ABSTRACT
This research group (FROM) aimed to develop biomarkers for exposure to environmental hazards and diseases, assess environmental diseases, and apply and verify these biomarkers in environmentally vulnerable areas. Environmentally vulnerable areasincluding refineries, abandoned metal mines, coal-fired power plants, waste incinerators, cement factories, and areas with high exposure to particulate matteralong with control areas, were selected for epidemiological investigations. A total of 1,157 adults, who had resided in these areas for over 10 years, were recruited between June 2021 and September 2023. Personal characteristics of the study participants were gathered through a survey. Biological samples, specifically blood and urine, were collected during the field investigations, separated under refrigerated conditions, and then transported to the laboratory for biomarker analysis. Analyses of heavy metals, environmental hazards, and adducts were conducted on these blood and urine samples. Additionally, omics analyses of epigenomes, proteomes, and metabolomes were performed using the blood samples. The biomarkers identified in this study will be utilized to assess the risk of environmental disease occurrence and to evaluate the impact on the health of residents in environmentally vulnerable areas, following the validation of diagnostic accuracy for these diseases.
ABSTRACT
Residents in areas with abandoned mines risk significant exposure to abundant heavy metals in the environment. However, current clinical indicators cannot fully reflect the health changes associated with abandoned mine exposure. The aim of this study was to identify biological changes in the residents of abandoned mine areas via proteomic analysis of their blood. Blood samples were collected from abandoned mine and control areas, and mass spectrometry was used for protein profiling. A total of 138 unique or common proteins that were differentially expressed in low-exposure abandoned mine area (LoAMA) or high-exposure abandoned mine area (HiAMA) compared to non-exposure control area (NEA) were analyzed, and identified 4 clusters based on functional similarity. Among the 10 proteins that showed specific change in LoAMA, 4 proteins(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) were cluded in cluster 1(plasma lipoprotein remodeling), and linked to proteins that showed specific change in protein expression in HiAMA. Therefore, it is suggested that 4 proteins are changed at low exposure to an abandoned mine (or initial exposure), and then at high exposure, changes in various proteins involved in linked plasma lipoprotein remodeling are induced, which might triggered by the 4 proteins. Interestingly, in addition to plasma lipoprotein remodeling, proteins involved in other functional networks were changed in the high exposure group. These were all directly or indirectly linked to the 4 biomarkers(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) that changed during low exposure. This suggests their potential utility in identifying areas impacted by abandoned mines. Especially, proteins involved in lipid metabolism and renal function-related diseases in individuals exposed to heavy metals in abandoned mine areas were correlated. Chronic kidney disease is predominantly instigated by cardiovascular disease and is commonly accompanied by dyslipidemia.
Subject(s)
Environmental Exposure , Mining , Proteomics , Humans , Male , Middle Aged , Adult , Metals, Heavy/toxicity , Female , Blood Proteins/analysisABSTRACT
Cadmium (Cd), a serious environmental contaminant, is associated with adverse health effects. However, the specific changes that the human body experiences in response to exposure to varying concentrations of cadmium remain unknown. The high levels of heavy metal contamination, especially Cd, in abandoned mines and smelter sites make them ideal locations to investigate the physiological manifestations of Cd exposure. This study found that individuals inhabiting abandoned mine and smelter areas had higher concentrations of Cd in their urine and blood compared to those living outside these areas (i.e., the controls). Furthermore, proteomic profiling of blood samples from all study groups was performed to identify proteomic biomarkers associated with chronic and severe Cd exposure. This analysis showed statistically significant correlations between urine Cd levels and sixteen proteins. Among these proteins, seven exhibited significantly altered expressions in samples from contaminated areas compared with those from control areas. Therefore, these proteins were selected as potential markers representing Cd-related protein alterations. Multiple reaction monitoring analysis was performed to validate the expression patterns of the proteins and four proteins were found to exhibit consistent trends. The findings show that Cd exposure significantly affects the expression of certain proteins in the human body. Understanding the underlying mechanisms and diseases associated with Cd-induced protein alterations can aid in the development of effective preventive and therapeutic strategies for individuals exposed to Cd-linked pollution.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Metals, Heavy , Humans , Cadmium/analysis , Proteomics , Metals, Heavy/analysis , Environmental Pollution/analysis , Mining , Environmental Monitoring , Environmental Exposure/analysisABSTRACT
Soil contamination is associated with a high potential for health issues. This study aimed to investigate the bioaccumulation of heavy metals and its associated health impact among residents near a mining area. We performed environmental monitoring by analyzing lead (Pb), cadmium (Cd), and arsenic (As) levels in soil and rice samples, as well as biomonitoring by analyzing blood and urine samples from 58 residents living near the mine. Additionally, concentration trends were investigated among 26 participants in a 2013 study. The Cd and As levels in the soil samples and Cd levels in the rice samples exceeded the criteria for concern. The geometric mean blood Cd level (2.12 µg/L) was two times higher than that in the general population aged > 40 years. The blood Cd level showed decreasing trends from the previous measurements of 4.56-2.25 µg/L, but was still higher than that in the general population. The blood and urine Cd levels were higher in those with a low estimated glomerular filtration rate (eGFR) than in those with normal eGFR. In conclusion, heavy metals from mining areas can accumulate in soil and rice, adversely impacting human health. Continuous environmental monitoring and biomonitoring are required to ensure the safety of residents.
ABSTRACT
Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals. This study examined the association between heavy metal exposure and renal function indicators. We studied a total of 298 participants, of which 74 and 68 resided in low- and high-exposure abandoned metal mine areas, respectively, with 121 in the refinery area and 35 in the control area. Blood and urine samples were collected from the participants to analyze the levels of blood lead, cadmium, and creatinine and urinary cadmium, NAG, and ß2-MG. The estimated glomerular filtration rate, which is calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, was used for assessments. The study participants comprised more females than males, and their mean age was 70.3 years. The blood lead and cadmium as well as urinary cadmium levels were 2.12 µg/dL, 1.89 µg/L, and 2.11 µg/L, respectively, in the heavy metal-exposure areas, and 1.18 µg/dL, 0.89 µg/L, and 1.11 µg/L, respectively, in the control area. The odds ratio (OR) for exceeding the reference value showed that blood cadmium in the refinery area was 38 times higher than that in the control area. Urinary cadmium was seven times higher in the low-exposure abandoned metal mine area than in the control area. NAG showed a positive correlation with urinary cadmium in all areas. In the refinery area, correlations were observed between ß2-MG and urinary cadmium levels and the eGFR and blood cadmium level; in the high-exposure abandoned metal mine area, correlations were observed between NAG, ß2-MG, and the eGFR and blood cadmium. In this study, the association between Cd exposure and some renal function indicators was observed. This study's findings and the obtained biological samples can serve as a basis for future molecular biological research.
Subject(s)
Cadmium , Metals, Heavy , Female , Male , Humans , Aged , Cadmium/toxicity , Metals, Heavy/toxicity , Creatinine , Odds Ratio , Kidney/physiologyABSTRACT
Pacific oyster (Crassostrea gigas), an abundant bivalve consumed across the Pacific, is known to possess a wide range of bioactivities. While there has been some work on its bioactive hydrolysates, the discovery of bioactive peptides (BAPs) remains limited due to the resource-intensive nature of the existing discovery pipeline. To overcome this constraint, in silico-based prospecting is employed to accelerate BAP discovery. Major oyster proteins were digested virtually under a simulated gastrointestinal condition to generate virtual peptide products that were screened against existing databases for peptide bioactivities, toxicity, bitterness, stability in the intestine and in the blood, and novelty. Five peptide candidates were shortlisted showing antidiabetic, anti-inflammatory, antihypertensive, antimicrobial, and anticancer potential. By employing this approach, oyster BAPs were identified at a faster rate, with a wider applicability reach. With the growing market for peptide-based nutraceuticals, this provides an efficient workflow for candidate scouting and end-use investigation for targeted functional product preparation.
Subject(s)
Anti-Infective Agents , Crassostrea , Animals , Crassostrea/metabolism , Peptides/pharmacology , Peptides/metabolism , Seafood , Anti-Infective Agents/metabolismABSTRACT
Chronic exposure to ultraviolet (UV) light promotes the breakdown of collagen in the skin and disrupts the extracellular matrix (ECM) structure, leading to skin wrinkling. Pacific whiting (Merluccius productus) is a fish abundant on the Pacific coast. In the current study, we investigated the anti-wrinkle effect of hydrolysate from Pacific whiting skin gelatin (PWG) in UVB-irradiated human dermal fibroblasts and the molecular mechanisms involved. PWG effectively restored type 1 procollagen synthesis reduced by UVB-irradiation. Also, we found that PWG inhibited collagen degradation by inhibiting MMP1 expression. Furthermore, PWG decreased cytokines TNF-α, IL-6, and IL-1ß associated with inflammatory responses and increased antioxidant enzymes, HO-1, SOD, GPx, CAT, and GSH content, a defense system against oxidative stress. In terms of molecular mechanisms, PWG increased collagen synthesis through activating the transforming growth factor ß (TGF-ß)/Smad pathway and decreased collagen degradation through inhibiting the mitogen-activated protein kinases/activator protein 1 (MAPK/AP-1) pathway. It also suppressed the inflammatory response through suppressing the nuclear factor-κB (NF-κB) pathway and increased antioxidant enzyme activity through activating the nuclear factor erythroid 2/heme oxygenase 1 (Nrf-2/HO-1) pathway. These multi-target mechanisms suggest that PWG may serve as an effective anti-photoaging material.
Subject(s)
Fibroblasts , Gadiformes , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Collagen Type I/metabolism , Fibroblasts/physiology , Fibroblasts/radiation effects , GATA1 Transcription Factor/metabolism , GATA1 Transcription Factor/pharmacology , Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase (Decyclizing)/pharmacology , Humans , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Protein Hydrolysates/pharmacology , Signal Transduction , Skin , Skin Aging/physiology , Tissue Extracts/therapeutic use , Transcription Factor AP-1/metabolism , Transforming Growth Factor beta/metabolism , Ultraviolet Rays/adverse effectsABSTRACT
Overly elevated circulating non-esterified fatty acids (NEFAs) is an emerging health concern of obesity-associated energy disorders. However, methods to reduce circulating NEFAs remain elusive. The present study determined the effect of piceatannol, a naturally occurring stilbene, on adipocyte lipolysis and its underlying mechanism. Differentiated 3T3-L1 adipocytes, brown adipocytes and isolated white adipose tissue were treated with various concentrations of piceatannol for 1.5-h both in the basal and stimulated lipolysis conditions. Piceatannol significantly inhibited NEFAs and glycerol release with a concomitant reduction of ATGL, CGI-58 and PLIN1 expression in adipocytes. Using a series of inhibitor assays, piceatannol-induced degradation of these proteins was found to be mediated by upregulation of the autophagy-lysosome pathway. Moreover, we demonstrated that piceatannol is capable of stimulating autophagy in vitro. Importantly, piceatannol administration tended to lower fasting-induced serum glycerol levels in healthy mice. Furthermore, piceatannol administration lowered lipolysis, central adiposity and hyperinsulinemia in diet-induced obese mice. Our study provides profound evidence of a novel inhibitory role of piceatannol in lipolysis through autophagy-lysosome-dependent degradation of the key lipolytic proteins in adipocytes. This study offers a mechanistic foundation for investigating the potential of piceatannol-containing foods in reducing lipolysis and its associated metabolic disorders.
Subject(s)
Lipolysis , Stilbenes , 3T3-L1 Cells , Adipocytes , Animals , Autophagy , Fatty Acids, Nonesterified/pharmacology , Glycerol/metabolism , Glycerol/pharmacology , Lipolysis/physiology , Lysosomes/metabolism , Mice , Stilbenes/metabolism , Stilbenes/pharmacologyABSTRACT
BACKGROUND: We evaluated the level and factors of heavy metal exposure to children residing in the Togttsetsii, Khanbogd, and Bayandalai soums of South Gobi province, Mongolia. METHODS: A total of 118 children aged 9-12 years were surveyed, and the level of heavy metal exposure in their bodies was investigated. Exposure was investigated by measuring concentrations of heavy metals such as cadmium, lead, and mercury in the blood; mercury concentration in the hair; and total arsenic in the urine. RESULTS: Blood cadmium concentration had geometric averages of 0.16 µg/L in the children from Bayandalai, 0.15 µg/L Tsogttsetsii, and 0.16 µg/L Khanbogd. Blood lead concentration showed a relatively higher geometric average of 7.42 µg/dL in the children from Bayandalai compared to 4.78 µg/dL and 5.15 µg/dL in those from Tsogttsetsii and Khanbogd, respectively. While blood mercury concentration was the highest in the children from Bayandalai, with a value of 0.38 µg/L, those from Tsogttsetsii and Khanbogd had similar concentrations of 0.29 µg/L and 0.29 µg/L, respectively. Hair mercury concentration was the highest in the children from Bayandalai, with a value of 78 µg/g, a particularly significant difference, with a concentration of 0.50 µg/g in those from Khanbogd. Urine arsenic concentration was the highest in the children from Khanbogd, with a value of 36.93 µg/L; it was 26.11 µg/L in those from Bayandalai and 23.89 µg/L in those from Tsogttsetsii. CONCLUSIONS: The high blood lead concentration of children in Bayandalai was judged to be due to other factors in addition to mine exposure; the reason why blood and hair mercury concentration was higher in children from Bayandalai may have been due to exposure to many small-scale gold mines in the area. In the case of Khanbogd, it was estimated that the high arsenic level in urine was caused by the effect of mines.
ABSTRACT
The interest in utilizing food-derived compounds therapeutically has been rising. With the growing prevalence of systematic chronic inflammation (SCI), efforts to find treatments that do not result in the side effects of current anti-inflammatory drugs are underway. Bioactive peptides (BAPs) are a particularly promising class of compounds for the treatment of SCI, and the abundance of high-quality seafood processing byproducts (SPB) makes it a favorable material to derive anti-inflammatory BAPs. Recent research into the structural properties of anti-inflammatory BAPs has found a few key tendencies including they tend to be short and of low molecular weight (LMW), have an overall positive charge, contain hydrophobic amino acids (AAs), and be rich in radical scavenging AAs. SPB-derived anti-inflammatory BAPs have been observed to work via inhibition of the NF-κB and MAPK pathways by disrupting the phosphorylation of IκBα and one or more kinases (ERK, JNK, and p38), respectively. Radical scavenging capacity has also been shown to play a significant role in the efficacy of SPB-derived anti-inflammatory BAPs. To determine if SPB-derived BAPs can serve as an effective treatment for SCI it will be important to understand their properties and mechanisms of action, and this review highlights such findings in recent research.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Peptides/chemistry , Amino Acids/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacology , DNA Damage , Extracellular Signal-Regulated MAP Kinases/metabolism , Fishes , Hydrophobic and Hydrophilic Interactions , Inflammation , MAP Kinase Kinase 4/metabolism , Macrophages/metabolism , Molecular Weight , NF-KappaB Inhibitor alpha/metabolism , Oxidative Stress , Reproducibility of Results , Shellfish , Shellfish Proteins , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Tuna backbone peptide (TBP) has been reported to exert potent inhibitory activity against lipid peroxidation in vitro. Since this bears relevant physiological implications, this study was undertaken to assess the impact of peptide modifications on its bioactivity and other therapeutic potential using in vitro and in silico approach. Some TBP analogs, despite lower purity than the parent peptide, exerted promising antioxidant activities in vitro demonstrated by ABTS radical scavenging assay and cellular antioxidant activity assay. In silico digestion of the peptides resulted in the generation of antioxidant, angiotensin-converting enzyme (ACE), and dipeptidyl peptidase-IV (DPPIV) inhibitory dipeptides. Using bioinformatics platforms, we found five stable TBP analogs that hold therapeutic potential with their predicted multifunctionality, stability, non-toxicity, and low bitterness intensity. This work shows how screening and prospecting for bioactive peptides can be improved with the use of in vitro and in silico approaches.
Subject(s)
Computer Simulation , Peptides/therapeutic use , Tuna/metabolism , Amino Acid Sequence , Animals , Antioxidants/pharmacology , Hydrolysis , Peptides/chemistry , Protein StabilityABSTRACT
BACKGROUND: Sea vegetables are rich sources of nutrients as well as bioactive components that are linked to metabolic health improvement. Algal polysaccharides improve satiety and modulate gut microbiota while proteins, peptides, and phenolic fractions exert anti-inflammatory, antioxidant, and antidiabetic effects. OBJECTIVE: We tested the hypothesis that dietary supplementation with either Pacific dulse (Palmaria mollis, red algae) or wakame (Undaria pinnatifida, brown algae) could remediate metabolic complications in high-fat diet-induced obesity. METHODS: Individually caged C57BL/6J mice (n = 8) were fed ad libitum with either a low-fat diet (LFD), 10% kcal fat; high-fat diet (HFD), 60% kcal fat; HFD + 5% (wt:wt) dulse (HFD + D); or HFD + 5% (wt:wt) wakame (HFD + W) for 8 weeks. Food intake and weight gain were monitored weekly. Glucose tolerance, hepatic lipids, fecal lipids, and plasma markers were evaluated, and the gut microbiome composition was assessed. RESULTS: Despite the tendency of higher food and caloric intake than the HFD (P = 0.04) group, the HFD + D group mice did not exhibit higher body weight, indicating lower food and caloric efficiency (P < 0.001). Sea vegetable supplementation reduced plasma monocyte chemotactic protein (MCP-1) (P < 0.001) and increased fecal lipid excretion (P < 0.001). Gut microbiome analysis showed that the HFD + D group had higher alpha-diversity than the HFD or LFD group, whereas beta-diversity analyses indicated that sea vegetable-supplemented HFD-fed mice (HFD + D and HFD + W groups) developed microbiome compositions more similar to those of the LFD-fed mice than those of the HFD-fed mice. CONCLUSION: Sea vegetable supplementation showed protective effects against obesity-associated metabolic complications in C57BL/6J male mice by increasing lipid excretion, reducing systemic inflammatory marker, and mitigating gut microbiome alteration. While the obese phenotype development was not prevented, metabolic issues related to lipid absorption, inflammation, and gut microbial balance were improved, showing therapeutic promise and warranting eventual mechanistic elucidations.
ABSTRACT
The soy isoflavone daidzein is bioconverted to 7,8,4'-trihydroxyisoflavone (7,8,4'-THIF) by microorganisms. Here, we investigated the matrix metalloproteinase (MMP)-1 inhibitory properties of 7,8,4'-THIF that arise through the suppression of UVB-induced MMP-1 expression. 7,8,4'-THIF reduced UVB-induced MMP-1 expression at the transcriptional level in primary human dermal fibroblasts and inhibited UVB-induced transcriptional activity of AP-1, a major activator of MMP-1 expression. Additionally, it was observed that the mitogen-activated protein kinase (MAPK) pathway, a crucial signalling cascade for MMP-1 expression, was suppressed by 7,8,4'-THIF. Protein kinase C iota (PKCι) was suspected to be a direct target of 7,8,4'-THIF. The direct interaction between 7,8,4'-THIF and PKCι was confirmed using pull-down assays and immobilized metal ion affinity-based fluorescence polarization assays. Finally, we observed that 7,8,4'-THIF inhibited UVB-induced MMP-1 expression in a human skin equivalent model. Taken together, these results suggest that 7,8,4'-THIF, a bioconversion product of daidzein, suppresses UVB-induced MMP-1 expression.
Subject(s)
Isoenzymes/antagonists & inhibitors , Isoflavones/pharmacology , Matrix Metalloproteinase 1/metabolism , Protein Kinase C/antagonists & inhibitors , Drug Evaluation, Preclinical , Humans , Skin Aging/drug effects , Ultraviolet RaysABSTRACT
Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz- GRP78-/-) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz- GRP78-/- mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz- GRP78-/- mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz- GRP78-/- mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.-Kim, J. H., Lee, E., Friedline, R. H., Suk, S., Jung, D. Y., Dagdeviren, S., Hu, X., Inashima, K., Noh, H. L., Kwon, J. Y., Nambu, A., Huh, J. R., Han, M. S., Davis, R. J., Lee, A. S., Lee, K. W., Kim, J. K. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.
Subject(s)
Heat-Shock Proteins/metabolism , Insulin Resistance , Macrophages/metabolism , Obesity/metabolism , Activating Transcription Factor 4/metabolism , Animals , Cell Line , Cells, Cultured , Diet, High-Fat/adverse effects , Endoplasmic Reticulum Chaperone BiP , Glucose/metabolism , Heat-Shock Proteins/genetics , Interleukin-13/genetics , Interleukin-13/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Macrophages/cytology , Male , Mice , Mice, Inbred C57BL , Muscle Cells/metabolism , Obesity/etiology , Unfolded Protein ResponseABSTRACT
SCOPE: Ginger exerts protective effects on obesity and its complications. Our objectives here are to identify bioactive compounds that inhibit adipogenesis and lipid accumulation in vitro, elucidate the anti-obesity effect of gingerenone A (GA) in diet-induced obesity (DIO), and investigate whether GA affects adipose tissue inflammation (ATI). METHODS AND RESULTS: Oil red O staining showed that GA had the most potent inhibitory effect on adipogenesis and lipid accumulation in 3T3-L1 cells among ginger components tested at a single concentration (40 µM). Consistent with in vitro data, GA attenuates DIO by reducing fat mass in mice. This was accompanied by a modulation of fatty acid metabolism via activation of AMP-activated protein kinase (AMPK) in vitro and in vivo. Additionally, GA suppressed ATI by inhibiting macrophage recruitment and downregulating pro-inflammatory cytokines. CONCLUSION: These results suggest that GA may be used as a potential therapeutic candidate for the treatment of obesity and its complications by suppressing adipose expansion and inflammation.
Subject(s)
Anti-Obesity Agents/pharmacology , Diarylheptanoids/pharmacology , Inflammation/drug therapy , Obesity/drug therapy , Polyphenols/pharmacology , Zingiber officinale/chemistry , 3T3-L1 Cells , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Adipocytes/cytology , Adipocytes/drug effects , Adipogenesis/drug effects , Adiposity/drug effects , Animals , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Cholesterol/blood , Coculture Techniques , Diet, High-Fat , Fatty Acids, Nonesterified/blood , Gene Expression Regulation , Lipid Metabolism/drug effects , Male , Mice , Mice, Inbred C57BL , RAW 264.7 Cells , Triglycerides/bloodABSTRACT
Cacao beans from Theobroma cacao are an abundant source of polyphenols, particularly flavonoids. Previous studies demonstrated that cacao flavanols decrease pro-inflammatory cytokines resulting in the alleviation of allergic symptoms. We sought to investigate the effects of cacao extract (CE) on Dermatophagoides farinae extract (DFE)-induced atopic dermatitis (AD)-like symptoms. CE attenuated DFE-induced AD-like symptoms as assessed by skin lesion analyses, dermatitis score, and skin thickness. Histopathological analysis revealed that CE suppressed DFE-induced immune cell infiltration into the skin. These observations occurred concomitantly with the downregulation of inflammatory markers including serum immunoglobulin (Ig) E, chemokine; thymus and activation-regulated chemokine and macrophage-derived chemokine as well as the skin-derived cytokines interleukin (IL)-4, IL-5, and interferon-γ. CE also significantly alleviated transepidermal water loss and increased skin hydration. These results suggest that CE, a natural phytochemical-rich food, has potential therapeutic efficacy for the treatment of AD.
Subject(s)
Cacao/chemistry , Dermatitis, Atopic/drug therapy , Dermatophagoides farinae , Plant Extracts/pharmacology , Allergens/immunology , Allergens/toxicity , Animals , Dermatitis, Atopic/etiology , Eosinophils/drug effects , Eosinophils/metabolism , Immunoglobulin E/blood , Immunoglobulin E/immunology , Inflammation/drug therapy , Interferon-gamma/blood , Interferon-gamma/immunology , Interleukin-4/blood , Interleukin-4/immunology , Interleukin-5/blood , Interleukin-5/immunology , Male , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Mice, Inbred Strains , Phytochemicals/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Skin/drug effectsABSTRACT
Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (MIL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, MIL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (â¼60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging MIL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.-Dagdeviren, S., Jung, D. Y., Friedline, R. H., Noh, H. L., Kim, J. H., Patel, P. R., Tsitsilianos, N., Inashima, K., Tran, D. A., Hu, X., Loubato, M. M., Craige, S. M., Kwon, J. Y., Lee, K. W., Kim, J. K. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.
Subject(s)
Aging/physiology , Inflammation/metabolism , Insulin Resistance/physiology , Interleukin-10/metabolism , Muscle, Skeletal/metabolism , Animals , Creatine Kinase, MM Form , Energy Metabolism , Interleukin-10/genetics , Male , Mice , Mice, TransgenicABSTRACT
Whereas green tea has historically been consumed in high quantities in Northeast Asia, its popularity is also increasing in many Western countries. Green tea is an abundant source of plant polyphenols exhibiting numerous effects that are potentially beneficial for human health. Accumulating evidence suggests that green tea polyphenols confer protective effects on the skin against ultraviolet (UV) irradiation-induced acceleration of skin aging, involving antimelanogenic, antiwrinkle, antioxidant, and anti-inflammatory effects as well as prevention of immunosuppression. Melanin pigmentation in the skin is a major defense mechanism against UV irradiation, but pigmentation abnormalities such as melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation can also cause serious health and aesthetic issues. Furthermore, UV irradiation initiates the degradation of fibrillar collagen and elastic fibers, promoting the process of skin aging through deep wrinkle formation and loss of tissue elasticity. UV irradiation-induced formation of free radicals also contributes to accelerated photoaging. Additionally, immunosuppression caused by UV irradiation plays an important role in photoaging and skin carcinogenesis. In this review, we summarize the current literature regarding the antimelanogenic, antiwrinkle, antioxidant, and immunosuppression preventive mechanisms of green tea polyphenols that have been demonstrated to protect against UV irradiation-stimulated skin photoaging, and gauge the quality of evidence supporting the need for clinical studies using green tea polyphenols as anti-photoaging agents in novel cosmeceuticals.
Subject(s)
Antioxidants/pharmacology , Polyphenols/pharmacology , Skin Aging/drug effects , Tea/chemistry , Humans , Immune Tolerance , Skin Aging/radiation effects , Ultraviolet Rays/adverse effectsABSTRACT
Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. We examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and Hs 578T, as well as the orthotopic 4T1 mouse TNBC tumor model. Among the 10 essential amino acids tested, methionine deprivation elicited the strongest inhibitory effects on the migration and invasion of these cancer cells. Methionine deprivation reduced the phosphorylation of focal adhesion kinase, as well as the activity and mRNA expression of matrix metalloproteinases MMP-2 and MMP-9, two major markers of metastasis, while increasing the mRNA expression of tissue inhibitor of metalloproteinase 1 in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior and upregulated plasminogen activator inhibitor 1 mRNA expression. Animals on the methionine-deprived diet showed lower lung metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine restriction could provide a potential nutritional strategy for more effective cancer therapy.
Subject(s)
Methionine/deficiency , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Movement/physiology , Female , Humans , Mice , Mice, Inbred BALB C , Neoplasm Invasiveness/pathologyABSTRACT
Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (MIL10). After 16 weeks of a high-fat diet (HFD), MIL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10ob/ob) did not affect spontaneous obesity, but MCK-IL10ob/ob mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R-/-) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R-/- mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.