélio/metabolismo
7.
Nano Lett ; 16(6): 3493-9, 2016 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-27148804

RESUMO

The hypoxia region in a solid tumor has been recognized as a complex microenvironment revealing very low oxygen concentration and deficient nutrients. The hypoxic environment reduces the susceptibility of the cancer cells to anticancer drugs, low response of free radicals, and less proliferation of cancer cells in the center of the solid tumors. However, the reduced oxygen surroundings provide an appreciable habitat for anaerobic bacteria to colonize. Here, we present the bacteria-mediated targeting hypoxia to offer the expandable spectra for diagnosis and therapy in cancer diseases. Two delivery approaches involving a cargo-carrying method and an antibody-directed method were designed to deliver upconversion nanorods for imaging and Au nanorods for photothermal ablation upon near-infrared light excitation for two forms of the anaerobic Bifidobacterium breve and Clostridium difficile. The antibody-directed strategy shows the most effective treatment giving stronger imaging and longer retention period and effective therapy to completely remove tumors.


Assuntos
Bifidobacterium breve/fisiologia , Clostridioides difficile/fisiologia , Portadores de Fármacos , Nanotubos/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Anticorpos/química , Bifidobacterium breve/imunologia , Linhagem Celular Tumoral , Clostridioides difficile/imunologia , Liberação Controlada de Fármacos , Ouro/química , Xenoenxertos , Humanos , Luz , Camundongos Endogâmicos C57BL , Camundongos Nus , Tamanho da Partícula , Fotoquimioterapia , Espectrometria de Fluorescência , Hipóxia Tumoral
8.
Biochem Biophys Res Commun ; 473(4): 1026-1032, 2016 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-27067050

RESUMO

Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases.


Assuntos
Interleucina-33/biossíntese , Rim/metabolismo , Rim/patologia , Animais , Proliferação de Células , Fibrose , Regulação da Expressão Gênica , Proteína 1 Semelhante a Receptor de Interleucina-1/biossíntese , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Rim/lesões , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Miofibroblastos/metabolismo , Regulação para Cima , Obstrução Ureteral/complicações
9.
J Nanobiotechnology ; 14(1): 75, 2016 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-27884158

RESUMO

BACKGROUND: Fingermarks are one of the most important and useful forms of physical evidence in forensic investigations. However, latent fingermarks are not directly visible, but can be visualized due to the presence of other residues (such as inorganic salts, proteins, polypeptides, enzymes and human metabolites) which can be detected or recognized through various strategies. Convenient and rapid techniques are still needed to provide obvious contrast between the background and the fingermark ridges and to then visualize latent fingermark with a high degree of selectivity and sensitivity. RESULTS: In this work, lysozyme-binding aptamer-conjugated Au nanoparticles (NPs) are used to recognize and target lysozyme in the fingermark ridges, and Au+-complex solution is used as a growth agent to reduce Au+ from Au+ to Au0 on the surface of the Au NPs. Distinct fingermark patterns were visualized on a range of professional forensic within 3 min; the resulting images could be observed by the naked eye without background interference. The entire processes from fingermark collection to visualization only entails two steps and can be completed in less than 10 min. The proposed method provides cost and time savings over current fingermark visualization methods. CONCLUSIONS: We report a simple, inexpensive, and fast method for the rapid visualization of latent fingermarks on the non-porous substrates using Au seed-mediated enhancement. Au seed-mediated enhancement is used to achieve the rapid visualization of latent fingermarks on non-porous substrates by the naked eye without the use of expensive or sophisticated instruments. The proposed approach offers faster detection and visualization of latent fingermarks than existing methods. The proposed method is expected to increase detection efficiency for latent fingermarks and reduce time requirements and costs for forensic investigations.


Assuntos
Aptâmeros de Nucleotídeos/química , Dermatoglifia , Ciências Forenses/métodos , Ouro/química , Nanopartículas Metálicas/química , Humanos , Muramidase
10.
Phys Chem Chem Phys ; 17(45): 30598-605, 2015 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-26524324

RESUMO

Hydrogen gas will play an important role in the future since it could be a replacement for gasoline, heating oil, natural gas, and other fuels. In previous reports ammonia (NH3), which has a high hydrogen content, provides a promising mode for the transferring and storing of hydrogen for its on-site generation. Therefore, the dehydrogenation of NH3 on a metal surface has been studied widely in the last few decades. In our study, we employed monolayer tungsten metal to modify the Fe(111) surface, denoted as W@Fe(111), and calculated the adsorption and dehydrogenation behaviors of NH3 on W@Fe(111) surface via first-principles calculations based on density functional theory (DFT). The three adsorption sites of the surface, top (T), 3-fold-shallow (S), and 3-fold-deep (D) were considered. The most stable structure of the NHx (x = 0-3) species on the surface of W@Fe(111) have been predicted. The calculated activation energies for NHx (x = 1-3) dehydrogenations are 19.29 kcal mol(-1) (for H2N-H bond activation), 29.17 kcal mol(-1) (for HN-H bond activation) and 27.94 kcal mol(-1) (for N-H bond activation), and the entire process is exothermic by 33.05 kcal mol(-1). To gain detailed knowledge of the catalytic processes of the NH3 molecule on the W@Fe(111) surface, the physical insights between the adsorbate/substrate interaction and interface morphology were subjected to a detailed electronic analysis.

11.
J Am Chem Soc ; 136(28): 10062-75, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-24953310

RESUMO

A new multifunctional nanoparticle to perform a near-infrared (NIR)-responsive remote control drug release behavior was designed for applications in the biomedical field. Different from the previous studies in formation of Fe3O4-Au core-shell nanoparticles resulting in a spherical morphology, the heterostructure with polyhedral core and shell was presented with the truncated octahedral Fe3O4 nanoparticle as the core over a layer of trisoctahedral Au shell. The strategy of Fe3O4@polymer@Au was adopted using poly-l-lysine as the mediate layer, followed by the subsequent seeded growth of Au nanoparticles to form a Au trisoctahedral shell. Fe3O4@Au trisoctahedra possess high-index facets of {441}. To combine photothermal and chemotherapy in a remote-control manner, the trisoctahedral core-shell Fe3O4@Au nanoparticles were further covered with a mesoporous silica shell, yielding Fe3O4@Au@mSiO2. The bondable oligonucleotides (referred as dsDNA) were used as pore blockers of the mesoporous silica shell that allowed the controlled release, resulting in a NIR-responsive DNA-gated Fe3O4@Au@mSiO2 nanocarrier. Taking advantage of the magnetism, remotely triggered drug release was facilitated by magnetic attraction accompanied by the introduction of NIR radiation. DNA-gated Fe3O4@Au@mSiO2 serves as a drug control and release carrier that features functions of magnetic target, MRI diagnosis, and combination therapy through the manipulation of a magnet and a NIR laser. The results verified the significant therapeutic effects on tumors with the assistance of combination therapy consisting of magnetic guidance and remote NIR control.


Assuntos
Compostos Férricos/química , Ouro/química , Nanoestruturas/química , Oligonucleotídeos/química , Dióxido de Silício/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Magnetismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Tamanho da Partícula
12.
Neurobiol Dis ; 71: 292-304, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25131447

RESUMO

Pressor response after stroke commonly leads to early death or susceptibility to stroke recurrence, and detailed mechanisms are still lacking. We assessed the hypothesis that the renin-angiotensin system contributes to pressor response after stroke by differential modulation of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) in the rostral ventrolateral medulla (RVLM), a key brain stem site that maintains blood pressure. We also investigated the beneficial effects of a novel renin inhibitor, aliskiren, against stroke-elicited pressor response. Experiments were performed in male adult Sprague-Dawley rats. Stroke induced by middle cerebral artery occlusion elicited significant pressor response, accompanied by activation of angiotensin II (Ang II)/type I receptor (AT1R) and AT2R signaling, depression of Ang-(1-7)/MasR and Ang IV/AT4R cascade, alongside augmentation of MCP-1/C-C chemokine receptor 2 (CCR2) signaling and neuroinflammation in the RVLM. Stroke-elicited pressor response was significantly blunted by antagonism of AT1R, AT2R or MCP-1/CCR2 signaling, and eliminated by applying Ang-(1-7) or Ang IV into the RVLM. Furthermore, stroke-activated MCP-1/CCR2 signaling was enhanced by AT1R and AT2R activation, and depressed by Ang-(1-7)/MasR and Ang IV/AT4R cascade. Aliskiren inhibited stroke-elicited pressor response via downregulating MCP-1/CCR2 activity and reduced neuroinflammation in the RVLM; these effects were potentiated by Ang-(1-7) or Ang IV. We conclude that whereas Ang II/AT1R or Ang II/AT2R signaling in the brain stem enhances, Ang-(1-7)/MasR or Ang IV/AT4R antagonizes pressor response after stroke by differential modulations of MCP-1 in the RVLM. Furthermore, combined administration of aliskiren and Ang-(1-7) or Ang IV into the brain stem provides more effective amelioration of stroked-induced pressor response.


Assuntos
Angiotensinas/metabolismo , Pressão Sanguínea/fisiologia , Tronco Encefálico/metabolismo , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica/fisiologia , Acidente Vascular Cerebral/patologia , Análise de Variância , Angiotensinas/genética , Animais , Isquemia Encefálica/complicações , Quimiocina CCL2/genética , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Exame Neurológico , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo
13.
J Gerontol A Biol Sci Med Sci ; 79(11)2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39093820

RESUMO

TIAM Rac1-associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmark expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor image analyses were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.


Assuntos
Envelhecimento , Fatores de Troca do Nucleotídeo Guanina , Hipocampo , Transtornos da Memória , Camundongos Transgênicos , Córtex Pré-Frontal , Memória Espacial , Animais , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Transtornos da Memória/metabolismo , Transtornos da Memória/genética , Memória Espacial/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Córtex Pré-Frontal/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Envelhecimento/genética , Humanos , Masculino
14.
APL Bioeng ; 8(3): 036110, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39165611

RESUMO

Cartilage damage, a common cause of osteoarthritis, requires medical imaging for accurate diagnosis of pathological changes. However, current instruments can acquire limited imaging information due to sensitivity and resolution issues. Therefore, multimodal imaging is considered an alternative strategy to provide valuable images and analyzes from different perspectives. Among all biomaterials, gold nanomaterials not only exhibit outstanding benefits as drug carriers, in vitro diagnostics, and radiosensitizers, but are also widely used as contrast agents, particularly for tumors. However, their potential for imaging cartilage damage is rarely discussed. In this study, we developed a versatile iodinated gadolinium-gold nanomaterial, AuNC@BSA-Gd-I, and its radiolabeled derivative, AuNC@BSA-Gd-131I, for cartilage detection. With its small size, negative charge, and multimodal capacities, the probe can penetrate damaged cartilage and be detected or visualized by computed tomography, MRI, IVIS, and gamma counter. Additionally, the multimodal imaging potential of AuNC@BSA-Gd-I was compared to current multifunctional gold nanomaterials containing similar components, including anionic AuNC@BSA, AuNC@BSA-I, and AuNC@BSA-Gd as well as cationic AuNC@CBSA. Due to their high atomic numbers and fluorescent emission, AuNC@BSA nanomaterials could provide fundamental multifunctionality for imaging. By further modifying AuNC@BSA with additional imaging materials, their application could be extended to various types of medical imaging instruments. Nonetheless, our findings showed that each of the current nanomaterials exhibited excellent abilities for imaging cartilage with their predominant imaging modalities, but their versatility was not comparable to that of AuNC@BSA-Gd-I. Thus, AuNC@BSA-Gd-I could be served as a valuable tool in multimodal imaging strategies for cartilage assessment.

15.
Neuroimage ; 82: 190-9, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23747290

RESUMO

A clinical hallmark of hypertension is impairment of the cardiac vagal baroreflex, which maintains stable blood pressure and heart rate under physiological conditions. There is also evidence that oxidative stress in the brain is associated with neurogenic hypertension. We tested the hypothesis that an augmented superoxide level in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents, contributes to the depression of cardiac vagal baroreflex by disrupting the connectivity between the NTS and the nucleus ambiguus (NA), the origin of the vagus nerve, during neurogenic hypertension. An experimental model of neurogenic hypertension that employed intracerebroventricular infusion of angiotensin II in male adult C57BL/6 mice was used. Based on tractographic evaluations using magnetic resonance imaging/diffusion tensor imaging of the medulla oblongata in the brain stem, we found that the connectivity between the NTS and NA was disrupted in neurogenic hypertension, concurrent with impairment of the cardiac vagal baroreflex as detected by radiotelemetry. We further found that the disrupted NTS-NA connectivity was reversible, and was related to oxidative stress induced by augmented levels of NADPH oxidase-generated superoxide in the NTS. We conclude that depression of the cardiac vagal baroreflex induced by oxidative stress in the NTS in the context of neurogenic hypertension may be manifested in the form of dynamic alterations in the connectivity between the NTS and NA.


Assuntos
Barorreflexo/fisiologia , Hipertensão/fisiopatologia , Vias Neurais/fisiopatologia , Estresse Oxidativo/fisiologia , Núcleo Solitário/fisiopatologia , Animais , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador , Imunoprecipitação , Imageamento por Ressonância Magnética , Masculino , Bulbo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Nervo Vago/fisiopatologia
16.
Front Bioeng Biotechnol ; 11: 1272492, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37877039

RESUMO

Gefitinib (GEF) is an FDA-approved anti-cancer drug for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). However, the efficacy of anticancer drugs is limited due to their non-specificity, lower accumulation at target sites, and systemic toxicity. Herein, we successfully synthesized a modified GEF (mGEF) drug and conjugated to Iron oxide nanoparticles (Fe3O4 NPs) for the treatment of NSCLC via magnetic resonance (MR) image-guided drug delivery. A traditional EDC coupling pathway uses mGEF to directly conjugate to Fe3O4 NPs to overcom the drug leakage issues. As a result, we found in vitro drug delivery on mGEF- Fe3O4 NPs exhibits excellent anticancer effects towards the PC9 cells selectively, with an estimated IC 50 value of 2.0 µM. Additionally, in vivo MRI and PET results demonstrate that the NPs could accumulate in tumor-specific regions with localized cell growth inhibition. Results also revealed that outer tumor region exhibiting a stronger contrast than the tinner tumor region which may due necrosis in inner tumor region. In vivo biodistribution further confirms Fe3O4 NPs are more biocompatible and are excreated after the treatment. Overall, we believe that this current strategy of drug modification combined with chemical conjugation on magnetic NPs will lead to improved cancer chemotherapy as well as understanding the tumor microenvironments for better therapeutic outcomes.

17.
Biomater Sci ; 11(6): 2177-2185, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36740962

RESUMO

Biosafety is a critical issue for the successful translocation of nanomaterial-based therapeutic/diagnostic agents from bench to bedside. For instance, after the withdrawal of clinically approved magnetic resonance (MR) imaging contrast agents (CAs) due to their biosafety issues, there is a massive demand for alternative, efficient, and biocompatible MR contrast agents for future MRI clinical applications. To this end, here we successfully demonstrate the in vivo MR contrast abilities and biocompatibilities of ligand-free FeSn2 alloy NPs for tracking in vivo lung tumors. In vitro and in vivo results reveal the FeSn2 alloy NPs acting as appreciable T2 weighted MR contrast agents to locate tumors. The construction of iron (Fe) on biocompatible tin (Sn) greatly facilitates the reduction of the intrinsic toxicities of Fe in vivo resulting in no significant abnormalities in liver and kidney functions. Therefore, we envision that constructing ligand-free alloy NPs will be a promising candidate for tracking in vivo tumors in future clinical applications.


Assuntos
Neoplasias Pulmonares , Nanopartículas , Humanos , Meios de Contraste , Imageamento por Ressonância Magnética/métodos , Ferro , Neoplasias Pulmonares/diagnóstico por imagem
18.
Nat Nanotechnol ; 18(12): 1492-1501, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37537274

RESUMO

Dynamic therapies have potential in cancer treatments but have limitations in efficiency and penetration depth. Here a membrane-integrated liposome (MIL) is created to coat titanium dioxide (TiO2) nanoparticles to enhance electron transfer and increase radical production under low-dose X-ray irradiation. The exoelectrogenic Shewanella oneidensis MR-1 microorganism presents an innate capability for extracellular electron transfer (EET). An EET-mimicking photocatalytic system is created by coating the TiO2 nanoparticles with the MIL, which significantly enhances superoxide anions generation under low-dose (1 Gy) X-ray activation. The c-type cytochromes-constructed electron channel in the membrane mimics electron transfer to surrounding oxygen. Moreover, the hole transport in the valence band is also observed for water oxidation to produce hydroxyl radicals. The TiO2@MIL system is demonstrated against orthotopic liver tumours in vivo.


Assuntos
Lipossomos , Shewanella , Elétrons , Fusão de Membrana , Transporte de Elétrons , Oxirredução
19.
Nat Commun ; 14(1): 4709, 2023 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543632

RESUMO

Chemodynamic therapy (CDT) uses the Fenton or Fenton-like reaction to yield toxic ‧OH following H2O2 → ‧OH for tumoral therapy. Unfortunately, H2O2 is often taken from the limited endogenous supply of H2O2 in cancer cells. A water oxidation CoFe Prussian blue (CFPB) nanoframes is presented to provide sustained, external energy-free self-supply of ‧OH from H2O to process CDT and/or photothermal therapy (PTT). Unexpectedly, the as-prepared CFPB nanocubes with no near-infrared (NIR) absorption is transformed into CFPB nanoframes with NIR absorption due to the increased Fe3+-N ≡ C-Fe2+ composition through the proposed proton-induced metal replacement reactions. Surprisingly, both the CFPB nanocubes and nanoframes provide for the self-supply of O2, H2O2, and ‧OH from H2O, with the nanoframe outperforming in the production of ‧OH. Simulation analysis indicates separated active sites in catalyzation of water oxidation, oxygen reduction, and Fenton-like reactions from CFPB. The liposome-covered CFPB nanoframes prepared for controllable water-driven CDT for male tumoral mice treatments.


Assuntos
Nanopartículas , Neoplasias , Masculino , Animais , Camundongos , Domínio Catalítico , Peróxido de Hidrogênio , Catálise , Água , Linhagem Celular Tumoral
20.
Molecules ; 17(8): 8762-72, 2012 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-22832878

RESUMO

A series of amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives was synthesized from isatoic anhydride, and their cytotoxicity against the MRC-5 and Mahlavu cell lines was evaluated. The results suggest that compound PBDT-7i with the meta-trifluoromethylbenzoyl substituent can selectively inhibit the growth of Mahlavu cells and has low toxicity towards MRC-5 cells.


Assuntos
Antineoplásicos/síntese química , Benzodiazepinas/síntese química , Pirróis/síntese química , Triazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Benzodiazepinas/farmacologia , Benzodiazepinas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Pirróis/farmacologia , Pirróis/toxicidade , Sincalida/metabolismo , Triazóis/farmacologia , Triazóis/toxicidade
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