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1.
Rom J Morphol Embryol ; 63(2): 357-367, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374141

RESUMO

OBJECTIVES: This study aims to establish a correlation between placental histopathological and immunohistochemical (IHC) changes and preterm birth with fetal growth restriction (FGR, formerly called intrauterine growth restriction - IUGR). PATIENTS, MATERIALS, AND METHODS: This prospective study was performed on a group of 30 parturients, with singleton gestation, of which 15 patients gave birth at term, and the other 15 patients gave birth prematurely. After the statistical correlation of the clinical and demographic data with premature birth (PB) and term birth (TB), we performed histological and IHC research on the respective placentae. To observe normal and pathological microscopic placental structures, we used the Hematoxylin-Eosin (HE) and Periodic Acid Schiff-Hematoxylin (PAS-H) classical stainings, but also special immunostaining with anti-cluster of differentiation 34 (CD34) and anti-vascular endothelial growth factor (VEGF) antibodies. RESULTS: We found a statistically significant difference between the TB∕PB categories and the age of the patients, their antepartum weight, the weight of the newborns, and the placenta according to the sex of the newborn. Histological analysis revealed in the case of TB, small areas of perivillous amyloid deposition, with the significant extension of these areas both intravillous and perivillous in the case of PB. Massive intravillous calcifications, syncytial knots, and intravillous vascular thrombosis were also frequently present in PB. With PAS-H staining were highlighted the intra∕extravillous vascular basement membranes, but especially the massive fibrin deposits rich in glycosaminoglycans. By the IHC technique with the anti-CD34 antibody, we noticed the numerical vascular density, higher in the case of TB, but in the case of PB, there were large areas of placental infarction, with a lack of immunostaining in these areas. Through the anti-VEGF antibody, we observed the presence of signal proteins that determined and stimulated the formation of neoformation vessels in the areas affected by the lack of post-infarction placental vascularization. We observed a highly significant difference between placental vascular density between TB∕PB and newborn weight, sex, or placental weight. CONCLUSIONS: Any direct proportional link between the clinical maternal-fetal and histological elements yet studied must be considered. Thus, establishing an antepartum risk group can prevent a poor pregnancy outcome.


Assuntos
Complicações na Gravidez , Nascimento Prematuro , Humanos , Recém-Nascido , Gravidez , Feminino , Placenta/patologia , Nascimento Prematuro/metabolismo , Nascimento Prematuro/patologia , Estudos Prospectivos , Hematoxilina/metabolismo , Nascimento a Termo , Retardo do Crescimento Fetal/patologia , Complicações na Gravidez/patologia , Infarto/patologia
2.
Ren Fail ; 44(1): 1780-1790, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36285371

RESUMO

PURPOSE: Glomerular mesangial cell (GMC) dysfunction plays a vital role in the pathogenesis of diabetic kidney disease (DKD). Transient receptor potential canonical 6 (TRPC6) has been demonstrated to be involved in the development of DKD. However, the underlying mechanism remains unclear. The present study investigated the role of TRPC6 in GMC dysfunction and the related mechanism. METHODS: Diabetic rats and cultured GMCs were used in the experiment. The diabetic rat model was created by intraperitoneal injection of streptozotocin. Protein and mRNA levels were assessed by Western blotting and quantitative RT-PCR, respectively. Histological changes in the kidneys were observed by immunochemistry and hematoxylin and eosin. TRPC6 knockdown was achieved by adenovirus-mediated TRPC6 shRNA delivery in vivo and TRPC6 siRNA transfection in vitro. RESULTS: TRPC6 expression was increased in diabetic rat kidneys. Knockdown of TRPC6 attenuated diabetes-induced kidney functional deterioration. In addition, the increases in extracellular matrix components, including collagen IV, collagen I, and fibronectin production, as well as NFAT2 expression were also suppressed. In cultured GMCs, high glucose (25 mM, HG) treatment increased the expression of TRPC6. Knockdown of TRPC6 alleviated HG-induced increases in collagen IV, fibronectin, and NFAT2 expression. Knockdown of NFAT2 also inhibited the upregulation of proteins, including collagen IV and fibronectin, in HG-treated GMCs. CONCLUSION: These results demonstrate that inhibition of TRPC6/NFAT2 signaling attenuates GMC dysfunction and the development of DKD and suggest that pharmacological targeting of TRPC6/NFAT2 in GMCs may provide beneficial effects for DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ratos , Animais , Células Mesangiais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Fibronectinas/metabolismo , Canal de Cátion TRPC6/genética , Canal de Cátion TRPC6/metabolismo , RNA Interferente Pequeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Linfócitos T , Glucose/metabolismo , RNA Mensageiro/metabolismo , Colágeno/metabolismo , Células Cultivadas
3.
Int J Chron Obstruct Pulmon Dis ; 17: 2383-2399, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185172

RESUMO

Objective: Skeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron-dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction. Methods: A mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes. Results: Compared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe2+, lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH. Conclusion: CS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction.


Assuntos
Ferroptose , Doença Pulmonar Obstrutiva Crônica , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/uso terapêutico , Hematoxilina/metabolismo , Hematoxilina/uso terapêutico , Ferro , Peróxidos Lipídicos/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Miostatina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
J Orthop Surg Res ; 17(1): 440, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195913

RESUMO

BACKGROUND: Conditions affecting skeletal muscle, such as chronic rotator cuff tears, low back pain, dystrophies, and many others, often share changes in muscle phenotype: intramuscular adipose and fibrotic tissue increase while contractile tissue is lost. The underlying changes in cell populations and cell ratios observed with these phenotypic changes complicate the interpretation of tissue-level transcriptional data. Novel single-cell transcriptomics has limited capacity to address this problem because muscle fibers are too long to be engulfed in single-cell droplets and single nuclei transcriptomics are complicated by muscle fibers' multinucleation. Therefore, the goal of this project was to evaluate the potential and challenges of a spatial transcriptomics technology to add dimensionality to transcriptional data in an attempt to better understand regional cellular activity in heterogeneous skeletal muscle tissue. METHODS: The 3' Visium spatial transcriptomics technology was applied to muscle tissue of a rabbit model of rotator cuff tear. Healthy control and tissue collected at 2 and 16 weeks after tenotomy was utilized and freshly snap frozen tissue was compared with tissue stored for over 6 years to evaluate whether this technology is retrospectively useful in previously acquired tissues. Transcriptional information was overlayed with standard hematoxylin and eosin (H&E) stains of the exact same histological sections. RESULTS: Sequencing saturation and number of genes detected was not affected by sample storage duration. Unbiased clustering matched the underlying tissue type-based on H&E assessment. Connective-tissue-rich areas presented with lower unique molecular identifier counts are compared with muscle fibers even though tissue permeabilization was standardized across the section. A qualitative analysis of resulting datasets revealed heterogeneous fiber degeneration-regeneration after tenotomy based on (neonatal) myosin heavy chain 8 detection and associated differentially expressed gene analysis. CONCLUSIONS: This protocol can be used in skeletal muscle to explore spatial transcriptional patterns and confidently relate them to the underlying histology, even for tissues that have been stored for up to 6 years. Using this protocol, there is potential for novel transcriptional pathway discovery in longitudinal studies since the transcriptional information is unbiased by muscle composition and cell type changes.


Assuntos
Lesões do Manguito Rotador , Animais , Amarelo de Eosina-(YS)/metabolismo , Hematoxilina/metabolismo , Músculo Esquelético/patologia , Cadeias Pesadas de Miosina/metabolismo , Coelhos , Estudos Retrospectivos , Manguito Rotador/metabolismo , Lesões do Manguito Rotador/patologia , Transcriptoma/genética
5.
Int J Nanomedicine ; 17: 4947-4960, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275479

RESUMO

Introduction: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism. Methods: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress. Results: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2α, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group. Conclusion: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.


Assuntos
Nanopartículas , Óxido de Zinco , Feminino , Camundongos , Animais , Óxido de Zinco/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Ovário , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Antioxidantes/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Progesterona , Estresse Oxidativo , Malondialdeído/metabolismo , Acetilcisteína/farmacologia , Superóxido Dismutase/metabolismo , Estradiol/farmacologia
6.
Mediators Inflamm ; 2022: 5400592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36254157

RESUMO

Background: Traumatic optic neuropathy (TON) refers to damage to the optic nerve resulting from direct and indirect trauma to the head and face. One of the important pathological processes in TON is the death of retinal ganglion cells (RGCs), but the cause of RGCs death remains unclear. We aimed to explore the mechanisms of RGCs death in an experimental TON model. Methods: Optic nerve crush injury was induced in ten New Zealand white rabbits. On the 1st, 3rd, 7th, 14th, and 28th days after the operation, the retinal tissues of the rabbits were observed pathologically by hematoxylin-eosin staining. The expression of POU-homeodomain transcription factor Brn3a and glial fibrillary acidic protein (GFAP) was measured by immunofluorescence to evaluate the number of RGCs and astrocytes, respectively. miRNA expression and protein levels were assessed by RT-qPCR and western blot methods, respectively. Finally, the malondialdehyde content, superoxide dismutase activity, and proinflammatory factor levels were measured by ELISA. Western blot and dual-luciferase reporter assays were used to elucidate the relationship between miR-181d-5p and nuclear factor I-A (NFIA). Results: Blunt ocular trauma increased oxidative stress and apoptosis and reduced ganglion cell layer (GCL) density. The expression of miR-181d-5p was decreased in retinal tissues, and its overexpression relieved RGCs death, astrocyte development, oxidative stress, and inflammation of the retina, which were reversed by NFIA overexpression. Conclusion: miR-181d-5p can protect against the deterioration of TON by inhibiting RGCs death, astrocyte development, oxidative stress, and inflammation by targeting NFIA. This study provides new insight into early medical intervention in patients with TON.


Assuntos
MicroRNAs , Traumatismos do Nervo Óptico , Animais , Coelhos , Astrócitos/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/uso terapêutico , Proteína Glial Fibrilar Ácida/metabolismo , Hematoxilina/metabolismo , Hematoxilina/uso terapêutico , Inflamação/metabolismo , Malondialdeído/metabolismo , MicroRNAs/metabolismo , Fatores de Transcrição NFI/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Superóxido Dismutase/metabolismo
7.
Phytomedicine ; 107: 154477, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36215790

RESUMO

BACKGROUND: Danshen injection (DSI) is an agent extracted from the Salvia miltiorrhiza Bunge, a natural drug commonly used to alleviate kidney diseases. However, the material basis and therapeutic effects of DSI on nephrotic syndrome (NS) remain unclear. PURPOSE: To investigate the material basis of DSI and the therapeutic effects and underlying mechanisms of NS. METHODS: NS models were established using adriamycin-induced BALB/c mice and lipopolysaccharide-induced mouse podocytes (MPC-5). Following DSI and prednisone administration, kidney coefficients, 24 h urine protein, blood urea nitrogen, and serum creatinine levels were tested. Histomorphology was observed by periodic acid-Schiff staining and hematoxylin and eosin staining of the kidney sections. The glomerular basement membrane and autophagosomes of the kidneys were observed using transmission electron microscopy. Nephrin and desmin levels in the glomeruli were tested using immunohistochemistry. The viability of MPC-5 cells was tested using cell counting kit-8 after chloroquine and rapamycin administration in combination with DSI. The in vivo and in vitro protein levels of phosphatidylinositol 3-kinase (PI3K), AKT, phosphorylated AKT (Ser473), mammalian target of rapamycin (mTOR), microtubule-associated protein light chain 3 (LC3), beclin1, cleaved caspase-3, and caspase-3 were detected using western blotting. RESULTS: Our results showed that DSI contained nine main components: caffeic acid, danshensu, lithospermic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, salvianolic acid C, salvianolic acid D, and 3, 4-Dihydroxybenzaldehyde. In in vivo studies, the NS mice showed renal function and pathological impairment. Podocytes were damaged, with decreased levels of autophagy and apoptosis, accompanied by inhibition of the PI3K/AKT/mTOR signaling. DSI administration resulted in improved renal function and pathology in NS mice, with the activation of autophagy and PI3K/AKT/mTOR signaling in the kidneys. Additionally, podocytes were less damaged and intracellular autophagosomes were markedly increased. In vitro studies have shown that DSI activated MPC-5 autophagy and reduced apoptosis via the PI3K/AKT/mTOR pathway. CONCLUSION: Collectively, this study demonstrated that DSI activated podocyte autophagy and reduced apoptosis via the PI3K/AKT/mTOR signaling, ultimately attenuating NS. Our study clarified the main components of DSI and elucidated its therapeutic effects and potential mechanisms for NS, providing new targets and agents for the clinical treatment of NS.


Assuntos
Síndrome Nefrótica , Podócitos , Salvia miltiorrhiza , Animais , Autofagia , Proteína Beclina-1/metabolismo , Caspase 3/metabolismo , Cloroquina/farmacologia , Creatinina , Desmina/metabolismo , Desmina/farmacologia , Doxorrubicina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Lipopolissacarídeos/farmacologia , Mamíferos/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/metabolismo , Ácido Periódico/metabolismo , Ácido Periódico/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Podócitos/metabolismo , Prednisona/metabolismo , Prednisona/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
8.
Invest Ophthalmol Vis Sci ; 63(11): 5, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36205991

RESUMO

Purpose: This study aimed to explore the role of the RAS p21 protein activator 1 (RASA1) signaling pathway in apoptosis in choroid tissues from guinea pigs with negative lens-induced myopia (LIM). Methods: Biometric measurements were performed to examine refractive status, ocular parameters, and choroidal thickness (ChT) after myopia induction. The choroidal morphology was observed by hematoxylin and eosin (H&E) staining and TUNEL assay. The expression of the RASA1 signaling pathway at the mRNA and protein levels in choroidal tissues was measured by real-time quantitative PCR (qPCR) and western blot assays. Results: Compared with the normal control (NC) group, the ocular length of the guinea pigs in LIM increased remarkably, as did the myopic refraction. ChT decreased after myopia induction. H&E staining showed that the thickness and laxity of the choroidal tissues in LIM were strikingly reduced. The number of apoptotic cells in the LIM eyes was increased. Moreover, qPCR and western blot assays showed that the expression levels of both RASA1 and BCL-2-associated agonist of cell death (BAD) were higher in the LIM group than in the NC group, whereas the expression level of B-cell lymphoma 2 (BCL-2) was decreased after 2 weeks of experimental myopia. However, the trend of RASA1, BAD, and BCL-2 expression was reversed after 4 weeks of experimental myopia compared with levels after 2 weeks of experimental myopia. Conclusions: Results showed that the RASA1 signaling pathway is activated in choroid tissues in myopic guinea pigs. Activated RASA1 signaling induces high BAD expression and low BCL-2 expression, which in turn promotes apoptosis and ultimately causes ChT thinning in myopic guinea pigs.


Assuntos
Miopia , Animais , Apoptose , Corioide/patologia , Modelos Animais de Doenças , Amarelo de Eosina-(YS)/metabolismo , Cobaias , Hematoxilina/metabolismo , Miopia/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Visão Ocular
9.
Eur Rev Med Pharmacol Sci ; 26(18): 6523-6535, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36196701

RESUMO

OBJECTIVE: Magnesium is considered as potential neuroprotective and therapeutic agent, but certain studies have provided evidence of its apoptotic effectiveness in neurons. We aimed to evaluate the possible apoptotic effects of long-term magnesium use in healthy adult rat brains. MATERIALS AND METHODS: Magnesium citrate and magnesium glycinate compounds were administered orally to rats for 8 weeks (36 mg/kg). Expression levels of Bcl-2, Bax and Cyt-C genes were analyzed by real-time polymerase chain reactions (RT-PCR) in the prefrontal cortex, hippocampus and striatum regions. Bcl-2, Bax and CytC protein levels were measured using ELISA kits. Tissue sections were evaluated histopathologically with hematoxylin-eosin staining. RESULTS: Compared to the control group, the magnesium-administered groups indicated gene expression reductions in almost all brain regions; pro-apoptotic Bax, anti-apoptotic Bcl-2 and Cyt-C gene expression levels were reduced. With magnesium, the Bcl-2 and Bax protein levels were increased. Bax/Bcl-2 gene and protein ratio were also increased in the striatum and hippocampus, whereas Cyt-C protein levels were decreased or did not change in the magnesium treated groups. There was no pathological finding in histological evaluation. CONCLUSIONS: Long-term magnesium usage can promote apoptotic cascade in brain tissue by increasing Bax/Bcl-2 ratio. Cyt-C, a prominent factor processing caspase pathway, was decreased or unchanged. In addition, taking into account the histological evaluation, we supposed that the absence of Cyt-C in the cytosol can prevent the subsequent apoptotic pathway. Consequently, we obtained the findings of apoptotic initiation with magnesium in brain, but this cascade seems to be arrested at later stages.


Assuntos
Magnésio , Proteínas Proto-Oncogênicas c-bcl-2 , Animais , Apoptose , Encéfalo/metabolismo , Caspases , Citocromos c/metabolismo , Citosol/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Magnésio/metabolismo , Magnésio/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
J Orthop Surg Res ; 17(1): 453, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36243708

RESUMO

BACKGROUND: Osteoarthritis (OA) is a prevalent inflammatory joint disorder. microRNAs (miRNAs) are increasingly involved in OA. AIM: Our study is proposed to clarify the role of miR-124-3p in chondrocyte pyroptosis and cartilage injury in OA. METHODS: OA mouse model was established via the treatment of destabilization of the medial meniscus (DMM), and the in vitro cell model was also established as mouse chondrocytes were induced by lipopolysaccharide (LPS). Mouse cartilage injury was assessed using safranin-O-fast green staining, hematoxylin-eosin staining, and OARSI grading method. Expressions of miR-124-3p, MALAT1, KLF5, and CXCL11 were determined. Cartilage injury (MMP-13, osteocalcin), inflammation (IL-6, IL-2, TNF-, IL-1ß, and IL-18)- and pyroptosis-related factors (Cleaved Caspase-1 and GSDMD-N) levels were detected. Mechanically, MALAT1 subcellular localization was confirmed. The binding relationships of miR-124-3p and MALAT1 and MALAT1 and KLF5 were verified. MALAT1 half-life period was detected. Then, miR-124-3p was overexpressed using agomiR-124-3p to perform the rescue experiments with oe-MALAT1 or oe-CXCL11. RESULTS: miR-124-3p was downregulated in DMM mice and LPS-induced chondrocytes where cartilage injury, and increased levels of inflammation- and pyroptosis-related factors were found. miR-124-3p overexpression relieved cartilage injury and repressed chondrocyte pyroptosis. miR-124-3p bounds to MALAT1 to downregulate its stability and expression, and MALAT1 bounds to KLF5 to enhance CXCL11 transcription. Overexpression of MALAT1 or CXCL11 annulled the repressive function of miR-124-3p in chondrocyte pyroptosis. CONCLUSION: miR-124-3p reduced MALAT1 stability and inhibited the binding of MALAT1 and KLF5 to downregulate CXCL11, thereby suppressing chondrocyte pyroptosis and cartilage injury in OA.


Assuntos
MicroRNAs , Osteoartrite , RNA Longo não Codificante , Animais , Camundongos , Apoptose , Cartilagem/metabolismo , Caspases/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Hematoxilina/metabolismo , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Metaloproteinase 13 da Matriz/metabolismo , MicroRNAs/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteocalcina/metabolismo , Piroptose/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-36185701

RESUMO

Introduction: Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD), which is termed cardiorenal syndrome type 4 (CRS-4). Here, we report the development of pathological cardiac remodeling and fibrosis in unilateral urinary obstruction (UUO) rats. Methods: Hematoxylin and eosin (H&E) staining was performed to observe the pathology of myocardial tissue. The degree of myocardial tissue fibrosis was observed by Masson and Sirius red staining. Immunohistochemical staining was applied to detect the expression of CD34 and CD105 in myocardial tissue, and immunofluorescent staining was performed to examine the expression of CD34, collagen I/collagen III, and alpha smooth muscle actin (α-SMA). The expression of the signal pathway-related proteins vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), nuclear factor κB (NF-κB), and interleukin (IL)-1ß was tested by western blotting. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of serum and glucocorticoid-inducible kinase (SGK)-1, NF-κB, and interleukin-1ß (IL-1ß). Results: The results showed the development of pathological cardiac remodeling and cardiac dysfunction in UUO rats. Moreover, there was more angiogenesis and endothelial-mesenchymal transition (End-MT) in the UUO group, and these effects were inhibited by eplerenone. Conclusions: The results indicated that this cardiac fibrosis was associated with angiogenesis and that End-MT was related to aldosterone and mineralocorticoid receptor (MR) activation. Moreover, in association with the MR/IL-1ß/VEGFA signaling pathway, early treatment with the MR antagonist eplerenone in rats with UUO-induced CKD may significantly attenuate MR activation and cardiac fibrosis.


Assuntos
Insuficiência Renal Crônica , Obstrução Ureteral , Actinas/metabolismo , Aldosterona/metabolismo , Animais , Colágeno/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Eplerenona/farmacologia , Fibrose , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Interleucina-1beta , Rim/patologia , NF-kappa B/metabolismo , NF-kappa B/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/complicações , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Remodelação Ventricular
12.
Phytomedicine ; 107: 154479, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36194972

RESUMO

BACKGROUND: Rheumatoid arthritis (RA), the most common type of inflammatory arthritis, can cause bone damage and disability. Triptolide, a prominent treatment for RA, has satisfactory anti-inflammatory effects. However, the mechanism of action of triptolide in RA remains unknown. PURPOSE: This study aimed to explore the molecular mechanisms underlying triptolide-mediated improvements in RA and identify the miRNA pathway responsible for these effects. METHODS: We identified various dysregulated miRNAs associated with RA by mining previously described microarray data and verified and screened these candidates using RT-qPCR. Hematoxylin-eosin staining was then applied to identify pathological changes in the affected joints, and cell counting kit-8 analysis and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. Extracted exosomes were verified using transmission electron microscopy. RESULTS: Our results revealed that the legs of rats with collagen-induced arthritis presented with obvious swelling and bone damage, a high degree of inflammatory cell infiltration into the synovium, and structural changes to the cartilage. Data mining identified 39 dysregulated miRNAs in these tissues, and RT-qPCR further refined these observations to highlight miR-221 as a potential RA biomarker. Subsequent evaluations revealed that fibroblast-like synovial (FLS) cells secrete Exs carrying dysregulated miR-221 in vitro. These Exs mediate miR-221 levels, inflammation, and TLR4/MyD88 signaling via their fusion with chondrocytes, leading to changes in chondrocyte growth and metabolic factor levels. Additionally, the addition of triptolide impaired miR-221 expression, cell proliferation, inflammatory factors, and the protein levels of TLR4/MyD88 in RA-FLS and promoted the apoptosis of FLS. The therapeutic effect of triptolide on miR-221 Exs was reversed by miR-221 inhibitor in both normal and RA FLS. CONCLUSION: Our research shows that effective treatment with triptolide is mediated by its regulation of growth and secretory functions of chondrocytes via the inhibition of miR-221 secretion by FLS, providing a new target and natural medicinal candidate for future RA treatments.


Assuntos
Artrite Reumatoide , Exossomos , MicroRNAs , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células , Células Cultivadas , Condrócitos/metabolismo , Diterpenos , Regulação para Baixo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Compostos de Epóxi , Exossomos/metabolismo , Exossomos/patologia , Fibroblastos/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Fenantrenos , Ratos , Membrana Sinovial/patologia , Receptor 4 Toll-Like/metabolismo
13.
Respir Res ; 23(1): 270, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182915

RESUMO

OBJECTIVE: The therapeutic effect of umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in combination with pirfenidone (PFD) on pulmonary fibrosis in mice and its possible mechanism were investigated. METHODS: C57BL/6 mice were randomly divided into six groups: control group, model group, P10 group, P30 group, P100 group, and P300 group. Modeled by tracheal intubation with 3 mg/kg bleomycin drip, each dose of PFD was administered daily by gavage from day 7 onwards. The mice were observed continuously for 21 days and survival was recorded. Lung tissues were collected on day 21, and hematoxylin-eosin (HE) and Masson staining were performed to assess morphological changes and collagen deposition in the lungs. Collagen content was measured by the Sircol method, and fibrosis marker levels were detected by PCR and Western blot. Another batch of C57BL/6 mice was then randomly divided into five groups: hUC-MSC control group, model group, P100 group, hUC-MSC treatment group, and hUC-MSCs + P30 group. On day 7, 5 × 105 hUC-MSCs were injected into the tail vein, the mice were administered PFD gavage daily from day 7 onwards, and their survival was recorded. Lung tissues were collected on day 21 to detect pathological changes, the collagen content, and the expression of regulator of G protein signaling 2 (RGS2). Pulmonary myofibroblasts (MFBs) were divided into an MFB group and an MFB + hUC-MSCs group; different doses of PFD were administered to each group, and the levels of RGS2, intracellular Ca2+, and fibrosis markers were recorded for each group. RESULTS: Compared with other PFD group doses, the P100 group had significantly improved mouse survival and lung pathology and significantly reduced collagen and fibrosis marker levels (p < 0.05). The hUC-MSCs + P30 group had significantly improved mouse survival and lung pathology, significantly reduced collagen content and fibrosis marker levels (p < 0.05), and the efficacy was better than that of the P100 and hUC-MSCs groups (p < 0.05). RGS2 expression was significantly higher in the MSCs + P30 group compared with the P100 and hUC-MSCs groups (p < 0.05). PFD increased RGS2 expression in MFBs (p < 0.05) in a dose-dependent manner. Compared with PFD and hUC-MSCs treatment alone, combination of hUC-MSCs and PFD increased RGS2 protein levels, significantly decreased intracellular Ca2+ concentration, and significantly reduced fibrosis markers. CONCLUSION: The findings suggest that hUC-MSCs combined with low-dose PFD have a therapeutic effect better than that of the two treatments used separately. Its effect on attenuating bleomycin-induced pulmonary fibrosis in mice is related to the increase of RGS2.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Fibrose Pulmonar , Proteínas RGS , Animais , Bleomicina , Amarelo de Eosina-(YS)/metabolismo , Fibrose , Proteínas de Ligação ao GTP/metabolismo , Hematoxilina/metabolismo , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/terapia , Piridonas , Proteínas RGS/metabolismo , Cordão Umbilical
14.
Beijing Da Xue Xue Bao Yi Xue Ban ; 54(5): 846-852, 2022 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-36241227

RESUMO

OBJECTIVE: To investigate the effects and mechanisms of Kindlin-2 on uterus development and reproductive capacity in female mice. METHODS: Cdh16-Cre tool mice and Kindlin-2flox/flox mice were used to construct the mouse model of uterus specific knockout of Kindlin-2, and the effects of Kindlin-2 deletion on uterine development and reproduction capacity of female mice were observed. High expression and knockdown of Kindlin-2 in endometrial cancer cell lines HEC-1 and Ish were used to detect the regulation of mammalian target of rapamycin (mTOR) signaling pathway. In addition, uterine proteins of the female mice with specific knockout of Kindlin-2 and female mice in the control group were extracted to detect the protein levels of key molecules of mTOR signaling pathway and Hippo signaling pathway. RESULTS: The mouse model of uterine specific knockout of Kindlin-2 was successfully constructed. The knockout efficiency of Kindlin-2 in mouse uterus was identified and verified by mouse tail polymerase chain reaction (PCR), Western blot protein identification, immunohistochemical staining (IHC) and other methods. Compared with the control group, the female mice with uterus specific deletion of Kindlin-2 lost weight, seriously impaired reproductive ability, and the number of newborn mice decreased, but the proportion of the female mice and male mice in the newborn mice did not change. Hematoxylin eosin staining (HE) experiment showed that the endometrium of Kindlin-2 knockout group was incomplete and the thickness of uterine wall became thinner. In terms of mechanism, the deletion of Kindlin-2 in endo-metrial cancer cell lines HEC-1 and Ish could downregulate the protein levels of mTOR, phosphorylated mTOR, adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK and phosphorylated ribosomal protein S6 (S6), and the mTOR signal pathway was inhibited. It was found that the specific deletion of Kindlin-2 could upregulate the protein levels of Mps one binding 1 (MOB1) and phosphorylated Yes-associated protein (YAP) in the uterus of the female mice, and the Hippo signal pathway was activated. CONCLUSION: Kindlin-2 inhibits the development of uterus by inhibiting mTOR signal pathway and activating Hippo signal pathway, thereby inhibiting the fertility of female mice.


Assuntos
Proteínas Quinases Ativadas por AMP , Via de Sinalização Hippo , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Caderinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Endométrio/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Feminino , Hematoxilina/metabolismo , Masculino , Mamíferos/metabolismo , Camundongos , Proteínas Musculares , Proteína S6 Ribossômica/metabolismo , Sirolimo/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Sinalização YAP
15.
Biomed Res Int ; 2022: 7659765, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132078

RESUMO

Background: The present study aimed to evaluate the effect of nanocurcumin and curcumin on liver transaminases, lipid profile, oxidant and antioxidant system, and pathophysiological changes in aluminium phosphide (ALP) induced hepatoxicity. Material and Methods. In this experimental study, thirty-six male Wistar rats were randomly divided into six groups curcumin (Cur), nanocurcumin (Nanocur), ALP, ALP+Cur, and ALP+Nanocur. All treatments were performed by oral gavage for seven days. After treatment, animals were sacrificed, and liver and blood samples were taken. Serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), total bilirubin, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) were measured by photometric methods. Total antioxidant capacity (TAC) and malondialdehyde (MDA) as parameters of oxidative stress and mRNA expression of the nonenzyme protein including Sirtuin 1 (STR1), Forkhead box protein O1 (FOXO1) and protein O3 (FOXO3), catalase (CAT), and glutathione peroxidase (GPX) as the enzyme protein in homogenized tissues have been investigated. A histologist analyzed liver tissue sections after staining with hematoxylin-eosin. Results: In the aluminium phosphide group, there was a significant increase in MDA, ALT, AST, and AP and total bilirubin, cholesterol, triglyceride, LDL, and VLDL; AST, ALT, total bilirubin, LDL, VLDL, cholesterol, and MDA were significantly decreased; and HDL and TAC were significantly increased compared to ALP (P < 0.05). In the ALP+Nanocur group, ALT, AST, ALP, total bilirubin, cholesterol, LDL, VLDL, triglyceride, and MDA were significantly decreased and HDL and TAC were increased significantly (P < 0.05). The effect of nanocurcumin on controlling serum levels of LDL, VLDL, triglyceride, and MDA in ALP-poisoned rats was significantly more than curcumin (P < 0.05). The ALP group had significant changes in genes SIRT1, FOXO1a, FOXO3a, CAT, and GPX compared to healthy controls (P < 0.05). Nanocurcumin mice expressed more SIRT1, FOXO1a, CAT, and GPX genes than controls, and curcumin-treated mice expressed more SIRT1 and FOXO1a genes (P < 0.05). Histopathological findings also indicated a more significant protective effect of nanocurcumin relative to curcumin against ALP-induced hepatotoxicity. Conclusion: Nanocurcumin significantly protects the liver against aluminum phosphide toxicity. It is suggested that nanocurcumin-based drugs be developed to reduce the toxic effects of ALP in poisoned patients.


Assuntos
Antioxidantes , Curcumina , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Compostos de Alumínio , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases , Bilirrubina/metabolismo , Catalase/metabolismo , LDL-Colesterol/metabolismo , Curcumina/metabolismo , Curcumina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Proteína Forkhead Box O1/metabolismo , Glutationa Peroxidase/metabolismo , Hematoxilina/metabolismo , Lipoproteínas HDL , Lipoproteínas VLDL/metabolismo , Lipoproteínas VLDL/farmacologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Oxidantes/metabolismo , Estresse Oxidativo , Fosfinas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Triglicerídeos/metabolismo
16.
Int J Nanomedicine ; 17: 4277-4292, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36134200

RESUMO

Purpose: The objective of this study was to evaluate and compare the histopathological implications of silica nanoparticles (Nano-SiO2) and indium-tin oxide nanoparticles (Nano-ITO), in vivo. Methods: Male Sprague-Dawley rats were exposed to Nano-SiO2 (50 mg/kg) and Nano-ITO (6 mg/kg) by a single intratracheal instillation, respectively. Broncho-alveolar lavage fluid (BALF) and lung tissue were obtained at 7, 14, 28, and 56 days post exposure for analysis of BALF inflammatory factors, total protein, and for lung tissue pathology. Histopathological and ultrastructural change in lungs were investigated by hematoxylin and eosin, Masson's trichrome, sirius red staining, periodic acid Schiff stain, and transmission electron microscopy. The expression of SP-A, collagen type I and III in lung tissue was determined by immunohistochemistry and ELISA. Results: The rats in both models exhibited obvious collagen fibrosis and the severity of the lung injury increased with time after exposure to respective dosage increased. Several parameters of pulmonary inflammation and fibrosis significantly increased in both groups, which was reflected by increased LDH activity, total proteins, TNF-α, and IL-6 levels in BALF, and confirmed by histopathological examination. The results also showed that the two models exhibited different features. Exposure to Nano-ITO caused persistent chronic lung inflammation, illustrated by the infiltration of a large amount of enlarged and foamy macrophages and neutrophils into the lung parenchyma. In Nano-SiO2 exposed rat lung tissue, granulomatous inflammation was most prominent followed by progressive and massive fibrotic nodules. Compared with the Nano-SiO2 rats, Nano-ITO exposed rats exhibited significantly severe pulmonary alveolar proteinosis (PAP) pathological changes, lower fibrosis, and higher levels of inflammatory biomarkers. However, Nano-SiO2 exposed rats had greater fibrosis pathological changes and more severe granulomas than Nano-ITO exposed rats. Conclusion: This study suggests that the Nano-SiO2-induced model has greater value in research into granulomas and fibrosis, while the Nano-ITO-induced model has greater repeatability in area of PAP.


Assuntos
Nanopartículas , Pneumonia , Animais , Líquido da Lavagem Broncoalveolar , Colágeno Tipo I/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Fibrose , Hematoxilina/metabolismo , Índio , Interleucina-6/metabolismo , Pulmão/patologia , Masculino , Nanopartículas Metálicas , Nanopartículas/toxicidade , Ácido Periódico/metabolismo , Pneumonia/patologia , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/toxicidade , Compostos de Estanho , Fator de Necrose Tumoral alfa/metabolismo
17.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144494

RESUMO

Aims: Annexin A5 (ANXA5) exhibited potent antithrombotic, antiapoptotic, and anti-inflammatory properties in a previous study. The role of ANXA5 in traumatic brain injury (TBI)-induced intestinal injury is not fully known. Main methods: Recombinant human ANXA5 (50 µg/kg) or vehicle (PBS) was administered to mice via the tail vein 30 min after TBI. Mouse intestine tissue was gathered for hematoxylin and eosin staining 0.5 d, 1 d, 2 d, and 7 d after modeling. Intestinal Western blotting, immunofluorescence, TdT-mediated dUTP nick-end labeling staining, and enzyme-linked immunosorbent assays were performed 2 days after TBI. A series of kits were used to assess lipid peroxide indicators such as malonaldehyde, superoxide dismutase activity, and catalase activity. Key findings: ANXA5 treatment improved the TBI-induced intestinal mucosa injury at different timepoints and significantly increased the body weight. It significantly reduced apoptosis and matrix metalloproteinase-9 and inhibited the degradation of tight-junction-associated protein in the small intestine. ANXA5 treatment improved intestinal inflammation by regulating inflammation-associated factors. It also mitigated the lipid peroxidation products 4-HNE, 8-OHDG, and malonaldehyde, and enhanced the activity of the antioxidant enzymes, superoxide dismutase and catalase. Lastly, ANXA5 significantly enhanced nuclear factor E2-related factor 2 (Nrf2) and hemeoxygenase-1, and decreased high mobility group box 1 (HMGB1). Significance: Collectively, the results suggest that ANXA5 inhibits TBI-induced intestinal injury by restraining oxidative stress and inflammatory responses. The mechanisms involved sparking the Nrf2/hemeoxygenase-1-induced antioxidant system and suppressing the HMGB1 pathway. ANXA5 may be an attractive therapeutic candidate for protecting against TBI-induced intestinal injury.


Assuntos
Lesões Encefálicas Traumáticas , Proteína HMGB1 , Enteropatias , Animais , Anexina A5/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Catalase/metabolismo , Amarelo de Eosina-(YS) , Fibrinolíticos/farmacologia , Proteína HMGB1/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Enteropatias/metabolismo , Peróxidos Lipídicos , Malondialdeído/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase/metabolismo
18.
Food Funct ; 13(19): 10186-10199, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36111578

RESUMO

Nonalcoholic fatty liver disease (NAFLD), an increasingly serious health issue around the world, is characterized as a lipid metabolic disorder without any satisfactory treatment. Nobiletin (NOB), a citrus flavonoid, is considered a promising candidate for NAFLD prevention although there is limited research towards its exact mechanism. In this study, the preventative effect of NOB on NAFLD was investigated using high fat diet-fed ApoE-/- mice and free fatty acid-treated HepG2 cells. The results of hematoxylin and eosin staining of liver sections revealed that L-NOB (50 mg kg-1 d-1 NOB), M-NOB (100 mg kg-1 d-1 NOB) and H-NOB (200 mg kg-1 d-1 NOB) could significantly ameliorate NAFLD. Further exploration illustrated that NOB alleviated hepatic steatosis mainly via TFEB-mediated lysosomal biogenesis and lipophagy. Besides, NOB could mitigate NLRP3 inflammasome assembly and modulate M1/M2 macrophage polarization in vivo and in vitro. The mechanisms above allowed NOB to attenuate NAFLD, but their close association needed further investigation. Our research not only illustrated NOB as a potential candidate for NAFLD prevention, but also provided new insight into the pathogenic mechanisms of NAFLD development.


Assuntos
Flavonas , Hepatopatia Gordurosa não Alcoólica , Animais , Apolipoproteínas E , Autofagia , Dieta Hiperlipídica , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Ácidos Graxos não Esterificados/metabolismo , Flavonas/metabolismo , Flavonas/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Inflamassomos/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
19.
Biomed Pharmacother ; 155: 113639, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36088853

RESUMO

BACKGROUND AND AIMS: TMAO is a microbiota-dependent metabolite associated with increased risk of various cardiovascular diseases. However, the relationship between TMAO and vascular injury-related neointimal hyperplasia is unclear. This study aimed to explore whether TMAO promotes neointimal hyperplasia after balloon injury and elucidate the underlying mechanism. METHODS AND RESULTS: Through hematoxylin and eosin staining and immunohistochemistry staining, we found that supplementary TMAO promoted balloon injury-induced neointimal hyperplasia, while reducing TMAO by antibiotic administration produced the opposite result. TMAO showed limited effect on rat aortic vascular smooth muscle cells (RAOSMCs) proliferation and migration. However, TMAO notably induced dysfunction of rat aortic vascular endothelial cells (RAOECs) in vitro and attenuated reendothelialization of carotid arteries after balloon injury in vivo. Autophagic flux was measured by fluorescent mRFP-GFP-LC3, transmission electron microscopy, and western blot. TMAO impaired autophagic flux, as evidenced by the accumulation of p62 and LC3II and high autophagosome to autolysosome ratios. Furthermore, we confirmed that Beclin1 level increased in TMAO-treated RAOECs and carotid arteries. Knocking down Beclin1 alleviated TMAO-induced autophagic flux impairment and neointimal hyperplasia. CONCLUSIONS: TMAO promoted neointimal hyperplasia through Beclin1-induced autophagic flux blockage, suggesting that TMAO is a potential target for improvement of vascular remodeling after injury.


Assuntos
Lesões das Artérias Carótidas , Ratos , Animais , Hiperplasia/metabolismo , Proteína Beclina-1/metabolismo , Lesões das Artérias Carótidas/patologia , Músculo Liso Vascular , Células Endoteliais/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Proliferação de Células , Ratos Sprague-Dawley , Neointima/patologia , Antibacterianos/farmacologia , Óxidos/farmacologia
20.
World J Gastroenterol ; 28(32): 4574-4599, 2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36157934

RESUMO

BACKGROUND: Radiotherapy and chemotherapy can kill tumor cells and improve the survival rate of cancer patients. However, they can also damage normal cells and cause serious intestinal toxicity, leading to gastrointestinal mucositis[1]. Traditional Chinese medicine is effective in improving the side effects of chemotherapy. Wumei pills (WMP) was originally documented in the Treatise on Exogenous Febrile Diseases. It has a significant effect on chronic diarrhea and other gastrointestinal diseases, but it is not clear whether it affects chemotherapy-induced intestinal mucositis (CIM). AIM: To explore the potential mechanism of WMP in the treatment of CIM through experimental research. METHODS: We used an intraperitoneal injection of 5-fluorouracil (5-Fu) to establish a CIM mouse model and an oral gavage of WMP decoction (11325 and 22650 mg/kg) to evaluate the efficacy of WMP in CIM. We evaluated the effect of WMP on CIM by observing the general conditions of the mice (body weight, food intake, spleen weight, diarrhea score, and hematoxylin and eosin stained tissues). The expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and myeloperoxidase (MPO), as well as the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway proteins and tight junction proteins (zonula occludens-1, claudin-1, E-cadherin, and mucin-2) was determined. Furthermore, intestinal permeability, intestinal flora, and the levels of short-chain fatty acids (SCFA) were also assessed. RESULTS: WMP effectively improved the body weight, spleen weight, food intake, diarrhea score, and inflammatory status of the mice with intestinal mucositis, which preliminarily confirmed the efficacy of WMP in CIM. Further experiments showed that in addition to reducing the levels of TNF-α, IL-1ß, IL-6, and MPO and inhibiting the expression of the TLR4/MyD88/NF-κB pathway proteins, WMP also repaired the integrity of the mucosal barrier of mice, regulated the intestinal flora, and increased the levels of SCFA (such as butyric acid). CONCLUSION: WMP can play a therapeutic role in CIM by alleviating inflammation, restoring the mucosal barrier, and regulating gut microbiota.


Assuntos
Antineoplásicos , Microbioma Gastrointestinal , Mucosite , Animais , Antineoplásicos/uso terapêutico , Peso Corporal , Butiratos , Caderinas/metabolismo , Claudina-1/metabolismo , Claudina-1/farmacologia , Claudina-1/uso terapêutico , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/patologia , Medicamentos de Ervas Chinesas , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Fluoruracila/uso terapêutico , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Camundongos , Mucina-2/metabolismo , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Peroxidase/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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