6'-Sialyllactose Alleviates Muscle Fatigue through Reduced Blood Lactate Level after Treadmill Exercise in Mice.

6'-Sialyllactose (6'-SL), found in human breast milk, exhibits anti-inflammatory, immune function-enhancing, brain development-promoting, and gut health-improving effects. However, its effects on muscle fatigue remain unknown. Here, we aimed to investigate the effects of 6'-SL on blood lactate level, muscle fiber type, and oxidative phosphorylation protein complexes (OXPHOS) in muscle after exercise using C57BL/6J male mice. C57BL/6J mice were randomly assigned to control or 100 mg/kg 6'-SL. After 12 weeks of 6'-SL administration, the mice were made to perform treadmill exercise; their blood lactate and glucose levels were measured at the basal level (rest) and 0, 5, and 10 min after treadmill exercise. Results showed that 6'-SL treatment in C57BL/6J mice significantly reduced blood lactate level and improved blood glucose level. Moreover, 6'-SL increased the expression of slow-myosin heavy chain (MHC) and OXPHOS in gastrocnemius muscle. In addition, 6'-SL treatment for 12 weeks did not affect food intake, serum biomarkers of tissue injury, and lipid profiles compared with those of the controls. These findings indicate that non-toxic 6'-SL suppressed muscle fatigue during exercise by promoting protein expression of muscle fibers, especially slow-twitch muscle fibers characterized by abundant OXPHOS complexes and decreased blood lactate level. This study suggests that 6'-SL holds promise as a nutritional supplement in exercise and clinical settings, subject to further validation.

1,2,4-trihydroxybenzene induces non-apoptotic cell death via the structural damage of intracellular organelles.

Benzene occurs naturally and is widely applied in the production process of petrochemical products. It is mainly exposed through the respiratory tract and dermal and metabolized in the liver, leading to systemic health effects, and 1,2,4-trihydroxybenzene (THB) is a benzene metabolite used as a hair dye ingredient in some countries. In an effort to identify a toxic mechanism of THB, we first analyzed the hair of consumers who used a shampoo containing THB, and contrary to our expectations, THB was not persistent in the hair. Following, we treated THB to human keratinocytes and HeLa Chang liver cells. Membrane damage was observed in both cell lines, which was more notable in HeLa Chang liver cells than in keratinocytes. Thus, we decided on HeLa Chang liver cells as target cells for further study. Cell viability decreased sharply between 20 µg/ml and 40 µg/mL, inducing G2/M phase arrest and non-apoptotic cell death. The expression of carcinogenesis-, DNA damage-, and transcriptional dysregulation-related genes were notably up-regulated, and the structure and function of mitochondria were disrupted. The volume of the ER and acidic compartments decreased, and intracellular ROS and calcium ion levels increased. More interestingly, we found that THB formed unique structures within the cells, especially around the nuclear membrane, and that those structures seemed to dig into the nucleus over time. A reverse docking analysis also showed that SULT1A1, CYP2E1, and CAT, known to play a significant role in protecting cells from harmful factors, might be potential target proteins for THB. Taken together, we suggest that THB induces non-apoptotic cell death via structural damage of intracellular organelles, especially the nuclear membrane.

Insect-derived extracts and peptides in neuroprotection.

Throughout history, various cultures have recognized the significance of insects and have integrated them into traditional medicinal practices. In addition to medicines, insects are garnering attention as a sustainable and nutritious dietary alternative. Although edible insects have long been recognized as food sources in many Asian cultures, recent scientific studies have highlighted their potential therapeutic benefits, particularly in the field of neuroprotection. This review explores insect-derived extracts and peptides, elucidating their neuroprotective potential. This review highlights the potential use of insects as a source of neuroprotective agents. Advancements in neuroprotection may find a key ally in insects as our understanding of the symbiotic relationship between insects and human health becomes more profound.

6'-Sialyllactose Enhances Exercise Performance via Increased Muscle Mass and Strength.

Sialyllactose (SL) is a functional human milk oligosaccharide essential for immune support, brain development, intestinal maturation, and antiviral defense. However, despite its established health benefits, the effect of SL on exercise performance and muscle mass in mice remains unknown. Here, we aimed to investigate, for the first time, the effects of 6'-SL on muscle functions. Seven-week-old male C57BL/6J mice were administered 100 mg/kg 6'-SL for 12 weeks, after which exhaustive treadmill performance was conducted. Moreover, muscle strength was examined by grip strength, and muscle phenotype characteristics such as muscle mass, muscle fiber size, and muscle protein expression were also examined. The administration of 6'-SL significantly improved exhaustive treadmill performance metrics, including distance and exhaustion time. Grip strength was also increased by 6'-SL administration. Additionally, 6'-SL increased muscle mass in both the gastrocnemius (GAS) and soleus. 6'-SL administration led to an increase in the minimum Feret's diameter and the protein expression of total myosin heavy chain in the GAS muscle. In conclusion, 6'-SL administration in vivo led to increased running distance and time by increasing muscle mass and strength. These findings collectively indicate that 6'-SL is a potential agent for improving muscle health and exercise performance.

General toxicity and screening of reproductive and developmental toxicity following bioaccumulation of oral-dosed perfluorooctanoic acid: Loss of the Golgi apparatus.

Despite its widespread use as a stabilizer across various industries over the past several decades, the health effects of chronic exposure to PFOA are still unclear. We administered PFOA by oral gavage (0, 12.5, 50, and 200 µg/day/mouse, eight groups) to male and female mice for six months. Body weight gain decreased with dose accompanied by increased liver weight, and PFOA altered liver damage-related-blood biochemical indicators and induced pathological lesions, including hepatocellular hypertrophy, cholangiofibrosis, and centrilobular hepatocellular vacuolation. Loss of the Golgi apparatus, formation of lamellar body-like structures, and lipid accumulation were observed in the liver of PFOA-treated mice. We also cohabited five pairs of male and female mice for the last ten days of administration, dosed PFOA to dam up to 28 days after birth, and investigated effects on reproduction and development. The survival rate of pups and the sex ratio of surviving mice decreased significantly at the highest dose. PFOA tissue concentration increased with the dose in the parent mice's liver and the pups' blood and brain. Taken together, we suggest that PFOA primarily affects the liver and reproduction system and that disturbance in lipid metabolism and Golgi's structural stability may be involved in PFOA-induced toxicity.

High-molecular-weight Fucoidan exerts an immune-enhancing effect in RAW 264.7 cells and cyclophosphamide-induced immunosuppression rat by altering the gut microbiome.

High-molecular-weight fucoidan (Fucoidan P), sourced from Undaria pinnatifida exhibits several health benefits, including immunomodulation. However, the mechanisms underlying the immune-enhancing effects of Fucoidan P remain unclear. Here, we investigated the immune-enhancing effects and the potential mechanisms of Fucoidan P using RAW 264.7 macrophages and cyclophosphamide (CP)-induced immunosuppression rat model. In macrophages, Fucoidan P showed dose-dependent stimulation by increasing cell proliferation, nitric oxide production, and gene expression of inducible nitric oxide synthase, cyclooxygenase-2, and proinflammatory cytokines. These effects are mediated through the activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Moreover, orally administered Fucoidan P was evaluated in immunosuppressed rats treated with CP. Fucoidan P administration increased hematological values and natural killer cell activity, and positively affected nitrite and prostaglandin E2 levels. The Fucoidan P treatment groups exhibited improved serum cytokine levels as well as splenic and intestinal cytokine mRNA expression compared to the model group. Fucoidan P also mitigated splenic damage and increased the phosphorylation of NF-κB and NF-κB inhibitor alpha (IκBα). Furthermore, Fucoidan P treatment altered the gut microbiota composition, enhancing the alpha diversity, evenness, and abundance of Bacteroidetes, which are associated with immune function. Taken together, our findings suggest that Fucoidan P exerts beneficial effects on immune function by activating NF-κB and modulating gut microbiota. These findings suggested its potential as a therapeutic agent for immune enhancement.

Long-Term Dietary Consumption of Grapes Affects Kidney Health in C57BL/6J Mice.

Starting at 4 weeks of age, male and female C57BL/6J mice were provided with a semi-synthetic diet for a period of one year and then continued on the semi-synthetic diet with or without grape supplementation for the duration of their lives. During the course of the study, no variation of body weights was noted between the groups. At 2.5 years of age, the body-weight-to-tissue-weight ratios did not vary for the liver, colon, muscle, prostate, or ovary. However, relative to the standard diet, the body/kidney weight ratio was significantly lower in the male and female groups with grape-supplemented diets. With the mice provided with the standard diet, the BUN/creatinine ratios were 125 and 152 for males and females, respectively, and reduced to 63.7 and 40.4, respectively, when provided with the grape diet. A histological evaluation suggested that this may be due to enhanced/improved perfusion in the kidney as a preventive/protective effect. In response to the dietary grapes, an RNA seq analysis revealed up-regulation of 21 and 109 genes with male and female mice, respectively, with a corresponding down-regulation of 108 and 65 genes. The downward movement of the FPKM values in the males (alox5, btk, fga, fpr1, hmox1, lox, ltf, lyve1, marco, mmp8, prg4, s100a8/9, serpina3n, and vsig4) and upward movement of the FPKM values in the females (camp, cd300lf, cd72, fcgr4, fgr, fpr2, htra4, il10, lilrb4b, lipg, pilra, and tlr8) suggest beneficial kidney effects. The expression of some genes related to the immunological activity was also modulated by the grape diet, mainly downward in the males and upward in the females. The reactome pathway analysis, KEGG analysis, and GSEA normalized enrichment scores illustrate that several pathways related to immune function, collagenase degradation, extracellular matrix regulation, metabolism of vitamins and cofactors, pancreatic secretion, aging, and mitochondrial function were enriched in both the males and females provided with the grape diet. Overall, these results indicate that the long-term dietary consumption of grapes contributes to renal health and resilience against fibrosis and related pathologies.

The formation of lamellar body-like structures may be a trigger of cetylpyridinium chloride-induced cell death and inflammatory response.

Cetylpyridinium chloride (CPC) is a quaternary ammonium compound used widely in health and personal care products. Meanwhile, due to its increasing use, its potential adverse health effects are emerging as a topic of public concern. In this study, we first administered CPC by pharyngeal aspiration to determine the survival level (the maximum concentration at which no death is observed) and then administered CPC to mice repeatedly for 28 days using the survival level as the highest concentration. CPC increased the total number of pulmonary cells secreting pro- and anti-inflammatory cytokines and chemokines. Infiltration of inflammatory cells, production of foamy alveolar macrophages, and chronic inflammatory lesions were found in the lung tissue of male and female mice exposed to the highest dose of CPC. We also investigated the toxicity mechanism using BEAS-2B cells isolated from normal human bronchial epithelium. At 6 h after exposure to CPC, the cells underwent non-apoptotic cell death, especially at concentrations greater than 2 µg/mL. The expression of the transferrin receptor was remarkably enhanced, and the expression of proteins that contribute to intracellular iron storage was inhibited. The expression of both mitochondrial SOD and catalase increased with CPC concentration, and PARP protein was cleaved, suggesting possible DNA damage. In addition, the internal structure of mitochondria was disrupted, and fusion between damaged organelles was observed in the cytoplasm. Most importantly, lamellar body-like structures and autophagosome-like vacuoles were found in CPC-treated cells, with enhanced expression of ABCA3 protein, a marker for lamellar body, and a docking score between ABCA3 protein and CPC was considered to be approximately -6.8969 kcal/mol. From these results, we propose that mitochondrial damage and iron depletion may contribute to CPC-induced non-apoptotic cell death and that pulmonary accumulation of cell debris may be closely associated with the inflammatory response. Furthermore, we hypothesize that the formation of lamellar body-like structures may be a trigger for CPC-induced cell death.

The obesogen bisphenol A promotes adipogenesis in canine adipose-derived stem cells: Potential implication in dog obesity.

The growing number of companion dogs has contributed to a rapidly growing market for pet products, including dog toys. However, little is known about the hazardous substances released from dog toys. This study aims to examine the potential presence of obesogens, a subset of endocrine-disrupting chemicals (EDCs) that are widely utilized as raw materials in the manufacture of dog toy components, and their effects on dog health. To achieve this, we adapted and employed a migration method typically used for children's products to simulate obesogen exposure in dogs through sucking or chewing toys. We demonstrated that out of various obesogens, bisphenol A (BPA) was released from dog toys into synthetic saliva, whereas phthalates and azo dyes were not detected in any of the leachates. Additionally, we found that BPA induced adipogenic differentiation in canine adipose-derived stem cells (cADSCs). Our RNA sequencing experiments revealed that BPA alters the adipogenesis-related gene signature in cADSCs by elevating the expression levels of ADIPOQ, PLIN1, PCK1, CIDEC, and FABP4. The associated transcriptional changes are involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which may contribute to the promotion of adipogenesis by BPA. Our findings suggest that companion dogs are at risk of BPA exposure, which may contribute to obesity in dogs. Therefore, the implementation of precautionary measures is crucial.

Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage.

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable. Mitochondrial volume was increased with concentration and time, whereas the mitochondrial membrane potential and produced ATP amounts were significantly reduced. Autophagosome-like vacuoles and contraction of the mitochondrial inner membrane were observed in PFOA-treated cells. The expression of acetyl CoA carboxylase (ACC) and p-ACC proteins rapidly decreased, and that of mitochondrial dynamics-related proteins increased. The expression of solute carrier family 7 genes, ChaC glutathione-specific gamma-glutamylcyclotransferase 1, and 5S ribosomal RNA gene was up-regulated the most in cells exposed to PFOA for 24 h, and the KEGG pathway analysis revealed that PFOA the most affected metabolic pathways and olfactory transduction. More importantly, PPAR alpha, fatty acid binding protein 1, and CYP450 family 1 subfamily A member 1 were identified as the target proteins for binding between PFOA and cells. Taken together, we suggest that disruption of mitochondrial integrity and function may contribute closely to PFOA-induced cell proliferation inhibition.

Combined effects of smoking and alcohol consumption on the risk of liver cancer according to metabolic syndrome: A nested case-control study in South Korea.

Tobacco and alcohol may interact to increase the risk of liver cancer, which might be modified by other risk factors. Their combined effects in the context of metabolic syndrome (MetS) remain unclear. Given the increasing prevalence of MetS, this nested case-control study was conducted to evaluate the combined effects of smoking and alcohol consumption on liver cancer risk with stratification by MetS. We included 15,352 liver cancer patients and 92,112 matched controls who attended the nationwide general health examination during 2009-2019, using a customized database (N = 5,545,835) from the Korean National Health Insurance Service. Liver cancer risk according to smoking and alcohol consumption was estimated using conditional multivariable logistic regression. Additive and multiplicative interactions between these two factors were assessed. Results showed that in men, dual current users were at a significantly higher risk of liver cancer compared with dual nonusers, adjusted odds ratio (aOR) = 1.61, 95% confidence interval: (1.50, 1.72). Interactions were detected between light-to-moderate alcohol consumption (0.1-28 g/day) and heavy smoking (>20 pack-years) on additive scale, relative excess risk due to interaction = 0.34 (0.16, 0.51), attributable proportion = 0.22 (0.11, 0.33), synergy index = 2.75 (1.85, 3.66), and multiplicative scale, aOR for the product term = 1.28 (1.11, 1.49). An additive interaction was also revealed between light-to-moderate drinking and light-to-moderate smoking in the MetS subgroup. In women, light-to-moderate drinking/nonsmoking was negatively associated with the risk in the non-MetS subgroup. In conclusion, a holistic health promotion program should target male dual users of tobacco cigarettes and alcohol, including light-to-moderate users, especially those with MetS.

Cancer Risk Following Smoking Cessation in Korea.

Importance: Tobacco smoking is associated with increased risk of various cancers, and smoking cessation has been associated with reduced cancer risks, but it is still unclear how many years of smoking cessation are required to significantly reduce the cancer risk. Therefore, investigating the association of smoking cessation with cancer is essential. Objective: To investigate the time course of cancer risk according to the time elapsed since smoking cessation and the benefits of smoking cessation according to the age at quitting. Design, Setting, and Participants: This population-based, retrospective cohort study included Korean participants aged 30 years and older who underwent 2 or more consecutive health examinations under the National Health Insurance Service since 2002 and were followed-up until 2019. Data analysis was performed from April to September 2023. Exposures: Exposures included (1) time-updated smoking status based on biennial changes in smoking status, defined as complete quitters, transient quitters, relapsed quitters, continuous smokers, and never smokers; (2) duration of smoking cessation, defined as years since quitting; and (3) categorical variable for age at quitting. Main Outcomes and Measures: The primary cancer was ascertained using the cancer registry data: all-site cancer (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes C00-43, C45-96, or D45-D47), lung cancer (ICD-10 code C34), liver cancer (ICD-10 code C22), stomach cancer (ICD-10 code C16), and colorectal cancer (ICD-10 codes C18-20). Hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards regression model with follow-up years as the timescale. Results: Of the 2 974 820 participants, 1 727 340 (58.1%) were men (mean [SD] age, 43.1 [10.0] years), and 1 247 480 (41.9%) were women (mean [SD] age, 48.5 [9.9] years). Over a mean (SD) follow-up of 13.4 (0.1) years, 196 829 cancer cases were confirmed. Compared with continuous smokers, complete quitters had a lower risk of cancer, with HRs of 0.83 (95% CI, 0.80-0.86) for all cancer sites, 0.58 (95% CI, 0.53-0.62) for lung, 0.73 (95% CI, 0.64-0.82) for liver, 0.86 (95% CI, 0.79-0.93) for stomach, and 0.80 (95% CI, 0.72-0.89) for colorectum. The cancer risk exhibited a slightly higher value for 10 years after quitting compared with continued smoking and then it decreased over time, reaching 50% of the risk associated with continued smoking after 15 or more years. Lung cancer risk decreased 3 years earlier than that of other cancer types, with a larger relative reduction. Regardless of quitting age, a significant reduction in the cancer risk was observed. Quitting before the age of 50 years was associated with a greater reduction in lung cancer risk (HR, 0.43; 95% CI, 0.35-0.53) compared with quitting at age 50 years or later (HR, 0.61; 95% CI, 0.56-0.66). Conclusions and Relevance: In this population-based retrospective cohort study, sustained smoking cessation was associated with significantly reduced risk of cancer after 10 years since quitting. Quitting at any age helped reduce the cancer risk, and especially for lung cancer, early cessation before middle age exhibited a substantial risk reduction.

Cancer risk according to fasting blood glucose trajectories: a population-based cohort study.

INTRODUCTION: Diabetes mellitus is known to increase the risk of cancer. Fasting blood glucose (FBG) levels can be changed over time. However, the association between FBG trajectory and cancer risk has been insufficiently studied. This research aims to examine the relationship between FBG trajectories and cancer risk in the Korean population. RESEARCH DESIGN AND METHODS: We analyzed data from the National Health Insurance Service-National Health Screening Cohort collected between 2002 and 2015. Group-based trajectory modeling was performed on 256,271 Koreans aged 40-79 years who had participated in health examinations at least three times from 2002 to 2007. After excluding patients with cancer history before 2008, we constructed a cancer-free cohort. The Cox proportional hazards model was applied to examine the association between FBG trajectories and cancer incidence by cancer type, after adjustments for covariates. Cancer case was defined as a person who was an outpatient thrice or was hospitalized once or more with a cancer diagnosis code within the first year of the claim. RESULTS: During the follow-up time (2008-2015), 18,991 cancer cases were identified. Four glucose trajectories were found: low-stable (mean of FBG at each wave <100 mg/dL), elevated-stable (113-124 mg/dL), elevated-high (104-166 mg/dL), and high-stable (>177 mg/dL). The high-stable group had a higher risk of multiple myeloma, liver cancer and gastrointestinal cancer than the low-stable group, with HR 4.09 (95% CI 1.40 to 11.95), HR 1.68 (95% CI 1.25 to 2.26) and HR 1.27 (95% CI 1.11 to 1.45), respectively. In elevated-stable trajectory, the risk increased for all cancer (HR 1.08, 95% CI 1.02 to 1.16) and stomach cancer (HR 1.24, 95% CI 1.07 to 1.43). Significant associations were also found in the elevated-high group with oral (HR 2.13, 95% CI 1.01 to 4.47), liver (HR 1.50, 95% CI 1.08 to 2.08) and pancreatic cancer (HR 1.99, 95% CI 1.20 to 3.30). CONCLUSIONS: Our study highlights that the uncontrolled high glucose level for many years may increase the risk of cancer.

Comparative study on estrogen receptor alpha dimerization and transcriptional activity of parabens.

Parabens are used as preservatives in various household products, including oral products, cosmetics, and hair/body washes. In recent years, the widespread use of parabens has raised concerns due to the potential health risks associated with their estrogenic effects. In the present study, we evaluated and compared the estrogenic activity of parabens using two cell-based in vitro tests: (1) bioluminescence resonance energy transfer (BRET)-based estrogen receptor alpha (ERα) dimerization using HEK293 cells that were stably transfected with ERα-fused NanoLuc luciferase (Nluc) and HaloTag (HT) expression vector, and (2) stably transfected transcriptional activation (STTA) assays using ERα-HeLa9903 cells. The following parabens were tested using the BRET-based ERα dimerization assay and showed estrogenic activity (PC20 values): methyl paraben (MP, 5.98 × 10-5 M), ethyl paraben (EP, 3.29 × 10-5 M), propylparaben (PP, 3.09 × 10-5 M), butyl paraben (BP, 2.58 × 10-5 M), isopropyl paraben (IsoPP, 1.37 × 10-5 M), and isobutyl paraben (IsoBP, 1.43 × 10-5 M). Except MP, all other parabens tested using the STTA assay also showed estrogenic activity: EP, 7.57 × 10-6 M; PP, 1.18 × 10-6 M; BP, 3.02 × 10-7 M; IsoPP, 3.58 × 10-7 M; and IsoBP, 1.80 × 10-7 M. Overall, EP, PP, BP, IsoPP, and IsoBP tested positive for estrogenic activity using both assays. These findings demonstrate that most parabens, albeit not all, induce ERα dimerization and possess estrogenic activity.

Association between Proinflammatory Cytokines and Lung Cancer Risk: A Case-Cohort Study from a Community-Based Prospective Cohort.

Recent studies have shed light on alterations to the proinflammatory tumor microenvironment as a significant carcinogenic mechanism. Despite previous studies on associations between proinflammatory cytokines and lung cancer risk, few studies have been conducted in Asian populations. This study aimed to investigate associations between proinflammatory cytokines and lung cancer risk, considering histological types, in the Korean general population. We carried out a case-cohort study on the Korean National Cancer Center Community (KNCCC) cohort (lung cancer cases: 136, subcohort: 822). Pre-diagnostic serum levels of proinflammatory cytokines (i.e., IL-6, TNF-α, IL-1ß, IFN-γ, and IL-10) were measured using Quantikine® ELISA. A Cox proportional-hazards regression analysis was conducted. In this study, serum levels of IL-6, IL-1ß, and IFN-γ were associated with lung cancer risk. IL-6 was associated with lung cancer, regardless of the histological type. IL-1ß had an association only with adenocarcinoma, while IFN-γ had an association only with squamous-cell carcinoma. This study shows associations between serum levels of IL-6, IL-1ß, and IFN-γ and lung cancer risk, underscoring the potential of these cytokines to act as risk biomarkers. The utilization of these biomarkers for risk prediction may hold the promise of facilitating the identification of the high-risk population.

Association of Urinary Benzene Metabolite and the Ratio of Triglycerides to High-Density Lipoprotein Cholesterol: A Cross-Sectional Study Using the Korean National Environmental Health Survey (2018-2020).

The aim of this study was to investigate the association between benzene and toluene, and the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C). This cross-sectional study analyzed 1928 adults using nationally representative data from the Korean National Environmental Health Survey (KoNEHS) Cycle 4 (2018-2020). Urinary trans, trans-muconic acid (t,t-MA) and benzylmercapturic acid (BMA) were measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS), and high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) were analyzed by colorimetry. Survey logistic regression analysis was applied to examine the association between urinary t,t-MA and BMA and the TG/HDL-C ratio. Urinary t,t-MA is significantly associated with an elevated TG/HDL-C ratio in both men and women (for men, OR [95% (CI)]: 2nd quartile: 2.10 [1.04, 4.22]; 3rd quartile: 2.13 [0.98, 4.62]; 4th quartile: 2.39 [1.05, 5.45]; for women, OR [95% (CI)]: 2nd quartile: 1.21 [0.71, 2.06]; 3rd quartile: 1.65 [0.94, 2.90]; 4th quartile: 1.78 [1.01, 3.11]), with significant dose-response relationships (P for trend: for men, 0.029; women, 0.024). This study shows that environmental exposure to benzene is associated with the TG/HDL-C ratio in the Korean general population. This suggests that more stringent environmental health policies are needed to reduce benzene exposure.

Cyclosporin A inhibits prostate cancer growth through suppression of E2F8 transcription factor in a MELK­dependent manner.

The treatment of advanced prostate cancer remains a formidable challenge due to the limited availability of effective treatment options. Therefore, it is imperative to identify promising druggable targets that provide substantial clinical benefits and to develop effective treatment strategies to overcome therapeutic resistance. Cyclosporin A (CsA) showed an anticancer effect on prostate cancer in cultured cell and xenograft models. E2F8 was identified as a master transcription factor that regulated a clinically significant CsA specific gene signature. The expression of E2F8 increased during prostate cancer progression and high levels of E2F8 expression are associated with a poor prognosis in patients with prostate cancer. MELK was identified as a crucial upstream regulator of E2F8 expression through the transcriptional regulatory network and Bayesian network analyses. Knockdown of E2F8 or MELK inhibited cell growth and colony formation in prostate cancer cells. High expression levels of E2F8 and androgen receptor (AR) are associated with a worse prognosis in patients with prostate cancer compared with low levels of both genes. The inhibition of E2F8 improved the response to AR blockade therapy. These results suggested that CsA has potential as an effective anticancer treatment for prostate cancer, while also revealing the oncogenic role of E2F8 and its association with clinical outcomes in prostate cancer. These results provided valuable insight into the development of therapeutic and diagnostic approaches for prostate cancer.

Multi-Organ Nutrigenomic Effects of Dietary Grapes in a Mouse Model.

As a whole food, the potential health benefits of table grapes have been widely studied. Some individual constituents have garnered great attention, particularly resveratrol, but normal quantities in the diet are meniscal. On the other hand, the grape contains hundreds of compounds, many of which have antioxidant potential. Nonetheless, the achievement of serum or tissue concentrations of grape antioxidants sufficient to mediate a direct quenching effect is not likely, which supports the idea of biological responses being mediated by an indirect catalytic-type response. We demonstrate herein with Hsd:ICR (CD-1® Outbred, 18-24 g, 3-4 weeks old, female) mice that supplementation of a semi-synthetic diet with a grape surrogate, equivalent to the human consumption of 2.5 servings per day for 12 months, modulates gene expression in the liver, kidney, colon, and ovary. As might be expected when sampling changes in a pool of over 35,000 genes, there are numerous functional implications. Analysis of some specific differentially expressed genes suggests the potential of grape consumption to bolster metabolic detoxification and regulation of reactive oxygen species in the liver, cellular metabolism, and anti-inflammatory activity in the ovary and kidney. In the colon, the data suggest anti-inflammatory activity, suppression of mitochondrial dysfunction, and maintaining homeostasis. Pathway analysis reveals a combination of up- and down-regulation in the target tissues, primarily up-regulated in the kidney and down-regulated in the ovary. More broadly, based on these data, it seems logical to conclude that grape consumption leads to modulation of gene expression throughout the body, the consequence of which may help to explain the broad array of activities demonstrated in diverse tissues such as the brain, heart, eye, bladder, and colon. In addition, this work further supports the profound impact of nutrigenomics on mammalian phenotypic expression.

Pharmacokinetics and clinical efficacy of 6'-sialyllactose in patients with GNE myopathy: Randomized pilot trial.

GNE myopathy, caused by biallelic mutations in the GNE gene, is characterized by initial ankle dorsiflexor weakness and rimmed vacuoles in the muscle histopathology, resulting in reduced sialic acid production. Sialyllactose is a source of sialic acid. We performed a pilot clinical trial to analyze the pharmacokinetic properties of 6'-sialyllactose (6SL) and evaluated the safety, and efficacy of oral 6SL in patients with GNE myopathy. Ten participants were in the pharmacokinetic study, and 20 in the subsequent clinical trial. For the pharmacokinetic study, participants were administered either 3 g (low-dose) or 6 g (high-dose) of 6SL in a single dose. Plasma concentrations of 6SL, sialic acid, and sialic acid levels on the surface of red blood cells were periodically assessed in blood samples. Patients were randomly allocated to test (low- and high-dose groups) or placebo groups for the trial. Motor function, ambulation, plasma 6SL and sialic acid concentrations, GNE myopathy-functional activity scale scores, and MRI findings were assessed. 6SL was well tolerated, except for self-limited gastrointestinal discomfort. Free sialic acid in both low- and high-dose groups significantly increased at 6 and 12 weeks, but not in the placebo group. In the high-dose group, proximal limb powers improved with daily 6SL. Considering the fat fraction on muscle MRI, results in the high-dose group were superior to those in the low-dose group. 6SL may be a good candidate for GNE myopathy therapeutics as it induces an increase or reduces the decrease in limb muscle power, attenuates muscle degeneration, and improves the biochemical properties of sialic acid.

Subway station dust-induced pulmonary inflammation may be due to the dysfunction of alveolar macrophages: Possible contribution of bound elements.

With its increasing value as a means of public transportation, the health effects of the air in subway stations have attracted public concern. In the current study, we investigated the pulmonary toxicity of dust collected from an air purifier installed on the platform of the busiest subway station in Seoul. We found that the dust contained various elements which are attributable to the facilities and equipment used to operate the subway system. Particularly, iron (Fe), chromium (Cr), zirconium (Zr), barium (Ba), and molybdenum (Mo) levels were more notable in comparison with those in dust collected from the ventilation chamber of a subway station. To explore the health effects of inhaled dust, we first instilled via the trachea in ICR mice for 13 weeks. The total number of pulmonary macrophages increased significantly with the dose, accompanying hematological changes. Dust-laden alveolar macrophages and inflammatory cells accumulated in the perivascular regions in the lungs of the treated mice, and pulmonary levels of CXCL-1, TNF-α, and TGF-ß increased clearly compared with the control. The CCR5 and CD54 level expressed on BAL cell membranes was also enhanced following exposure to dust, whereas the CXCR2 level tended to decrease in the same samples. In addition, we treated the dust to alveolar macrophages (known as dust cells), lysosomal and mitochondrial function decreased, accompanied by cell death, and NO production was rapidly elevated with concentration. Moreover, the expression of autophagy- (p62) and anti-oxidant (SOD-2)-related proteins increased, and the expression of inflammation-related genes was dramatically up-regulated in the dust-treated cells. Therefore, we suggest that dysfunction of alveolar macrophages may importantly contribute to dust-induced inflammatory responses and that the exposure concentrations of Cr, Fe, Mo, Zr, and Ba should be considered carefully when assessing the health risks associated with subway dust. We also hypothesize that the bound elements may contribute to dust-induced macrophage dysfunction by inhibiting viability.