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1.
Molecules ; 28(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36677958

RESUMO

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC 'click' (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing ß-galactosidase (T. gondii ß-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC50) measurement on T. gondii ß-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC50 values and reduced effect on HFF viability when applied at 2.5 µM (23: IC50 = 0.032 µM/HFF viability 92% and 26: IC50 = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity.


Assuntos
Rutênio , Toxoplasma , Humanos , Antiparasitários/farmacologia , Rutênio/farmacologia , Galactose/farmacologia
2.
Shock ; 59(1): 91-98, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36609501

RESUMO

ABSTRACT: Ischemic postconditioning (I/Post) reduces I/R injury by activating endogenous cardioprotection mechanisms, such as the JAK/signal transducer and activator of transcription 3 (STAT3) and PI3K/Akt pathways, which offer a traditional approach to myocardial protection. According to a previous study, cardioprotection by I/Post may be lost in aged mice, and in our previous research, hypoxic postconditioning (H/Post) lacked a protective effect in senescent cardiomyocytes, which was associated with low expression of long noncoding RNA H19. The N6-methyladenosine (m 6 A) modification is a dynamic and reversible process that has been confirmed to play a role in cardiovascular diseases. However, the mechanisms of m 6 A modification in myocardial I/Post remain to be explored. Neonatal cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats, and senescence was induced by d -galactose, followed by stimulation of hypoxia-reoxygenation and H/Post. Hypoxic injury was evaluated by cell viability and the Bcl-2/Bax protein ratio. Total m 6 A levels were measured using a colorimetric m 6 A RNA Methylation Quantification Kit, and the m 6 A modified and differentially expressed mRNA was determined by MeRIP (methylated RNA immunoprecipitation). We found that H/Post increased m 6 A methylation and decreased RNA mA demethylase alkB homolog 5 (ALKBH5) expression in aged cardiomyocytes. Furthermore, ALKBH5 knockdown exacerbated injury following H/Post in senescent cardiomyocytes. In addition, ALKBH5 regulated STAT3 expression by mediating its m 6 A modification and long noncoding RNA H19/miR-124-3p. ALKBH5 also alleviated the H/Post injury induced by the low expression of STAT3 in senescent cardiomyocytes.


Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Camundongos , Ratos , Galactose/farmacologia , Hipóxia/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo
3.
Eur J Pharmacol ; 939: 175476, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36539073

RESUMO

Primary sarcopenia is a multicausal skeletal muscle disease associated with muscle strength and mass loss. Skeletal muscle fibrosis is one of the significant pathological manifestations associated with the development of age-related sarcopenia. Irisin, which is cleaved by the extracellular domain of fibronectin type Ⅲ domain-containing protein 5 (FNDC5), has previously been reported to exert antifibrotic effects on the heart, liver, and pancreas, but whether it can rescue skeletal muscle fibrosis remains unknown. In this study, we examined the effects of irisin on D-galactose (D-gal)-induced skeletal muscle fibroblasts. We found that D-gal-induced senescence, fibrosis, and redox imbalance were inhibited by irisin treatment. Mechanistically, irisin or FNDC5 overexpression attenuated D-gal-induced senescence, redox imbalance, and fibrosis by regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Overall, irisin might be a promising therapeutic candidate for age-related skeletal muscle fibrosis.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Sarcopenia , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibronectinas/metabolismo , Galactose/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Sarcopenia/metabolismo , Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo , Fibrose
4.
Front Biosci (Landmark Ed) ; 27(11): 315, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36472113

RESUMO

BACKGROUND: The theory of free radical oxidative stress (ROS) is one of the leading theories of ageing, and antioxidants play an important role in antiaging. Dendrobium has always been popular as a natural antioxidant. METHODS: This study investigated the effects of various polarity fractions of ethanol extracts from Dendrobium nobile Lindl. (D. nobile) on D-galactose-induced aging mice. D. nobile stems were extracted by ethanol to form the crude extract (EA), which was sequentially extracted by trichloromethane, ethyl acetate, and n-butanol to yield the secondary extracts, named TCM, EAC, and NBA, respectively. EA, TCM, EAC and NBA were intragastrically administered at a dose of 200 mg/kg b.w. to the aging mice induced by D-galactose for 8 weeks. RESULTS: Compared with the aging control group (AC), D. nobile extracts reduced body weight and lipid accumulation and enhanced endurance and immunity by increasing the index of the spleens and thymus. Meanwhile, D. nobile extracts showed antioxidant properties by lowering Malondialdehyde (MDA) levels and increasing the activities of superoxide dismutase (SOD), catalase (CAT), and Glutathione peroxidase (GSH-Px) in the skin, blood, liver, and brain. Furthermore, D. nobile extracts had a good protective effect on the cell structure and function against lesions of the skin, liver, brain, kidney, and ovary of aging mice. In particular, EA and EAC had better antioxidant and antiaging effects, suggesting that the most effective components were flavonoids and polyphenols that existed in EAC. Both EA and EAC downregulated the expression of aging-related genes such as Il1a, Il1b, Il1rn, Ccl3, Ccl4, Fos and Gck in the brain at the transcriptome level. Both EA and EAC reversed the increase in the Firmicutes/Bacteroidota ratio in aging mice, increased the abundance of probiotic bacteria Lactobacillus and Muribaculum, and decreased the abundance of pathogenic bacteria such as Staphylococcus, Corynebacterium and Brevibacterium. CONCLUSIONS: The EA and EAC extracts of D. nobile have better effects on immunity improvement, antioxidation and antiaging by remodelling the intestinal microecosystem and downregulating the expression of age-promoting genes in the brain. D. nobile, especially EA and EAC extracts, could be used as an antiaging drug or functional food.


Assuntos
Antioxidantes , Dendrobium , Feminino , Animais , Camundongos , Antioxidantes/farmacologia , Galactose/farmacologia , Dendrobium/química , Estresse Oxidativo , Envelhecimento , Etanol
5.
Dement Geriatr Cogn Disord ; 51(4): 297-309, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36273456

RESUMO

INTRODUCTION: In this study, it was aimed to investigate the effect of thymoquinone (TQ) on oxidative stress and apolipoprotein E (ApoE) in an experimental Alzheimer's model created with AlCl3 and D-galactose in rats. METHODS: Thirty-six Wistar Albino male rats saline group (Group 1), aluminum chloride (AlCl3) + D-galactose (D-Gal) group (Group 2), AlCl3 + D-Gal + TQ group (Group 3) were divided into 3 groups. The study was completed with 33 rats. Group 1 was given saline intraperitoneally (i.p) for 28 days. 2nd group; D-Gal at a dose of 60 mg/kg/day and AlCl3 at a dose of 40 mg/kg/day were given i.p. daily for 28 days. 3rd group; D-Gal at a dose of 60 mg/kg/day and AlCl3 at a dose of 40 mg/kg/day were given i.p. daily for 28 days. Group 3 rats were given 20 mg/kg/day TQ in corn oil by gavage for 14 days. Malonyl dialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAS), total oxidant capacity (TOS), glutathione peroxidase (GsH-Px), and ApoE levels were determined in the blood and brain tissues of rats in all three groups. One-way ANOVA test was used in the statistical analysis of the data. RESULTS: Means of TAS, TOS, GSH-Px, SOD, MDA, and ApoE in blood and brain tissue of all three groups (excluding ApoE in brain tissue) were different from each other and this difference was statistically significant (p < 0.05). CONCLUSION: In this study, TQ, it was determined that all oxidative stress parameters examined had positively affected and decreased blood tissue ApoE levels. TQ can be used as an antioxidant and curative in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Antioxidantes , Humanos , Animais , Ratos , Cloreto de Alumínio/farmacologia , Antioxidantes/farmacologia , Galactose/farmacologia , Doença de Alzheimer/tratamento farmacológico , Ratos Wistar , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Apolipoproteínas E
6.
Sci Rep ; 12(1): 17084, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224264

RESUMO

Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1-control group, which received saline solution, 2-D-galactose (D-gal) group, which received D-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3-D-galactose + Metformin (D-gal + Met) treated group, which received D-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.


Assuntos
Galactose , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Galactose/farmacologia , Masculino , Metformina/farmacologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Solução Salina/farmacologia , Sinaptofisina/metabolismo
7.
Ecotoxicol Environ Saf ; 246: 114158, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36228358

RESUMO

Increased production and environmental release of multi-walled carbon nanotubes (MWCNTs) increase soil exposure and potential risk to earthworms. However, MWCNT toxicity to earthworms remains unclear, with some studies identifying negative effects and others negligible effects. In this study, to determine whether exposure to MWCNTs negatively affects earthworms and to elucidate possible mechanisms of toxicity, earthworms were exposed to sublethal soil concentrations of MWCNTs (10, 50, and 100 mg/kg) for 28 days. Earthworm growth and reproduction, activities of cytochrome P450 (CYP) isoforms (1A2, 2C9, and 3A4) and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione-s-transferase (GST)), and metabolomics were determined. Effects of MWCNTs on earthworms depended on exposure concentration. Exposure to MWCNTs did not significantly affect growth and reproduction of individual earthworms. Exposure to 50 mg/kg MWCNTs significantly increased activities of CYP2C9, CYP3A4, SOD, CAT, and GST but clearly reduced levels of L-aspartate, L-asparagine, and glutamine. With exposure to 100 mg/kg MWCNTs, toxic effects on earthworms were observed, with significant inhibition in activities of CYP isoenzymes and SOD, significant reductions in L-aspartate, L-asparagine, glutamine, and tryptophan, and simultaneous accumulations of citrate, isocitrate, fumarate, 2-oxoglutarate, pyruvate, D-galactose, carbamoyl phosphate, formyl anthranilate, hypoxanthine, and xanthine. Results suggest that toxicity of MWCNTs to earthworms is associated with reduced detoxification capacity, excessive oxidative stress, and disturbance of multiple metabolic pathways, including amino acids metabolism, the tricarboxylic acid cycle, pyruvate metabolism, D-galactose metabolism, and purine metabolism. The study provides new insights to better understand and predict the toxicity of MWCNTs in soil.


Assuntos
Nanotubos de Carbono , Oligoquetos , Poluentes do Solo , Animais , Nanotubos de Carbono/toxicidade , Nanotubos de Carbono/química , Solo , Glutamina , Galactose/farmacologia , Ácido Aspártico , Asparagina/metabolismo , Asparagina/farmacologia , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Poluentes do Solo/química , Glutationa Transferase/metabolismo , Reprodução , Piruvatos/farmacologia
8.
Exp Gerontol ; 170: 111978, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36244586

RESUMO

The present study aimed to evaluate the anti-aging effect of the leaves of Scutellaria baicalensis Georgi (LSBG) and investigate its mechanisms. For this purpose, SD rats were received D-galactose (D-gal) subcutaneously (0.3 g/kg) and LSBG intragastrically (0.4 g/kg or 0.8 g/kg) for 7 weeks. Behavior tests were conducted to evaluate the cognitive function of all rats. Results showed that memory impairment was reversed by LSBG. Then, metabolomics of the cortex and hippocampus were used to investigate the potential mechanisms. 21 metabolites in the cortex and 22 metabolites in the hippocampus of aging rats were altered, respectively. Additionally, results showed that the content of key metabolites and activities of enzymes in glutamate metabolism and its downstream metabolism (glutathione metabolism) could be regulated by the LSBG. Additionally, proteins in the Nrf2 signaling pathway were analyzed by western blot. And the protein expression levels of Nrf2, GCLC, HO-1, NQO-1 were significantly regulated by the LSBG in the cortex and hippocampus. Above all, the anti-aging effects of the LSBG were involved in regulating the glutamate metabolism and Nrf2 signaling pathway.


Assuntos
Galactose , Scutellaria baicalensis , Animais , Ratos , Scutellaria baicalensis/metabolismo , Galactose/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Envelhecimento/metabolismo , Encéfalo/metabolismo , Estresse Oxidativo , Transdução de Sinais , Glutamatos/farmacologia
9.
Curr Med Sci ; 42(5): 991-999, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36107305

RESUMO

OBJECTIVE: The main pathological feature of immunoglobulin A nephropathy (IgAN), an autoimmune kidney disease, is the deposition of IgA immune complexes, accompanied by mesangial cell proliferation and elevated urine protein. The Guben Tongluo formula (GTF) is a traditional Chinese medicine prescription, which has predominant protective effects on IgAN. However, the therapeutic mechanism of the GTF in IgAN remains elusive. The present study aimed to determine the effects of GTF in treating IgAN via regulating the TLR4/MyD88/NF-κB pathway. METHODS: In the present study, lamina propria B lymphocytes were treated with different concentrations of lipopolysaccharide (LPS) (0, 1, 5, 10 and 20 ng/mL). Flow cytometry was used to define positive CD86+CD19+ cells. CCK-8 assay was used to examine cell proliferation. RNAi was used to induce TLR4 silencing. qRT-PCR and Western blotting were used to determine gene expression. RESULTS: It was found that the LPS dose-dependently increased the content of IgA and galactose-deficient IgA1 (Gd-IgA), the levels of TLR4, Cosmc, MyD88 and phosphorylated (p)-NF-κB, and the ratio of CD86+CD19+ and IgA-producing B cells. However, the TLR4 knockdown reversed the role of LPS. This suggests that TLR4 mediates the effects of LPS on lamina propria B lymphocytes. Furthermore, the GTF could dose-dependently counteract the effects of LPS and TLR4 overexpression on lamina propria B lymphocytes through the TLR4/MyD88/NF-κB pathway. CONCLUSION: Collectively, these results demonstrate that the GTF can regulate the TLR4/MyD88/NF-κB pathway to treat IgAN model lamina propria B lymphocytes stimulated by LPS.


Assuntos
Glomerulonefrite por IGA , NF-kappa B , Humanos , NF-kappa B/metabolismo , Lipopolissacarídeos/efeitos adversos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Complexo Antígeno-Anticorpo/metabolismo , Complexo Antígeno-Anticorpo/farmacologia , Complexo Antígeno-Anticorpo/uso terapêutico , Sincalida/metabolismo , Sincalida/farmacologia , Sincalida/uso terapêutico , Galactose/farmacologia , Galactose/uso terapêutico , Transdução de Sinais , Linfócitos B/metabolismo , Imunoglobulina A/metabolismo , Membrana Mucosa/metabolismo
10.
Exp Gerontol ; 169: 111953, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36116694

RESUMO

Longitudinal studies are mandatory to study aging, however, they have certain drawbacks, for example, they require strict maintenance that is expensive given the breeding time (approximately 2 years) and with a low survival rate, having some animals to study very limitedly. In vitro studies provide useful and invaluable information on the cellular and molecular mechanisms that help understand the aging process to overcome these aspects. In particular, the model of premature aging induced by chronic exposure to D-galactose (D-Gal) offers a very similar picture to that which occurs in natural aging. This model mimics most of the old animals' cellular processes, such as oxidative stress, mitochondrial dysfunction, increased advanced glycation end products (AGEs), inflammation, and senescence-associated secretory phenotype (SASP). However, the information related to the endoplasmic reticulum (ER) stress and, subsequently, the unfolded protein response (UPR) is not fully elucidated. Therefore, this review brings together the most current information on this response in the D-Gal-induced aging model and its effect on cardiac structure and function.


Assuntos
Envelhecimento , Galactose , Animais , Galactose/farmacologia , Envelhecimento/metabolismo , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Produtos Finais de Glicação Avançada/metabolismo
11.
Food Funct ; 13(18): 9268-9284, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-35993148

RESUMO

The effect of different extraction processes on the physicochemical characterization, digestibility, antioxidant activity and prebiotic activity of Isaria cicadae Miquel (ICM) fruiting body polysaccharides was studied. Furthermore, the effect of ultrasound-assisted extraction of ICM (U-ICM) on gut microbiota, the intestinal barrier and immune response was deeply explored. This study found that ICMs showed high indigestibility in both α-amylase and artificial gastric juice, indicating that ICMs have the potential as dietary fiber. In contrast, U-ICM had the best antioxidant activity and prebiotic potential. Meanwhile, there was a structure-activity relationship between the antioxidant activity of ICMs and the content of uronic acid, arabinose and galactose. When healthy mice were fed U-ICM for 42 days, the relative abundances of Lactobacillus, Akkermansia, and Bacteroides were found to increase significantly, while that of Clostridium decreased significantly. Meanwhile, U-ICM significantly promotes the expression of tight junction protein and the production of cytokines, indicating that U-ICM had the function of enhancing the intestinal barrier and regulating the host immune response. In conclusion, U-ICM as dietary fiber has the potential to be developed as a gut health-promoting prebiotic component or functional food. This research provided a valuable resource for further exploring the structure-activity relationship and prebiotic activity of ICMs.


Assuntos
Microbioma Gastrointestinal , Animais , Antioxidantes/farmacologia , Arabinose/farmacologia , Cordyceps , Citocinas/farmacologia , Fibras na Dieta/farmacologia , Galactose/farmacologia , Imunidade , Camundongos , Polissacarídeos/química , Polissacarídeos/farmacologia , Proteínas de Junções Íntimas , Ácidos Urônicos/farmacologia , alfa-Amilases/farmacologia
12.
Int J Clin Pract ; 2022: 4593443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936064

RESUMO

Methods: Sixteen male mice were randomly divided into 4 groups: control (ordinary feeding), D-gal (D-galactose) group, D-gal + MSC (human umbilical cord Wharton jelly cells), and D-gal + MSC-TNFα groups. Except for the control group (fed with same amount of saline solution), other mice received gastric feeding of 250 mg/kg D-galactose every day for 8 weeks. TNFα (10 ng/mL for 24 h) cocultured or noncocultured HUCWJCs (5 × 105) were suspended in 0.1 ml of sterile PBS and injected into tail veins every other week in D-gal + MSC-TNFα and D-gal + MSC groups, respectively, and only 0.1 ml of sterile PBS for control and D-gal groups. The bone mass was detected by qPCR, ELISA, microcomputed tomography (µCT), and hematoxylin-eosin staining. Proliferation, apoptosis, and differentiation of periosteal-derived osteoblasts (POB) were assessed. Transwell assay and scratch healing were performed to detect POB migration and invasion ability. The effect of HUCWJCs on POB signaling pathway expression was evaluated by immunoblotting. Results: The malondialdehyde (MDA) in serum was higher and superoxide dismutase (SOD) was lower in the D-gal group compared to the other groups (p < 0.05). Mice in D-gal group showed significantly decreased bone mass when compared to the control group, while HUCWJCs treatment partially rescued the phenotype, as demonstrated by µCT and histology (p < 0.05). Mechanically, HUCWJCs treatment partially promoted proliferation and migration and decreased apoptosis of POB induced by oxidative stress via activating the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusion: HUCWJCs can prevent the progression of osteoporosis by inhibiting oxidative stress, which may act by regulating osteoblasts fate through the MAPK signaling pathway.


Assuntos
Células-Tronco Mesenquimais , Osteoporose , Animais , Galactose/metabolismo , Galactose/farmacologia , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Cordão Umbilical/metabolismo , Microtomografia por Raio-X
13.
Neurosci Res ; 185: 40-48, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35970311

RESUMO

Aging is fundamental to neurodegeneration and dementia. Preventing oxidative stress and neuroinflammation are potential methods of delaying the onset of aging-associated neurodegenerative diseases. The acidic oligosaccharide sugar chain (AOSC) and hyperbaric oxygen (HBO) can increase the expression of antioxidants and have a neuroprotective function. In this study, we investigate the ability of AOSC, HBO, and AOSC + HBO to prevent D-gal-induced brain senescence. The Morris water maze and Y-maze test results showed that all three therapies significantly attenuated D-gal-induced memory disorders. A potential mechanism of this action was decreasing elevated levels of oxidative stress and neuroinflammation. The western blot and morphological results showed that all three therapies decreased D-gal-induced neuroinflammation and downregulated inflammatory mediators including the nuclear factor κ-light-chain-enhancer of activated B cells, cyclooxygenase-2, interleukin-1ß, and tumor necrosis factor alpha. Taken together, our results indicated that AOSC, HBO, and AOSC + HBO therapies attenuated D-gal-induced brain aging in mice by repressing RAGE/NF-KB-induced inflammation, the activation of astrocytes and microglia, and a decrease in neuronal degeneration. These could be useful therapies for treating age-related neurodegenerative diseases such as Alzheimer's disease. Furthermore, HBO combined with AOSC had a better effect than HBO or AOSC alone.


Assuntos
Oxigenoterapia Hiperbárica , Doenças Neurodegenerativas , Animais , Camundongos , Galactose/metabolismo , Galactose/farmacologia , Oxigenoterapia Hiperbárica/métodos , Açúcares/metabolismo , Açúcares/farmacologia , Doenças Neuroinflamatórias , Estresse Oxidativo , Encéfalo/metabolismo , Doenças Neurodegenerativas/metabolismo , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacologia
14.
Int J Mol Sci ; 23(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35887126

RESUMO

Aging is a multi-factorial process developing through a complex net of interactions between biological and cellular mechanisms and it involves oxidative stress (OS) as well as protein glycation. The aim of the present work was to verify the protective role of Quercetin (Q), a polyphenolic flavonoid compound, in a d-Galactose (d-Gal)-induced model of aging in human erythrocytes. The anion-exchange capability through the Band 3 protein (B3p) measured by the rate constant of the SO42- uptake, thiobarbituric acid reactive substances (TBARS) levels-a marker of lipid peroxidation-total sulfhydryl (-SH) groups, glycated hemoglobin (A1c), and a reduced glutathione/oxidized glutathione (GSH-GSSG) ratio were determined following the exposure of erythrocytes to 100 mM d-Gal for 24 h, with or without pre-incubation with 10 µM Q. The results confirmed that d-Gal activated OS pathways in human erythrocytes, affecting both membrane lipids and proteins, as denoted by increased TBARS levels and decreased total sulfhydryl groups, respectively. In addition, d-Gal led to an acceleration of the rate constant of the SO42- uptake through the B3p. Both the alteration of the B3p function and oxidative damage have been improved by pre-treatment with Q, which preferentially ameliorated lipid peroxidation rather than protein oxidation. Moreover, Q prevented glycated A1c formation, while no protective effect on the endogenous antioxidant system (GSH-GSSG) was observed. These findings suggest that the B3p could be a novel potential target of antioxidant treatments to counteract aging-related disturbances. Further studies are needed to confirm the possible role of Q in pharmacological strategies against aging.


Assuntos
Estresse Oxidativo , Quercetina , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Eritrócitos/metabolismo , Galactose/metabolismo , Galactose/farmacologia , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Quercetina/metabolismo , Quercetina/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
15.
Phytomedicine ; 104: 154341, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35870376

RESUMO

BACKGROUND: Aging is an inevitable gradual process of the body, which can cause dysfunction or degeneration of the nervous or immune system, thus becoming a critical pathogenic factor inducing neurodegenerative diseases. Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C.A. Meyer exerted obvious memory-enhancing and anti-aging effects, and the simpler the structure of ginsenosides, the better the biological activity. Ginsenoside Rg2 (Rg2) is a prominent and representative panaxatriol-type ginsenoside produced during ginseng processing, which has been reported to have pretty good neuroprotective activity. PURPOSE: The work was aimed at exploring the therapeutic effects and possible molecular mechanisms of Rg2 by establishing the subacute brain aging model induced by D-galactose (D-gal) in mice. METHODS: The anti-aging activity of G-Rg2 (10, 20 mg/kg for 4 weeks) was assessed using the D-gal induced brain aging model (800 mg/kg for 8 weeks). The Morris water maze (MWM) and histopathological analysis were used to evaluate the cognitive function and pathological changes of the brain in mice, respectively. The protein expression levels of p53, p21, p16ink4α, IL-6, CDK4, ATG3, ATG5, ATG7, LC3, p62, LAMP2, and TFEB were quantified through western blot analysis. The degree of mitochondrial damage and the number of mitochondrial autophagolysosomes in hippocampal neurons were monitored using TEM analysis. RESULTS: The results showed that Rg2 could significantly restore D-gal-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Rg2 treatment also considerably decreased the over-expression of aging-related proteins such as p53/p21/p16ink4α induced by D-galactose, which demonstrated that Rg2 possessed good anti-aging activity. Meanwhile, Rg2 could evidently reduce the pathological changes caused by D-gal exposure. Moreover, the results from transmission electron microscopy and western blot analysis indicated that Rg2 could delay the brain aging induced by D-gal in mice via promoting the degradation of the autophagy substrate p62 while increasing the protein expression level of LAMP2/TFEB to maintain mitochondrial function. CONCLUSION: These results indicate that Rg2 could postpone brain aging by increasing mitochondrial autophagy flux to maintain mitochondrial function, which greatly enriched the research on the pharmacological activity of ginsenosides for delaying brain aging.


Assuntos
Ginsenosídeos , Panax , Envelhecimento , Animais , Autofagia , Galactose/farmacologia , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacologia , Hipocampo , Camundongos , Mitocôndrias/metabolismo , Panax/química , Proteína Supressora de Tumor p53/metabolismo
16.
Food Funct ; 13(14): 7560-7571, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35815429

RESUMO

Aging is a natural process accompanied by inflammation and oxidative stress and is closely associated with age-related diseases. As a direct precursor of glutathione, γ-glutamylcysteine (γ-GC) possesses antioxidant and anti-inflammatory properties; however, whether γ-GC plays an important role in anti-aging remains unknown. Here, we investigated the protective effects and mechanisms of γ-GC in D-galactose (D-gal)-induced senescence in PC12 cells and aging mice. Our results showed that γ-GC treatment significantly reduced the percentage of senescence-associated-ß-galactosidase (SA-ß-Gal)-positive cells and inhibited D-gal-induced cell cycle arrest in PC12 cells. The results of Nissl and hematoxylin and eosin (H&E) staining in mouse brain showed that γ-GC treatment markedly reversed the damage in the hippocampus of D-gal-induced aging mice. Moreover, γ-GC increased the phosphorylation of AMP-activated protein kinase (AMPK) to promote the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) while inhibiting the nuclear translocation of deleted in breast cancer 1 (DBC1), which leads to the activation of sirtuin 1 (SIRT1) and deacetylation of p53 in the nucleus. Therefore, γ-GC may be a potential therapeutic candidate compound for the prevention and treatment of age-related diseases.


Assuntos
Galactose , Sirtuína 1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Senescência Celular , Dipeptídeos , Galactose/farmacologia , Camundongos , Estresse Oxidativo , Células PC12 , Ratos , Sirtuína 1/genética , Sirtuína 1/metabolismo
17.
PLoS One ; 17(6): e0270123, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35767571

RESUMO

Aging-induced memory impairment is closely associated with oxidative stress. D-Galactose (D-gal) evokes severe oxidative stress and mimics normal aging in animals. Curcumin, a natural flavonoid, has potent antioxidant and anti-aging properties. There are several proteins like glutathione S-transferase A1 (GSTA1), glutathione S-transferase omega-1 (GSTO1), kelch-like ECH-associated protein 1 (KEAP1), beta-secretase 1 (BACE1), and amine oxidase [flavin-containing] A (MAOA) are commonly involved in oxidative stress and aging. This study aimed to investigate the interaction of curcumin to these proteins and their subsequent effect on aging-associated memory impairment in two robust animal models: D-Gal and normal aged (NA) mice. The aging mice model was developed by administering D-gal intraperitoneally (i.p). Mice (n = 64) were divided into the eight groups (8 mice in each group): Vehicle, Curcumin-Control, D-gal (100mg/kg; i.p), Curcumin + D-gal, Astaxanthin (Ast) + D-gal, Normal Aged (NA), Curcumin (30mg/kg Orally) + NA, Ast (20mg/kg Orally) + NA. Retention and freezing memories were assessed by passive avoidance (PA) and contextual fear conditioning (CFC). Molecular docking was performed to predict curcumin binding with potential molecular targets. Curcumin significantly increased retention time (p < 0.05) and freezing response (p < 0.05) in PA and CFC, respectively. Curcumin profoundly ameliorated the levels of glutathione, superoxide dismutase, catalase, advanced oxidation protein products, nitric oxide, and lipid peroxidation in mice hippocampi. In silico studies revealed favorable binding energies of curcumin with GSTA1, GSTO1, KEAP1, BACE1, and MAOA. Curcumin improves retention and freezing memory in D-gal and nature-induced aging mice. Curcumin ameliorates the levels of oxidative stress biomarkers in mice. Anti-aging effects of curcumin could be attributed to, at least partially, the upregulation of antioxidant enzymes through binding with GSTA1, GSTO1, KEAP1, and inhibition of oxidative damage through binding with BACE1 and MAOA.


Assuntos
Curcumina , Galactose , Envelhecimento/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antioxidantes/efeitos adversos , Ácido Aspártico Endopeptidases/metabolismo , Curcumina/efeitos adversos , Galactose/farmacologia , Glutationa Transferase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
18.
Int J Mol Sci ; 23(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35742908

RESUMO

Aging is a process associated with blood-brain barrier (BBB) damage and the reduction in neurogenesis, and is the greatest known risk factor for neurodegenerative disorders. However, the effects of Fe3O4 nanozymes on neurogenesis have rarely been studied. This study examined the effects of Fe3O4 nanozymes on neuronal differentiation in the dentate gyrus (DG) and BBB integrity of D-galactose-induced aged mice. Long-term treatment with Fe3O4 nanozymes (10 µg/mL diluted in ddH2O daily) markedly increased the doublecortin (DCX) immunoreactivity and decreased BBB injury induced by D-galactose treatment. In addition, the decreases in the levels of antioxidant proteins including superoxide dismutase (SOD) and catalase as well as autophagy-related proteins such as Becin-1, LC3II/I, and Atg7 induced by D-galactose treatment were significantly ameliorated by Fe3O4 nanozymes in the DG of the mouse hippocampus. Furthermore, Fe3O4 nanozyme treatment showed an inhibitory effect against apoptosis in the hippocampus. In conclusion, Fe3O4 nanozymes can relieve neuroblast damage and promote neuroblast differentiation in the hippocampal DG by regulating oxidative stress, apoptosis, and autophagy.


Assuntos
Giro Denteado , Galactose , Animais , Barreira Hematoencefálica , Diferenciação Celular , Proliferação de Células , Giro Denteado/metabolismo , Galactose/metabolismo , Galactose/farmacologia , Hipocampo , Camundongos , Neurogênese
19.
Food Funct ; 13(14): 7507-7519, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35678708

RESUMO

The nicotinamide adenine dinucleotide (NAD+) level shows a temporal decrease during the aging process, which has been deemed as an aging hallmark. Nicotinamide mononucleotide (NMN), a key NAD+ precursor, shows the potential to retard the age-associated functional decline in organs. In the current study, to explore whether NMN has an impact on the intestine during the aging process, the effects of NMN supplementation on the intestinal morphology, microbiota, and NAD+ content, as well as its anti-inflammatory, anti-oxidative and barrier functions were investigated in aging mice and D-galactose (D-gal) induced senescent IPEC-J2 cells. The results showed that 4 months of NMN administration had little impact on the colonic microbiota and NAD+ content in aging mice, while it significantly increased the jejunal NAD+ content and improved the jejunal structure including increasing the villus length and shortening the crypt. Moreover, NMN supplementation significantly up-regulated the mRNA expression of SIRT3, SIRT6, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the catalytic subunit of glutamate-cysteine ligase (GCLC), superoxide dismutase 2 (SOD2), occludin, and claudin-1, but down-regulated the mRNA expression of tumor necrosis factor alpha (TNF-α). Specifically, in the D-gal induced senescent IPEC-J2 cells, 500 µM NMN restored the increased mRNA expression of interleukin 6 (IL6ST), IL-1A, nuclear factor (NF-κB1), and claudin-1 to normal levels to some extent. Furthermore, NMN treatment significantly affected the mRNA expression of antioxidant enzymes including NQO1, GCLC, SOD 2 and 3, and GSH-PX1, 3 and 4. In addition, 200 µM NMN enhanced the cell viability and total antioxidant capacity and lowered the reactive oxygen species level of senescent IPEC-J2 cells. Notably, NMN restored the down-regulated protein expression of occludin and claudin-1 induced by D-gal. The above data demonstrated the potential of NMN in ameliorating the structural and functional decline in the intestine during aging.


Assuntos
Mononucleotídeo de Nicotinamida , Sirtuínas , Envelhecimento , Animais , Antioxidantes/farmacologia , Senescência Celular , Claudina-1/genética , Suplementos Nutricionais , Galactose/farmacologia , Camundongos , NAD/metabolismo , NAD/farmacologia , Mononucleotídeo de Nicotinamida/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Ocludina , RNA Mensageiro
20.
Aging Cell ; 21(7): e13659, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35712918

RESUMO

Aging-related sarcopenia is currently the most common sarcopenia. The main manifestations are skeletal muscle atrophy, replacement of muscle fibers with fat and fibrous tissue. Excessive fibrosis can impair muscle regeneration and function. Lysyl oxidase-like 2 (LOXL2) has previously been reported to be involved in the development of various tissue fibrosis. Here, we investigated the effects of LOXL2 inhibitor on D-galactose (D-gal)-induced skeletal muscle fibroblast cells and mice. Our molecular and physiological studies show that treatment with LOXL2 inhibitor can alleviate senescence, fibrosis, and increased production of reactive oxygen species in fibroblasts caused by D-gal. These effects are related to the inhibition of the TGF-ß1/p38 MAPK pathway. Furthermore, in vivo, mice treatment with LOXL2 inhibitor reduced D-gal-induced skeletal muscle fibrosis, partially enhanced skeletal muscle mass and strength and reduced redox balance disorder. Taken together, these data indicate the possibility of using LOXL2 inhibitors to prevent aging-related sarcopenia, especially with significant fibrosis.


Assuntos
Galactose , Sarcopenia , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/farmacologia , Animais , Fibrose , Galactose/farmacologia , Camundongos , Músculo Esquelético/metabolismo , Proteína-Lisina 6-Oxidase/farmacologia , Sarcopenia/induzido quimicamente , Sarcopenia/tratamento farmacológico , Sarcopenia/patologia
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