RESUMEN
Candida albicans is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of C. albicans. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of C. albicans. In the present study, the antifungal activities of equol against C. albicans were investigated. In vitro, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against C. albicans. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of C. albicans. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors RFG1 and TUP1. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.
Asunto(s)
Antifúngicos , Biopelículas , Candida albicans , Candidiasis , Equol , Candida albicans/efectos de los fármacos , Candida albicans/genética , Animales , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Ratones , Candidiasis/microbiología , Candidiasis/tratamiento farmacológico , Equol/farmacología , Femenino , Modelos Animales de Enfermedad , Pruebas de Sensibilidad Microbiana , Hifa/efectos de los fármacos , Hifa/crecimiento & desarrollo , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMEN
Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, ß-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.
Asunto(s)
Anexina A2 , Coriocarcinoma , Equol , Ubiquitinación , Humanos , Femenino , Anexina A2/metabolismo , Anexina A2/genética , Coriocarcinoma/metabolismo , Coriocarcinoma/genética , Equol/farmacología , Línea Celular Tumoral , Ubiquitinación/efectos de los fármacos , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Embarazo , Ratones Desnudos , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Ratones Endogámicos BALB CRESUMEN
Osteoarthritis (OA) is a chronic degenerative disease leading to articular cartilage destruction. Menopausal and postmenopausal women are susceptible to both OA and osteoporosis. S-equol, a soy isoflavone-derived molecule, is known to reduce osteoporosis in estrogen-deficient mice, but its role in OA remains unknown. This study aimed to explore the effect of S-equol on different degrees of menopausal OA in female Sprague-Dawley (SD) rats induced by estrogen deficiency caused by bilateral ovariectomy (OVX) combined with intra-articular injection of mono-iodoacetate (MIA). Knee joint histopathological change; serum biomarkers of bone turnover, including N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX-I) and N-terminal telopeptide of type I collagen (NTX-I); the cartilage degradation biomarkers hyaluronic acid (HA) and N-terminal propeptide of type II procollagen (PIINP); and the matrix-degrading enzymes matrix metalloproteinases (MMP)-1, MMP-3 and MMP-13, as well as the oxidative stress-inducing molecules nitric oxide (NO) and hydrogen peroxide (H2O2), were assessed for evaluation of OA progression after S-equol supplementation for 8 weeks. The results showed that OVX without or with MIA injection induced various severity levels of menopausal OA by increasing pathological damage, oxidative stress, and cartilage matrix degradation to various degrees. Moreover, S-equol supplementation could significantly reduce these increased biomarkers in different severity levels of OA. This indicates that S-equol can lessen menopausal OA progression by reducing oxidative stress and the matrix-degrading enzymes involved in cartilage degradation.
Asunto(s)
Cartílago Articular , Equol , Menopausia , Ovariectomía , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Estrés Oxidativo/efectos de los fármacos , Femenino , Menopausia/efectos de los fármacos , Ratas , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Equol/farmacología , Biomarcadores/sangre , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Modelos Animales de Enfermedad , Óxido Nítrico/metabolismoRESUMEN
OBJECTIVES: This study evaluates the impact of equol, a metabolite of soy isoflavone, on bladder dysfunction in rats with bladder outlet obstruction (BOO). In addition, we investigate its potential as a neuroprotective agent for the obstructed bladder and discuss its applicability in managing overactive bladder (OAB). METHODS: Eighteen male Sprague-Dawley rats were divided into three groups (six rats per group) during the rearing period. The Sham and C-BOO groups received an equol-free diet, while the E-BOO group received equol supplementation (0.25 g/kg). At 8 weeks old, rats underwent BOO surgery, followed by continuous cystometry after 4 weeks of rearing. The urinary oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde) were measured, and the bladder histology was analyzed using hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining (neurofilament heavy chain for myelinated nerves, peripherin for unmyelinated nerves, and malondialdehyde). RESULTS: Equol reduced BOO-induced smooth muscle layer fibrosis, significantly prolonged the micturition interval (C-BOO: 193 s, E-BOO: 438 s) and increased the micturition volume (C-BOO: 0.54 mL, E-BOO: 1.02 mL) compared to the C-BOO group. Equol inhibited the increase in urinary and bladder tissue malondialdehyde levels. While the C-BOO group exhibited reduced peripherin alone positive nerve fibers within the smooth muscle layer, equol effectively attenuated this decline. CONCLUSIONS: Equol reduces lipid peroxidation and smooth muscle layer fibrosis in the bladder and exhibited neuroprotective effects on bladder nerves (peripheral nerves) and prevented the development of bladder dysfunction associated with BOO in rats. Consumption of equol is promising for the prevention of OAB associated with BOO.
Asunto(s)
Modelos Animales de Enfermedad , Equol , Estrés Oxidativo , Ratas Sprague-Dawley , Obstrucción del Cuello de la Vejiga Urinaria , Vejiga Urinaria , Animales , Masculino , Equol/farmacología , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Obstrucción del Cuello de la Vejiga Urinaria/patología , Ratas , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Estrés Oxidativo/efectos de los fármacos , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria Hiperactiva/prevención & control , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Malondialdehído/metabolismo , Fármacos Neuroprotectores/farmacología , Micción/efectos de los fármacos , FibrosisRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is characterized by immune-mediated, chronic inflammation of the intestinal tract. The occurrence of IBD is driven by the complex interactions of multiple factors. The objective of this study was to evaluate the therapeutic effects of IAA in colitis. METHOD: C57/BL6 mice were administered 2.5% DSS in drinking water to induce colitis. IAA, Bifidobacterium pseudolongum, and R-equol were administered by oral gavage and fed a regular diet. The Disease Activity Index was used to evaluate disease activity. The degree of colitis was evaluated using histological morphology, RNA, and inflammation marker proteins. CD45+ CD4+ FOXP3+ Treg and CD45+ CD4+ IL17A+ Th17 cells were detected by flow cytometry. Analysis of the gut microbiome in fecal content was performed using 16S rRNA gene sequencing. Gut microbiome metabolites were analyzed using Untargeted Metabolomics. RESULT: In our study, we found IAA alleviates DSS-induced colitis in mice by altering the gut microbiome. The abundance of Bifidobacterium pseudolongum significantly increased in the IAA treatment group. Bifidobacterium pseudolongum ATCC25526 alleviates DSS-induced colitis by increasing the ratio of Foxp3+T cells in colon tissue. R-equol alleviates DSS-induced colitis by increasing Foxp3+T cells, which may be the mechanism by which ATCC25526 alleviates DSS-induced colitis in mice. CONCLUSION: Our study demonstrates that IAA, an indole derivative, alleviates DSS-induced colitis by promoting the production of Equol from Bifidobacterium pseudolongum, which provides new insights into gut homeostasis regulated by indole metabolites other than the classic AHR pathway.
Asunto(s)
Bifidobacterium , Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Ratones , Animales , Equol/metabolismo , Equol/farmacología , Equol/uso terapéutico , ARN Ribosómico 16S/genética , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Ácidos Indolacéticos/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Inflamación/patología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/farmacología , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Colon/metabolismoRESUMEN
BACKGROUND: While cannabidiol (CBD) and 4',7-isoflavandiol (Equol) have been examined individually in various skin studies, the present investigation tested whether topically applied CBD with Equol may yield enhanced effects on human skin biomarkers. METHODS: After 24 hours exposure human skin gene expression was measured by quantitative polymerase chain reaction-messenger ribonucleic acid (qPCR-mRNA) analysis across 9 functional skin categories covering 97 biomarkers. RESULTS: In general, among the biomarkers analyzed the CBD with Equol treatment displayed greater efficacy compared to CBD only or the Equol treatment alone (e.g., 4 out 5 for anti-acne, 15 out of 17 for anti-aging [e.g., collagen, elastin, calcium binding protein A7, tissue inhibitor of matrix metalloproteinase 1 (TIMP 1), etc.], 19 out of 21 for anti-inflammatory (pain), 10 out of 11 for antioxidants to protect against oxidative stress, 6 out of 6 for circadian rhythm regulation for cell repair/restoration, 10 out of 15 for anti-pigmentation properties, 4 out of 5 for skin hydration, 6 out of 6 for tissue integrity, and 11 out of 12 for wound healing properties). CONCLUSIONS: CBD with Equol displayed synergistic effects that may be an effective topical treatment for dermatology and cosmetic applications to improve human skin health and reduce photo-aging.
Asunto(s)
Cannabidiol , Equol , Humanos , Equol/farmacología , Equol/metabolismo , Cannabidiol/farmacología , Cannabidiol/metabolismo , Piel , Antioxidantes/farmacología , Antioxidantes/metabolismo , Perfilación de la Expresión Génica , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg fermented soy containing 10 mg equol and 25 mg resveratrol or a placebo for 12 months. Whole-body BMD and bone turnover biomarkers, such as deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), osteocalcin, and bone-specific alkaline phosphatase (BAP), were measured at baseline and after 12 months of treatment. At the end of treatment, DPD, osteocalcin, and BAP significantly improved in the active group (p < 0.0001 for all) compared to the placebo group. Conversely, TRACP-5b levels were unaffected by supplementation (p = 0.051). Statistically significant changes in the concentrations of DPD (p < 0.0001), osteocalcin (p = 0.0001), and BAP (p < 0.0001) compared to baseline were also identified. Overall, the intervention significantly increased BMD measured in the whole body (p = 0.0220) compared with the placebo. These data indicate that the combination of equol and resveratrol may positively modulate bone turnover biomarkers and BMD, representing a potential approach to prevent age-related bone loss in postmenopausal women.
Asunto(s)
Osteoporosis Posmenopáusica , Posmenopausia , Humanos , Femenino , Equol/farmacología , Resveratrol/farmacología , Resveratrol/uso terapéutico , Fosfatasa Ácida Tartratorresistente , Osteocalcina , Densidad Ósea , Fosfatasa Alcalina/uso terapéutico , Biomarcadores , Remodelación Ósea , Osteoporosis Posmenopáusica/tratamiento farmacológicoRESUMEN
BACKGROUD: Estrogen deficiency is the leading cause of postmenopausal osteoporosis(PMOP) and phytoestrogens soy isoflavones (SI) have been shown to improve PMOP. Equol (Eq), an in vivo metabolite of phytoestrogens soy isoflavones (SI), has a more stable structure and stronger biological activity than its parent compound and has the greatest estrogenic activity. However, there are few studies on the therapeutic effect of Eq on PMOP. PURPOSE: To explore the therapeutic effect and mechanisms of Eq on POMP. METHODS: Osteoblast-like cells ROS1728 were cultured with different doses of Eq, estradiol (E2), separately. The effect of Eq on the proliferation, apoptosis, cell cycle of osteoblasts were detected by CCK-8 and flow cytometry, and the expression of OPG/RANK/RANKL signaling pathway of osteoblasts was detected by Quantitative real-time PCR (qRT-PCR) and Western blot (WB), and RNA silencing technology were carried out to explore the receptors through which Eq plays a role. Then PMOP rat model was established and treated by Eq or E2 to further verification of the effect and mechanism of Eq on PMOP. RESULT: Eq promoted the proliferation and inhibited the apoptosis of osteoblasts and increased the proportion of osteoblasts in the S phase and G2/M phase in a dose-dependent manner. Mechanistically, Eq treatment upregulated the expression of OPG and OPG/RANKL ratio in osteoblasts and this regulatory effect was mainly mediated through the ERß receptor. Furthermore, in vivo study, Eq improved microstructure and BMD of the femur of PMOP rat model, which imitated the osteoprotective effect of E2. Moreover, the Eq or E2 treatment increased serum levels of Ca, 1,25(OH)2D3, bone Gla-protein(BGP), and Type I procollagen (PC1), and reduced serum levels of phosphorus (P), parathyroid hormone(PTH), pyridinol (PYD), tartrate-resistant acid phosphatase (TRAP) and urinary level of deoxypyridinoline (DPD) in the treatment OVX group compared with the untreated OVX group. Meanwhile, Eq or E2 markedly induced the mRNA and protein expression of OPG and OPG/RANKL ratio. CONCLUSION: Eq can combine with ERß and exert a protective effect on PMOP by upregulating OPG/RANKL pathway.
Asunto(s)
Osteoporosis Posmenopáusica , Humanos , Femenino , Ratas , Animales , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/prevención & control , Osteoprotegerina/metabolismo , Equol/farmacología , Equol/metabolismo , Receptor beta de Estrógeno/metabolismo , Fitoestrógenos/farmacología , Ligando RANK/metabolismo , OsteoblastosRESUMEN
Hydroxyequols are promising analogues of the biologically active flavonoid, equol. We recently found that the flavin-dependent monooxygenase HpaBro-3 of Rhodococcus opacus regioselectively synthesizes 3'-hydroxyequol from equol, whereas HpaBpl-1 of Photorhabdus luminescens synthesizes 6-hydroxyequol. In this study, we investigated the cascade synthesis of a dihydroxyequol compound from equol using these two enzymes. When Escherichia coli cells expressing HpaBro-3 and cells expressing HpaBpl-1 were simultaneously incubated with equol, the cells efficiently synthesized 6,3'-dihydroxyequol (8.7 mM, 2.4 g/L) via 3'- and 6-hydroxyequols in one pot. The antioxidant activity of the equol derivatives increased with an increase in the number of hydroxyl groups on the equol scaffold. 6,3'-Dihydroxyequol exhibited potent antioxidant activity. In addition, 6-hydroxyequol significantly inhibited the growth of E. coli. Cell survival studies suggested that 6-hydroxyequol is a bactericidal rather than bacteriostatic compound. To our knowledge, this is the first report describing the antibacterial activity of hydroxyequols.
Asunto(s)
Equol , Isoflavonas , Antibacterianos/farmacología , Antioxidantes/farmacología , Biocatálisis , Equol/farmacología , Escherichia coli , Isoflavonas/farmacologíaRESUMEN
BACKGROUND: Equol, a metabolite of daidzein, binds to the estrogen receptor with greater affinity than daidzein and exhibits various biological properties. It exists as an enantiomer, either (S)-equol or (R)-equol. OBJECTIVES: We have previously shown that the inhibitory effect of (S)-equol on bone fragility is stronger than that of racemic equol in ovariectomized (OVX) mice; however, the effect of (R)-equol has not been elucidated. The aim of this study was to compare the activities of equol enantiomers on bone metabolism in vitro and in vivo. METHODS: Bone marrow cells (BMCs) and RAW 264.7 cells were treated with equol enantiomers. The number of osteoclasts and caspase-3/7 activity were measured. We examined the effect of equol enantiomers on osteoblast differentiation in MC3T3-E1 cells. In vivo, 8-wk-old female ddY mice were assigned to 4 groups: sham-operated (sham), OVX, OVX + 0.5 mg/d of (S)-equol (S-eq), and OVX + 0.5 mg/d of (R)-equol (R-eq). Four weeks after the intervention, femoral bone mineral density (BMD) and osteoclastic gene expression were analyzed, along with concentrations of equol enantiomers in the serum and tissues. RESULTS: (S)-equol and (R)-equol inhibited osteoclast differentiation in BMCs (97% and 60%, P < 0.05) and RAW 264.7 cells (83% and 68%, P < 0.05). (S)-equol promoted apoptosis of mature osteoclasts by inducing caspase-3/7 activity (29%, P < 0.05) and enhanced osteoblast differentiation (29%, P < 0.05). In OVX mice, BMD was ameliorated in (S)-equol-treated mice (11%, P < 0.05), but not in (R)-equol-treated mice. The concentrations of (S)-equol were greater than those of (R)-equol in the serum, tibia, liver, and kidney (by 148%, 80%, 22%, and 139%, respectively). CONCLUSIONS: These results suggest that (S)-equol is more effective than (R)-equol in inhibiting osteoclast formation and enhancing osteoclast apoptosis in vitro, supporting the beneficial effect of (S)-equol to reduce estrogen deficiency-induced bone loss in OVX mice.
Asunto(s)
Enfermedades Óseas Metabólicas , Resorción Ósea , Animales , Apoptosis , Densidad Ósea , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/prevención & control , Caspasa 3 , Caspasa 7 , Equol/farmacología , Equol/uso terapéutico , Estrógenos/farmacología , Femenino , Ratones , Ratones Endogámicos , Osteoclastos , OvariectomíaRESUMEN
BACKGROUND: Many extracts and purified alkaloids of M. cordata (Papaveraceae family) have been reported to display promising anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis in many cancer types. However, no evidence currently exists for anti-pancreatic cancer activity of alkaloids extracted from M. cordata, including a novel alkaloid named 6methoxy dihydrosphingosine (6-Methoxydihydroavicine, 6-ME) derived from M. cordata fruits. PURPOSE: The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism. METHODS: CCK-8, RTCA, and colony-formation assays were used to analyze PC cell growth. Cell death ratios, changes in MMP and ROS levels were measured by flow cytometry within corresponding detection kits. A Seahorse XFe96 was employed to examine the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect changes in target molecules. RESULTS: 6-ME effectively reduced the growth of PC cells and promoted PCD by activating RIPK1, caspases, and GSDME. Specifically, 6-ME treatment caused a disruption of OAA metabolism and increased ROS production, thereby affecting mitochondrial homeostasis and reducing aerobic glycolysis. These responses resulted in mitophagy and RIPK1-mediated cell death. CONCLUSION: 6-ME exhibited specific anti-tumor effects through interrupting OAA metabolic homeostasis to trigger ROS/RIPK1-dependent cell death and mitochondrial dysfunction, suggesting that 6-ME could be considered as a highly promising compound for PC intervention.
Asunto(s)
Alcaloides , Antineoplásicos , Caspasas , Equol/análogos & derivados , Ácido Oxaloacético , Neoplasias Pancreáticas , Especies Reactivas de Oxígeno , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Alcaloides/farmacología , Antineoplásicos/farmacología , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Equol/farmacología , Humanos , Ácido Oxaloacético/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Papaveraceae/química , Especies Reactivas de Oxígeno/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Antioxidant effects of soy-derived isoflavones are predicted to be mediated by the Keap1-Nrf2 pathway. Recently, we constructed an assay system to evaluate the antioxidant effects of dietary phytochemicals in zebrafish and revealed a relationship between these effects and the Keap1-Nrf2 pathway. In this study, we used this system to examine the antioxidant effects of seven isoflavones. Among those seven, equol showed strong antioxidant effects when arsenite was used as an oxidative stressor. The antioxidant effect of equol was also shown in Nrf2-mutant zebrafish nfe2l2afh318, suggesting that this effect was not mediated by the Keap1-Nrf2 pathway. To elucidate this unidentified mechanism, the gene expression profiles of equol-treated larvae were analyzed using RNA-seq and qRT-PCR, while no noticeable changes were detected in the expression of genes related to antioxidant effects, except weak induction of Nrf2 target genes. Because nfe2l2afh318 is an amino acid-substitution mutant (Arg485Lue), we considered that the antioxidant effect of equol in this mutant might be due to residual Nrf2 activity. To examine this possibility, we generated an Nrf2-knockout zebrafish nfe2l2ait321 using CRISPR-Cas9 and analyzed the antioxidant effect of equol. As a result, equol showed strong antioxidant effects even in Nrf2-knockout larvae, suggesting that equol indeed upregulates antioxidant activity in zebrafish in an Nrf2-independent manner.
Asunto(s)
Equol , Isoflavonas , Factor 2 Relacionado con NF-E2 , Animales , Antioxidantes/metabolismo , Equol/farmacología , Isoflavonas/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Larva/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Pez Cebra/genéticaRESUMEN
Isoflavone is a species of polyphenol found mainly in soy and soy products. Many studies have demonstrated its estrogen receptor (ER)-dependent action. Equol is an intestinal metabolite of a major soy isoflavone daidzein. We aimed to elucidate the mechanism for ER-independent actions of equol. Equol has been shown to inhibit proliferation of HeLa human cervical cancer cells and mouse melanoma B16 cells in an ER-independent manner. Using functional genetic screening, PAP associated domain containing 5 (PAPD5), which is a non-canonical poly(A) polymerase, was identified as an essential molecule in the ER-independent action. While peroral administration of equol inhibited tumor growth of control B16 cells subcutaneously inoculated in mice, it had little effect on the growth of PAPD5-ablated B16 cells. Intriguingly, equol progressed tumor growth of the PAPD5-ablated human breast cancer MCF-7 cells, which have high ERα expression. Equol has been found to induce polyadenylation of snoRNAs in a PAPD5-depdendent manner. Furthermore, peroral equol administration increased microRNA miR-320a expression in tumors. Together, these results suggest that equol may have a dual effect on ER-positive cancer cells, acting with, antiproliferative activity through PAPD5 and exhibiting proliferative activity via ERα and the former could be associated with miR-320a.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Equol/farmacología , Melanoma Experimental/patología , ARN Nucleotidiltransferasas/metabolismo , Receptores de Estrógenos/metabolismo , Línea Celular Tumoral , Receptor alfa de Estrógeno/metabolismo , Células HeLa , Humanos , Isoflavonas/farmacología , Células MCF-7 , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Trasplante de Neoplasias , ARN Nucleolar Pequeño/metabolismoRESUMEN
Equol, a soy isoflavone-derived metabolite of the gut microbiome, may be the key cardioprotective component of soy isoflavones. Systematic reviews have reported that soy isoflavones have no to very small effects on traditional cardiovascular disease risk factors. However, the potential mechanistic mode of action of equol on non-traditional cardiovascular risk factors has not been systematically reviewed. We searched the PubMed through to July 2021 by using terms for equol and each of the following markers: inflammation, oxidation, endothelial function, vasodilation, atherosclerosis, arterial stiffness, and coronary heart disease. Of the 231 records identified, 69 articles met the inclusion criteria and were summarized. Our review suggests that equol is more lipophilic, bioavailable, and generally more potent compared to soy isoflavones. Cell culture, animal, and human studies show that equol possesses antioxidative, anti-inflammatory, and vasodilatory properties and improves arterial stiffness and atherosclerosis. Many of these actions are mediated through the estrogen receptor ß. Overall, equol may have a greater cardioprotective benefit than soy isoflavones. Clinical studies of equol are warranted because equol is available as a dietary supplement.
Asunto(s)
Cardiotónicos/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Equol/uso terapéutico , Glycine max/química , Isoflavonas/uso terapéutico , Antioxidantes/metabolismo , Equol/química , Equol/farmacología , Humanos , Isoflavonas/química , Isoflavonas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
The overarching theme for this review is perspective. Superfoods (a marketing term for fruits and vegetables, etc.) have a positive connotation, while many superfoods contain phytoestrogens, a term that is alarming to the public and has a negative connotation because phytoestrogens are endocrine-disruptors, even though they are strong antioxidants that have many health benefits. To understand phytoestrogens, this paper provides a brief summary of the characteristics of: (a) estrogens, (b) estrogen receptors (ER), (c) estrogen-deficient skin, (d) how perspective(s) get off track, (e) phytoestrogen food sources, and (f) misconceptions of phytoestrogens and food safety, in general, that influence person(s) away from what is true. Finally, a brief history of cosmetics to nutraceuticals is covered plus the characteristics of phytoestrogens, resveratrol and equol on: (g) estrogen receptor binding, (h) topical and oral dosing, and (i) in vitro, molecular mechanisms and select clinical evidence, where both phytoestrogens (resveratrol and equol) demonstrate promising applications to improve skin health is presented along with future directions of nutraceuticals. Perspective is paramount in understanding the controversies associated with superfoods, phytoestrogens, and endocrine-disruptors because they have both positive and negative connotations. Everyone is exposed to and consumes these molecules everyday regardless of age, gender, or geographic location around the world, and how we understand this is a matter of perspective.
Asunto(s)
Envejecimiento , Cosméticos/administración & dosificación , Suplementos Dietéticos/análisis , Estrógenos/deficiencia , Fitoestrógenos/farmacología , Piel/efectos de los fármacos , Antioxidantes/farmacología , Comunicación , Disruptores Endocrinos/farmacología , Equol/farmacología , Humanos , Resveratrol/farmacología , Piel/patologíaRESUMEN
Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.
Asunto(s)
Condrocitos/citología , Equol/farmacología , Nitroprusiato/efectos adversos , Osteoartritis/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Modelos Biológicos , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/metabolismo , RatasRESUMEN
Oestrogenic pastures are known to cause infertility in the ewe, due primarily to the oestrogen-like actions of the metabolite equol. Despite strong evidence that phytoestrogens and their metabolites compromise male reproductive function in many other species, there is little information concerning the effect of oestrogenic pastures on ram sperm quality and function. To investigate this, ram spermatozoa were exposed in vitro to physiologically relevant concentrations of either 0, 0.001, 0.01, 0.1 and 1 µM equol and incubated over 6 h. Sperm motility, viability, DNA integrity, membrane lipid disorder, mitochondrial superoxide production, lipid peroxidation and intracellular reactive oxygen species were assessed via computer assisted sperm analysis and flow cytometry at 0.5, 3 and 6 h post-equol exposure. Whilst sperm viability was decreased only at 1 µM equol at 0.5 h post-exposure, exposure to equol at concentrations of 0.1 and 1 µM reduced sperm total and progressive motility (P < 0.001), increased sperm membrane fluidity (P < 0.001), increased mitochondrial superoxide production (P < 0.001) and promoted lipid peroxidation (P < 0.001) across all timepoints. At 6 h post-exposure to 0.1 and 1 µM equol, DNA fragmentation was greater compared that of non-exposed spermatozoa (P = 0.045). Intracellular reactive oxygen species did not change between treatment groups throughout the study (P > 0.05). It is concluded that even low concentrations of equol negatively impact the functionality of ram spermatozoa, these effects likely driven through increased mitochondrial superoxide production. This work indicates that equol may exert oestrogen-like actions upon ram spermatozoa, bringing into question as to whether oestrogenic pastures could influence ram fertility.
Asunto(s)
Preservación de Semen , Motilidad Espermática , Animales , Fragmentación del ADN , Equol/farmacología , Masculino , Análisis de Semen/veterinaria , Preservación de Semen/veterinaria , Ovinos , EspermatozoidesRESUMEN
Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-ß. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein's protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-ß and subsequent suppression of inflammation. Dietary daidzein's protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.
Asunto(s)
Equol/uso terapéutico , Aneurisma Intracraneal/prevención & control , Aneurisma Intracraneal/fisiopatología , Isoflavonas/uso terapéutico , Fitoestrógenos/uso terapéutico , Animales , Equol/farmacología , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/sangre , Isoflavonas/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovariectomía/efectos adversos , Fitoestrógenos/farmacologíaRESUMEN
Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor ß agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.
Asunto(s)
Apatía/efectos de los fármacos , Equol/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Motivación , Animales , Animales Modificados Genéticamente , Fármacos Anti-VIH/farmacología , Conducta Adictiva , Conducta Animal , Cateterismo , Conducta de Elección , Cocaína , Dendritas , Espinas Dendríticas , Modelos Animales de Enfermedad , Receptor beta de Estrógeno/biosíntesis , Femenino , Genotipo , Seropositividad para VIH , Venas Yugulares , Motivación/efectos de los fármacos , Trastornos Neurocognitivos/complicaciones , Ratas , Sacarosa/farmacología , Resultado del TratamientoRESUMEN
Systemic injection with lipopolysaccharide can lead to depressive-like behavior in experimental animals by inducing neuroinflammation and is considered to be a classic model of depression. S-equol is a major metabolite of dietary soy isoflavones with antioxidant and anti-inflammatory effects, and it has many beneficial effects on human health, including alleviation of menopausal symptoms, osteoporosis, cancer, obesity, chronic kidney disease, and cognitive dysfunction. A recent study reported that S-equol inhibited lipopolysaccharide-stimulated neuroinflammation in astrocytes. However, there is no research on the antidepressant-like effects of S-equol. Therefore, the present study was conducted to evaluate the antidepressant-like effects of S-equol in a lipopolysaccharide-induced depression model in mice and explore its underlying mechanisms. Our results demonstrated that treatment with S-equol (10, 20 and 40 mg kg-1) for 19 days markedly reversed the behavior of acute LPS (1.0 mg kg-1) treated mice in sucrose preference, tail suspension and forced swimming tests, exerting antidepressant-like effects. In addition, S-equol administration significantly decreased the levels of pro-inflammatory cytokines (tumor necrosis factor, interleukin-6, interleukin-10, interleukin-1ß), increased the levels of 5-hydroxytryptamine and norepinephrine, and normalized the release of tryptophan and kynurenine in the hippocampi of lipopolysaccharide-treated mice. Moreover, treatment with S-equol significantly up-regulated the expression of synaptic plasticity-related proteins (phospho synapsin, synapsin, postsynaptic density-95) and down-regulated the toll-like receptor 4/nuclear factor kappa B signaling pathway in the hippocampi of lipopolysaccharide-treated mice. These findings demonstrated that S-equol significantly alleviated the depressive-like behavior induced by acute systemic injection of LPS, and its antidepressant action was related to mediation of neuroinflammation via the TLR4/NF-κB signaling pathway, normalization of the monoamine neurotransmitter levels, reversal of tryptophan metabolism dysfunction, and enhancement of synaptic plasticity. The current study provides insight into the potential of S-equol in the prevention of depression.