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1.
J Cell Mol Med ; 28(6): e18176, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38454800

RESUMO

Senescent kidney can lead to the maladaptive repairment and predispose age-related kidney diseases. Here, we explore the renal anti-senescence effect of a known kind of drug, sodium-dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence-accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence-related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK-2) cells induced by H2 O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti-senescence role. Dapagliflozin down-regulate the LTBP2 expression in kidney tissues and HK-2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein-docking analysis implies there is salt-bridge formation between them; these all indicate the possibility of weak-interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2 O2 , dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non-diabetes environment; the mechanism may be through regulating the role of LTBP2.


Assuntos
Nefropatias , Inibidores do Transportador 2 de Sódio-Glicose , Camundongos , Humanos , Animais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Rim/metabolismo , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Nefropatias/metabolismo , Proteínas de Ligação a TGF-beta Latente
2.
Reprod Biol Endocrinol ; 22(1): 52, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711160

RESUMO

BACKGROUND: Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. METHODS: The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. RESULTS: The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. CONCLUSIONS: FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.


Assuntos
Receptores de Activinas Tipo II , Oócitos , Animais , Feminino , Oócitos/efeitos dos fármacos , Camundongos , Receptores de Activinas Tipo II/metabolismo , Ovulação/efeitos dos fármacos , Gonadotropina Coriônica/farmacologia , Hormônio Foliculoestimulante/sangue , Oogênese/efeitos dos fármacos , Indução da Ovulação/métodos , Fragmentos Fc das Imunoglobulinas/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Gravidez , Ativinas
3.
Brain Behav Immun ; 119: 14-27, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38548184

RESUMO

BACKGROUND: Alzheimer's disease (AD), the most prevalent type of dementia, still lacks disease-modifying treatment strategies. Recent evidence indicates that maintaining gut microbiota homeostasis plays a crucial role in AD. Targeted regulation of gut microbiota, including probiotics, is anticipated to emerge as a potential approach for AD treatment. However, the efficacy and mechanism of multi-strain probiotics treatment in AD remain unclear. METHODS: In this study, 6-month-old senescence-accelerated-mouse-prone 8 (SAMP8) and senescence-accelerated-mouse-resistant 1 (SAMR1) were utilized. The SAMP8 mice were treated with probiotic-2 (P2, a probiotic mixture of Bifidobacterium lactis and Lactobacillus rhamnosus) and probiotic-3 (P3, a probiotic mixture of Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus rhamnosus) (1 × 109 colony-forming units) once daily for 8 weeks. Morris water maze (MWM) and novel object recognition (NOR) tests were employed to assess the memory ability. 16S sequencing was applied to determine the composition of gut microbiota, along with detecting serum short-chain fatty acids (SCFAs) concentrations. Neural injury, Aß and Tau pathology, and neuroinflammation level were assessed through western blot and immunofluorescence. Finally, potential molecular mechanisms was explored through transcriptomic analysis and western blotting. RESULTS: The MWM and NOR test results indicated a significant improvement in the cognitive level of SAMP8 mice treated with P2 and P3 probiotics compared to the SAMP8 control group. Fecal 16S sequencing revealed an evident difference in the α diversity index between SAMP8 and SAMR1 mice, while the α diversity of SAMP8 mice remained unchanged after P2 and P3 treatment. At the genus level, the relative abundance of ten bacteria differed significantly among the four groups. Multi-strain probiotics treatment could modulate serum SCFAs (valeric acid, isovaleric acid, and hexanoic acid) concentration. Neuropathological results demonstrated a substantial decrease in neural injury, Aß and Tau pathology and neuroinflammation in the brain of SAMP8 mice treated with P3 and P2. Transcriptomic analysis identified the chemokine signaling pathway as the most significantly enriched signaling pathway between SAMP8 and SAMR1 mice. Western blot test indicated a significant change in the phosphorylation level of downstream AKT/GSK-3ß between the SAMP8 and SAMR1 groups, which could be reversed through P2 and P3 treatment. CONCLUSIONS: Multi-strain probiotics treatment can ameliorate cognitive impairment and pathological change in SAMP8 mice, including neural damage, Aß and Tau pathology, and neuroinflammation. This effect is associated with the regulation of the phosphorylation of the AKT/GSK-3ß pathway.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Modelos Animais de Doenças , Microbioma Gastrointestinal , Glicogênio Sintase Quinase 3 beta , Probióticos , Proteínas Proto-Oncogênicas c-akt , Animais , Probióticos/farmacologia , Probióticos/uso terapêutico , Camundongos , Doença de Alzheimer/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Disfunção Cognitiva/metabolismo , Masculino , Envelhecimento/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lacticaseibacillus rhamnosus , Proteínas tau/metabolismo
4.
J Toxicol Environ Health A ; 87(11): 471-479, 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38590254

RESUMO

Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer's disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aß). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive. The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model. Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death. Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.


Assuntos
Doença de Alzheimer , Canabidiol , Disfunção Cognitiva , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Eixo Encéfalo-Intestino , Cognição , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças
5.
J Toxicol Environ Health A ; 87(10): 428-435, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38551404

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease associated with long non-coding RNAs and DNA methylation; however, the mechanisms underlying the role of lncRNA small nucleolar RNA host gene 1 (lncRNA SNHG1) and subsequent involvement of DNA methylation in AD development are not known. The aim of this study was to examine the regulatory mechanisms attributed to lncRNA SNHG1 gene utilizing 2 strains of senescence-accelerated mouse prone 8 (SAMP8) model of AD and compared to senescence-accelerated mouse resistant (SAMR) considered a control. Both strains of the mouse were transfected with either blank virus, psLenti-U6-SNHG1(low gene expression) virus, and psLenti-pA-SNHG1(gene overexpression) virus via a single injection into the brains for 2 weeks. At 2 weeks mice were subjected to a Morris water maze to determine any behavioral effects followed by sacrifice to extract hippocampal tissue for Western blotting to measure protein expression of p-tau, DNMT1, DNMT3A, DNMT3B, TET1, and p-Akt. No marked alterations were noted in any parameters following blank virus transfection. In SAMP8 mice, a significant decrease was noted in protein expression of DNMT1, DNMT3A, DNMT3B, and p-Akt associated with rise in p-tau and TET1. Transfection with ps-Lenti-U6-SNHG1 alone in SAMR1 mice resulted in a significant rise in DNMTs and p-Akt and a fall in p-tau and TET1. Transfection of SAMP8 with ps-Lenti-U6-SNHG1 blocked effects on overexpression noted in this mouse strain. However, knockdown of lncRNA SNHG1 yielded the opposite results as found in SAMR1 mice. In conclusion, the knockdown of lncRNA SNHG1 enhanced DNA methylation through the PI3K/Akt signaling pathway, thereby reducing the phosphorylation levels of tau in SAMP8 AD model mice with ameliorating brain damage attributed to p-tau accumulation with consequent neuroprotection.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , RNA Longo não Codificante , Camundongos , Animais , Doença de Alzheimer/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Metilação de DNA , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doenças Neurodegenerativas/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
6.
Int J Mol Sci ; 25(2)2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38255794

RESUMO

Hydroxyhydroquinone (HHQ) is an oxidative component produced by roasting coffee beans and has been reported to generate relatively large amounts of reactive oxygen species (ROS). In this study, we used senescence-accelerated mouse prone 8 (SAMP8) mice to determine whether HHQ consumption increases oxidative-stress-induced injury, because in SAMP8 mice, the activity of 8-oxoguanine DNA glycosylase 1, which repairs oxidative modifications in DNA, is decreased. The results showed that two out of twelve (16.7%) HHQ-treated mice presented polyuria and glucosuria around 2 months after the start of treatment, indicating that HHQ may act as a mutagen against SAMP8 mice, which is sensitive to oxidative damage. No abnormalities were observed in the chlorogenic acid (coffee polyphenol, CPP)-treated group. The concentration of hydrogen peroxide in the serum of SAMP8 mice was significantly higher than that in SAMR1 (senescence-resistant) control mice, and the concentration was further increased in the HHQ-treated group. CPP, when coexisting with HHQ at the rate contained in roasted coffee, decreased the amount of hydrogen peroxide in the serum of SAMP8 mice. Although CPP can act both oxidatively and antioxidatively as a polyphenol, CPP acts more antioxidatively when coexisting with HHQ. Thus, the oxidative effect of HHQ was shown to be counteracted by CPP.


Assuntos
Ácido Clorogênico , Hidroquinonas , Polifenóis , Animais , Camundongos , Ácido Clorogênico/farmacologia , Polifenóis/farmacologia , Mutagênicos/toxicidade , Peróxido de Hidrogênio , Estresse Oxidativo , DNA
7.
Curr Issues Mol Biol ; 45(2): 1287-1305, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36826029

RESUMO

Alzheimer's disease (AD) is a worldwide problem. Currently, there are no effective drugs for AD treatment. Scrophularia buergeriana Miquel (SB) is a traditional herbal medicine used in Korea to treat various diseases. Our previous studies have shown that ethanol extract of SB roots (SBE, Brainon®) exhibits potent anti-amnesic effects in Aß1-42- or scopolamine-treated memory impairment mice model and neuroprotective effects in a glutamate-induced SH-SY5Y cell model. In this study, we evaluated the therapeutic effects of Brainon® and its mechanism of action in senescence-accelerated mouse prone 8 (SAMP8) mice. Brainon® (30 or 100 mg/kg/day) was orally treated to six-month-old SAMP8 mice for 12 weeks. Results revealed that Brainon® administration effectually ameliorated cognitive deficits in Y-maze and passive avoidance tests. Following the completion of behavioral testing, western blotting was performed using the cerebral cortex. Results revealed that Brainon® suppressed Aß1-42 accumulation, Tau hyperphosphorylation, oxidative stress, and inflammation and alleviated apoptosis in SAMP8 mice. Brainon® also promoted synaptic function by downregulating the expression of AChE and upregulating the expression of p-CREB/CREB and BDNF. Furthermore, Brainon® restored SAMP8-reduced expression of ChAT and -dephosphorylated of ERK and also decreased AChE expression in the hippocampus. Furthermore, Brainon® alleviated AD progression by promoting mitophagy/autophagy to maintain normal cellular function as a novel finding of this study. Our data suggest that Brainon® can remarkably improve cognitive deficiency with the potential to be utilized in functional food for improving brain health.

8.
Neurobiol Learn Mem ; 203: 107791, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37380098

RESUMO

Learning and memory impairment is commonly noted in Alzheimer's disease (AD), which is regarded as a progressive synaptic failure disease. Exercise is a nonpharmacological strategy that may help prevent cognitive decline and reduce the risk of AD, which is usually thought to be related to synaptic damage in the hippocampus. However, the effects of exercise intensity on hippocampal memory and synaptic function in AD remain unclear. In this study, senescence-accelerated mouse prone-8 (SAMP8) mice were randomly assigned to the control group (Con), low-intensity exercise group (Low), and moderate-intensity exercise group (Mid). Here, we showed that eight weeks of treadmill exercise beginning in four-month-old mice improved spatial memory and recognition memory in six-month-old SAMP8 mice, while the Con group exhibited impaired spatial memory and recognition memory. Treadmill exercise also improved hippocampal neuron morphology in SAMP8 mice. Furthermore, dendritic spine density and the levels of postsynaptic density protein-95 (PSD95) and Synaptophysin (SYN) increased significantly in the Low and Mid groups as compared with the Con group. We further showed that moderate-intensity exercise (60 % of maximum speed) was more efficacious in increasing dendritic spine density、PSD95 and SYN, than low-intensity exercise (40 % of maximum speed). In conclusion, the positive effect of treadmill exercise is closely related to exercise intensity, with moderate-intensity exercise showing the most optimal effects.


Assuntos
Doença de Alzheimer , Memória Espacial , Camundongos , Animais , Envelhecimento/psicologia , Hipocampo , Transtornos da Memória , Proteína 4 Homóloga a Disks-Large , Modelos Animais de Doenças
9.
Oral Dis ; 2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37357357

RESUMO

OBJECTIVE: Loss of occlusal support due to tooth loss has been indicated as one of the risk factors for Alzheimer's disease. This study aimed to investigate the relationship between tooth loss and cognitive dysfunction and illustrate the role of neuroinflammation in advancing Alzheimer's disease. MATERIALS AND METHODS: Male 5-month-old senescence-accelerated mouse strain P8 (SAMP8) mice were divided into three groups (n = 7): the C (control), S (sham-operated), and TL (tooth loss) groups. The Morris water maze (MWM) test was performed to assess spatial memory. Additionally, histopathological and molecular assessments of hippocampal tissues were performed. RESULTS: The TL groups exhibited impaired spatial memory in the water maze. Tooth loss induced higher protein expression levels of the neuroinflammation cytokine interleukin-1ß (IL-1ß) in the hippocampus than in the S and C groups. Tooth loss activated the NLRP3 inflammasome and increased the expression of Caspase-1 in the hippocampus. CONCLUSIONS: The findings indicated that tooth loss impairs cognitive function in SAMP8 mice and is closely related to the activation of NLRP3/Caspase-1 in the hippocampus.

10.
Int J Mol Sci ; 24(18)2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37762170

RESUMO

With the progression of an aging society, cognitive aging has emerged as a pressing concern necessitating attention. The senescence-accelerated mouse-prone 8 (SAMP8) model has proven instrumental in investigating the early stages of cognitive aging. Through an extensive examination of molecular changes in the brain cortex, utilizing integrated whole-genome transcriptomics, our principal aim was to uncover potential molecular targets with therapeutic applications and relevance to drug screening. Our investigation encompassed four distinct conditions, comparing the same strain at different time points (1 year vs. 16 weeks) and the same time point across different strains (SAMP8 vs. SAMR1), namely: physiological aging, accelerated aging, early events in accelerated aging, and late events in accelerated aging. Focusing on key functional alterations associated with aging in the brain, including neurogenesis, synapse dynamics, neurometabolism, and neuroinflammation, we identified candidate genes linked to these processes. Furthermore, employing protein-protein interaction (PPI) analysis, we identified pivotal hub genes involved in interactions within these functional domains. Additionally, gene-set perturbation analysis allowed us to uncover potential upstream genes or transcription factors that exhibited activation or inhibition across the four conditions. In summary, our comprehensive analysis of the SAMP8 mouse brain through whole-genome transcriptomics not only deepens our understanding of age-related changes but also lays the groundwork for a predictive model to facilitate drug screening for cognitive aging.


Assuntos
Envelhecimento Cognitivo , Transcriptoma , Animais , Camundongos , Encéfalo , Envelhecimento/genética , Córtex Cerebral , Modelos Animais de Doenças
11.
Int J Mol Sci ; 24(17)2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37685895

RESUMO

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The causes of the disease are not well understood, as it involves a complex interaction between genetic, environmental, and epigenetic factors. SAMP8 mice have been proposed as a model for studying late-onset AD, since they show age-related learning and memory deficits as well as several features of AD pathogenesis. Epigenetic changes have been described in SAMP8 mice, although sex differences have never been evaluated. Here we used western blot and qPCR analyses to investigate whether epigenetic markers are differentially altered in the dorsal hippocampus, a region important for the regulation of learning and memory, of 9-month-old male and female SAMP8 mice. We found that H3Ac was selectively reduced in male SAMP8 mice compared to male SAMR1 control mice, but not in female mice, whereas H3K27me3 was reduced overall in SAMP8 mice. Moreover, the levels of HDAC2 and JmjD3 were increased, whereas the levels of HDAC4 and Dnmt3a were reduced in SAMP8 mice compared to SAMR1. In addition, levels of HDAC1 were reduced, whereas Utx and Jmjd3 were selectively increased in females compared to males. Although our results are preliminary, they suggest that epigenetic mechanisms in the dorsal hippocampus are differentially regulated in male and female SAMP8 mice.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Feminino , Masculino , Animais , Camundongos , Hipocampo , Doença de Alzheimer/genética , Amnésia , Epigênese Genética , Transtornos da Memória
12.
Mod Rheumatol ; 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37522619

RESUMO

OBJECTIVES: Aging and obesity are major risk factors for osteoarthritis (OA), a widespread disease currently lacking efficient treatments. Senescence-accelerated mouse prone 8 (SAMP8) display early-onset aging phenotypes, including OA. This study investigates the impacts of high-fat diet (HFD)-induced obesity on OA development in SAMP8. METHODS: SAMP8 at five weeks were fed either a normal chow diet or an HFD for ten weeks to induce obesity. Parameters related to obesity, liver function, and lipid and glucose metabolism were analyzed. At 14 weeks of age, knee joint pathology, bone mineral density, and muscle strength were assessed. Immunohistochemistry and TUNEL staining were performed to evaluate markers for cartilage degeneration and chondrocyte apoptosis. RESULTS: At 14 weeks of age, HFD-induced obesity increased liver and adipose tissue inflammation in SAMP8 without further exacerbating diabetes. Histological scoring revealed aggravated cartilage, menisci deterioration, and synovitis, while no further loss of bone mineral density or muscle strength was observed. Increased chondrocyte apoptosis was detected in knee joints following HFD feeding. CONCLUSIONS: Ten weeks of HFD feeding promotes spontaneous OA progression in 14-week-old SAMP8, potentially via liver damage subsequent chondrocyte apoptosis. This aging-obese mouse model may prove valuable for further exploration of spontaneous OA pathophysiology.

13.
Zhongguo Zhong Yao Za Zhi ; 48(18): 5032-5040, 2023 Sep.
Artigo em Zh | MEDLINE | ID: mdl-37802845

RESUMO

This study aimed to explore the possible effect of Xixin Decoction(XXD) on the learning and memory ability of Alzheimer's disease(AD) model senescence-accelerated mouse-prone 8(SAMP8) and the related mechanism in enhancing neuroprotective effect and reducing neuroinflammation. Forty SAMP8 were randomly divided into a model group(10 mL·kg~(-1)·d~(-1)), a probiotics group(0.39 g·kg~(-1)·d~(-1)), a high-dose group of XXD granules(H-XXD, 5.07 g·kg~(-1)·d~(-1)), a medium-dose group of XXD granules(M-XXD, 2.535 g·kg~(-1)·d~(-1)), and a low-dose group of XXD granules(L-XXD, 1.267 5 g·kg~(-1)·d~(-1)). Eight senescence-accelerated mouse-resistant 1(SAMR1) of the same age and strain were assigned to the control group(10 mL·kg~(-1)·d~(-1)). After ten weeks of intragastric administration, the Morris water maze was used to test the changes in spatial learning and memory ability of mice after treatment. Meanwhile, immunofluorescence staining was used to detect the positive expression of receptor for advanced glycation end products(AGER), Toll-like receptor 1(TLR1), and Toll-like receptor 2(TLR2) in the hippocampal CA1 region of mice. Western blot was employed to test the protein expression levels of silencing information regulator 2 related enzyme 1(SIRT1), AGER, TLR1, and TLR2 in the hippocampus of mice. Enzyme linked immunosorbent assay(ELISA) was applied to assess the levels of Aß_(1-42) in the hippocampus of mice and the levels of nuclear factor κB p65(NF-κB p65), NOD-like receptor protein 3(NLRP3), tumor necrosis factor-α(TNF-α), and interleukin-1ß(IL-1ß) in the serum and hippocampus of mice. Compared with the model group, XXD significantly improved the spatial learning and memory ability of SAMP8, increased the expression of neuroprotective factors in the hippocampus, decreased the levels of neuroinflammatory factors, and inhibited the expression of Aß_(1-42). In particular, H-XXD significantly increased the expression of SIRT1 in the hippocampus of mice, reduced the expression levels of NF-κB p65, NLRP3, TNF-α, and IL-1ß in the serum and hippocampus of mice, and decreased the expression of AGER, TLR1, and TLR2 in the hippocampus of mice(P<0.05 or P<0.01). XXD may improve the spatial learning and memory ability of AD model SAMP8 by enhancing the neuroprotective effect and inhibiting neuroinflammation.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Sirtuína 1/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 1 Toll-Like/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Hipocampo
14.
Biochem Biophys Res Commun ; 616: 33-40, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-35636253

RESUMO

INTRODUCTION: Considering that neurodegeneration is an irreversible process, an efficient, low-burden approach to prevent dementia is strongly needed. Here, we show that the daily intake of myricetin normalised cognitive dysfunction in senescence-accelerated mouse prone 8 (SAMP8) mice. METHODS: SAMP8 mice were fed a diet supplemented with myricetin and novel object recognition tests and Y-maze tests were performed. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brains of SAMP8 mice were measured. The phosphorylation level of cAMP-response-element-binding protein (CREB) level in brains of SAMP8 mice were evaluated. Also, SH-SY5Y cells were treated with myricetin and cAMP levels were measured. RESULTS: In SAMP8 mice, neurotrophins, including BDNF and NGF, were downregulated relative to levels in their normal counterparts. In addition, myricetin intake upregulated the phosphorylation of CREB, the major transcription factor for BDNF and NGF. Also, myricetin induced cAMP upregulation, and CREB phosphorylation via a cAMP-dependent protein kinase-dependent manner in SH-SY5Y cells. CONCLUSION: Taken together, myricetin improves cognitive function in SAMP8 mice and upregulates BDNF and NGF.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Cognição , Flavonoides , Neuroblastoma , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Fator de Crescimento Neural/metabolismo , Neuroblastoma/metabolismo
15.
Biochem Biophys Res Commun ; 609: 9-14, 2022 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-35413542

RESUMO

The endocannabinoid 2-arachidonoylglycerol (2AG) is an important modulator of stress responses. Its level in the brain increases in response to stress, but region-specific effects of stress on brain 2AG are not well known yet. Moreover, green nut oil (GNO), oil extracted from the seeds of Plukenetia volubilis has several health benefits, but its effects on brain 2AG levels are unknown. Therefore, we conducted this study to explore the effects of stress and GNO supplementation on 2AG levels in specific brain regions of senescence-accelerated mouse prone 8 (SAMP8). In this study, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) revealed that water-immersion stress for three days significantly increased 2AG levels in several brain regions of SAMP8 mice, including the hypothalamus, midbrain, and hindbrain. No significant change was observed in the relative abundance of brain 2AG in stress given SAMP8 mice after eighteen days of removing stress load compared to control SAMP8 mice. GNO supplementation also increased brain 2AG in SAMP8 mice without stress load. Additionally, GNO supplementation sustained the increased brain 2AG levels in stress given SAMP8 mice after eighteen days of removing stress load. Among all brain regions, a relatively higher accumulation of 2AG was noted in the hypothalamus, midbrain, and hindbrain of GNO-fed SAMP8. Our data explored the potentiality of GNO supplementation to improve brain 2AG levels which might be used to treat anxiety and depressive behaviors.


Assuntos
Encéfalo , Nozes , Envelhecimento , Animais , Ácidos Araquidônicos , Suplementos Nutricionais , Endocanabinoides , Glicerídeos , Hipotálamo , Mesencéfalo , Camundongos , Rombencéfalo
16.
Metab Brain Dis ; 37(4): 1197-1205, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35143023

RESUMO

The inflammasome assembles leading to increased cleavage and activity of caspase-1 and downstream IL-1ß release, which plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that caspase-1-mediated neuroinflammation occurs early in AD process. However, the detailed role of caspase-1 in aging-related AD-like neuropathology is still unclear so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we detected the levels of caspase-1 in brains of 3-, 7-, and 11-month-old mice and observed that caspase-1 was activated during aging process. More importantly, we provided the evidence that VX-765, a selective inhibitor of caspase-1, significantly rescued spatial learning and memory impairments and reduced tau hyperphosphorylation in brains of SAMP8 mice at early stages of the disease. This amelioration might be attributed to IL-1ß-induced hypoactivation of tau kinases. Our results imply that caspase-1 may represent as a potential therapeutic target for neurodegenerative tauopathies.


Assuntos
Doença de Alzheimer , Caspase 1/metabolismo , Disfunção Cognitiva , Tauopatias , Animais , Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória , Camundongos , Tauopatias/tratamento farmacológico
17.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232484

RESUMO

Physical frailty is an aging-related clinical syndrome involving decreases in body weight, mobility, activity, and walking speed that occurs in individuals with sarcopenia and is accelerated by increased oxidative stress. Ninjin'yoeito, a traditional Japanese Kampo medicine, is used for treating conditions, including anemia and physical weakness. Here, we investigated whether ninjin'yoeito could improve physical frailty by controlling oxidative stress in the senescence-accelerated mouse prone 8 (SAMP8) model. First, SAMP8 mice were divided into two groups, ninjin'yoeito treated and untreated, with the former consuming a diet containing 3% ninjin'yoeito from 3 months of age. At 7 months of age, body weight, motor function, locomotor activity, and mean walking speed were measured. Subsequently, mice were euthanized and measured for muscle weight, 8-hydroxy-2'-deoxyguanosine levels in muscle and brain, and cleaved caspase-3 expression in brain. The results showed reductions in weight, locomotor function, locomotion, and average walking speed in the untreated group, which were significantly improved by ninjin'yoeito. Furthermore, 8-hydroxy-2'-deoxyguanosine levels were reduced in muscle and brain from ninjin'yoeito-treated mice, compared with the levels in untreated mice; cleaved caspase-3 expression was similarly reduced in brain from the treated mice, indicating reduced apoptosis. Our findings suggest that ninjin'yoeito inhibits sarcopenia-based physical frailty through its antioxidant effects.


Assuntos
Fragilidade , Sarcopenia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Antioxidantes , Peso Corporal , Caspase 3 , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Camundongos , Sarcopenia/tratamento farmacológico
18.
Biochem Biophys Res Commun ; 572: 112-117, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364289

RESUMO

The senescence-accelerated mouse prone (SAMP) 8 strain exhibits age-related learning and memory deficits (LMD) at 2 months of age. We have found strong association of chromosome 12 locus with learning memory deficit (LMD) phenotype in SAMP8 strain. In the course of searching candidate gene, here we identified solute carrier family 24 sodium/potassium/calcium exchanger member 4 (Slc24a4) in SAMP8 chromosome 12 LMD possessing one single nucleotide polymorphism causing amino acid replacement of Threonine at 413 position with Methionine. Since SLC24A4 has been postulated as a candidate of late onset Alzheimer's diseases (LOAD), we further analyze the functional importance of this polymorphism. By expressing Slc24a4 protein in HEK293 cells, here we showed polymorphic SAMP8 type Slc24a4-T413 M causing significant loss of calcium ion (Ca2+) transporter activity in cells compared with that of wild type mouse (Slc24a4-WT). However, no study yet shows any functional association of human SLC24A4 polymorphism with the onset of LOAD pathogenesis. Thus, our present finding may further help to clarify the importance of this ion exchanger with age related cognitive dysfunction.


Assuntos
Doença de Alzheimer/genética , Transtornos da Memória/genética , Animais , Antiporters/genética , Senescência Celular/genética , Células HEK293 , Humanos , Masculino , Camundongos , Mutação
19.
J Neuroinflammation ; 18(1): 75, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33736657

RESUMO

BACKGROUND: Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process. METHODS: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1+ clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation. RESULTS: Aged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1+ clusters, but not an increase in the number of Iba1+ cells. We have further observed an increase of main inflammatory mediator IL-1ß, and an augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45+ cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1ß) transcription is enhanced in CD45+BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1ß expression is further augmented in aged SAMP8 compared to control SAMR1. CONCLUSION: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1ß, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.


Assuntos
Senilidade Prematura/genética , Envelhecimento/patologia , Encefalite/genética , Encefalite/patologia , Animais , Encéfalo/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Plexo Corióideo/metabolismo , Plexo Corióideo/patologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Meninges/metabolismo , Meninges/patologia , Camundongos , Proteínas dos Microfilamentos/metabolismo
20.
Cell Mol Neurobiol ; 41(7): 1509-1520, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32642922

RESUMO

It was already shown that microdoses of lithium carbonate (Li2CO3) promoted memory stabilization in humans and mice. Prolonged treatment also reduced neuronal loss and increased the density of the neurotrophin BDNF in transgenic mice for Alzheimer's disease. The aim of this study was to evaluate whether lithium ions affect inflammatory profiles and neuronal integrity in an animal model of accelerated senescence (SAMP-8). Organotypic hippocampal cultures obtained from 11 to 12-month-old SAMP-8 mice were treated with 2 µM, 20 µM and 200 µM Li2CO3. 2 µM Li2CO3 promoted a significant reduction in propidium iodide uptake in the CA2 area of hippocampus, whereas 20 µM promoted neuroprotection in the CA3 and GrDG areas. 200 µM caused an increase in cellular death, showing toxicity. Measured with quantitative PCR, IL-1α, IL-6 and MIP-1B/CCL-4 gene expression was significantly reduced with 20 µM Li2CO3, whereas IL-10 gene expression was significantly increased with the same concentration. In addition, 2 µM and 20 µM Li2CO3 were also effective in reducing the activation of NFkB and inflammatory cytokines densities, as evaluated by ELISA. It is concluded that very low doses of Li2CO3 can play an important role in neuroprotection as it can reduce neuronal loss and neuroinflammation in older individuals.


Assuntos
Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos de Fenilmercúrio/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
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