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1.
J Asian Nat Prod Res ; : 1-7, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38945155

RESUMO

In this study, a previously undescribed cassane diterpenoid, named caesalpinin JF (1), along with two known cassane diterpenoids caesanine C (2) and tomocinol B (3), was isolated from 95% EtOH extract of the seeds of Caesalpinia sappan Linn. Additionally, three known compounds including pulcherrin R (4), syringaresinol-4'-O-ß-D-glucopyranoside (5) and kaempferol (6) were also identified. The structures of the isolated compounds were elucidated by comprehensive 1D and 2D NMR spectroscopic analyses. Additionally, electronic circular dichroism (ECD) calculation was used to identify the absolute structure of compound 1. Among the isolated compounds, compound 1 displayed a potent anti-neuroinflammation with an IC50 value of 9.87 ± 1.71 µM.

2.
Environ Res ; 257: 119084, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823617

RESUMO

Ocean acidification (OA) is known to influence biological and ecological processes, mainly focusing on its impacts on single species, but little has been documented on how OA may alter plankton community interactions. Here, we conducted a mesocosm experiment with ambient (∼410 ppmv) and high (1000 ppmv) CO2 concentrations in a subtropical eutrophic region of the East China Sea and examined the community dynamics of microeukaryotes, bacterioplankton and microeukaryote-attached bacteria in the enclosed coastal seawater. The OA treatment with elevated CO2 affected taxa as the phytoplankton bloom stages progressed, with a 72.89% decrease in relative abundance of the protist Cercozoa on day 10 and a 322% increase in relative abundance of Stramenopile dominated by diatoms, accompanied by a 29.54% decrease in relative abundance of attached Alphaproteobacteria on day 28. Our study revealed that protozoans with different prey preferences had differing sensitivity to high CO2, and attached bacteria were more significantly affected by high CO2 compared to bacterioplankton. Our findings indicate that high CO2 changed the co-occurrence network complexity and stability of microeukaryotes more than those of bacteria. Furthermore, high CO2 was found to alter the proportions of potential interactions between phytoplankton and their predators, as well as microeukaryotes and their attached bacteria in the networks. The changes in the relative abundances and interactions of microeukaryotes between their predators in response to high CO2 revealed in our study suggest that high CO2 may have profound impacts on marine food webs.

3.
J Therm Biol ; 122: 103883, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38875961

RESUMO

Melatonin (MT) is an amine hormone secreted by the body that has antioxidant and anti-inflammatory properties. The aim of this study was to investigate pathophysiological protection of MT in heat-stressed chickens. By modelling heat-stressed chickens and treating them with MT. After 21 days of administration, serum antioxidant enzymes, biochemical indices, inflammatory cytokine and heat-stress indices were detected, along with cardiopulmonary function indices and histological observations in chickens. The results show heat-stress induced a decrease (P < 0.05) in body weight and an increase in body temperature, which was reversed after MT intervention. Treatment with MT inhibited (P < 0.05) the secretion of pro-inflammatory factors interleukin-1ß, interleukin-6, tumor necrosis factor α, serum heat shock protein 70, corticosterone, and elevated (P < 0.05) the levels of biochemical factors total protein, albumin, globulin, and increased (P < 0.05) the activities of antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase in chicken serum caused by heat stress, and the best effect was observed with the medium dose of MT. The heat-stress caused cardiac atrophy and pulmonary congestion, decreased (P < 0.05) the cardiac function indices creatine kinase isoenzyme, cardiac troponin I, angiotensin receptor I, creatine kinase and lung function indices myeloperoxidase, angiotensin-II, heat shock factor I, and increased (P < 0.05) the lung vascular endothelial growth factor II. Sections of the heart and lungs after administration of MT were observed to be more complete with more normal tissue indices. At the same time, compared with heat stress, heart and lung function indices of grade chickens after MT administration were significantly (P < 0.05)reduced and tended to normal levels, and the best effect was observed in the medium-dose MT. In conclusion, heat stress can cause pathophysiological damage in chickens, and 1 mg/kg/d of exogenous melatonin can attenuate this adverse effect.


Assuntos
Galinhas , Transtornos de Estresse por Calor , Resposta ao Choque Térmico , Melatonina , Animais , Melatonina/farmacologia , Melatonina/administração & dosagem , Resposta ao Choque Térmico/efeitos dos fármacos , Transtornos de Estresse por Calor/tratamento farmacológico , Transtornos de Estresse por Calor/veterinária , Antioxidantes , Citocinas/metabolismo , Citocinas/sangue , Masculino , Doenças das Aves Domésticas/tratamento farmacológico
4.
Artigo em Inglês | MEDLINE | ID: mdl-38887973

RESUMO

Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.

5.
Drug Metab Dispos ; 52(7): 597-605, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38697851

RESUMO

Pregnane X receptor (PXR) is essential in the regulation of liver homeostasis, and the gut microbiota is closely linked to liver physiologic and pathologic status. We previously found that activation of PXR significantly promotes liver enlargement through interaction with yes-associated protein (YAP). However, whether gut microbiota contributes to PXR-induced hepatomegaly and the involved mechanisms remain unclear. In this study, C57BL/6 mice were administered the mouse-specific agonist pregnenolone 16α-carbonitrile (PCN) for 5 days. Depletion of gut microbiota was achieved using broad-spectrum antibiotics (ABX) and fecal microbiota transplantation (FMT) was performed to restore the gut microbia. The composition of gut microbiota was analyzed by 16S rRNA sequencing, while the expression of PXR, YAP, and their downstream target genes and proteins were assessed. The results indicated that PCN treatment altered the composition and abundance of specific bacterial taxa. Furthermore, depletion of gut microbiota using ABX significantly attenuated PCN-induced hepatomegaly. FMT experiments further demonstrated that the fecal microbiota from PCN-treated mice could induce liver enlargement. Mechanistic studies revealed that ABX treatment impeded the PXR and YAP activation induced by PCN, as evidenced by decreased expression of PXR, YAP, and their downstream targets. Moreover, alterations in PXR and YAP activation were likely contributing to hepatomegaly in recipient mice following FMT from PCN-treated mice. Collectively, the current study demonstrated that gut microbiota is involved in PCN-induced hepatomegaly via regulating PXR and YAP activation, providing potential novel insights into the involvement of gut microbiota in PXR-mediated hepatomegaly. SIGNIFICANCE STATEMENT: This work describes that the composition of gut microbiota is altered in mouse pregnane X receptor (PXR) agonist pregnenolone 16α-carbonitrile (PCN)-induced hepatomegaly. Treatment with an antibiotic cocktail depletes the intestinal microbiota, leading to the impairment of liver enlargement caused by PCN. Additionally, fecal microbiota transplantation from PCN-treated mice induces liver enlargement. Further study revealed that gut microbiota is involved in hepatomegaly via regulating PXR and yes-associated protein activation.


Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Hepatomegalia , Camundongos Endogâmicos C57BL , Receptor de Pregnano X , Carbonitrila de Pregnenolona , Proteínas de Sinalização YAP , Animais , Hepatomegalia/induzido quimicamente , Hepatomegalia/metabolismo , Receptor de Pregnano X/agonistas , Receptor de Pregnano X/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Carbonitrila de Pregnenolona/farmacologia , Proteínas de Sinalização YAP/metabolismo , Masculino , Transplante de Microbiota Fecal/métodos , Fígado/efeitos dos fármacos , Fígado/metabolismo
6.
Anal Chem ; 96(23): 9503-9511, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38780632

RESUMO

In this work, a micron-sized flower-like metal-organic frameworks (MOFs)-based boronate-affinity sandwich-type immunoassay was fabricated for the dual-mode glycoprotein assay. For proof of concept, the flower-like MOFs were synthesized from transition Cu nodes and tetrakis (4-carboxyphenyl) porphyrin (TCPP) ligands by spontaneous standing assembly. In addition, the specificity toward glycoprotein involved the antigen recognition as well as covalent bonding via the boronate-glycan affinity, and the immediate signal responses were initiated by textural decomposition of the flower-like MOFs. Intriguingly, Cu nodes, of which the valence state is dominant by CuI species, can endow the Fenton-like catalytic reaction of the fluorogenic substrate for generating fluorescence signals. For benefits, TCPP ligands, in which each TCPP molecule has four guest donors, can provide multiple valences for the assembly of cyclodextrin-capped gold nanoparticles via host-guest interaction for colorimetry output. Albeit important, the scaling micrometer patterns for the flower-like MOFs carrying numerous Cu nodes and TCPP ligands can also function as amplifying units, signifying the output signal. The detection limit of the dual-mode glycoprotein assay can reach 10.5 nM for the fluorescence mode and 18.7 nM for the colorimetry mode, respectively. Furthermore, the merits of harvesting different signal generators toward the multimodal readout patterns can allow the mutual verification and make the analytical results more reliable. Collectively, our proposed assay may offer a new idea in combining the inherent textural merits from MOFs for dual signal generators, which can also emphasize accurate detection capability for glycoprotein assay.


Assuntos
Glicoproteínas , Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Glicoproteínas/análise , Glicoproteínas/química , Cobre/química , Porfirinas/química , Imunoensaio/métodos , Ouro/química , Nanopartículas Metálicas/química , Humanos , Ácidos Borônicos/química , Limite de Detecção , Tamanho da Partícula
7.
ACS Appl Mater Interfaces ; 16(22): 29049-29059, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38770760

RESUMO

High-performance photodetectors with the detection capability of linearly polarized light have broad applications in both military and civilian fields. Quasi-one-dimensional ZrS3 as an emerging anisotropic two-dimensional material has come under the spotlight owing to its intriguing properties. However, the performance of the ZrS3 photodetector is seriously restricted by its low responsivity. Herein, a novel high-performance photodetector based on the van der Waals ZrS3/MoS2 heterostructure is proposed. Attributed to the charge trapping-assisted photogating effect, interlayer carrier transitions, and fast spatial separation of the photogenerated electron-hole pairs, the device displays superior photoresponse characteristics ranging from the ultraviolet to the visible spectrum in terms of high responsivity up to 212 A/W, an extraordinary external quantum efficiency of 8.5 × 104%, and a prompt rise/decay time of 0.19/0.38 ms. In addition, owing to the profound birefringence and dichroism effects in ZrS3 together with strong light-matter interactions in the heterostructure, profound linear-polarization sensitivity is demonstrated with a dichroic ratio of about 2.8. Overall, this photodetector not only is integrated with the excellent properties of ZrS3 and monolayer MoS2 but also further enhances the advantages through interlayer couplings, which demonstrate the strong potential of the ZrS3-based devices for high-performance, ultrafast, and polarization-sensitive photodetection.

8.
Food Chem ; 451: 139418, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38677133

RESUMO

A dual-color ratiometric fluorescence sensor based on photonic crystals (PCs) was developed to detect tetracycline (TC) in food. PC was fabricated via self-assembly of carbon dots (CDs)-loaded SiO2 nanoparticles. Gold nanoclusters (AuNCs) and copper ions (Cu2+) were then adsorbed onto the PC for sensor fabrication. The fluorescence of AuNCs was amplified by the PC with an enhancement ratio of 7.6, providing higher sensitivity. The fluorescence of AuNCs was quenched by Cu2+, whereas that of CDs remained unchanged as an internal reference. TC restored the fluorescence of AuNCs owing to its complexation with Cu2+, resulting in a change in the fluorescence intensity ratio. The sensor exhibited a good linear relationship with TC concentrations ranging from 0.1 to 10 µM, with a detection limit of 34 nM. Furthermore, the sensor was applied for TC detection in food with satisfactory recoveries and relative standard deviations, revealing great potential in practical application.


Assuntos
Contaminação de Alimentos , Ouro , Tetraciclina , Tetraciclina/análise , Contaminação de Alimentos/análise , Ouro/química , Espectrometria de Fluorescência/métodos , Limite de Detecção , Pontos Quânticos/química , Fluorescência , Nanopartículas Metálicas/química , Fótons
9.
CNS Neurosci Ther ; 30(3): e14642, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38430464

RESUMO

BACKGROUND: Inhibiting secondary inflammatory damage caused by glial cells and creating a stable microenvironment is one of the main strategies to investigate drugs for the treatment of spinal cord injury. Acetyl-11-keto-beta-boswellic acid (AKBA) is the active component of the natural drug boswellia, which has anti-inflammatory and antioxidant effects and offers a possible therapeutic option for spinal cord injury. METHODS: In this study, a spinal cord injury model was established by crushing spinal cord, respectively, to detect the M1 macrophage inflammatory markers: iNOS, TNF-α, IL-1ß, and the M2 macrophage markers CD206, ARG-1, IL-10, and the detection of antioxidant enzymes and MDA. In vitro, macrophages were cultured to verify the main mechanism of the macrophage switch from Nrf2/HO-1 to M2 type by flow cytometry, immunofluorescence, and other techniques. Macrophage and Schwann cell co-culture validated the migration mechanism of Schwann cells promoted by AKBA. RESULTS: AKBA significantly enhanced the antioxidant enzyme activities of CAT, GSH-Px, T-AOC, and SOD, reduced MDA content, and reduced oxidative damage caused by spinal cord injury via the Nrf2/HO-1 signaling pathway; AKBA mediates Nrf2/HO-1/IL-10, converts macrophages from M1 to M2 type, reduces inflammation, and promotes Schwann cell migration, thereby accelerating the repair of spinal cord injury in rats. CONCLUSIONS: Our work demonstrates that AKBA can attenuate oxidative stress as well as the secondary inflammatory injury caused by macrophages after SCI, promote Schwann cell migration to the injury site, and thus accelerate the repair of the injured spinal cord.


Assuntos
Interleucina-10 , Traumatismos da Medula Espinal , Triterpenos , Ratos , Animais , Interleucina-10/metabolismo , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismos da Medula Espinal/metabolismo , Macrófagos/metabolismo , Medula Espinal/metabolismo , Movimento Celular
10.
Bioorg Chem ; 146: 107301, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38522392

RESUMO

In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.


Assuntos
Croton , Sesquiterpenos , Tropolona/análogos & derivados , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Ciclo-Oxigenase 2/metabolismo , Sesquiterpenos/farmacologia , Lipopolissacarídeos/farmacologia
11.
PLoS Biol ; 22(3): e3002565, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38527087

RESUMO

K+ channels regulate morphogens to scale adult fins, but little is known about what regulates the channels and how they control morphogen expression. Using the zebrafish pectoral fin bud as a model for early vertebrate fin/limb development, we found that K+ channels also scale this anatomical structure, and we determined how one K+-leak channel, Kcnk5b, integrates into its developmental program. From FLIM measurements of a Förster Resonance Energy Transfer (FRET)-based K+ sensor, we observed coordinated decreases in intracellular K+ levels during bud growth, and overexpression of K+-leak channels in vivo coordinately increased bud proportions. Retinoic acid, which can enhance fin/limb bud growth, decreased K+ in bud tissues and up-regulated regulator of calcineurin (rcan2). rcan2 overexpression increased bud growth and decreased K+, while CRISPR-Cas9 targeting of rcan2 decreased growth and increased K+. We observed similar results in the adult caudal fins. Moreover, CRISPR targeting of Kcnk5b revealed that Rcan2-mediated growth was dependent on the Kcnk5b. We also found that Kcnk5b enhanced depolarization in fin bud cells via Na+ channels and that this enhanced depolarization was required for Kcnk5b-enhanced growth. Lastly, Kcnk5b-induced shha transcription and bud growth required IP3R-mediated Ca2+ release and CaMKK activity. Thus, we provide a mechanism for how retinoic acid via rcan2 can regulate K+-channel activity to scale a vertebrate appendage via intercellular Ca2+ signaling.


Assuntos
Cálcio , Peixe-Zebra , Animais , Peixe-Zebra/genética , Cálcio/metabolismo , Tretinoína , Nadadeiras de Animais/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Regulação da Expressão Gênica no Desenvolvimento
12.
J Laryngol Otol ; 138(5): 540-547, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38348656

RESUMO

OBJECTIVE: Retropharyngeal lymphadenectomy is challenging. This study investigated a minimally invasive approach to salvage retropharyngeal lymphadenectomy in patients with nasopharyngeal carcinoma. METHODS: An anatomical study of four fresh cadaveric heads was conducted to demonstrate the relevant details of retropharyngeal lymphadenectomy using the endoscopic transoral medial pterygomandibular fold approach. Six patients with nasopharyngeal cancer with retropharyngeal lymph node recurrence, who underwent retropharyngeal lymphadenectomy with the endoscopic transoral medial pterygomandibular fold technique at the Eye and ENT Hospital of Fudan University from July to December 2021, were included in this study. RESULTS: The anatomical study demonstrated that the endoscopic transoral medial pterygomandibular fold approach offers a short path and minimally invasive approach to the retropharyngeal space. The surgical procedure was well tolerated by all patients, with no significant post-operative complications. CONCLUSION: The endoscopic transoral medial pterygomandibular fold approach is safe and efficient for retropharyngeal lymphadenectomy.


Assuntos
Excisão de Linfonodo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Excisão de Linfonodo/métodos , Masculino , Neoplasias Nasofaríngeas/cirurgia , Neoplasias Nasofaríngeas/patologia , Carcinoma Nasofaríngeo/cirurgia , Carcinoma Nasofaríngeo/patologia , Feminino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Cirurgia Endoscópica por Orifício Natural/métodos , Cadáver , Adulto , Faringe/cirurgia , Idoso , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Resultado do Tratamento
13.
Nat Microbiol ; 9(3): 727-736, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38374245

RESUMO

In sub-Saharan Africa, multidrug-resistant non-typhoidal Salmonella serovars are a common cause of fatal bloodstream infection. Malnutrition is a predisposing factor, but the underlying mechanisms are unknown. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated non-typhoidal Salmonella disease in mice and impairs terminal neutrophil maturation. Immature neutrophils had reduced expression of Slc11a1, a gene that encodes a metal ion transporter generally thought to restrict pathogen growth in macrophages. Adoptive transfer of SLC11A1-proficient neutrophils, but not SLC11A1-deficient neutrophils, reduced systemic Salmonella burden in Slc11a1-/- mice or mice with vitamin A deficiency. Loss of terminal granulopoiesis regulator CCAAT/enhancer-binding protein ϵ (C/EBPϵ) also decreased neutrophil-mediated control of Salmonella, but not that mediated by peritoneal macrophages. Susceptibility to infection increased in Cebpe-/- Slc11a1+/+ mice compared with wild-type controls, in an Slc11a1-expression-dependent manner. These data suggest that SLC11A1 deficiency impairs Salmonella control in part by blunting neutrophil-mediated defence.


Assuntos
Salmonelose Animal , Deficiência de Vitamina A , Criança , Camundongos , Humanos , Animais , Neutrófilos , Salmonella , Macrófagos
14.
Autophagy ; : 1-20, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38037248

RESUMO

Renal fibrosis is a typical pathological change in chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) is the predominant stage. Activation of macroautophagy/autophagy plays a crucial role in the process of EMT. Lycopene (LYC) is a highly antioxidant carotenoid with pharmacological effects such as anti-inflammation, anti-apoptosis and mediation of autophagy. In this study, we demonstrated the specific mechanism of LYC in activating mitophagy and improving renal fibrosis. The enrichment analysis results of GO and KEGG showed that LYC had high enrichment values with autophagy. In this study, we showed that LYC alleviated aristolochic acid I (AAI)-induced intracellular expression of PINK1, TGFB/TGF-ß, p-SMAD2, p-SMAD3, and PRKN/Parkin, recruited expression of MAP1LC3/LC3-II and SQSTM1/p62, decreased mitochondrial membrane potential (MMP), and ameliorated renal fibrosis in mice. When we simultaneously intervened NRK52E cells using bafilomycin A1 (Baf-A1), AAI, and LYC, intracellular MAP1LC3-II and SQSTM1 expression was significantly increased. A similar result was seen in renal tissue and cells when treated in vitro and in vivo with CQ, AAI, and LYC, and the inhibitory effect of LYC on the AAI-activated SMAD2-SMAD3 signaling pathway was attenuated. Molecular docking simulation experiments showed that LYC stably bound to the AKT active site. After intervention of cells with AAI and GSK-690693, the expression of PINK1, PRKN, MAP1LC3-II, BECN1, p-SMAD2 and p-SMAD3 was increased, and the expression of SQSTM1 was decreased. However, SC79 inhibited autophagy and reversed the inhibitory effect of LYC on EMT. The results showed that LYC could inhibit the AKT signaling pathway to activate mitophagy and reduce renal fibrosis.Abbreviation: AA: aristolochic acid; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB: actin beta; AKT/protein kinase B: thymoma viral proto-oncogene; BAF-A1: bafilomycin A1; BECN1: beclin 1, autophagy related; CCN2/CTGF: cellular communication network factor 2; CDH1/E-Cadherin: cadherin 1; CKD: chronic kidney disease; COL1: collagen, type I; COL3: collagen, type III; CQ: chloroquine; ECM: extracellular matrix; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; LYC: lycopene; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase ; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PPI: protein-protein interaction; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1/p62: sequestosome 1; TGFB/TGFß: transforming growth factor, beta; VIM: vimentin.

15.
Eur J Med Chem ; 262: 115888, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37866336

RESUMO

Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT1 and MT2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT1 receptor, the widely expressed MT2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT2 receptor ligands used in psychopharmacology and other MT2-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT2 receptor drug candidates.


Assuntos
Doença de Alzheimer , Melatonina , Humanos , Hipocampo/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptor MT1 de Melatonina/metabolismo
16.
IEEE Trans Image Process ; 32: 5494-5508, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37773903

RESUMO

Halftoning aims to reproduce a continuous-tone image with pixels whose intensities are constrained to two discrete levels. This technique has been deployed on every printer, and the majority of them adopt fast methods (e.g., ordered dithering, error diffusion) that fail to render structural details, which determine halftone's quality. Other prior methods of pursuing visual pleasure by searching for the optimal halftone solution, on the contrary, suffer from their high computational cost. In this paper, we propose a fast and structure-aware halftoning method via a data-driven approach. Specifically, we formulate halftoning as a reinforcement learning problem, in which each binary pixel's value is regarded as an action chosen by a virtual agent with a shared fully convolutional neural network (CNN) policy. In the offline phase, an effective gradient estimator is utilized to train the agents in producing high-quality halftones in one action step. Then, halftones can be generated online by one fast CNN inference. Besides, we propose a novel anisotropy suppressing loss function, which brings the desirable blue-noise property. Finally, we find that optimizing SSIM could result in holes in flat areas, which can be avoided by weighting the metric with the contone's contrast map. Experiments show that our framework can effectively train a light-weight CNN, which is 15x faster than previous structure-aware methods, to generate blue-noise halftones with satisfactory visual quality. We also present a prototype of deep multitoning to demonstrate the extensibility of our method.

17.
Planta Med ; 89(15): 1468-1482, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37541437

RESUMO

Boswellia is a traditional medicine for bruises and injuries. Its main active ingredient, acetyl-11-keto-beta-boswellic acid, has antioxidant and antiapoptotic effects. In this experiment, we used Sprague-Dawley rats to make a sciatic nerve injury model to detect the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway and apoptosis, combined with clinical indicators, for testing whether acetyl-11-keto-beta-boswellic acid can reduce oxidative stress and promote sciatic nerve repair. Our results showed that acetyl-11-keto-beta-boswellic acid administration promoted myelin regeneration and functional recovery in the rat sciatic nerve, reduced lipid peroxidation levels, upregulated the expression of various antioxidant enzymes and enhanced enzyme activity, decreased the expression levels of apoptosis-related proteins, and promoted nuclear translocation of the transcription factor NF-E2-related factor 2 protein. In vitro studies revealed that acetyl-11-keto-beta-boswellic acid reduced H2O2-induced reactive oxygen species production, restored mitochondrial membrane potential, upregulated the expression of various antioxidant enzymes, and downregulated apoptosis-related indicators in Schwann cells, and these therapeutic effects of acetyl-11-keto-beta-boswellic acid were reversed after ML385 treatment in Schwann cells. In summary, acetyl-11-keto-beta-boswellic acid alleviates oxidative stress and apoptosis caused by sciatic nerve injury in rats by activating the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway, promotes the recovery of sciatic nerve function in rats, and is a promising therapeutic agent to promote sciatic nerve repair by alleviating excessive oxidative stress.


Assuntos
Heme Oxigenase-1 , Triterpenos , Ratos , Animais , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo , Transdução de Sinais , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Triterpenos/metabolismo , Nervo Isquiático/metabolismo , Células de Schwann/metabolismo
18.
Immun Ageing ; 20(1): 29, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37353855

RESUMO

BACKGROUND: Progressive age-associated change in frequencies and functional capacities of immune cells is known as immunosenescence. Despite data linking chronic environmental, physiological, and psychosocial stressors with accelerated aging, how stress contributes to immunosenesence is not well characterized. OBJECTIVE: To help delineate the contribution of cumulative physiological stress on immunosensence we assessed relationships between a composite measurement of cumulative physiological stress, reflecting the functioning of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cardiovascular system, and metabolic processes, and lymphocyte changes typically affiliated with aging in a cohort of healthy volunteers ranging from 18 to 66 y. RESULTS: Physiological stress load positively correlated with subject age in the study cohort and was significantly higher in adults 50-66 y compared to adults 18-33 y and 34-49 y. Using physiological stress load, we identified a significant age-dependent association between stress load and frequencies of circulating regulatory T lymphocytes (Tregs). Frequencies were higher in younger participants, but only in participants exhibiting low physiological stress load. As stress load increased, frequencies of Tregs decreased in young participants but were unchanged with increasing stress load in middle and older age individuals. Follow-up analysis of stress load components indicated lower circulating DHEA-S and higher urinary norepinephrine as the primary contributors to the effects of total stress load on Tregs. In addition, we identified age-independent inverse associations between stress load and frequencies of naïve Tregs and naïve CD4 T cells and positive associations between stress load and frequencies of memory Tregs and memory CD4 T cells. These associations were primarily driven by stress load components waist circumference, systolic and diastolic blood pressure, CRP, and HbA1c. In summary, our study results suggest that, in younger people, physiological stress load may diminish regulatory T cell frequencies to levels seen in older persons. Furthermore, independent of age, stress load may contribute to contraction of the naïve Treg pool and accumulation of memory Treg cells. CLINICAL TRIAL: Registered on ClincialTrials.gov (Identifier: NCT02367287).

19.
Lung Cancer ; 182: 107279, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37364397

RESUMO

AIMS: The chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by angiogenesis. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 inhibitor ZLDI-8 we found before on angiogenesis and vasculogenic mimicry(VM) in drug-resistant NSCLC. MAIN METHODS: The tube formation assay was used to evaluate angiogenesis and VM. Migration and invasion were assessed with transwell assays in the co-culture condition. To explore the underlying mechanisms of how ZLDI-8 inhibited tubes formation, ELISA assay and western blot assay were preformed. The effects of ZLDI-8 on angiogenesis in vivo were investigated in Matrigel plug, CAM and Rat aortic ring assays. KEY FINDINGS: In the present study, ZLDI-8 significantly inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in either normal medium or in tumor supernatants. Furthermore, ZLDI-8 also inhibited VM tubes formation of A549/Taxol cells. In the co-culture assay, the interaction between lung cancer cells and HUVECs promotes increased cell migration and invasion, while ZLDI-8 eliminates this promotion. Moreover, the VEGF secretion were decreased by ZLDI-8 and the expression of Notch1, Dll4, HIF1α and VEGF were inhibited by ZLDI-8. In addition, ZLDI-8 can inhibit blood vessel formation in the Matrigel plug, CAM and Rat aortic ring assays. SIGNIFICANCE: ZLDI-8 inhibits angiogenesis and VM in drug-resistant NSCLC through suppressing Notch1-HIF1α-VEGF signaling pathway. This study lays the foundation for the discovery of drugs that inhibit angiogenesis and VM in drug resistant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Ratos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células Endoteliais/patologia , Fator A de Crescimento do Endotélio Vascular , Linhagem Celular Tumoral , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia
20.
Neuropharmacology ; 232: 109525, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37004752

RESUMO

Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3ß and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Proteínas tau/metabolismo , Fosforilação , Ácido Okadáico/metabolismo , Ácido Okadáico/farmacologia , Ácido Okadáico/uso terapêutico , Modelos Animais de Doenças
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