PMID: 

Metab Brain Dis. 2019 12 ;34(6):1531-1546. Epub 2019 Jul 16. PMID: 31313125

Abstract Title: 

High fat-low protein diet induces metabolic alterations and cognitive dysfunction in female rats.

Abstract: 

Approximately one-third of the world population is suffering from MetS, and the same is expected to rise in the years to come. Worldwide, most of the staple diets contain high amounts of carbohydrates, fats and comparatively low quantities of proteins. The goal of this study was to evaluate the effect of high fat-low protein diet in the development of the metabolic syndrome and associated cognitive deficits in the female rats. The rats fed with high fat-low protein diet (HFLPD) and 15% oral fructose solution for 24 weeks. Body weight, food intake, water intake, fasting blood glucose, oral glucose tolerance, glycosylated hemoglobin (HbA), and serum lipid profile were measured after every 4 weeks. Serum insulin, HOMA-IR index, rectal temperature, and systolic blood pressure were measured to confirm the manifestation of the hallmarks of metabolic syndrome. Behavioral tests for locomotion, anxiety, learning, and spatial memory were performed from the 12th week to till the end of the study. At the 24th week, oxidative stress assays and histopathology of liver, kidney, brain, and WAT were also performed. HFLPD significantly altered the physiologic and metabolic parameters which contributed to the manifestation of MetS. HFLPD also impaired the cognitive functions along with significant structural changes in the liver, kidney, WAT, and brain. The findings of this study reveal that HFLPD has the potential to induce the physiological, metabolic and histological alterations in rats, which eventually led to the development of MetS and also disrupted the cognitive functions in female rats.

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PMID: 

Physiol Res. 2019 Oct 25. Epub 2019 Oct 25. PMID: 31647302

Abstract Title: 

High-fructose diet-induced hypertriglyceridemia is associated with enhanced hepatic expression of ACAT2 in rats.

Abstract: 

High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.

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PMID: 

J Cardiovasc Pharmacol. 2019 Oct ;74(4):326-335. PMID: 31356553

Abstract Title: 

Kaempferol Prevents Against Ang II-induced Cardiac Remodeling Through Attenuating Ang II-induced Inflammation and Oxidative Stress.

Abstract: 

Heart failure characterized by cardiac remodeling is a global problem. Angiotensin II (Ang II) induces cardiac inflammation and oxidative stress, which also is implicated in the pathophysiology of adverse collagen accumulation-induced remodeling. Kaempferol (KPF), a kind of flavonoid compounds, is capable of anti-inflammatory and antioxidant activities. However, the target of KPF still remains blurred. In this study, we investigated the effect of KPF on Ang II-induced collagen accumulation and explored the underlying mechanisms. Our results suggested that KPF prevented Ang II-induced cardiac fibrosis and dysfunction, in mice challenged with subcutaneous injection of Ang II. In culture cells, KPF significantly reduced Ang II-induced collagen accumulation. Furthermore, KPF remarkably decreased inflammation and oxidative stress in Ang II-stimulated cardiac fibroblasts by modulating NF-κB/mitogen-activated protein kinase and AMPK/Nrf2 pathways.

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PMID: 

J Dermatol Sci. 2019 Oct ;96(1):8-17. Epub 2019 Aug 16. PMID: 31447184

Abstract Title: 

Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress.

Abstract: 

BACKGROUND: There is growing evidence that vasculopathy-induced hypoxia and oxidative stress enhance the process of fibrosis in systemic sclerosis (SSc). Kaempferol is a natural flavonoid widely found in various vegetables and fruits, and has been reported to have excellent antioxidant activity.OBJECTIVE: Objective was to elucidate the effect of kaempferol on skin fibrosis and the mechanism of the inhibitory regulation of fibrosis by kaempferol.METHODS: We assessed the effect of intraperitoneally administered kaempferol on bleomycin-induced dermal fibrosis in mice. The effect of kaempferol on oxidative stress in bleomycin-treated mice and SSc fibroblasts was assessed in vivo and in vitro.RESULTS: We identified that kaempferol injection significantly inhibited bleomycin-induced dermal fibrosis in mice. The number ofαSMAmyofibroblasts, CD3T-cells, and CD68macrophages in lesional skin was significantly decreased by kaempferol injections. Kaempferol administration also significantly suppressed the bleomycin-induced oxidative stress signal in OKD48 mice. Additionally, mRNA levels of oxidative stress-associated factors, such as HO-1 and NOX2, as well as inflammatory and pro-fibrotic cytokines, including IL-6, TGF-β and TNFα in sclerotic skin were significantly decreased by kaempferol. Kaempferol also reduced bleomycin-induced TUNELapoptotic cells in the lesional skin of bleomycin-treated mice. Furthermore, the oxidant-induced intracellular accumulation of reactive oxygen species (ROS) in SSc fibroblasts was inhibited by kaempferol treatment. In addition, the oxidant-induced apoptosis of SSc fibroblasts was decreased by kaempferol in vitro.CONCLUSION: Kaempferol might improve bleomycin-induced fibrosis by reducing oxidative stress, inflammation, and oxidative cellular damage. Administration of kaempferol might be an alternative treatment for skin fibrosis in SSc.

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PMID: 

J Food Biochem. 2019 Nov ;43(11):e13034. Epub 2019 Sep 5. PMID: 31489640

Abstract Title: 

Kaempferol reduces hepatic triglyceride accumulation by inhibiting Akt.

Abstract: 

In this paper, we studied the mechanism of the triglyceride (TG)-lowering effect of kaempferol in vitro and in vivo. Kaempferol showed LXR agonistic activities without inducing TGs or the expression of several lipogenic genes in cultured cells. A luciferase and qPCR analysis showed that kaempferol increased the transactivation of PPARα and PPARδ and stimulated gene expression associated with fatty acid oxidation and uptake in hepatocytes. More importantly, kaempferol inhibited protein kinase B (Akt) activity and suppressed SREBP-1 activation via multiple mechanisms, including through increasing Insig-2a expression, reducing SREBP-1 phosphorylation, and increasing GSK-3 phosphorylation. Collectively, these actions inhibited the SREBP-1 activation process. Furthermore, as an Akt/mTOR pathway inhibitor, kaempferol led to the induction of hepatic autophagy and resulted in a decrease in lipid droplet formation in the mouse liver. These findings demonstrate that kaempferol exerts its TG-lowering effect via Akt inhibition and activation of PPARα and PPARδ. PRACTICAL APPLICATIONS: Kaempferol is a major dietary flavonoid in various plant-based foods, and it is used as a valuable ingredient in functional foods, with numerous beneficial properties such as anticancer, antioxidant, and anti-atherosclerotic activities. Kaempferol exerts its TG-lowering effect via Akt inhibition and activation of PPARα and PPARδ. Currently, the number of people with hyperlipidemia is rapidly growing in both developed and developing societies; thus, we propose that kaempferol could be used for therapeutic interventions aimed at the treatment of these individuals.

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PMID: 

Immunopharmacol Immunotoxicol. 2019 Oct ;41(5):538-548. Epub 2019 Sep 24. PMID: 31549524

Abstract Title: 

Kaempferol alleviates LPS-ATP mediated inflammatory injury in splenic lymphocytes via regulation of the pyroptosis pathway in mice.

Abstract: 

The pharmacological application of kaempferol, a natural flavonol present in different plant species, has been demonstrated to have extensive anti-inflammatory, anti-apoptotic, anti-oxidative, and anti-cancer effects. Pyroptosis is an inflammatory form of programed cell death by membranolysis and associated leakage of cytoplasm. This study investigated the molecular mechanism of kaempferol-induced effects on the pyroptosis in splenic lymphocytes (SLCs) isolated from mice.Lipopolysaccharide (LPS)-primed and adenosine triphosphate (ATP)-stimulated SLCs were used to establish the pyroptosis model. The kaempferol pretreatment was tested in the model.The results show that kaempferol alleviates LPS-ATP mediated damage by increasing cell viability, improving membrane integrity, and decreasing the release of IL1b and IL-18. Kaempferol reduces pyroptosis by suppressing the expression and activity of caspase-1, increasing the protein expression of Toll-like receptor 4 (TLR4) and NOD-like receptor 3 (NLRP3), and inhibition of the decomposition of gasdermin D (GSDMD).Our data suggest that kaempferol exhibits anti-pyroptosis activities, which warrants further detailed investigation.

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PMID: 

DNA Cell Biol. 2019 Sep 27. Epub 2019 Sep 27. PMID: 31560574

Abstract Title: 

Kaempferol Modulates Autophagy and Alleviates Silica-Induced Pulmonary Fibrosis.

Abstract: 

Silicosis is an occupational disease characterized as inflammatory cells infiltration and severe progressive pulmonary fibrosis. Kaempferol (Kae), a flavonoid exists in many plants and fruits, has been proved to have anti-inflammatory and antifibrosis functions. However, the effects of Kae on silicosis remain unclear. In the present study, we analyzed the therapeutic effects of Kae in 1-, 7-, and 28-day silicosis models, respectively. In the 1-day model, Kae treatment did not vary the wet-to-dry weight ratios of the lung, apoptotic rate, autophagy, or the expression of inflammatory factors. In contrast, Kae significantly inhibited pulmonary inflammation in the 7-day silicosis models and inhibited silica-induced pulmonary fibrosis in the 28-day models. Besides, we found that Kae partially restored silica-induced LC3 lipidation without increasing the p62 levels. Blocking autophagy with chloroquine antagonized the inhibitory effects of Kae on inflammation, suggesting that autophagy might be required in the therapeutic effects of Kae on silicosis. These findings indicated that Kae inhibits the progression of silica-induced pulmonary fibrosis, which may provide experimental evidences for Kae in the treatment of silicosis.

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PMID: 

Drug Des Devel Ther. 2019 ;13:3497-3514. Epub 2019 Oct 7. PMID: 31631974

Abstract Title: 

The Osteoprotective Effects Of Kaempferol: The Evidence From In Vivo And In Vitro Studies.

Abstract: 

Kaempferol is a dietary bioflavonoid ubiquitously found in various types of plant. It possesses a wide range of medicinal properties suggesting its potential clinical utility that requires further investigation. The present review intends to highlight the efficacy of kaempferol and its molecular mechanisms of action in regulating bone metabolism. Many reports have acknowledged the bone-protecting property of kaempferol and kaempferol-containing plants using in vitro and in vivo experimental models. Kaempferol supplementation showed bone-sparing effects in newborn rats, glucocorticoid-induced and ovariectomy-induced osteoporotic models as well as bone fracture models. It achieves the bone-protective effects by inhibiting adipogenesis, inflammation, oxidative stress, osteoclastic autophagy and osteoblastic apoptosis while activating osteoblastic autophagy. The anti-osteoporotic effects of kaempferol are mediated through regulation of estrogen receptor, bone morphogenetic protein-2 (BMP-2), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways. In summary, kaempferol exhibits beneficial effects on skeleton, thus is potentially effective for the prophylaxis and treatment of osteoporosis.

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PMID: 

Mol Med Rep. 2019 Dec ;20(6):5197-5207. Epub 2019 Oct 16. PMID: 31638215

Abstract Title: 

Kaempferol promotes bone formation in part via the mTOR signaling pathway.

Abstract: 

Previous research indicates that kaempferol (Kae) promotes osteogenesis, but its underlying mechanism of action remains unclear. The present study hypothesized that the osteogenic effects of Kae were mediated through mammalian target of rapamycin (mTOR). To validate this hypothesis, bone marrow mesenchymal stem cells (BMSCs) from ovariectomized (OVX) rats were differentiated into osteoblasts. The bone mineral density and bone microarchitecture of the OVX rats was measured in vivo, while osteogenesis was evaluated in vitro via Alizarin Red S staining and alkaline phosphatase activity measurements in cultured BMSCs. The levels of phosphorylated eukaryotic translation initiation factor 4E‑binding protein 1 (p‑4E/BP1) and phosphorylated ribosomal protein S6 kinase B1(p‑S6K), and the expression of Runt‑related transcription factor 2 and Osterix, were concurrently quantified by western blot analysis. The data suggested that Kae prevented OVX‑induced osteoporosis in rats by promoting osteoblastogenesis. Furthermore, treatment with Kae in rat BMSCs enhancedmineralization, elevated ALP activity, increased the expression levels of Runx‑2 and Osterix and increased the levels of p‑S6K and decreased the levels of p‑4E/BP1 and, consistent with its ability to promote osteoblast differentiation. In contrast, treatment with rapamycin, an mTOR inhibitor,produced the opposite phenotype. Taken together, these data suggested that the protective effects of Kae in BMSCs and in the OVX rat model resulted from the induction of osteogenesis via mTOR signaling, or at least partially via the regulation of downstream effectors of the mTOR pathway.

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PMID: 

J BUON. 2019 Jul-Aug;24(4):1555-1561. PMID: 31646808

Abstract Title: 

Inhibition of endometrial carcinoma by Kaempferol is interceded through apoptosis induction, G2/M phase cell cycle arrest, suppression of cell invasion and upregulation of m-TOR/PI3K signalling pathway.

Abstract: 

PURPOSE: The main purpose of this study was to investigate the selective anticancer effects of Kaempferol against MFE-280 endometrial carcinoma cells along with evaluating its effects on apoptotic pathway, cell cycle phase distribution, cell invasion, cell migration and m-TOR/PI3K/Akt signalling pathway.METHODS: Cell viability of MFE-280 endometrial carcinoma cells was assessed by MTS [(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)] assay. Apoptosis was determined by acridine orange (AO)/ ethidium bromide (EB) double staining. Cell cycle analysis was determined by flow cytometry, while Boyden chamber assay was performed to study the effects of Kaempferol on cell migration and cell invasion, respectively. The effects of Kaempferol on the protein expression of m-TOR/PI3K/Akt signalling pathway were analysed by Western blot assay.RESULTS: Kaempferol exerted considerable and selective anticancer effects on MFE-280 endometrial carcinoma cells with IC50 of 10μM. The anticancer effects were found to be due to activation of mitochondrial-mediated apoptotic pathway and G2/M phase cell cycle arrest. Furthermore, the results also revealed that Kaempferol significantly inhibited cell migration and cell invasion trend of these cancer cells. Our results also showed that, in comparison to the untreated cells, Kaempferol-treated cells exhibited a dose-dependent downregulation of p-mTOR, p-PI3K and p-AKT proteins. However, mTOR, PI3K and Akt expression levels remained more or less unaltered.CONCLUSIONS: In conclusion, the present study indicates that Kaempferol could exert anticancer effects in MFE-280 endometrial carcinoma cells selectively and that these effects were mediated via apoptosis induction, cell cycle arrest and inhibition of m-TOR/PI3K/Akt signalling pathway.

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