RESUMEN
As a central molecule in complement system (CS), complement (C) 3 is upregulated in the patients and animal models of Alzheimer's disease (AD). C3 will metabolize to iC3b and C3a. iC3b is responsible for clearing ß-amyloid protein (Aß). In this scenario, C3 exerts neuroprotective effects against the disease via iC3b. However, C3a will inhibit microglia to clear the Aß, leading to the deposition of Aß and impair the functions of synapses. To their effects on AD, activation of C3a and C3a receptor (C3aR) will impair the mitochondria, leading to the release of reactive oxygen species (ROS), which activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes. The overloading of NLRP3 inflammasomes activate microglia, leading to the formation of inflammatory environment. The inflammatory environment will facilitate the deposition of Aß and abnormal synapse pruning, which results in the progression of AD. Therefore, the current review will decipher the mechanisms of C3a inducing the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms, which facilitates the understanding the AD.
RESUMEN
C1q, the initiator of the classical pathway of the complement system, is activated during Alzheimer's disease (AD) development and progression and is especially associated with the production and deposition of ß-amyloid protein (Aß) and phosphorylated tau in ß-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Activation of C1q is responsible for induction of synapse loss, leading to neurodegeneration in AD. Mechanistically, C1q could activate glial cells, which results in the loss of synapses via regulation of synapse pruning and phagocytosis in AD. In addition, C1q induces neuroinflammation by inducing proinflammatory cytokine secretion, which is partially mediated by inflammasome activation. Activation of inflammasomes might mediate the effects of C1q on induction of synapse apoptosis. On the other hand, activation of C1q impairs mitochondria, which hinders the renovation and regeneration of synapses. All these actions of C1q contribute to the loss of synapses during neurodegeneration in AD. Therefore, pharmacological, or genetic interventions targeting C1q may provide potential therapeutic strategies for combating AD.
RESUMEN
Post-translational modifications (PTMs) have been recently reported to be involved in the development and progression of Alzheimer's disease (AD). In detail, PTMs include phosphorylation, glycation, acetylation, sumoylation, ubiquitination, methylation, nitration, and truncation, which are associated with pathological functions of AD-related proteins, such as ß-amyloid (Aß), ß-site APP-cleavage enzyme 1 (BACE1), and tau protein. In particular, the roles of aberrant PTMs in the trafficking, cleavage, and degradation of AD-associated proteins, leading to the cognitive decline of the disease, are summarized under AD conditions. By summarizing these research progress, the gaps will be filled between PMTs and AD, which will facilitate the discovery of potential biomarkers, leading to the establishment of novel clinical intervention methods against AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Proteínas tau/metabolismo , Procesamiento Proteico-Postraduccional , Péptidos beta-Amiloides/metabolismoRESUMEN
AIMS: The increasing incidence of chronic kidney disease (CKD) urgently calls for effective nephroprotective agents. Traditional Chinese Medicine Angelica sinensis and its formula are well known for CKD therapy, but the underlying mechanisms and effective substances of reno-protective effects remain unclear. To this end, we isolated eleven ligustilide dimers (1-11) from A. sinensis and examined the molecular mechanism of their nephroprotective effects. MAIN METHODS: Because of internal RAS playing an important role in CKD, we used renin expression as a target and screened preliminarily for antifibrotic effects of ligustilide dimers (1-11) by constructing a dual luciferase reporter gene in vitro. Furthermore, the reno-protective effects of the ligustilides and their underlying mechanism were investigated in TGF-ß1-stimulated HK-2 cells and 5/6 nephrectomy (Nx) mice. KEY FINDINGS: The ligustilide dimers exhibited anti-fibrotic effects by inhibiting human renin (hREN) promoter activity to decrease renin expression and down-regulate the expression of fibrosis-related factors, including α-SMA, collagen I, and fibronectin in vitro. Levistolide A (LA) and angeolide keto ester (AK) were screened out to identify their ability and underlying mechanism for treating CKD. Experimental validation further indicated that LA or AK treatment inhibited the expression of key molecules in RAS, TGF-ß1/Smad, and MAPK pathways to downregulate ECM deposition. Furthermore, LA obviously meliorated renal injury in 5/6 Nx mice through ameliorating oxidant stress, inflammation, apoptosis and renal fibrosis. SIGNIFICANCE: The experimental results demonstrated that ligustilide dimers were potential nephroprotective agents. LA might be an attractive drug candidate for renin-targeted CKD therapy.
Asunto(s)
Insuficiencia Renal Crónica , Factor de Crecimiento Transformador beta1 , Humanos , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Renina , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , FibrosisRESUMEN
To discover ulcerative colitis (UC) treatment agents, 28 oleanane-type triterpenoid saponins (1-28) including three new saponins, pulsatillosides P-R (1-3), were isolated from Pulsatilla chinensis. The isolated saponins could observably ameliorate UC by improving the intestinal epithelial cell barrier and intestinal flora in vivo. The structure-activity relationship indicated that the oligosaccharide chain at C-28 was essential for their anti-UC activities; the methyl group at the C-23 site of triterpene saponins showed important effects on anti-UC efficacy; the chain length of oligosaccharides at position C-28 had little effect on their anti-UC activities. In vivo investigation of representative saponins 1 and 13 further confirmed that 23-methyl-3,28-bisdesmosidic oleanane-type saponins inhibited the TNFα-NFκB-MLCK axis to improve the intestinal epithelial cell barrier of the colon in UC mice. These findings revealed the potential of 23-methyl-3,28-bisdesmosidic oleanane-type saponins from P. chinensis as promising candidates for the treatment of UC.
Asunto(s)
Colitis Ulcerosa , Pulsatilla , Saponinas , Animales , Ratones , Colitis Ulcerosa/tratamiento farmacológico , Saponinas/farmacología , Saponinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Radix Astragali (RA) is an important Traditional Chinese Medicine widely used in the treatment of various diseases, such as pneumonia, atherosclerosis, diabetes, kidney and liver fibrosis. The role of isoflavonoids from RA in the treatment of liver injury remains unclear. The study aimed to explore hepatoprotective and anti-inflammatory effects of isoflavonoids from Astragalus mongholicus. Network pharmacological analysis showed that RA had a multi-target regulating effect on alleviating liver injury and inhibiting inflammation through its active ingredients, among which isoflavones were closely related to its key molecular targets. The anti-inflammatory and liver protection effects of isoflavonoids of RA were investigated using lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro and LPS/D-galactosamine (D-gal)-induced acute liver injury mice in vivo. The experimental results showed that methylnissolin (ML) and methylnissolin-3-O-ß-D-glucoside (MLG) presented more notable anti-inflammatory effects. Both of them suppressed the release of pro-inflammatory cytokines, such as iNOS, COX-2, IL-1ß, IL-6, and TNF-α in LPS-stimulated RAW 264.7 cells. In vivo investigation demonstrated that ML markedly meliorated liver injury in LPS/D-gal-induced mice. Western blot results revealed that ML and MLG down-regulated the expression of proinflammatory cytokines via NF-κB signaling pathway. The isoflavonoids, methylnissolin (ML), and methylnissolin-3-O-ß-D-glucoside (MLG), play a vital role in the hepatoprotective and anti-inflammatory effects of RA.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Flavonas , Ratones , Animales , Lipopolisacáridos/farmacología , Galactosamina/metabolismo , Galactosamina/farmacología , Hígado , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Citocinas/metabolismo , FN-kappa B/metabolismo , Flavonas/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoRESUMEN
Neuronal apoptosis is considered to be a critical cause of Alzheimer's disease (AD). Recently, meloxicam has shown neuroprotective effects; however, the inherent mechanisms are highly overlooked. Using APP/PS1 transgenic (Tg) mice as in vivo animal models, we found that meloxicam inhibits apoptosis in neurons by deactivating tumor necrosis factor receptor superfamily member 25 (TNFRSF25), leading to the suppression of the expression of fas-associated protein with death domain (FADD) and the cleavage of DNA fragmentation factor subunit α (DFFA) and cysteine aspartic acid protease-3 (caspase 3) via ß-amyloid protein (Aß)-depressing mechanisms. Moreover, the meloxicam treatment blocked the effects of ß-amyloid protein oligomers (Aßo) on stimulating the synthesis of tumor necrosis factor α (TNF-α) and TNF-like ligand 1A (TL1A) in neuroblastoma (N) 2a cells. TNF-α and TL1A induce apoptosis in neurons via TNFR- and TNFRSF25-dependent caspase 3-activating mechanisms, respectively. Knocking down the expression of TNFRSF25 blocked the effects of TL1A on inducing apoptosis in neurons by deactivating the signaling cascades of FADD, caspase 3, and DFFA. Consistently, TNFRSF25 shRNA blocked the effects of Aßo on inducing neuronal apoptosis, which was corroborated by the efficacy of meloxicam in inhibiting Aßo-induced neuronal apoptosis. By ameliorating neuronal apoptosis, meloxicam improved memory loss in APP/PS1 Tg mice.
Asunto(s)
Enfermedad de Alzheimer , Fragmentación del ADN , Meloxicam , Miembro 25 de Receptores de Factores de Necrosis Tumoral , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apoptosis , Caspasa 3/metabolismo , Meloxicam/farmacología , Ratones Transgénicos , Neuronas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
MicroRNAs (miRNAs), a group of small noncoding RNAs (approximately 20-24 nucleotides), act as essential regulators affecting endogenous gene expression in plants. MiR482/2118 is a unique miRNA superfamily in plants and represses NUCLEOTIDE BINDING SITE-LEUCINE-RICH REPEAT (NBS-LRR) genes to function in plant resistance to pathogens. In addition, over the past several years, it has been found that miR482/2118 not only targets NBS-LRRs but also acts on other molecular mechanisms to affect plant resistance. miR482/2118-5ps, phased small interfering RNAs (phasiRNAs) and long noncoding RNAs (lncRNAs) play important roles in plant disease resistance. This review summarizes the current knowledge of the interactions and links between miR482/2118 and its new interacting molecules, miR482/2118-5p, phasiRNAs and lncRNAs, in plant disease resistance. Here, we aim to provide a comprehensive view describing the new molecular mechanism associated with miR482/2118 in the plant immune system.
RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by the loss and apoptosis of neurons. Neurons abnormally enter the cell cycle, which results in neuronal apoptosis during the course of AD development and progression. However, the mechanisms underlying cell cycle re-entry have been poorly studied. Using neuroblastoma (N) 2a SW and APP/PS1 transgenic (Tg) mice as in vitro and in vivo AD models, we found that the expression of cyclin-dependent kinase (CDK)1/2/4 and cyclin A2/B1/D3/E1 was increased while the protein expression of p18 and p21 was decreased, which led to enhanced cell cycle re-entry in a ß-amyloid protein (Aß)-dependent mechanism. By preparing and treating with the temperature-sensitive chitosan-encapsulated drug delivery system (CS), the abnormal expression of CDK1/2/4, cyclin A2/B1/D3/E1 and p18/21 was partially restored by acetylsalicylic acid (ASA), which decreased the apoptosis of neurons in APP/PS1 Tg mice. Moreover, CDK4 and p21 mediated the effects of ASA on activating transcription factor (TF) EB via peroxisome proliferator-activated receptor (PPAR) α, thus leading to the uptake of Aß by astrocytes in a low-density lipoprotein receptor (Ldlr)-dependent mechanism. Moreover, the mechanisms of Aß-degrading mechanisms are activated, including the production of microtubule-associated protein light chain (LC) 3II and Lamp2 protein by ASA in a PPARα-activated TFEB-dependent manner. All these actions contribute to decreasing the production and deposition of Aß, thus leading to improved cognitive decline in APP/PS1 Tg mice.
Asunto(s)
Péptidos beta-Amiloides , FN-kappa B , Epoprostenol , Interferón gamma , Prostaglandinas ERESUMEN
ABATRACTNine compounds, five phenolic glycosides (1, 2, 4-6), three phenylpropanoids (7-9), and a furanone glycoside (3), were isolated from aqueous soluble extract of the dried roots of Anemone chinensis Bunge. The structures of new compounds (1-4) were elucidated by comprehensive spectroscopic data analysis as well as chemical evidence. Pulsatillanin A (1) demonstrated significant antioxidant effects through scavenging free radical in DPPH assay, and relieved the oxidative stress in LPS-induced RAW 264.7 cells by reducing ROS production, enhancing antioxidant enzyme SOD activity, replenishing depleted GSH in a dose-dependent manner. Western blot analysis revealed that 1 showed antioxidant activity via activating Nrf2 signaling pathway.[Formula: see text].
Asunto(s)
Anemone , Antioxidantes , Antioxidantes/química , Glicósidos/química , Glicósidos/farmacología , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Fenoles/análisis , Extractos Vegetales/química , Especies Reactivas de Oxígeno , Superóxido DismutasaRESUMEN
PURPOSE: Therapeutic engagement is a key component of psychological interventions. Robot-assisted psychological interventions appear to have therapeutic benefits for service users that are challenging to engage. However, engagement with robots in robot-assisted psychological interventions is not well understood. The aim of this systematic review is to evaluate the quality of therapeutic engagement in robot-assisted psychological interventions (PROSPERO: 122437). METHODS: Scopus, Web of Science, PsycInfo and Medline were searched until 15 January 2021 for studies which quantitatively evaluated therapeutic engagement in robot-assisted psychological interventions. The Effective Public Health Practice Project (EPHPP) quality assessment tool was used to assess methodological dimensions of studies. RESULTS: 3647 studies were identified through database searching. Thirty studies (N = 1462), published between 2004 and 2020, and from 14 countries, were included. Robots were typically toy animals or humanoids and were used to provide support and improve wellbeing through social interaction. Studies primarily tested robots on older adults with dementia and children with autism and indicated positive therapeutic engagement. Twelve studies included a control group. EPHPP ratings were 'strong' (N = 1), 'moderate' (N = 10) and 'weak' (N = 19). CONCLUSIONS: Therapeutic engagement between service users and robots is generally positive. Methodological limitations of studies, such as small sample sizes, and lack of control groups and longitudinal data, mean that the field is in early stages of its development and conclusions should be drawn with caution. There are important practical and ethical implications for policymakers to consider, such as responsible clinical practice and how service users may understand the therapeutic relationship with robots.
Asunto(s)
Robótica , Anciano , Humanos , Robótica/métodosRESUMEN
Riligustilide (RG), one of the dimeric phthalides of Angelica sinensis and Ligusticum chuanxiong, was confirmed effective against many diseases. However, its effects on type 2 diabetes mellitus (T2DM) and the underlying molecular mechanisms have not been clearly elucidated yet. The current study was designed to investigate the hypoglycemic potential by which RG affects the pathogenesis of T2DM. Comprehensive insights into the effects and underlying molecular mechanisms of RG on attenuating aberrant metabolism of glucose were determined in high-fat diet-induced T2DM mice and insulin-resistant (IR) HepG2 cells. In high-fat diet-induced C57BL/6J mice, RG administration significantly reduced hyperglycemia, decreased hyperinsulinemia, and ameliorated glucose intolerance. Mechanistically, RG activated PPARγ and insulin signaling pathway to improve insulin sensitivity, and increase glucose uptake as well as glycogenesis. In addition, RG also upregulated AMPK-TORC2-FoxO1 axis to attenuate gluconeogenesis in vivo and in vitro. According to the findings, RG may be a promising candidate for the treatment of T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Benzofuranos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gluconeogénesis , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Neuroinflammation is thought to be a cause of Alzheimer's disease (AD), which is partly caused by inadequate mitophagy. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD. METHODS: BV2 cells and APP/PS1 transgenic (Tg) mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN in neuroinflammation of AD. Sophisticated molecular technologies including quantitative (q) RT-PCR, western blot, enzyme linked immunosorbent assay (ELISA), co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were employed to reveal the inherent mechanisms. RESULTS: As a consequence, key roles of OPTN in regulating neuroinflammation were identified by depressing the activity of absent in melanoma 2 (AIM2) inflammasomes and receptor interacting serine/threonine kinase 1 (RIPK1)-mediated NF-κB inflammatory mechanisms. In detail, we found that expression of OPTN was downregulated, which resulted in activation of AIM2 inflammasomes due to a deficiency in mitophagy in APP/PS1 Tg mice. By ectopic expression, OPTN blocks the effects of Aß oligomer (Aßo) on activating AIM2 inflammasomes by inhibiting mRNA expression of AIM2 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), leading to a reduction in the active form of caspase-1 and interleukin (IL)-1ß in microglial cells. Moreover, RIPK1 was also found to be negatively regulated by OPTN via ubiquitin protease hydrolysis, resulting in the synthesis of IL-1ß by activating the transcriptional activity of NF-κB in BV2 cells. As an E3 ligase, the UBAN domain of OPTN binds to the death domain (DD) of RIPK1 to facilitate its ubiquitination. Based on these observations, ectopically expressed OPTN in APP/PS1 Tg mice deactivated microglial cells and astrocytes via the AIM2 inflammasome and RIPK-dependent NF-κB pathways, leading to reduce neuroinflammation. CONCLUSIONS: These results suggest that OPTN can alleviate neuroinflammation through AIM2 and RIPK1 pathways, suggesting that OPTN deficiency may be a potential factor leading to the occurrence of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Inflamasomas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Apoptosis/fisiología , Encéfalo/metabolismo , Caspasa 1/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular , Proteínas de Unión al ADN/genética , Humanos , Interleucina-1beta/metabolismo , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Transgénicos , Enfermedades Neuroinflamatorias/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genéticaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by the production and deposition of ß-amyloid protein (Aß) and hyperphosphorylated tau, leading to the formation of ß-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Although calcium ions (Ca2+) promote the formation of APs and NFTs, no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD has been published. Therefore, the current review aimed to fill the gaps between elevated Ca2+ levels and the pathogenesis of AD. Specifically, we mainly focus on the molecular mechanisms by which Ca2+ affects the neuronal networks of neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy. Furthermore, the roles of Ca2+ transporters located in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosome in mediating the effects of Ca2+ on activating neuronal networks that ultimately contribute to the development and progression of AD are discussed. Finally, the drug candidates derived from herbs used as food or seasoning in Chinese daily life are summarized to provide a theoretical basis for improving the clinical treatment of AD.
RESUMEN
Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer's disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of ß-amyloid protein (Aß) but also induced Aß efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aß. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aß production and clearing Aß from the brains of AD mice.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Indometacina/farmacología , Placa Amiloide/tratamiento farmacológico , alfa-Macroglobulinas/metabolismo , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Ciclooxigenasa 2/metabolismo , Humanos , Indometacina/uso terapéutico , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones , Ratones Endogámicos C57BL , Placa Amiloide/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Regulación hacia Arriba , alfa-Macroglobulinas/genéticaRESUMEN
Twenty seven dihydro-ß-agarofuran sesquiterpenoids, including fifteen new congeners, wilforsinines I-W (1-9, 12-13, 24-27), and twelve known compounds were isolated from the dried root of Tripterygium wilfordii. The structures of the new sesquiterpenoids, wilforsinines I-W, were elucidated by extensive spectroscopic data analysis. The anti-inflammatory activity of isolates 1-27 were evaluated by examining their inhibitory effects on nitric oxide (NO) production in LPS-induced RAW 264.7 macrophage cells. Among them, wilforsinine K (3) and angulatin M (16) exerted optimal inhibitory effects on the production of NO in LPS-induced RAW 264.7 cells. Moreover, Western blot results revealed that their anti-inflammatory activities were correlated with the suppression of the expression of nitric oxide synthase (iNOS) and down-regulation of the level of NF-κB p65 phosphorylation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inflamación/tratamiento farmacológico , Sesquiterpenos/farmacología , Tripterygium/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Fosforilación/efectos de los fármacos , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence rate. The main pathological features of AD are ß-amyloid plaques (APs), which are formed by ß-amyloid protein (Aß) deposition, and neurofibrillary tangles (NFTs), which are formed by the excessive phosphorylation of the tau protein. Although a series of studies have shown that the accumulation of metal ions, including calcium ions (Ca2+), can promote the formation of APs and NFTs, there is no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD. In view of this, the current review summarizes the mechanisms by which Ca2+ is transported into and out of cells and organelles, such as the cell, endoplasmic reticulum, mitochondrial and lysosomal membranes to affect the balance of intracellular Ca2+ levels. In addition, dyshomeostasis of Ca2+ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aß peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca2+ can affect the learning ability and memory of people with AD. In addition, the effects of these mechanisms on the synaptic plasticity are also discussed. Finally, the molecular network through which Ca2+ regulates the pathogenesis of AD is introduced, providing a theoretical basis for improving the clinical treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Calcio/metabolismo , Iones/metabolismo , Agregación Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Animales , Transporte Biológico , Membrana Celular/metabolismo , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Retículo Endoplásmico/metabolismo , Humanos , Lisosomas/metabolismo , Memoria , Mitocondrias/metabolismo , Plasticidad Neuronal , Neuronas/metabolismo , FosforilaciónRESUMEN
Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.
Asunto(s)
Diseño de Fármacos , Terapia Molecular Dirigida , Fenoles/síntesis química , Fenoles/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Células MCF-7 , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Fenoles/química , Fenoles/uso terapéutico , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Violacin A, a chromanone derivative, isolated from a fermentation broth of Streptomyces violaceoruber, has excellent anti-inflammatory potential. Herein, a biogenetically modeled approach to synthesize violacin A and twenty-five analogues was described, which involved the preparation of aromatic polyketide precursor through Claisen condensation and its spontaneous cyclization. The inhibitory effect on nitric oxide (NO) production of all synthetic molecules was evaluated by lipopolysaccharide (LPS)-induced Raw264.7 cells. The results revealed that introduction of aliphatic amine moieties on C-7 obviously improved the anti-inflammation effect of violacin A, and also the aromatic ether instead of ketone group at side chain was favorable to increase the activity. Among them, analogue 7a and 16d were screened as the most effective anti-inflammatory candidates. Molecular mechanism research revealed that 7a and 16d acquired anti-inflammatory ability due to the inhibition of NF-κB signaling pathway.