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1.
Acta Pharmacol Sin ; 44(2): 367-380, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35794373

RESUMEN

Disrupted redox homeostasis contributes to renal ischemia-reperfusion (IR) injury. Abundant natural products can activate nuclear factor erythroid-2-related factor 2 (Nrf2), thereby providing therapeutic benefits. Methyl eugenol (ME), an analog of the phenolic compound eugenol, has the ability to induce Nrf2 activity. In this study, we investigated the protective effects of ME against renal oxidative damage in vivo and in vitro. An IR-induced acute kidney injury (AKI) model was established in mice. ME (20 mg·kg-1·d-1, i.p.) was administered to mice on 5 consecutive days before IR surgery. We showed that ME administration significantly attenuated renal destruction, improved the survival rate, reduced excessive oxidative stress and inhibited mitochondrial lesions in AKI mice. We further demonstrated that ME administration significantly enhanced Nrf2 activity and increased the expression of downstream antioxidative molecules. Similar results were observed in vitro in hypoxia/reoxygenation (HR)-exposed proximal tubule epithelial cells following pretreatment with ME (40 µmol·L-1). In both renal oxidative damage models, ME induced Nrf2 nuclear retention in tubular cells. Using specific inhibitors (CC and DIF-3) and molecular docking, we demonstrated that ME bound to the binding pocket of AMPK with high affinity and activated the AMPK/GSK3ß axis, which in turn blocked the Nrf2 nuclear export signal. In addition, ME alleviated the development of renal fibrosis induced by nonfatal IR, which is frequently encountered in the clinic. In conclusion, we demonstrate that ME modulates the AMPK/GSK3ß axis to regulate the cytoplasmic-nuclear translocation of Nrf2, resulting in Nrf2 nuclear retention and thereby enhancing antioxidant target gene transcription that protects the kidney from oxidative damage.


Asunto(s)
Lesión Renal Aguda , Factor 2 Relacionado con NF-E2 , Ratones , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Eugenol/metabolismo , Eugenol/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Señales de Exportación Nuclear , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Riñón , Antioxidantes/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo
2.
J Insect Sci ; 21(4)2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-34327530

RESUMEN

We explored characterization of the mitochondrial genome (mitogenome or mtGenome) and phylogenetic analysis between 32 Fulgoroid species by sequencing and analyzing the mitogenome of Nisia fuliginosa Yang and Hu, 1985 (Hemiptera: Fulgoroidea: Meenoplidae), thereby making it the first determined mitogenome from the family Meenoplidae. The mitogenome was found to be 15,754 bp in length and contained 13 protein-coding genes (PCGs), 22 tRNA genes, two ribosomal RNA genes (rRNAs), and a control region. All PCGs started with typical ATN codons, except for nad1, which used GTG as the start codon. Canonical TAA termination codons were found in 10 PCGs and the remaining three genes (cox2, nad6, and nad1) had incomplete stop codons T. All tRNAs could fold into typical cloverleaf secondary structures, with the exception of trnC, trnV, and trnS1. Additionally, we compared the AT and GC skews of 13 PCGs of 32 Fulgoroidea mitogenomes, on the L-strand, the AT and GC skews were negative and positive, respectively. However, on the H-strand, the AT skew could be positive or negative and the GC skew was always negative. Phylogenetic results showed that the eight families of Fulgoroidea were divided into two large groups. Delphacidae formed a monophyletic group sister to a clade comprising Meenoplidae and other six families (Fulgoridae, Ricaniidae, Flatidae, Issidae, Caliscelidae, and Achilidae). Meenoplidae was located near the clade of Delphacidae, and Fulgoridae was located near the clade of Meenoplidae. Furthermore, Caliscelidae, Issidae, Ricaniidae, and Flatidae are closely related and they collectively formed a sister group to Achilidae.


Asunto(s)
Genoma Mitocondrial , Hemípteros/genética , Filogenia , Animales , Clasificación , Orden Génico , Genoma de los Insectos , ARN Ribosómico/genética
3.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572873

RESUMEN

To explore the differences in mitogenome variation and phylogenetics among lineages of the Hemiptera superfamily Fulgoroidea, we sequenced four new mitogenomes of Caliscelidae: two species of the genus Bambusicaliscelis (Caliscelinae: Caliscelini), namely Bambusicaliscelis flavus and B. fanjingensis, and two species of the genus Youtuus (Ommatidiotinae: Augilini), namely Youtuus strigatus and Y. erythrus. The four mitogenomes were 15,922-16,640 bp (base pair) in length, with 37 mitochondrial genes and an AT-rich region. Gene content and arrangement were similar to those of most other sequenced hexapod mitogenomes. All protein-coding genes (PCGs) started with a canonical ATN or GTG and ended with TAA or an incomplete stop codon single T. Except for two transfer RNAs (tRNAs; trnS1 and trnV) lacking a dihydrouridine arm in the four species and trnC lacking a dihydrouridine stem in the Youtuus species, the remaining tRNAs could fold into canonical cloverleaf secondary structures. Phylogenetic analyses based on sequence data of 13 PCGs in the 28 Fulgoroidea species and two outgroups revealed that Delphacidae was monophyletic with strong support. Our data suggest that Fulgoridae is more ancient than Achilidae. Furthermore, Flatidae, Issidae, and Ricaniidae always cluster to form a sister group to Caliscelidae.


Asunto(s)
Genoma de los Insectos , Hemípteros/genética , Animales , Uso de Codones , Genes Mitocondriales , Genoma Mitocondrial , Proteínas de Insectos/genética , Proteínas Mitocondriales/genética , Filogenia , ARN Ribosómico/genética , ARN de Transferencia/genética
4.
Zhongguo Zhong Yao Za Zhi ; 46(24): 6502-6510, 2021 Dec.
Artículo en Zh | MEDLINE | ID: mdl-34994143

RESUMEN

This study aimed to investigate the effect of methyl eugenol(ME) on hypoxia/reoxygenation(H/R)-induced injury of human renal tubular epithelial HK-2 cells and its mechanism. The viability of HK-2 cells cultured with different concentrations of ME and exposed to H/R was detected by cell counting kit-8(CCK-8) assay. The effect of ME on the morphology of HK-2 cells was observed under an inverted microscope. The content of intracellular reactive oxygen species in different groups was detected after 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA) fluorescence staining. Cell apoptosis was determined by flow cytometry. Changes in mitochondrial membrane potential were monitored by JC-1 dye. The concentrations of nuclear factor erythroid 2 related factor 2(Nrf2), heme oxygenase-1(HO-1), and nicotinamide adenine dinucleotide phosphatase oxidase 4(Nox4) were measured by Western blot, followed by the assay of Nrf2 concentration changes in cytoplasm and nucleus by confocal fluorescence staining. The results showed that when the concentration of ME was 0-40 µmol·L~(-1), the activity of HK-2 cells was not affected. Compared with the model group, ME enhanced the activity of HK-2 cells and the cell morphology was normal. As revealed by further experiments, ME inhibited the release of reactive oxygen species and the decline in mitochondrial membrane potential of HK-2 cells after H/R injury, promoted Nrf2/HO-1 expression and Nrf2 translocation to the nucleus, and down-regulated the expression of Nox4, thereby significantly reducing apoptosis. This protective effect of ME could be reversed by the specific Nrf2 inhibitor ML385. These findings have preliminarily proved that ME effectively protected HK-2 cells against H/R injury, which might be related to its promotion of Nrf2/HO-1 signaling pathway and inhibition of Nox4. Such exploration on the possible mechanism of ME in the treatment of renal ischemia-reperfusion injury(IRI) and protection of organ function from the perspective of antioxidant stress has provided reference for related research on the treatment of acute kidney injury with traditional Chinese medicine.


Asunto(s)
Eugenol , Daño por Reperfusión , Apoptosis , Células Epiteliales/metabolismo , Eugenol/análogos & derivados , Eugenol/farmacología , Hemo-Oxigenasa 1/metabolismo , Humanos , Hipoxia , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno , Daño por Reperfusión/tratamiento farmacológico
5.
J Biol Chem ; 293(42): 16453-16463, 2018 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-30194282

RESUMEN

Up-regulation of thrombospondin-4 (TSP4) or voltage-gated calcium channel subunit α2δ1 (Cavα2δ1) proteins in the spinal cord contributes to neuropathic pain development through an unidentified mechanism. We have previously shown that TSP4 interacts with Cavα2δ1 to promote excitatory synaptogenesis and the development of chronic pain states. However, the TSP4 determinants responsible for these changes are not known. Here, we tested the hypothesis that the Cavα2δ1-binding domains of TSP4 are synaptogenic and pronociceptive. We mapped the major Cavα2δ1-binding domains of TSP4 within the coiled-coil and epidermal growth factor (EGF)-like domains in vitro Intrathecal injection of TSP4 fragment proteins containing the EGF-like domain (EGF-LIKE) into naïve rodents was sufficient for inducing behavioral hypersensitivity similar to that produced by an equal molar dose of full-length TSP4. Gabapentin, a drug that binds to Cavα2δ1, blocked EGF-LIKE-induced behavioral hypersensitivity in a dose-dependent manner, supporting the notion that EGF-LIKE interacts with Cavα2δ1 and thereby mediates behavioral hypersensitivity. This notion was further supported by our findings that a peptide within EGF-LIKE (EGFD355-369) could block TSP4- or Cavα2δ1-induced behavioral hypersensitivity after intrathecal injections. Furthermore, only TSP4 proteins that contained EGF-LIKE could promote excitatory synaptogenesis between sensory and spinal cord neurons, which could be blocked by peptide EGFD355-369. Together, these findings indicate that EGF-LIKE is the molecular determinant that mediates aberrant excitatory synaptogenesis and chronic pain development. Blocking interactions between EGF-LIKE and Cavα2δ1 could be an alternative approach in designing target-specific pain medications.


Asunto(s)
Factor de Crecimiento Epidérmico/química , Neuralgia/etiología , Trombospondinas/química , Animales , Canales de Calcio/metabolismo , Dimensión del Dolor , Dominios Proteicos , Ratas , Células Receptoras Sensoriales/metabolismo , Médula Espinal/metabolismo , Sinapsis
6.
J Biol Chem ; 291(25): 13335-48, 2016 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-27129212

RESUMEN

Peripheral nerve injury induces increased expression of thrombospondin-4 (TSP4) in spinal cord and dorsal root ganglia that contributes to neuropathic pain states through unknown mechanisms. Here, we test the hypothesis that TSP4 activates its receptor, the voltage-gated calcium channel Cavα2δ1 subunit (Cavα2δ1), on sensory afferent terminals in dorsal spinal cord to promote excitatory synaptogenesis and central sensitization that contribute to neuropathic pain states. We show that there is a direct molecular interaction between TSP4 and Cavα2δ1 in the spinal cord in vivo and that TSP4/Cavα2δ1-dependent processes lead to increased behavioral sensitivities to stimuli. In dorsal spinal cord, TSP4/Cavα2δ1-dependent processes lead to increased frequency of miniature and amplitude of evoked excitatory post-synaptic currents in second-order neurons as well as increased VGlut2- and PSD95-positive puncta, indicative of increased excitatory synapses. Blockade of TSP4/Cavα2δ1-dependent processes with Cavα2δ1 ligand gabapentin or genetic Cavα2δ1 knockdown blocks TSP4 induced nociception and its pathological correlates. Conversely, TSP4 antibodies or genetic ablation blocks nociception and changes in synaptic transmission in mice overexpressing Cavα2δ1 Importantly, TSP4/Cavα2δ1-dependent processes also lead to similar behavioral and pathological changes in a neuropathic pain model of peripheral nerve injury. Thus, a TSP4/Cavα2δ1-dependent pathway activated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development.


Asunto(s)
Canales de Calcio/metabolismo , Neuralgia/metabolismo , Trombospondinas/fisiología , Animales , Células HEK293 , Humanos , Masculino , Ratones Transgénicos , Células del Asta Posterior/fisiología , Sinapsis/fisiología , Potenciales Sinápticos
7.
J Neurosci ; 34(15): 5322-34, 2014 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-24719110

RESUMEN

This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60-90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked ß-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, ß-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/ß-endorphin inhibitory pathway in a variety of pain hypersensitivity states.


Asunto(s)
Hiperalgesia/metabolismo , Neuralgia/metabolismo , Células del Asta Posterior/metabolismo , Receptores de Glucagón/agonistas , Animales , Células Cultivadas , Exenatida , Glucagón/farmacología , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón , Células HEK293 , Humanos , Hiperalgesia/fisiopatología , Microglía/metabolismo , Neuralgia/fisiopatología , Nocicepción , Fragmentos de Péptidos/farmacología , Péptidos/farmacología , Células del Asta Posterior/fisiología , Ratas , Ratas Wistar , Receptores de Glucagón/genética , Receptores de Glucagón/metabolismo , Ponzoñas/farmacología , betaendorfina/metabolismo
8.
Pharmacol Res ; 102: 276-85, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26546042

RESUMEN

Both peptidic agonist exenatide and herbal agonist catalpol of the glucagon-like peptide-1 receptor (GLP-1R) are neuroprotective. We have previously shown that activation of spinal GLP-1Rs expresses ß-endorphin in microglia to produce antinociception. The aim of this study was to explore whether exenatide and catalpol exert neuroprotection via activation of the hippocampal GLP-1R/ß-endorphin pathway. The rat middle cerebral artery occlusion model was employed, and the GLP-1R immunofluorescence staining and ß-endorphin measurement were assayed in the hippocampus and primary cultures of microglia, neurons and astrocytes. The immunoreactivity of GLP-1Rs on microglia in the hippocampus was upregulated after ischemia reperfusion. Intracerebroventricular (i.c.v.) injection of exenatide and catalpol produced neuroprotection in the rat transient ischemia/reperfusion model, reflected by a marked reduction in brain infarction size and a mild recovery in neurobehavioral deficits. In addition, i.c.v. injection of exenatide and catalpol significantly stimulated ß-endorphin expression in the hippocampus and cultured primary microglia (but not primary neurons or astrocytes). Furthermore, exenatide and catalpol neuroprotection was completely blocked by i.c.v. injection of the GLP-1R orthosteric antagonist exendin (9-39), specific ß-endorphin antiserum, and selective opioid receptor antagonist naloxone. Our results indicate, for the first time, that the neuroprotective effects of catalpol and exenatide are GLP-1R-specific, and that these effects are mediated by ß-endorphin expression probably in hippocampal microglia. We postulate that in contrast to the peripheral tissue, where the activation of GLP-1Rs in pancreas islet ß-cells causes secretion of insulin to perform glucoregulation, it leads to ß-endorphin expression in microglial cells to produce neuroprotection and analgesia in the central nervous system.


Asunto(s)
Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipocampo/efectos de los fármacos , Glucósidos Iridoides/farmacología , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Ponzoñas/farmacología , betaendorfina/metabolismo , Animales , Células Cultivadas , Exenatida , Péptido 1 Similar al Glucagón/metabolismo , Hipocampo/metabolismo , Insulina/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Wistar , Receptores Opioides/metabolismo
9.
Anesthesiology ; 120(4): 962-75, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23928652

RESUMEN

BACKGROUND: D-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide-dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of D-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO-hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance. METHODS: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. RESULTS: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d]isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d]isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. CONCLUSIONS: For the first time, the authors' result identify a novel spinal astroglial DAAO-hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.


Asunto(s)
Astrocitos/enzimología , D-Aminoácido Oxidasa/metabolismo , Tolerancia a Medicamentos/fisiología , Peróxido de Hidrógeno/metabolismo , Morfina/metabolismo , Médula Espinal/enzimología , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Astrocitos/metabolismo , Masculino , Ratones , Morfina/farmacología , Dolor/tratamiento farmacológico , Ratas , Ratas Wistar , Médula Espinal/metabolismo
10.
Anesthesiology ; 121(4): 835-51, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25247855

RESUMEN

BACKGROUND: Lamiophlomis rotata is an orally available Tibetan herb prescribed for the management of pain, with shanzhiside methylester (SM) and 8-O-acetyl-SM as quality control ingredients. This study aimed to evaluate the antinociceptive properties of L. rotata, determine whether SM and 8-O-acetyl-SM are principle effective ingredients, and explore whether L. rotata produces antinociception through activation of spinal glucagon-like peptide-1 receptors (GLP-1Rs). METHODS: Formalin test, neuropathic pain, and bone cancer pain models were used, and the animal sample size was 5 to 6 in each group. Hydrogen peroxide-induced oxidative damage was also assayed. RESULTS: The L. rotata aqueous extract blocked formalin-induced tonic hyperalgesia and peripheral nerve injury- and bone cancer-induced mechanical allodynia by 50 to 80%, with half-effective doses of 130 to 250 mg/kg, close to the human dosage. The herb was not effective in alleviating acute nociceptive pain. A 7-day gavage with L. rotata aqueous extract did not lead to antiallodynic tolerance. Total iridoid glycosides, rather than total flavonoids, were identified by the activity-tracking method as effective ingredients for antihyperalgesia, whereas both SM and 8-O-acetyl-SM were principal components. Further demonstrations using the GLP-1R antagonist and gene silencer against GLP-1R at both the spinal and the cellular levels indicated that L. rotata inhibited pain hyperactivity by activation of spinal GLP-1Rs, and SM and 8-O-acetyl-SM appeared to be orthosteric, reversible, and fully intrinsic agonists of both rat and human GLP-1Rs. CONCLUSIONS: Results support the notion that the activation of spinal GLP-1Rs leads to specific antinociception in pain hypersensitivity and further suggest that GLP-1R is a human-validated target molecule for the treatment of chronic pain.


Asunto(s)
Analgésicos/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Receptores de Glucagón/metabolismo , Administración Oral , Analgésicos/aislamiento & purificación , Animales , Medicamentos Herbarios Chinos/aislamiento & purificación , Receptor del Péptido 1 Similar al Glucagón , Células HEK293 , Calor/efectos adversos , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Neuralgia/tratamiento farmacológico , Células PC12 , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Preparaciones de Plantas/administración & dosificación , Preparaciones de Plantas/aislamiento & purificación , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Tibet
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