RESUMEN
Patients may find it challenging to accept several FDA-approved drugs for Alzheimer's disease (AD) treatment due to their unaffordable prices and side effects. Despite the known antioxidant, anti-inflammatory, and microbiota-regulating effects of common buckwheat (Fagopyrum esculentum) polysaccharides (FEP), their specific role in preventing AD has not been determined. Here, this study investigated the preventive effects of FEP on AD development in AlCl3-treated rats. The physical properties of FEP were evaluated using X-ray diffraction, FTIR, TGA, DSC, monosaccharide composition, molecular weight, and scanning electron microscopy. The results demonstrated that FEP administration improved memory and learning ability in AlCl3-treated rats. Additionally, AD pathological biomarkers (APP, BACE1, Aß1-42, and p-TauSer404), inflammatory-associated proteins (IL-1ß, IL-6, TNF-α, and Iba1), and MDA and the RAGE/p38/NF-κB pathway were elevated in AlCl3-treated rats. Moreover, these effects were reversed by the upregulation of LRP1, anti-inflammatory cytokines (IL-4 and IL-10), antioxidant enzymes (SOD and catalase), and autophagy proteins (Atg5, Beclin-1, and LC3B). Furthermore, FEP treatment increased the levels of short-chain fatty acids (SCFAs) and the abundance of SCFAs-producing microbes ([Eubacterium]_xylanophilum_group, Lachnospiraceae_NK4A136_group, Lactobacillus). Overall, FEP mitigated oxidative stress, RAGE/p38/NF-κB-mediated neuroinflammation, and AD-associated proteins by upregulating autophagy and SCFA levels, which led to the amelioration of cognitive impairment through microbiota-gut-brain communication in AlCl3-treated rats.
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Cloruro de Aluminio , Disfunción Cognitiva , Disbiosis , Fagopyrum , FN-kappa B , Polisacáridos , Transducción de Señal , Animales , Ratas , Disbiosis/inducido químicamente , Fagopyrum/química , Polisacáridos/farmacología , Polisacáridos/química , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/inducido químicamente , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Ratas Sprague-Dawley , Modelos Animales de EnfermedadRESUMEN
The impact of leptin resistance on intestinal mucosal barrier integrity, appetite regulation, and hepatic lipid metabolism through the microbiota-gut-brain-liver axis has yet to be determined. Water extract of Phyllanthus emblica L. fruit (WEPE) and its bioactive compound gallic acid (GA) effectively alleviated methylglyoxal (MG)-triggered leptin resistance in vitro. Therefore, this study investigated how WEPE and GA intervention relieve leptin resistance-associated dysfunction in the intestinal mucosa, appetite, and lipid accumulation through the microbiota-gut-brain-liver axis in high-fat diet (HFD)-fed rats. The results showed that WEPE and GA significantly reduced tissues (jejunum, brain, and liver) MG-evoked leptin resistance, malondialdehyde (MDA), proinflammatory cytokines, SOCS3, orexigenic neuropeptides, and lipid accumulation through increasing leptin receptor, tight junction proteins, antimicrobial peptides, anorexigenic neuropeptides, excretion of fecal triglyceride (TG), and short-chain fatty acids (SCFAs) via a positive correlation with the Allobaculum and Bifidobacterium microbiota. These novel findings suggest that WEPE holds the potential as a functional food ingredient for alleviating obesity and its complications.
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Apetito , Eje Cerebro-Intestino , Frutas , Homeostasis , Obesidad , Phyllanthus emblica , Extractos Vegetales , Animales , Humanos , Masculino , Ratas , Apetito/efectos de los fármacos , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Encéfalo/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Dieta Alta en Grasa , Frutas/química , Microbioma Gastrointestinal/efectos de los fármacos , Homeostasis/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Leptina/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/microbiología , Phyllanthus emblica/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas Sprague-DawleyRESUMEN
Increased leptin resistance and methylglyoxal (MG) levels are observed in obese patients. However, whether MG deposits contribute to leptin resistance, oxidative stress, and inflammation in peripheral tissues remains unclear. In addition, the edible fruit of Indian gooseberry (Phyllanthus emblica L.) contains abundant bioactive components such as vitamin C, ß-glucogallin (ß-glu), gallic acid (GA), and ellagic acid (EA). Water extract of Indian gooseberry fruit (WEIG) and GA has been shown to improve cognitive decline by suppressing brain MG-induced insulin resistance in rats administered a high-fat diet (HFD). Accordingly, this study investigated the functions of WEIG and GA in inhibiting MG-induced leptin resistance, oxidative stress, and inflammation in the peripheral tissues of HFD-fed rats. The results showed that MG, advanced glycation end products (AGEs), and leptin resistance accumulation in the liver, kidney, and perinephric fat were effectively restored by elevated glyoxalase-1 (Glo-1) activity after WEIG and GA administration comparable to that of alagebrium chloride (positive control) treatment in HFD-fed rats. Furthermore, WEIG and GA supplementation increased adiponectin and antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase) and decreased inflammatory cytokines (IL-6, IL-1ß, TNF-α) in the peripheral tissues of HFD-fed rats. In conclusion, these findings demonstrated that MG may trigger leptin resistance, oxidative stress, and inflammation in peripheral tissues, which could be abolished by WEIG and GA treatment. These results show the potential of P. emblica for functional food development and improving obesity-associated metabolic disorders.
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Phyllanthus emblica , Ribes , Humanos , Animales , Ratas , Leptina , Dieta Alta en Grasa/efectos adversos , Piruvaldehído , Ácido Gálico , InflamaciónRESUMEN
Sunitinib (SUN) is the first-line targeted therapeutic drug for advanced renal cell carcinoma (RCC). However, SUN resistance is frequently observed to result in tumor metastasis, with a poor survival rate. Therefore, finding an effective and safe adjuvant to reduce drug resistance is important for RCC treatment. Pterostilbene (PTE) and 6-shogaol (6-S) are natural phytochemicals found in edible sources and have potential applications against various cancers. However, the biological mechanisms of PTE and 6-S in SUN-resistant RCC are still unclear. Accordingly, this study investigated the regulatory effects of PTE and 6-S on cell survival, drug resistance, and cell invasion in 786-O and SUN-resistant 786-O (786-O SUNR) cells, respectively. The results demonstrated that PTE and 6-S induced apoptosis in both cell lines by upregulating the Bax/Bcl-2 ratio. Additionally, PTE and 6-S increased SUN sensitivity by inhibiting the expression of the RLIP76 transport protein, reduced cell invasion and downregulated MMP expression in both 786-O and 786-O SUNR cells. Mechanistically, PTE, and 6-S significantly and dose-dependently suppressed the RLIP76-initiated Ras/ERK and Akt/mTOR pathways. In summary, PTE and 6-S induce apoptosis, enhance SUN sensitivity, and inhibit migration in both 786-O and 786-O SUNR cells. These novel findings demonstrate the potential of PTE and 6-S as target therapeutic adjuvants for RCC treatment.
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Carcinoma de Células Renales , Catecoles , Neoplasias Renales , Humanos , Carcinoma de Células Renales/metabolismo , Sunitinib/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Neoplasias Renales/patología , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular TumoralRESUMEN
Pharmacological treatments for colitis have limited efficacy and side effects. Plant polysaccharides improve colitis by modulating the gut microbiota. However, the specific benefits of Phyllanthus emblica L. polysaccharides (PEPs) in colitis remain unclear. Therefore, this study aimed to assess the physical characteristics and health advantages of PEP in rats subjected to 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment. The results showed that PEP (1.226 × 103 kDa) was an α-acidic pyran heteropolysaccharide rich in galactose and galacturonic acid. Prefeeding rats with PEP significantly decreased the levels of NO, MDA, proinflammatory cytokines (IL-6, IL-1ß, TNF-α), apoptosis, and the activities of mucinase and ß-glucuronidase. These changes were accompanied by increases in the levels of anti-inflammatory cytokines (IL-4, IL-10) and antioxidant enzymes (SOD, catalase, GPx) in colitis rats. Mechanistically, PEP suppressed the abundance of inflammatory-related bacteria (Bacteroides, Intestinimonas, and Parabacteroides) while promoting the growth of short-chain fatty acid (SCFA)-producing bacteria (Romboutsia, Clostridium_sensu_stricto_1, and Lactobacillus), along with an increase in SCFA secretion. SCFAs may engage with the GPR43 receptor and inhibit downstream HDAC3, consequently downregulating the activation of the RAGE/NF-κB and MAPK pathways. In conclusion, PEP demonstrated preventive effects through its antioxidant, anti-inflammatory, and microbiota modulation properties, thereby ameliorating TNBS-induced colitis in rats.
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Colitis , Microbioma Gastrointestinal , Phyllanthus emblica , Ratas , Animales , FN-kappa B/metabolismo , Phyllanthus emblica/metabolismo , Antioxidantes/farmacología , Colitis/tratamiento farmacológico , Transducción de Señal , Citocinas/metabolismo , Polisacáridos/farmacología , Antiinflamatorios/farmacología , Ácido Trinitrobencenosulfónico/efectos adversos , Ácido Trinitrobencenosulfónico/metabolismo , Colon/metabolismoRESUMEN
Hypertrophy of adipose tissues and dysbiosis are hallmarks of obesity. Although drugs are applied for obesity treatment, side effects limit their use. The anti-obesity capacity of rosmarinic acid (RA) has been documented. Trichodesma khasianum Clarke is an edible RA-rich plant grown in Taiwan. Our previous study found that an 80 % ethanol extract of T. khasianum Clarke leaves (80EETC) ameliorates gastric mucosal damage through its anti-inflammatory, antioxidant, and microbiota modulation abilities. However, the anti-obesity effect of 80EETC remains unclear. Therefore, the objective of this study was to explore the protective effects of low-dose 80EETC (125 mg/kg b.w., 80EETCL) or high-dose 80EETC (250 mg/kg b.w., 80EETCH) on obesity development through gut microbiota modulation in high-fat diet (HFD)-induced C57BL/6 mice. The results showed a high RA content (89.2 ± 7.4 mg/g) in 80EETC. 80EETC administration significantly decreased body weight, body fat ratio, serum lipid levels (TC, TG, and LDL-C), adipose tissue accumulation, malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) in HFD-fed mice. Furthermore, supplementation with 80EETC reduced the Firmicutes/Bacteroidetes ratio and enhanced the relative abundance of gut microbiota (p_Bacteroidetes, f_Lactobacillus, f_Muribaculaceae, f_Prevotellaceae, g_Lactobacillus, g_Prevotellaceae_NK3B31_group, g_Ruminococcaceae_UCG-013, and g_Ruminococcaceae_UCG-014), which negatively correlated with obesity-related factors such as body weight, energy intake, fat accumulation in adipose tissue, TC, TG, LDL, and MDA. In conclusion, RA-rich 80EETC had a protective effect against obesity development and it has potential in healthy food applications.
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Dieta Alta en Grasa , Microbiota , Ratones , Animales , Ratones Obesos , Dieta Alta en Grasa/efectos adversos , Disbiosis/tratamiento farmacológico , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Peso Corporal , Bacteroidetes , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ácido RosmarínicoRESUMEN
SCOPE: Methylglyoxal (MG)-derived advanced glycation end products (AGEs) directly bind to the receptor for advanced glycation end products (RAGE), subsequently exacerbating obesity and obesity-induced cognitive decline. Indian gooseberry (Phyllanthus emblica L.) fruit has antiobesity properties. However, the underlying mechanism by which Indian gooseberry fruit prevents obesity-induced cognitive decline remains unclear. METHODS AND RESULTS: This study aims to investigate the preventive effect of a water extract of Indian gooseberry fruit (WEIG) and its bioactive compound gallic acid (GA) on the obesity-induced cognitive decline through MG suppression and gut microbiota modulation in high-fat diet (HFD)-fed rats. Trapping MG, WEIG, and GA significantly ameliorate fat accumulation in adipose tissue and learning and memory deficits. Mechanistically, WEIG and GA administration effectively reduces brain MG and AGE levels and subsequently reduces insulin resistance, inflammatory cytokines, MDA production, and Alzheimer's disease-related proteins, but increases both antioxidant enzyme activities and anti-inflammatory cytokine with inhibiting RAGE, MAPK, and NF-κB levels in HFD-fed rats. Additionally, WEIG and GA supplementation increases the relative abundances of Bacteroidetes, Gammaproteobacteria, and Parasutterella, which negatively correlate with MG, inflammatory cytokine, and Alzheimer's disease-related protein expressions. CONCLUSION: This novel finding provides a possible mechanism by which WEIG prevents obesity-induced cognitive decline through the gut-brain axis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Phyllanthus emblica , Ribes , Ratas , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Extractos Vegetales/farmacología , Frutas , Obesidad/metabolismo , Citocinas , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/metabolismo , Ratones Endogámicos C57BLRESUMEN
Plant polysaccharides act as prebiotics by modulating gut microbiota. However, the functional characteristics of buckwheat Fagopyrum tataricum polysaccharides (FTP) and F. esculentum polysaccharides (FEP) on colitis prevention are not valid. This study evaluated the ameliorative effects of FTP and FEP against TNBS-induced colitis via gut microbiota modulation in rats. The characterizations of FTP and FEP were analyzed, including FTIR, TGA, DSC, and monosaccharide composition. In addition, the pathological features of colon length and symptoms in TNBS-induced colitis were improved via the intragastric preadministration of FTP and FEP. The results showed that prefeeding with FTP and FEP decreased inflammatory cytokines (IL-6, IL-1ß, and TNF-α), ß-glucuronidase, and mucinase, as well as increasing superoxide dismutase, catalase, and glutathione peroxidase levels, in TNBS-induced rats. A decrease in inflammatory signaling-associated proteins (NF-κB, MAPK, COX-2, and iNOS) improved the treatment of TNBS-induced colitis by buckwheat polysaccharides. Moreover, prefeeding with buckwheat polysaccharides increased the Firmicutes/Bacteroidetes ratio and short-chain fatty acid (SCFA) production and decreased the abundance of inflammation-related bacteria (Oscillospiraceae and Oscillibacter). In conclusion, FTP and FEP strongly improved TNBS-induced colitis through antioxidant, anti-inflammatory, and microbiota modulation properties, especially in the high-dose FEP group. Buckwheat polysaccharides have the potential for utilization in functional ingredients or food development.
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Colitis , Fagopyrum , Microbioma Gastrointestinal , Ratas , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colon , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Polisacáridos/metabolismo , Modelos Animales de EnfermedadRESUMEN
Okara is a by-product of tofu or soymilk production processes. The disposal of huge quantities of okara is a significant issue. Based on previous reports, protein hydrolysis can release excess free amino acids and small peptides from okara and exhibit anti-fatigue function. We aimed to investigate the anti-fatigue effect of okara protein hydrolysate (OPH) in vitro and in vivo. In the first phase, we treated C2C12 myotubes with different processed OPHs to detect mitochondrial functions. The results revealed that OPH hydrolyzed with alcalase containing 2% E/S for 2 h increased the mitochondrial mRNA level (cytochrome b and cytochrome c oxidase I) and enzyme activity (citrate synthase and cytochrome c oxidase) most efficiently. In the second phase, we conducted animal studies to assess the anti-fatigue function of OPH. After acclimatization, 8 week-old male Sprague-Dawley (SD) rats were randomly classified into four groups: (1) control group, (2) 1X-OPH, (3) 2X-OPH, and (4) 5X-OPH (8 rats per group, treated for 28 days). The results indicated that the intake of OPH for 28 days increased the exhaustive swimming time of rats and lowered the increment of the lactate ratio, as well as the activity of lactate dehydrogenase and creatine kinase. These results indicated that OPH improves exercise performance and anti-fatigue function in male SD rats. Therefore, OPH could be a potential health supplement for anti-fatigue function.
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Suplementos Dietéticos , Fatiga Muscular , Fibras Musculares Esqueléticas , Proteínas de Plantas , Polisacáridos , Alimentos de Soja , Animales , Masculino , Ratas , Complejo IV de Transporte de Electrones , Ratas Sprague-Dawley , Proteínas de Plantas/farmacología , Polisacáridos/farmacología , Línea Celular , Fatiga Muscular/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismoRESUMEN
Plant polysaccharides have prebiotic properties for gut microbiota and immune modulation. This study aimed to investigate the prevention abilities of edible Rhinacanthus nasutus polysaccharide (RNP) and okara polysaccharide (OP) in Sprague-Dawley rats with acetic acid-induced colitis. The characterizations of RNP and OP were analyzed, including Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, and monosaccharide composition. The prebiotic properties of RNP and OP were determined in vitro. In addition, the pathological features of colon length and inflammatory cytokine levels in acetic acid-induced colitis were improved by intragastric preadministration of RNP and OP for 3 weeks. There was no nephrotoxicity or hepatotoxicity in rats via histopathological assessment after RNP and OP intake. Moreover, the abundance of short-chain fatty acids-producing bacteria (Lachnospiraceae, Lactobacilli, and Prevotellaceae) were increased after RNP supplementation. In conclusion, intragastric gavage of RNP and OP significantly modulated the gut microbiota and immune response, consequently alleviating the symptoms of colitis. This novel finding provides an alternative strategy and potential application of these two polysaccharides for colitis prevention and treatment.
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Acetatos , Polisacáridos , Ratas , Animales , Ratas Sprague-Dawley , Polisacáridos/farmacologíaRESUMEN
The prevalence of metabolic disease has rising and affected over 1,000 million populations globally. Since the metabolic disease and its related complication are board, it has become the major health hazard of modern world. However, Long term medication of metabolic disease may cause serious side effects and risk for adverse health problems. Recently, emerging studies focus on exploring the mechanistic details of metabolic state in disease development and progression. Gut bacteria ecosystem was considered to play a pivotal role in regulating energy homeostasis and great associated with the development of metabolic disease. Accumulated evidences indicated that Akkermansia muciniphila, Faecalibacterium prausnitzii, and Roseburia hominis improve the balance of the microecology in the intestine of the host and have positive effects on enhancing nutrients absorption. Hence, the novel probiotics as therapeutic target to modify gut microbiota generally focus on improving microbiota dysbiosis, and offers new prospects for treating metabolic disease. In the present review, we discuss the significant roles and regulatory properties of specific bacterium in the context of intestinal microbial balance, explores the kinds of harmful/beneficial bacteria that were likely to act as indicator for metabolic disease. Further proposed a stepwise procedure in the basis of sequencing technology with that of innovative option to reestablish the microbial equilibrium and prevent metabolic disease.
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Microbioma Gastrointestinal , Enfermedades Metabólicas , Microbiota , Probióticos , Bacterias/genética , Bacterias/metabolismo , Humanos , Enfermedades Metabólicas/tratamiento farmacológico , Probióticos/uso terapéuticoRESUMEN
Food intake influences neurofunction via the gut microbiota-brain axis. Monounsaturated fatty acid (MUFA) consumption is highly associated with neuroprotection; the mechanism behind the effects of olive oil and camellia oil on gut microbiota remains unclear. In this study, the objective was to compare the neuroprotective role of oleic acid-rich camellia oil and olive oil against AlCl3-induced mild cognitive impairment (MCI) in rats. Morris water maze tests revealed that learning and memory capacities improved in AlCl3-induced rats subjected to camellia oil administration better than olive oil treatment. Moreover, the results showed that the camellia oil- and olive oil-treated AlCl3-induced rat groups had significantly reduced oxidative stress and inflammatory cytokines. Notably, Spearman correlation analysis indicated that the inflammatory cytokines negatively correlated with the microbial strains (Bacteroides pectinophilus_group and Blautia) in response to camellia oil administration. Furthermore, Ruminococcaceae_UCG014 abundance was significantly enhanced by camellia oil intake, which was highly positively associated with antioxidant activity expression. In conclusion, the novel data suggest that the outcomes of camellia oil consumption were superior to those of olive oil intake as camellia oil may have a beneficial effect on MCI protection and improvement through the gut microbiota-brain communication.
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Camellia , Disfunción Cognitiva , Microbioma Gastrointestinal , Animales , Encéfalo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Citocinas/farmacología , Aceite de Oliva/farmacología , Aceites de Plantas/farmacología , RatasRESUMEN
Dysbiosis of gut microbiota is intimately related to ulcerative colitis. The literature has revealed the gut microbiota metabolism of dietary fiber, which is a key resource for short-chain fatty acids (SCFAs) production and subsequently leads to anti-inflammatory effects. It is known that okara (a soybean byproduct) is rich in dietary fiber, but the effect of fermented okara on relieving colitis remains unclear. The object of this study was to investigate the effects of Aspergillus oryzae-fermented okara (FO) on colitis prevention through gut microbiota manipulation in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model. The results showed that administration of FO elevated the relative abundance of SCFAs-producing bacteria (Lachnospiraceae and Bifidobacteriaceae) and SCFAs production, which engaged with GPR43 (SCFAs receptor) consequently decreased the production of proinflammatory cytokines (IL-6, IL-1ß, and TNF-α), inflammatory mediators (COX-2, iNOS, PGE2, and NO), and MCP-1 chemokine and increased anti-inflammatory cytokine (IL-10 and IL-4) production through inhibition of HDAC3/MAPK-related proteins and the NF-κB inflammatory pathway in TNBS-induced colitis in rats. Moreover, increased activity of antioxidants, such as SOD, CAT, GSH, and GPx, and decreased MDA and MPO production were also observed after FO administration in TNBS-induced colitis in rats. This study demonstrated the novel potential of soybean byproducts for alleviating TNBS-induced intestinal inflammation and enhancing antioxidant capacity for colitis improvement. This new finding may enhance the value of okara for functional food development.
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Colitis , Microbioma Gastrointestinal , Animales , Antiinflamatorios/efectos adversos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/prevención & control , Citocinas/metabolismo , Fibras de la Dieta/uso terapéutico , Ácidos Grasos Volátiles , Inflamación , Ratas , Ácido TrinitrobencenosulfónicoRESUMEN
Gemcitabine (GEM) is a typical chemotherapeutic drug used to treat pancreatic cancer, but GEM resistance develops within weeks after chemotherapy. Hence, the development of a new strategy to overcome drug resistance is urgent. 4-Acetylantroquinonol B (4-AAQB), a ubiquinone derived from Taiwanofungus camphoratus, has hepatoprotective, anti-obesity, and antitumor activities. However, the role of 4-AAQB in enhancing GEM sensitivity is unclear. This study aimed to determine the underlying mechanisms by which 4-AAQB enhances cytotoxicity and GEM sensitivity. Cell viability was dramatically reduced by 4-AAQB (2 and 5 µM) treatment in the MiaPaCa-2 and GEM-resistant MiaPaCa-2 (MiaPaCa-2GEMR) human pancreatic cancer cells. 4-AAQB led to cell cycle arrest, upregulated the levels of reactive oxygen species (ROS), promoted apoptosis, and inhibited autophagy, which subsequently enhanced GEM chemosensitivity by suppressing the receptor for advanced glycation end products (RAGE)/high mobility group box 1 (HMGB1)-initiated PI3K/Akt/multidrug resistance protein 1 (MDR1) signaling pathway in both cell lines. Vascular endothelial growth factor A (VEGFA) expression, cell migration, and invasion were also inhibited by the 4-AAQB incubation. Overall, this combination treatment strategy might represent a novel approach for GEM-resistant pancreatic cancer.
RESUMEN
Gemcitabine (GEM) drug resistance remains a difficult challenge in pancreatic ductal adenocarcinoma (PDAC) treatment. Therefore, identifying a safe and effective treatment strategy for PDAC is urgent. Lucidone is a natural compound extracted from the fruits of Lindera erythrocarpa Makino. However, the role of lucidone in PDAC inhibition remains unclear. In addition, high-mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) are involved in multidrug resistance protein 1 (MDR1) regulation and GEM resistance. Thus, this study aimed to explore the function of lucidone in tumor cytotoxicity and chemosensitivity through the suppression of RAGE-initiated signaling in PDAC cells. The data showed that lucidone significantly promoted apoptotic cell death and inhibited the expression of autophagic proteins (Atg5, Beclin-1, LC3-II, and Vps34) and MDR1 by inhibiting the HMGB1/RAGE/PI3K/Akt axis in both MIA Paca-2 cells and MIA Paca-2GEMR cells (GEM-resistant cells). Notably, convincing data were also obtained in experiments involving RAGE-specific siRNA transfection. In addition, remarkable cell proliferation was observed after treatment with lucidone combined with GEM, particularly in MIA Paca-2GEMR cells, indicating that lucidone treatment enhanced chemosensitivity. Collectively, this study provided the underlying mechanism by which lucidone treatment inhibited HMGB1/RAGE-initiated PI3K/Akt/MDR1 signaling and consequently enhanced chemosensitivity in PDAC.
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Carcinoma Ductal Pancreático , Proteína HMGB1 , Neoplasias Pancreáticas , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Autofagia , Línea Celular Tumoral , Ciclopentanos , Humanos , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Neoplasias PancreáticasRESUMEN
Products of dark brown sugar (DBS) from different production processes and raw materials may bring different risks and benefits to human health. Therefore, this study was aimed to evaluate the quality of natural and commercial DBS products. Results showed that physicochemical properties, including pH value, turbidity, and browning degree have no significant difference between natural and commercial DBS products. Total flavonoid content of natural DBS was found to be significantly higher than that of commercial DBS (p < 0.05). Notably, the levels of harmful Maillard reaction products in natural DBS were significantly lower than that in commercial DBS as evidenced by analyses of methylglyoxal and fluorescent advanced glycation end products (p < 0.05). However, the amount of acrylamide in natural DBS was significantly higher than that in commercial DBS. In conclusion, this study provides useful information for risk-benefit assessment of DBS products, which is helpful for food safety management.
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Productos Finales de Glicación Avanzada/química , Fenoles/química , Azúcares/química , Acrilamida/química , Manipulación de Alimentos , Inocuidad de los Alimentos , Calor , Humanos , Reacción de Maillard , Azúcares/economíaRESUMEN
Gemcitabine (GEM) is a first-line drug for pancreatic cancer therapy, but GEM resistance is easily developed in patients. Growing evidence suggests that cancer chemoprevention and suppression are highly associated with dietary phytochemical and microbiota composition. Ursolic acid (UA) has anti-inflammatory and anticancer effects; however, its role in improving cancer drug resistance in vivo remains unclear. In this study, the aim was to explore the role of UA in managing drug resistance-associated molecular mechanisms and the influence of gut microbiota. The in vitro results showed that receptor for advanced glycation end products (RAGE), nuclear factor kappa B p65 (NF-κB/p65), and multidrug resistance protein 1 (MDR1) protein levels were significantly increased in GEM-resistant pancreatic cancer cells (named MIA PaCa-2 GEMR) compared to MIA PaCa-2 cells. Downregulation of RAGE, pP65, and MDR1 protein expression not only was observed following UA treatment but also was seen in MIA PaCa-2 GEMR cells after transfection with a RAGE siRNA. Remarkably, the enhanced effects of UA coupled with GEM administration dramatically suppressed the RAGE/NF-κB/MDR1 cascade and consequently inhibited subcutaneous tumor growth. Moreover, UA could increase alpha diversity and regulate the composition of gut microbiota, especially in Ruminiclostridium 6. Taken together, these results provide the first direct evidence of MDR1 attenuation and chemosensitivity enhancement through inhibition of the RAGE/NF-κB signaling pathway in vitro and in vivo, implying that UA may be used as an adjuvant for the treatment of pancreatic cancer in the future.
Asunto(s)
FN-kappa B , Neoplasias Pancreáticas , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Animales , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Xenoinjertos , Humanos , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Triterpenos , Gemcitabina , Ácido Ursólico , Neoplasias PancreáticasRESUMEN
BACKGROUND: Although gastroprotective drugs have been used for peptic ulcer disease prevention and treatment, side effects have been observed. Finding a safe and effective treatment strategy is important. PURPOSE: Edible Trichodesma khasianum (T. khasianum) Clarke leaves are considered to protect against peptic ulcers. However, scientific evidence of this effect of T. khasianum Clarke leaves remains limited. STUDY DESIGN/METHODS: In this study, we aimed to evaluate the effect of T. khasianum Clarke leaves on ethanol-induced gastric injury and gut microbiota using RAW 264.7 cells, RGM-1 cells, and BALB/c mice, respectively. RESULT: The rosmarinic acid was identified as the major component of T. khasianum Clarke leaves extracted by 80% ethanol (80EETC). The results showed that 80EETC suppressed inflammatory mediator protein levels in LPS-induced RAW 264.7 cells. Additionally, heat shock protein expression, antiapoptotic ability, and wound healing migration capability were increased by 80EETC pretreatment in RGM-1 cells with the ethanol-induced injury. Remarkably, pretreatment with 80EETC (150 mg/kg b.w.) promoted gastric mucosal healing by decreasing oxidative stress, inflammatory response, proapoptotic protein expression, and gastric mucosa damage in ethanol-induced gastric injury in mice. Crucially, no liver or kidney toxicities were observed by 80EETC oral gavage. Moreover, 80EETC increased gut microbiota diversity and short-chain fatty acid production. CONCLUSION: Our results illustrated the remarkable gastroprotective effect by 80EETC treatment in vitro and in vivo. These findings are the first to demonstrate the powerful protective effect of T. khasianum Clarke leaves against gastric mucosal injury development.
Asunto(s)
Boraginaceae/química , Cinamatos/farmacología , Depsidos/farmacología , Mucosa Gástrica/efectos de los fármacos , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/metabolismo , Cinamatos/análisis , Depsidos/análisis , Etanol/toxicidad , Ácidos Grasos Volátiles/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Úlcera Péptica/prevención & control , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Hojas de la Planta/química , Sustancias Protectoras/química , Células RAW 264.7 , Ácido RosmarínicoRESUMEN
The aim of the study was to evaluate the effects of Hsian-tsao (Mesona procumbens Hemsl.) and its polysaccharides on impaired wound healing in diabetes. The results indicate that ethanol extracts of Hsian-tsao (EE) and crude polysaccharides from water extracts of Hsian-tsao (WEP) had strong inhibitory effects on methylglyoxal (MG)-induced glycation and reactive oxygen species (ROS) production. EE and WEP also decreased MG-induced inflammation-related factors in RAW 264.7 macrophages and restored MG-impaired wound-healing factors in 3T3-L1 fibroblasts. Furthermore, EE and WEP were found to dose-dependently enhance the MG-impaired phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa by macrophages. Excitingly, EE and WEP significantly enhanced wound healing on the dorsal skin through regulation of macrophage inflammatory protein-2 (MIP-2), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expressions in diabetic mice, as evidenced by the percentage reduction in wound surface area and the results of histopathologic scoring analysis. In conclusion, these results suggest that Hsian-tsao extract and its polysaccharides might be utilized in alternative natural therapy to promote wound healing in diabetic individuals.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Medicamentos Herbarios Chinos/farmacología , Lamiaceae , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Saltwater fish is rich in health-promoting polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Excessive fish intake may also cause health hazards due to methylmercury (MeHg). A novel dose estimation method was proposed in this study to improve the quality of food matching by considering the usage ratio of cooking and processing methods in sampling design. In total, 39 table-ready samples were specified according to 2-3 common cooking methods, and MeHg and total mercury (THg) were analyzed. The results showed that mercury was detected in 20 samples (LOD = 0.01 µg/g). High MeHg samples included fried-Spanish mackerel (1.23 µg/g), non-cooked shredded swordfish (0.325 µg/g), pan-fried Spanish mackerel (0.248 µg/g), and non-cooked shredded salmon (0.208 µg/g). Consumption data (n = 166,911) were obtained from 24-h recalls in the 2005-2008 Nutrition and Health Surveys in Taiwan (NAHSIT). The average whole-group estimated daily intake (EDI_WG) was 0.018 (7.9% tolerable daily intake, TDI) for women of child-bearing age and 0.031 µg/day per kg body weight (13.6% TDI) for children. However, 95th percentile values (P95) of 90.4% TDI and 185% TDI were estimated for the two consumer-only populations, which have raised public health concerns. The ratio of % TDI to % daily reference intake (% DRI) was used as a risk-benefit (R/B) indicator. The top 4 R/B foods were: tuna sashimi (0.089 and 0.14), non-cooked shredded swordfish (0.033 and 0.052), fried-Spanish mackerel (0.027 and 0.043) and deep-fried fish balls (0.022 and 0.035) in the two perspective populations.