RESUMO
During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.
Assuntos
Ocitocina , Células Ganglionares da Retina , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/metabolismoRESUMO
A growing number of clinical and animal studies suggest that the nucleus accumbens (NAc), especially the shell, is involved in the pathogenesis of temporal lobe epilepsy (TLE). However, the role of parvalbumin (PV) GABAergic neurons in the NAc shell involved in TLE is still unclear. In this study, we induced a spontaneous TLE model by intrahippocampal administration of kainic acid (KA), which generally induce acute seizures in first 2 h (acute phase) and then lead to spontaneous recurrent seizures after two months (chronic phase). We found that chemogenetic activation of NAc shell PV neurons could alleviate TLE seizures by reducing the number and period of focal seizures (FSs) and secondary generalized seizures (sGSs), while selective inhibition of PV exacerbated seizure activity. Ruby-virus mapping results identified that the hippocampus (ventral and dorsal) is one of the projection targets of NAc shell PV neurons. Chemogenetic activation of the NAc-Hip PV projection fibers can mitigate seizures while inhibition has no effect on seizure ictogenesis. In summary, our findings reveal that PV neurons in the NAc shell could modulate the seizures in TLE via a long-range NAc-Hip circuit. All of these results enriched the investigation between NAc and epilepsy, offering new targets for future epileptogenesis research and precision therapy.
Assuntos
Epilepsia do Lobo Temporal , Animais , Epilepsia do Lobo Temporal/patologia , Núcleo Accumbens/metabolismo , Parvalbuminas/metabolismo , Convulsões/patologia , Hipocampo/patologia , Neurônios GABAérgicos/metabolismo , Ácido Caínico/toxicidade , Modelos Animais de DoençasRESUMO
By employing [IrCp*Cl2]2/Mg(OMe)2/(CH2O)n as an applicable catalyst system, we report a reductive ß-alkylation of (iso)quinolinium salts with cost-effective and readily available ß-chloro ketones, proceeding with good chemoselectivity, mild reaction conditions, and without the need for introduction of a substituent at position-3 of the quinolyl skeleton. Mechanistic investigations suggest that the reaction proceeds via a sequence of hydride transfer-initiated dearomatization of (iso)quinolinium salts, in situ enamine-trapping of enone and a second round of hydride transfer to the coupling adducts. The present work offers an important complement to the synthesis of functionalized (iso)tetrahydroquinolines.
RESUMO
Gold nanoclusters (AuNCs) are a class of novel luminescent nanomaterials that exhibit unique properties of ultra-small size, featuring strong anti-photo-bleaching ability, substantial Stokes shift, good biocompatibility, and low toxicity. Various biomolecules have been developed as templates or ligands to protect AuNCs with enhanced stability and luminescent properties for biomedical applications. In this review, the synthesis of AuNCs based on biomolecules including amino acids, peptides, proteins and DNA are summarized. Owing to the advantages of biomolecule-protected AuNCs, they have been employed extensively for diverse applications. The biological applications, particularly in bioimaging, biosensing, disease therapy and biocatalysis have been described in detail herein. Finally, current challenges and future potential prospects of bio-templated AuNCs in biological research are briefly discussed.
Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Humanos , Técnicas Biossensoriais/métodos , Luminescência , Animais , Peptídeos/química , DNA/química , Proteínas/química , Substâncias Luminescentes/química , Aminoácidos/químicaRESUMO
Natural products are closely associated with human health. Luteolin (LUT), a flavonoid polyphenolic compound, is widely found in fruits, vegetables, flowers, and herbs. It is noteworthy that LUT exhibits a variety of beneficial pharmacological properties and holds significant potential for clinical applications, particularly in antitumor, anti-convulsion, diabetes control, anti-inflammatory, neuroprotection, anti-oxidation, anti-cardiovascular, and other aspects. The potential mechanism of action has been partially elucidated, including the mediation of NF-κB, toll-like receptor, MAPK, Wnt/ß-catenin, PI3K/Akt, AMPK/mTOR, and Nrf-2, among others. The review that aimed to comprehensively consolidate essential information on natural sources, pharmacological effects, therapeutic and preventive potential, as well as potential mechanisms of LUT. The objective is to establish a theoretical basis for the continued development and application of LUT.
Assuntos
Luteolina , Humanos , Luteolina/farmacologia , Flavonoides/farmacologia , Flavonoides/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Animais , Antioxidantes/farmacologiaRESUMO
Porphyra haitanensis (P. haitanensis), an important food source for coastal residents in China, has a long history of medicinal and edible value. P. haitanensis polysaccharides are some of the main active ingredients in P. haitanensis. It is worth noting that P. haitanensis polysaccharides have a surprising and satisfactory biological activity, which explains the various benefits of P. haitanensis to human health, such as anti-oxidation, immune regulation, anti-allergy, and anticancer properties. Hence, a systematic review aimed at comprehensively summarizing the recent research advances in P. haitanensis polysaccharides is necessary for promoting their better understanding. In this review, we systematically and comprehensively summarize the research progress on the extraction, purification, structural characterization, modification, and biological activity of P. haitanensis polysaccharides and address the shortcomings of the published research and suggest area of focus for future research, providing a new reference for the exploitation of polysaccharides from P. haitanensis in the fields of medicine and functional foods.
Assuntos
Polissacarídeos , Porphyra , Porphyra/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/isolamento & purificação , Humanos , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/isolamento & purificaçãoRESUMO
Moslae Herba (MH) can be used for both medicine and food and has a long history of medicine. MH has the effects of sweating and relieving the exterior, removing dampness and harmonizing, and is mainly used for colds caused by damp heat in summer. It is called "Xiayue Zhi Mahuang" in China. So far, 123 chemical compounds have been isolated and identified from MH, including flavonoids, terpenoids, phenolic acids, phenylpropanoids, and other chemical compounds. Its chemical components have a wide range of pharmacological activities, including antibacterial, antiviral, anti-inflammatory, antioxidant, analgesic sedation, antipyretic, immune regulation, insecticidal, and other effects. In addition, because of its aromatic odor and health care function, MH also has development and utilization value in food, chemical, and other fields. This paper reviewed the research progress of MH in botany, traditional uses, phytochemistry, and pharmacology and provided a possible direction for further research.
Assuntos
Medicina Tradicional Chinesa , Compostos Fitoquímicos , Animais , Humanos , Antioxidantes/química , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêuticoRESUMO
Cancer represents one of the most significant health challenges currently facing humanity, and plant-derived antitumour drugs represent a prominent class of anticancer medications in clinical practice. Isovaleryl sucrose esters, which are natural constituents, have been identified as having potential antitumour effects. However, the mechanism of action remains unclear. In this study, 12 isovaleryl sucrose ester components, including five new (1-5) and seven known compounds (6-12), were isolated from the roots of Atractylodes japonica. The structures of the compounds were elucidated using 1D and 2D-NMR spectroscopy, complemented by HR-ESI-MS mass spectrometry. The cytotoxic activities of all the compounds against human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549) were also evaluated using the CCK8 assay. The results demonstrated that compounds 2, 4, and 6 were moderately inhibitory to HCT-116 cells, with IC50 values of 7.49 ± 0.48, 9.03 ± 0.21, and 13.49 ± 1.45 µM, respectively. Compounds 1 and 6 were moderately inhibitory to A549, with IC50 values of 8.36 ± 0.77 and 7.10 ± 0.52 µM, respectively. Molecular docking revealed that compounds 1-9 exhibited a stronger affinity for FGFR3 and BRAF, with binding energies below -7 kcal/mol. Compound 2 exhibited the lowest binding energy of -10.63 kcal/mol to FGFR3. We screened the compounds with lower binding energies, and the protein-ligand complexes already obtained after molecular docking were subjected to exhaustive molecular dynamics simulation experiments, which simulated the dynamic behaviour of the molecules in close proximity to the actual biological environment, thus providing a deeper understanding of their functions and interaction mechanisms. The present study provides a reference for the development and use of iso-valeryl sucrose esters in the antitumour field.
Assuntos
Atractylodes , Ésteres , Simulação de Acoplamento Molecular , Sacarose , Humanos , Sacarose/química , Sacarose/análogos & derivados , Sacarose/farmacologia , Ésteres/química , Ésteres/farmacologia , Atractylodes/química , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Células HCT116 , Linhagem Celular Tumoral , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células A549 , Simulação de Dinâmica Molecular , Proliferação de Células/efeitos dos fármacosRESUMO
NMDA receptors play an important physiological role in regulating synaptic plasticity, learning and memory. GluN2A subunits are the most abundant functional subunits of NMDA receptors expressed in mature brain, and their dysfunction is related to various neurological diseases. According to subunit composition, GluN2A-containing NMDA receptors can be divided into two types: diheteromeric and triheteromeric receptors. In this review, the expression, functional and pharmacological properties of different kinds of GluN2A-containing NMDA receptors as well as selective GluN2A regulators were described to further understand this type of NMDA receptors.
Assuntos
Plasticidade Neuronal , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologiaRESUMO
BACKGROUND: Idiopathic generalized epilepsy (IGE) is a common epilepsy syndrome with early age onset and generally good seizure outcomes. This study aims to determine the incidence and predictive risk factors for drug-resistant IGE. METHODS: We systematically searched three databases (PubMed, Embase, and Cochrane Library) in November 2022 and included 12 eligible studies which reported long-term outcomes (mean = 14.05) after antiseizure medications (ASMs) from 2001 to 2020. We defined drug resistance as the persistence of any seizure despite ASMs treatment (whether as monotherapies or in combination) given the criteria of drug resistance varied in original studies. A random-effects model was used to evaluate the prevalence of refractory IGE. Studies reporting potential poor prognostic factors were included for subsequent subgroup meta-analysis. RESULTS: The pooled prevalence of drug resistance in IGE cohorts was 27% (95% CI: 0.19-0.36). Subgroup analysis of the risk factors revealed that the psychiatric comorbidities (odds ratio (OR): 4.87, 95% confidence interval (CI): 2.97-7.98), combined three seizure types (absences, myoclonic jerks, and generalized tonic-clonic seizures) (OR: 5.37, 95% CI: 3.16-9.13), the presence of absence seizure (OR: 4.38, 95% CI: 2.64-7.28), generalized polyspike trains (GPT) (OR: 4.83, 95% CI: 2.42-9.64), sex/catamenial epilepsy (OR: 3.25, 95% CI: 1.97-5.37), and status epilepticus (OR: 5.94, 95% CI: 2.23-15.85) increased the risk of poor prognosis. Other factors, including age onset, family history, and side effects of ASMs, were insignificantly associated with a higher incidence of refractory IGE. CONCLUSION: Drug resistance is a severe complication of IGE. Further standardized research about clinical and electroencephalography factors is warranted.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Humanos , Anticonvulsivantes/uso terapêutico , Prevalência , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/epidemiologia , Convulsões/tratamento farmacológico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/epidemiologia , Epilepsia Resistente a Medicamentos/induzido quimicamente , Fatores de Risco , Imunoglobulina E/uso terapêuticoRESUMO
OBJECTIVES: Although the negative effect of pain on cognitive function has been widely reported, it is unclear how the effect is mediated. The aim of this study is to analyze the mediating role of loneliness and depressive symptoms in the association between pain and cognitive function. METHODS: A total of 6,309 participants aged ≥50 years from 2012/13 (T1), 2014/15 (T2), 2016/17 (T3) and 2018/19 (T4) of the English Longitudinal Study of Aging (ELSA) were included. Of them, 55.8% were females, and the median age (rang) was 65 (50-99) years at T1. Serial mediation analysis was performed using Mplus 8.3. RESULTS: The mediation model explained 10.1% of the variance in loneliness, 22.1% of the variance of depressive symptoms, and 22.7% of the variance of cognitive function. Higher level pain was associated with poorer cognitive function (c: ß = -0.057; p < 0.001). The negative effect of pain on cognition was mediated separately and sequentially through loneliness and depressive symptoms, with loneliness and depressive symptoms explaining 8.8% of the total effect, respectively, and the pathway of loneliness and subsequent depression explaining 1.8%. CONCLUSIONS: Diversified interventions aimed at treating pain in older adults would be beneficial for their mental health and cognitive function.
Assuntos
Depressão , Solidão , Feminino , Humanos , Idoso , Idoso de 80 Anos ou mais , Masculino , Solidão/psicologia , Depressão/psicologia , Estudos Longitudinais , Dor , CogniçãoRESUMO
The purpose of this work was to illustrate the effect of processing with vinegar on saikosaponins of Bupleurum chinense DC. (BC) and the protective effects of saikosaponin A (SSA), saikosaponin b1 (SSb1), saikosaponin b2 (SSb2), and saikosaponin D (SSD) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice. We comprehensively evaluated the anti-inflammatory effects and potential mechanisms of SSA, SSb1, SSb2, and SSD through an LPS-induced ALI model using intratracheal injection. The results showed that SSA, SSb1, SSb2, and SSD significantly decreased pulmonary edema; reduced the levels of IL-6, TNF-α, and IL-1ß in serum and lung tissues; alleviated pulmonary pathological damage; and decreased the levels of the IL-6, TNF-α, and IL-1ß genes and the expression of NF-κB/TLR4-related proteins. Interestingly, they were similar in structure, but SSb2 had a better anti-inflammatory effect at the same dose, according to a principal component analysis. These findings indicated that it may not have been comprehensive to only use SSA and SSD as indicators to evaluate the quality of BC, especially as the contents of SSb1 and SSb2 in vinegar-processed BC were significantly increased.
Assuntos
Lesão Pulmonar Aguda , Ácido Oleanólico , Saponinas , Animais , Camundongos , Lipopolissacarídeos/efeitos adversos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ácido Acético , Interleucina-6 , Saponinas/farmacologia , Saponinas/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/química , NF-kappa B/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologiaRESUMO
Bear bile powder is an essential, traditional and valuable Chinese herbal medicine that clears heat, calms the liver, and improves eyesight. Early studies have shown that bear bile powder has lipid-lowering activity, but due to the scarcity of natural bear bile powder resources, it has yet to be used on a large scale. Researchers have found that tauroursodeoxycholic acid (TUDCA) is the primary characteristic bioactive substance of bear bile powder. This study aimed to investigate the therapeutic effect of TUDCA on high-fat diet (HFD)-induced hyperlipidemia. A hyperlipidemia model was established by feeding mice high-fat chow, following the intervention of different concentrations of TUDCA (25/50/100 mg/kg) orally, the hallmark biochemical indexes (total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)), histopathological examination (hematoxylin-eosin (HE) staining and oil red O (ORO) staining), and metabolomic analysis of serum and liver. The results showed that TUDCA could downregulate total TC, TG, LDL-C, upregulate HDL-C, reduce fat deposition in hepatocytes, reverse hepatocyte steatosis, and exhibit prominent lipid-lowering activity. In addition, it may play a therapeutic role by regulating glycerophospholipid metabolism.
Assuntos
Lipidômica , Ursidae , Animais , Camundongos , LDL-Colesterol , Pós , Metabolômica , HDL-ColesterolRESUMO
CONTEXT: Polygonum hydropiper L. (Polygonaceae) (PH) is a traditional Chinese traditional medicine with a pungent flavor and mild drug properties. PH is mainly distributed in the channel tropism in the stomach and large intestine. PH has multiple uses and can be used to treat a variety of diseases for a long time. OBJECTIVE: This review summarizes the phytochemical and pharmacological activities, and applications of PH from 1980 to 2022. We also provide suggestions for promoting further research and developing additional applications of PH. METHODS: The data and information on PH from 1980 to 2022 reviewed in this article were obtained from scientific databases, including Science Direct, PubMed, Science Citation Index, SciFinder Scholar (SciFinder), Springer, American Chemical Society (ACS) Publications, and China National Knowledge Infrastructure (CNKI), etc. Some information was obtained from classic literature on traditional Chinese medicines. The search terms were Polygonum hydropiper, phytochemistry compositions of Polygonum hydropiper, pharmacological activities of Polygonum hydropiper, and applications of Polygonum hydropiper. RESULTS: The comprehensive analysis of the literature resulted in 324 compounds being isolated, identified, and reported from PH. Regarding traditional uses, the majority of phytochemical and pharmacological studies have indicated the diverse bioactivities of PH extracts, flavonoids, and volatile oil elements, including antibacterial, antifungal, insecticidal, antioxidant, and anti-inflammatory. CONCLUSIONS: PH has a long history of diversified medicinal uses, some of which have been verified in modern pharmacological studies. Further detailed studies are required to establish scientific and reasonable quality evaluation standards and action mechanisms of active constituents from PH.
Assuntos
Óleos Voláteis , Polygonum , Polygonum/química , Medicina Tradicional Chinesa , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , EtnofarmacologiaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding. METHODS: In our study, using single-cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34+ cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry. RESULTS: We established a landscape for AML CD34+ cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1high LGALS1high S100Ashigh showing features of granulocyte-monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34+ CD52+ or CD34+ CD74+ DAP12+ were related to good response to induction therapy, showing characteristics of hematopoietic stem cells. CONCLUSION: Our study indicates the subclones of CD34+ cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy.
Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , Medula Óssea/patologia , Leucemia Mieloide Aguda/terapia , Antígenos CD34/uso terapêutico , Citarabina/uso terapêutico , Antraciclinas/uso terapêuticoRESUMO
The development of modern technologies has acclimatized biosensors to complicated applicable scenarios with integrated properties as a whole instead of the pursuit of a single-point breakthrough. Here, we targeted a few concerns in the development of enzyme-based biosensors, including stability, analyte enrichment, and signal transduction, and developed a general biosensing model utilizing enzymes, aggregation-induced emission (AIE) luminogens, and stimuli-responsive framework materials as the units. We propose such proof-of-concept of glucose biosensors by coencapsulating glucose oxidase and AIE-type gold nanoclusters into acid-sensitive zeolite imidazolate framework (ZIF)-8 nanocrystals. The acid-activated degradation of ZIF-8 bridges the molecular signals produced by the enzyme-catalytic reaction of glucose and the photon signals generated by ZIF-8-induced AIE effects of gold nanoclusters, resulting in the "turn-off" model nanoprobes for glucose detection with high selectivity. After embedding the nanoprobes into hollow-out tapes, the formed paper biosensors can conveniently detect glucose with the help of a smartphone.
Assuntos
Técnicas Biossensoriais , Zeolitas , Técnicas Biossensoriais/métodos , Glucose Oxidase/química , Ouro/química , Luminescência , Zeolitas/químicaRESUMO
Luminescent covalent organic frameworks (LCOFs) have attracted significant attention due to their tunability of structures and photophysical properties at molecular level. LCOFs are built to highly ordered and periodic 2D or 3D framework structures through covalently assembling with various luminophore building blocks. Recently, the advantages of LCOFs including predesigned properties of structure, unique photoluminescence, hypotoxicity and good biocompatibility and tumor penetration, broaden their applications in biorelated fields, such as biosensing, bioimaging, and drug delivery. A specific review that analyses the advances of LCOFs in the field of biosensing and bioimaging is thus urged to emerge. Here the construction of LCOFs is reviewed first. The synthetic chemistry of LCOFs highlights the key role of chemical linkages, which not only concrete the building blocks but also affect the optical properties and even can act as the responsive sites for potential sensing applications. How to brighten LCOFs are clarified through description of structure managements. The ability to utilize the luminescence of LCOFs for applications in biosensing and bioimaging is discussed using state-of-the-art examples of varied practical goals. A prospect finally addresses opportunities and challenges the development of LCOFs facing from chemistry, physics to the applications, according to their current progress.
Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Sistemas de Liberação de Medicamentos , Luminescência , Estruturas Metalorgânicas/químicaRESUMO
The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.
Assuntos
Inibidores Enzimáticos , Epóxido Hidrolases , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Inibidores Enzimáticos/química , Dor , Ratos , Relação Estrutura-Atividade , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.
Assuntos
Inibidores Enzimáticos , Epóxido Hidrolases , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Dor , Ratos , Solubilidade , Ureia/farmacologiaRESUMO
Ferrihydrite (Fh), a precursor of more crystalline Fe (hydr)oxides, exhibits decent catalytic behavior; however, the instability of its amorphous structure limits its engineering applications. Siliceous ferrihydrite (FhSi) was readily synthesized in this study by co-precipitation. The formation of Fe-O-Si linkages did not alter the amorphous state of pure Fh, but increased the surface area (SBET), reduced the point of zero charge (pHZPC), and prevented the leaching of more iron. X-ray diffraction, Mössbauer and pyridine-Fourier transform infrared (FTIR) spectroscopies, and potentiometric titration revealed the presence of silicon-occupied portions of growth sites on the Fh surface, which increased the coordination symmetry around the Fe atom and inhibited the transition of Fh to more stable crystalline Fe (hydr)oxides during repeated use. Meanwhile, the density of surface hydroxyl groups (Ds) and the total acid content of the catalytic system after five cycles of catalytic ozonation were 56.75 % and 63.58 % higher than those of freshly prepared system, thereby benefiting the catalysis of ozone for generating ·OH. In addition, the lower pHZPC of the FhSi/O3 system compared to that of the Fh/O3 system promoted the generation of neutral surface-hydroxyl species on the surface of FhSi, which enabled a decent catalytic performance in alkaline solutions, regardless of the catalytic cycle. Moreover, the removal of humic acids (HA) followed a hydroxy radical reaction, which involved self-decomposition (14.15 %), catalytic ozonation (21.58 %), and peroxone and Fenton-like reactions (64.27 %).