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Objectives: This study aimed to compare the distinct socio-ecological characteristics, nutritional status, and nutrient intake quality of the older adults based on breakfast skipping (EBF, eating breakfast vs. SBF, skipping breakfast). This study also investigated the association between breakfast skipping, socioecological features, and quality of nutrient consumption., Method: From the 8th Korea National Health and Nutrition Examination Survey (KNHANES, 2020), data of 92,093 subjects aged ≥ 65 years old (male: 43,910 and female: 48,183) having data with eating habits, such as nutrient intake and skipping breakfast were analyzed., Results: The average age of SBF was markedly lower than EBF. EBF had a lower employed status, education level, heavy alcohol intake frequency, smoking, and eating out regularly than SBF. Compared to EBF, SBF showed a significantly higher BMI and waist circumference. Moreover, EBF showed a markedly higher average intake in energy, protein, fiber, calcium, and iron compared with SBF, while SBF had a noticeably higher mean intake in fat, saturated fat, and sugar. In addition, SBF had a significantly reduced mean adequacy ratio (MAR, adjusted OR: 0.260 [95% CI: 0.245-0.276]) and the value of index nutritional quality (INQ, adjusted OR: 0.847 [95% CI: 0.799-0.898]) compared with EBF., Discussion: There were distinct socioecological features and nutritional conditions of older adults relying on breakfast skipping; and a strong association between breakfast skipping, socioecological parameters, and nutrient intake quality. These observations provide the significance of breakfast skipping in the nutritional status of older adults and offer fundamental information for nutritional education and implications for older adults., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This open-labeled and comparative study aimed to test the efficacy and safety of a fermented rice extract-based substance containing yeast-fermented powder having aldehyde dehydrogenase (KisLip ® , Pico Entech, Republic of Korea) in healthy male individuals. Healthy male subjects (n = 20) consumed 90 g of alcohol at their first visit. At the second visit, participants consumed 90 g of alcohol or alcohol with a low dose of KISLip ® (2000 mg, KL-L) and then 90 g of alcohol or alcohol with a high dose of KISLip ® (3000 mg, KL-H) at the third visit. The efficacy of KISLip ® depends on the mutational status of important genes related to alcohol metabolism, including alcohol dehydrogenase ( ADH1B ), cytochrome P4502E1 ( CYP2E1 ( 5B ) and CYP2E1 ( 6 )), and aldehyde dehydrogenase ( ALDH2 ). KISLip ® significantly reduced the highest level (Cmax) of alcohol and overall levels of acetaldehyde compared to the alcohol-only group in a dose-dependent manner. These significant effects of KISLip ® on alcohol metabolism were observed independent of mutations in the four genes. In addition, hangover symptoms were significantly decreased in the KISLip ® treated groups. During the study, the participants did not show any adverse events after KISLip ® intake. This clinical study suggested that supplementation of KISLip ® had beneficial effects on alcohol metabolism and might ameliorate the severity of hangovers without any adverse events.

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.

Hyperlipidemia, characterized by elevated cholesterol, lipids, and triglycerides in the bloodstream, is linked to hepatic oxidative damage. Doenjang , a traditional Korean condiment made from fermented soybeans, is known for its health benefits, yet its anti-hyperlipidemic effects remain understudied. Our study aimed to assess the hypolipidemic and hepatic protective effects of Doenjang on male ICR mice fed a high-fat cholesterol diet for 8 weeks. Mice were divided into three groups: the normal diet (ND), the high-fat cholesterol diet (HD), and the Doenjang -supplemented HD diet (DS) group. Doenjang supplementation significantly regulated total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol levels compared to the HD group. It also downregulated lipogenic genes, including PPARγ, FAS, and ACC, and positively influenced the cholesterol metabolism-related genes HMGCR and LXR. Moreover, Doenjang intake increased serum glutathione levels, activated oxidative stress defense genes (NRF2, SOD, GPx1, and CAT), positively modulated inflammation genes (NF-kB and IL6) in hepatic tissue, and reduced malondialdehyde levels. Our findings highlight the effectiveness of traditional Doenjang in preventing diet-induced hyperlipidemia and protecting against hepatic oxidative damage.

The current study aimed to investigate the distinct outcomes of table salt and salt in Gochujang on blood pressure (BP). Animals were divided into 3 groups, including normal diet (NS, 0.5 % NaCl), high-salt diet (HS, normal diet with 8 % NaCl), or high-salt Gochujang diet (HSG, normal diet with Gochujang containing 8 % NaCl). Compared to the NS groups, the HS group showed significantly increased systolic blood pressure (SBP), while the HSG group did not elevate SBP. The HS group had lower serum angiotensin II and aldosterone levels than the NS group, while the HSG group showed higher levels of those parameters than the HS group. The renal mRNA expression related to the renin-angiotensin-aldosterone system (RAAS) was significantly higher in the HS group than the NS group, while the HSG group had markedly lower expression of those markers. The urinary and fecal Na + /K + proportion was higher in both HS and HSG groups relative to the NS group, but the HSG group showed a decreased Na + /K + ratio in urine and feces compared to the HS group. Moreover, the HS group had a significantly upregulated mRNA level of Na + /HCO 3 - co-transporter (Slc4a4) in the kidney than the NS group, whereas the HSG group showed downregulated mRNA expression of Slc4a4 compared to the HS group. This study demonstrates that Gochujang has anti-hypertensive effects regardless of its high salt content and provide the evidence regarding the distinct impacts between salt in Gochujang and the table salt., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Gastric cancer (GC) is a prevalent malignancy of the digestive system. Distant metastasis and chemotherapy resistance are the crucial obstacles to prognosis in GC. Recent research has discovered that the glucose-6-phosphatase catalytic subunit (G6PC) plays an important role in tumor malignant development. However, little evidence has highlighted its role in GC. Herein, through a comprehensive analysis including profiling of tissue samples and functional validation in vivo and in vitro, we identify G6PC as a crucial factor in GC tumorigenesis. Importantly, we found that the FOXO1/G6PC axis could accelerate GC cell proliferation, metastasis, and 5-Fluorouracil (5-FU) resistance by targeting the PI3K/AKT/mTOR signaling pathway, implicating that as a prospective therapeutic approach in GC., (© 2024 Wiley Periodicals LLC.)

The increased life expectancy and the occurrence of premature menopause prolong the mean postmenopausal phase in women's lifespans. Although the roles of poor socioeconomic status (SES), anthropometric characteristics, and nutritional status in premature menopause and the health of postmenopausal women are well understood, the differences in nutritional status and metabolic syndrome (MetS) prevalence in postmenopausal women depending on their menopause age are less explored. Furthermore, the association between SES and MetS risk in postmenopausal women is not studied. Thus, this study aimed to compare distinct nutritional status and MetS risk between women with premature menopause and natural menopause. Additionally, the association among SES, health-related lifestyle behaviors (HLBs), and MetS risk in postmenopausal women was studied. This study included 31,799 postmenopausal women from the 8th National Health and Nutrition Examination Survey (KNHANES). The relationship between disease prevalence and nutrient intake of the subjects was analyzed using analysis of variance (GLM), and Scheffé test was performed. Multiple logistic regression analysis was used to evaluate the association among SES, HLBs, and MetS as well as premature menopause. Women with premature menopause showed poor SES, anthropometric characteristics, and HLBs compared with women with natural menopause. Additionally, premature menopausal women had markedly lower intakes of protein, polyunsaturated fatty acid, n -3 fatty acid, and β-carotene, but higher intakes of energy, carbohydrate, saturated fatty acid, and sugar than women with natural menopause ( p < 0.0001). Premature menopausal women showed significantly higher MetS prevalence by having hypertriglyceridemia ( p < 0.0001), hypertension ( p = 0.0145), and reduced HDL cholesterol levels ( p < 0.0001) relative to natural menopausal women. Furthermore, our findings indicate a substantial link among SES, HLBs, and the risk of premature menopause. In postmenopausal women, deteriorating SES and HLBs appear to influence the prevalence of MetS. Notably, our study reveals that higher intakes of protein, calcium, phosphate, and iron are correlated with a lower risk of developing MetS. These observations suggest that proactive nutritional education for premature menopausal women is necessary to improve MetS risk and their nutritional status. Also, SES-dependent interventions regarding nutrition and HLBs in postmenopausal women will be significant to lower MetS risk, MetS-derived chronic disease, and mortality in postmenopausal women.

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. A custom siRNA screen targeting these kinases demonstrated that knockdown of microtubule affinity regulating kinase 3 (MARK3) and serine/threonine kinase 10 (STK10) significantly reduced uveal melanoma cell growth and decreased expression of cell cycle proteins. Additionally, knockdown of MARK3 but not STK10 decreased ERK1/2 phosphorylation. Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. E. A. has an ownership interest in patent number 9880150 and a pending patent, PCT/US22/76492. No potential conflicts of interest were disclosed by the other authors. M. A. D. has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, ABM Therapeutics, and LEAD Pharma. J. S. G. has been a consultant for Domain Pharmaceuticals, Pangea Therapeutics, and io9, and is the founder of Kadima Pharmaceuticals, all unrelated to the current study. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Soy sauce (SS) is a traditional fermented seasoning. Although fermented foods have diverse health beneficial effects, SS intake has been discouraged because of its high salt level. This study was designed to evaluate the antiobesity outcomes of SS and the potential involvement of salt content in SS by adding a high-salt group. Sprague-Dawley rats were randomly assigned into four groups: normal diet (ND, 10% fat of total kcal), high-fat diet (HD, 60% fat of total kcal), HD with salt water (HDSW, NaCl = 8%), and HD with SS (HDSS, NaCl = 8%). SS significantly decreased HD-induced body weight gain and lipogenic gene expression without affecting food consumption. Moreover, SS also reduced hepatic injury and lipid accumulation, and also improved hyperlipidemia. Furthermore, SS decreased the mRNA levels related to obesity-derived inflammatory responses, while HDSW did not change the levels of those markers. These observations indicate that SS ameliorates obesity in HD-fed obese rats by attenuating dyslipidemia. Moreover, SS might also have an anti-inflammatory effect in HD-induced obesity, which requires further investigation. Most importantly, SS offers these beneficial effects regardless of its high salt content, implying that different dietary salt sources lead to the distinct health outcomes. In conclusion, the findings of this study improve the understanding of the functional effect of SS.

The health-beneficial outcomes of doenjang, a Korean fermented food have been questioned due to its high salt content; moreover, the detailed underlying mechanisms of its health beneficial effects are not fully investigated. Thus, this study aimed to investigate doenjang's anti-obesity effects, anti-hypertensive effects, and its underlying mechanisms in high-fat diet -induced obesity. Sprague-Dawley rats fed with normal diet (ND), high-fat diet (HD), HD with 8% additive salt (HDS), or HD with doenjang containing 8% salt (HDJ) for 13 weeks. Compared to HD and HDS groups, the HDJ group had lower body and epididymal fat tissue weight gain and showed hypotrophy and hypoplasia. The RAS-related mRNA levels in the adipose tissue, including Renin and Ace were downregulated in the HDJ group compared to HD and HDS groups. Additionally, HDJ groups had significant improvements in systolic blood pressure, serum RAS-associated parameters (e.g., angiotensin II and aldosterone), renal mRNA levels related to RAS (e.g., angiotensin II receptor type 1 and 2), and aldosterone-associated mRNA expressions (e.g., mineralocorticoid receptor) in the kidney of HD-induced obese rats. Most importantly, HDS and HDJ groups showed distinct outcomes regarding adipogenesis and electrolytes metabolism, even though both diets contain a high level of salt. HDS group showed a higher epididymal fat tissue weight, mass, and adipocyte size than HDJ group. In addition, compared with HDJ group, HDS group significantly decreased the release of Na+ and K+ throughout the urine and feces. The present study addresses that doenjang has anti-obesity effects and anti-hypertensive effects by activating RAS in the adipose tissue and kidney, respectively. Additionally, this study also demonstrates that salt in doenjang and the additive salt differently influences adipogenesis and electrolytes metabolism, supporting doenjang has health advantageous effects regardless of its high salt contents., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Woo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent studies have demonstrated that CPT1A plays a critical role in tumor metabolism and progression. However, the molecular mechanisms by which CPT1A affects tumorigenicity during PAAD progression remain unclear. In the current research, the bioinformatics analysis and immunohistochemical staining results showed that CPT1A was overexpressed in PAAD tissues and that its overexpression was associated with a shorter survival time in patients with PAAD. Overexpression of CPT1A increased cell proliferation and promoted EMT and glycolytic metabolism in PAAD cells. Mechanistically, CPT1A is able to bind to Snail and facilitate PAAD progression by regulating Snail stability. In summary, our findings revealed Snail-dependent glycolysis as a crucial metabolic pathway by which CPT1A accelerates PAAD progression. Targeting the CPT1A/Snail/glycolysis axis in PAAD to suppress cell proliferation and metastatic dissemination is a new potential treatment strategy to improve the anticancer therapeutic effect and prolong patient survival., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)

The prevalence of constipation, one of the common gastrointestinal (GI) diseases, has been gradually increasing. Gochujang , a traditional Korean fermented paste, has various microbiota and exerts diverse health beneficial effects. However, the ameliorative effect of Gochujang on constipation is unexplored. Seven-week-old ICR mice were divided into five groups: the normal group, the loperamide (LOP) group, the LOP + mosapride citrate (3 mg per kg BW, MOSA) treated group, the LOP + BMG Gochujang (2 g per kg BW) group, and the LOP + VMG Gochujang (2 g per kg BW) group. Gochujang alleviated constipation by increasing defecation frequency and water content in feces by reducing AQP3 mRNA expression. Additionally, Gochujang increased GI transit time and excitatory neurotransmitter levels and decreased inhibitory neurotransmitter levels. Moreover, Gochujang reduced mitogen-activated protein kinase (MAPK) activation and increased the c-Kit/SCF signaling pathway, suggesting that Gochujang regulates the enteric nervous system (ENS). Interestingly, BMG and VMG differently influenced the gut microbiota composition. Both Gochujang groups significantly decreased the Bacteroidetes and Firmicutes ratio compared to the LOP group. However, among Firmicutes genera, Acetatifactor was only reduced in BMG, and VMG only decreased Caproiciproducens and Acutalibacter . In summary, Gochujang effectively alleviated LOP-induced constipation outcomes regardless of their different microbial communities by ameliorating GI motility and changing the gut microbiota composition.

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

High-fat and high-salt diets are risk factors for metabolic syndrome development. However, gochujang, which has a high salt content, possesses antiobesity properties in cell and animal models. We aimed to evaluate the effects of Sunchang traditional and modern factory produced gochujang on metabolic syndrome factors in high-fat diet (HFD)-induced obese mice. For 14 weeks, 4-week-old C57BL/6J male mice were separated into five groups and fed a normal diet (ND), a high-fat diet only (HD), a HD with salt (SALT), a HD with traditional Sunchang gochujang (TS), and HD with modern factory made Sunchang gochujang (FS). Compared to HD and SALT groups, the gochujang groups had lower body weight, blood leptin, and insulin levels with reduced Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and improved serum and liver lipid profiles. In addition, gochujang supplemented groups exhibited a significant reduction in mRNA expression of anabolic lipid metabolism related factors; PPARγ , CEBPα , and FABP4 , and a significant increase in mRNA expression of energy expenditure-related factors; PPARα and CPT1 . Protein expressions of SREBP1 were downregulated in the gochujang fed groups. TS and FS intakes improved obesity in HFD-induced obese mice. Compared to the gochujang groups, the SALT group did not exhibit any of those benefits suggesting that the high salt content of gochujang has different effects compared with added salt alone. Our findings provide evidence that gochujang could be a functional food to attenuate metabolic syndrome.

Abnormal fat accumulation with gut microbiota dysbiosis results in hepatic inflammation by upregulating the release of lipopolysaccharide (LPS) and inflammatory cytokine. Gochujang , a traditional fermented condiment, has beneficial effects, such as anti-colonic inflammatory effects. However, Gochujang has been controversial because of its high salt content (the Korean Paradox). Thus, the present study aimed to investigate the preventative effects of Gochujang on hepatic inflammation and related gut microbiota through discussing the Korean Paradox. The mice were divided into groups including a normal diet (ND), high-fat diet (HD), HD with salt (SALT), HD with a high percentage of beneficial microbiota Gochujang (HBM), and HD with diverse beneficial microbiota Gochujang (DBM). Gochujang markedly reduced lipid accumulation, hepatic injury, and inflammation response. Furthermore, Gochujang attenuated protein expression involved in the JNK/IκB/NF-κB pathway. Additionally, Gochujang regulated the gut microbiota-derived LPS production and Firmicutes/Bacteroidetes ratio. Gochujang regulated the levels of gut microbiota such as Bacteroides, Muribaculum , Lactobacillus, and Enterorhabdus, which were correlated with hepatic inflammation. Salt did not have foregoing effects, meaning that the salt content in Gochujang did not affect its anti-inflammatory effect. In conclusion, Gochujang showed anti-hepatic inflammation effects via reduced lipid accumulation, hepatic injury, and inflammatory response together with reorganization of gut microbiota dysbiosis regardless of salt content and the difference of micro bacteria composition.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, and its abnormal metabolism affects the survival and prognosis of patients. Recent studies have found that NAD(P)H quinone oxidoreductase-1 (NQO1) played an important role in tumor metabolism and malignant progression. However, the molecular mechanisms by which NQO1 regulates lipid metabolism during HCC progression remain unclear. In this study, bioinformatics analysis and immunohistochemical results showed that NQO1 was highly expressed in HCC tissues and its high expression was closely related to the poor prognosis of HCC patients. Overexpression of NQO1 promoted the cell proliferation, epithelial-to-mesenchymal transition (EMT) process, and angiogenesis of HCC cells. Luciferase reporter assay further revealed that NQO1/p53 could induce the transcriptional activity of SREBP1, consequently regulating HCC progression through lipid anabolism. In addition, Snail protein was stabilized by NQO1/p53/SREBP1 axis and triggered the EMT process, and participated in the regulatory role of NQO1/p53/SREBP1 axis in HCC. Together, these data indicated that NQO1/SREBP1 axis promoted the progression and metastasis of HCC, and might be a potential therapeutic target for HCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Adequate vitamin D status is essential for bone health. New randomized controlled trials investigating the effect of vitamin D supplementation on bone health have recently been published. This position statement updates and expands on the previous 2015 position statement of the Korean Society for Bone and Mineral Research on the adequate vitamin D status for healthy older adults (age ≥ 70 years) and those at high risk of osteoporosis and fracture (adults on osteoporosis medications) to maintain serum 25-hydroxy-vitamin D (25[OH]D) levels ≥ 20 ng/mL but < 50 ng/mL. A serum 25(OH)D level of 30 ng/mL may be beneficial for those on anti-resorptives. Vitamin D can be obtained from ultraviolet light exposure and diet. To reach the target vitamin D status through intake, adults must consume at least 400 IU/day to reach 20 ng/mL and 800 to 1,000 IU/day to reach 30 ng/mL. Foods familiar to the Korean diet that are high in vitamin D content or consumed frequently enough to positively impact vitamin D status are introduced in addition to the amount required to help reach one's target vitamin D status.

Background/objectives: Oxidative stress is caused by an imbalance between harmful free radicals and antioxidants. Long-term oxidative stress can lead to an "exhausted" status of antioxidant defense system triggering development of metabolic syndrome and chronic inflammation. Green perilla ( Perilla frutescens ) is commonly used in Asian cuisines and traditional medicine in southeast Asia. Green perilla possesses numerous beneficial effects including anti-inflammatory and antioxidant functions. To investigate the potentials of green perilla leaf extract (PE) on oxidative stress, we induced oxidative stress by high-fat diet (HFD) in aging mice., Materials/methods: C57BL/6J male mice were fed HFD continuously for 53 weeks. Then, mice were divided into three groups for 12 weeks: a normal diet fed reference group (NDcon), high-fat diet fed group (HDcon), and high-fat diet PE treated group (HDPE, 400 mg/kg of body weight). Biochemical analyses of serum and liver tissues were performed to assess metabolic and inflammatory damage and oxidative status. Hepatic gene expression of oxidative stress and inflammation related enzymes were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: PE improved hepatopathology. PE also improved the lipid profiles and antioxidant enzymes, including hepatic glutathione peroxidase (GPx) and superoxide dismutase (SOD) and catalase (CAT) in serum and liver. Hepatic gene expressions of antioxidant and anti-inflammatory related enzymes, such as SOD-1, CAT, interleukin 4 (IL-4) and nuclear factor erythroid 2-related factor (Nrf2) were significantly enhanced by PE. PE also reduced the levels of hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) in the serum and liver; moreover, PE suppressed hepatic gene expression involved in pro-inflammatory response; Cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6)., Conclusions: This research opens opportunities for further investigations of PE as a functional food and possible anti-aging agent due to its attenuative effects against oxidative stress, resulting from HFD and aging in the future., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2022 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

T lymphoma invasion and metastasis 1 (Tiam1) as a tumor-associated gene specifically activates Rho-like GTPases Rac1 and implicates in the invasive phenotype of many cancers. Altering the glycolytic pathway is foreseen as a sound approach to trigger cancer regression. However, the mechanism of Tiam1 in breast cancer (BC) glycolysis reprogramming remains to be clarified. Here, we reported the Tiam1 high expression and prognostic significance in BC. In vitro and in vivo experimental assays identified the functional role of Tiam1 in promoting BC cell proliferation, metastasis and glycolysis reprogramming. Mechanistically, we showed for the first time that Tiam1 could interact with the crucial glycolytic enzyme phosphofructokinase, liver type (PFKL) and promote the evolution of BC in a PFKL-dependent manner. Moreover, miR-21-5p was found to exacerbate the BC proliferation and aggression by targeting Tiam1. Altogether, our study highlights the critical role of Tiam1 in BC development and that the miR-21-5p/Tiam1/PFKL signaling pathway may serve as a target for new anti-BC therapeutic strategies., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma. Loss-of-function BAP1 mutations are associated with uveal melanoma metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell-cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in uveal melanoma patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAM), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in uveal melanoma cell lines and single-cell RNA-sequencing data from uveal melanoma patient samples. BAP1 reexpression in uveal melanoma cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1-mutant uveal melanoma cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits., Implications: BAP1 mutations and increased metastasis may be due to upregulation of CAMs., (©2022 American Association for Cancer Research.)

Effective therapeutic options are still lacking for uveal melanoma (UM) patients who develop metastasis. Metastatic traits of UM are linked to BRCA1-associated protein 1 (BAP1) mutations. Cell metabolism is re-programmed in UM with BAP1 mutant UM, but the underlying mechanisms and opportunities for therapeutic intervention remain unclear. BAP1 mutant UM tumors have an elevated glycolytic gene expression signature, with increased expression of pyruvate dehydrogenase (PDH) complex and PDH kinase (PDHK1). Furthermore, BAP1 mutant UM cells showed higher levels of phosphorylated PDHK1 and PDH that was associated with an upregulated glycolytic profile compared to BAP1 wild-type UM cells. Suppressing PDHK1-PDH phosphorylation decreased glycolytic capacity and cell growth, and induced cell cycle arrest of BAP1 mutant UM cells. Our results suggest that PDHK1-PDH phosphorylation is a causative factor of glycolytic phenotypes found in BAP1 mutant UM and propose a therapeutic opportunity for BAP1 mutant UM patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited., Methods: We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations., Results: The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8 + T-lymphocyte and a decreased CD3 + T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8 + T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach., Conclusions: Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors., (© 2022. The Author(s).)

Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1-altered (or mutant) compared to BAP1-unaltered (or wild-type [WT]) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Melanoma is derived from melanocytes located in multiple regions of the body. Cutaneous melanoma (CM) represents the major subgroup, but less-common subtypes including uveal melanoma (UM), mucosal melanoma (MM), and acral melanoma (AM) arise that have distinct genetic profiles. Treatments effective for CM are ineffective in UM, AM, and MM, and patient survival remains poor. As reprogrammed cancer metabolism is associated with tumorigenesis, the underlying mechanisms are well studied and provide therapeutic opportunities in many cancers; however, metabolism is less well studied in rarer melanoma subtypes. We summarize current knowledge of the metabolic alterations in rare melanoma and potential applications of targeting cancer metabolism to improve the therapeutic options available to UM, AM, and MM patients., Competing Interests: Declaration of Interests A.E.A. reports receiving a commercial research grant from Pfizer Inc. (2013–2017) and has ownership interest in patent number 9880150. The other authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

BRCA1-associated protein 1 ( BAP1 ) is emerging as an intensively studied cancer-associated gene. Germline mutations in BAP1 lead to a cancer syndrome, and somatic loss is found in several cancer types. BAP1 encodes a deubiquitinase enzyme, which plays key roles in cell-cycle regulation, cell death, and differentiation. Recent studies have demonstrated that BAP1 is also involved in several aspects of cellular metabolism, including metabolic homeostasis, glucose utilization, control of ferroptosis, and stress response. A better knowledge of the metabolic roles of cancer-associated genes is important to understanding tumor initiation and progression, as well as highlighting potential therapeutic avenues. With this review, we summarize the current knowledge regarding BAP1-mediated regulation of metabolic activities that may support new strategies to treat BAP1-mutated cancers., (©2021 American Association for Cancer Research.)

Human hydroxysteroid dehydrogenase-like 2 (HSDL2) is a potent regulator in cancers and is also involved in lipid metabolism, but the role of HSDL2 in cervical cancer and whether it regulates the progress of cervical cancer through lipid metabolism remains unclear. In this study, we found that the overexpression of HSDL2 was in relation with cervical cancer progression including lymph nodes metastasis and recurrence. HSDL2 could serve as a novel marker of early diagnosis in cervical cancer. HSDL2 also gave impetus to tumorigenesis by initiating and promoting proliferation, invasion and migration of cervical cancer cells (Hela, C33A and SiHa) through EMT. Interestingly, we also searched that HSDL2 participated in oncogenesis by regulating lipid metabolism. In sum, our results gave the novel insight of HSDL2 functions which could be the potential for being the biomarker of prognosis and new target of therapy., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Antioxidant intake has been suggested to be associated with a reduced osteoporosis risk, but the effect of dietary total antioxidant capacity (TAC) on bone health and the risk of osteoporosis remains unclear. We aimed to assess the hypothesis that dietary TAC is positively associated with bone mass and negatively related to the risk of osteoporosis in Korean women. This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey. Dietary TAC was estimated using task automation and an algorithm with 24-h recall data. In total, 8230 pre- and postmenopausal women were divided into four groups according to quartiles of dietary TAC. Dietary TAC was negatively associated with the risk of osteoporosis (odds ratio, 0.73; 95% confidence interval, 0.54-0.99; p -value = 0.045) in postmenopausal women, but not in premenopausal women. Dietary TAC was positively associated with bone mineral content (BMC) and bone mineral density of the femoral neck and lumbar spine in postmenopausal women and BMC of the total femur and lumbar spine in premenopausal women. Our study suggests that dietary TAC is inversely associated with the risk of osteoporosis in postmenopausal women and positively associated with bone mass in both pre- and postmenopausal women.

Background: Pancreatic cancer (PC) is a leading cause of cancer mortality worldwide. Hydroxysteroid dehydrogenase like protein 2 (HSDL2) is overexpressed in a variety of malignant tumors and is might be closely related to the development of cancer. It also regulates different metabolism and signaling pathways., Purpose: The purpose of this research was to find HSDL2 expression levels and investigate its underlying molecular mechanism in PC., Patients and Methods: In the present study, a total of 66 PC samples and 54 normal tissues were used to examine the expression of HSDL2. In order to gain a broader insight into the molecular mechanism of HSDL2 in PC, the HSDL2 siRNA sequences were transfected into PC cell lines (Bxpc-3 and Panc-1), respectively. Cell proliferation was measured by MTT, colony formation assay and EdU assays. Furthermore, the lipid metabolism process was evaluated by triglyceride and phospholipid assay kits, BODIPY 493/503 staining and the expression of several pivotal lipid metabolic enzymes in PC., Results: In this study, HSDL2 was highly expressed in PC and connected with shorter overall survival. When HSDL2 was silenced, the cell proliferation was significantly reduced, and the lipid metabolism was further inhibited., Conclusion: High expression of HSDL2 plays an important role in the progression of PC and might be a potential new biomarker of poor prognosis as well as a therapeutic target in the future., Competing Interests: The authors confirm that they have no conflicts of interest., (© 2021 Han et al.)

Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOS high or OXPHOS low subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOS high BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOS low BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.

Uveal melanoma is a rare cancer in adults, but its treatment is one of the clinical unmet needs in the melanoma field. Metastatic disease develops in approximately 50% of patients and is associated with poor survival due to the lack of effective treatment options. It provides a paradigm for cancers that show evidence of aberrant G protein-coupled receptor signaling, tumor dormancy, and liver-selective metastatic tropism and are associated with the loss of the BAP1 tumor suppressor. At the Melanoma Research Foundation CURE OM Science Meeting at the Society for Melanoma Research Meeting held in Utah on November 20, 2019, clinicians and researchers presented findings from their studies according to three themes within uveal melanoma: (i) ongoing clinical trials, (ii) molecular determinants, and (iii) novel targets that could be translated into clinical trials. This meeting underscored the high interest in the uveal melanoma research field and the unmet need for effective treatment strategies for late-stage disease. Findings from ongoing clinical trials are promising, and multiple studies show how novel combinatorial strategies increase response rates. Novel targets and tumor vulnerabilities identified bioinformatically or through high-throughput screens also reveal new opportunities to target uveal melanoma. The future directions pursued by the uveal melanoma research field will likely have an impact on other cancer types that harbor similar genetic alterations and/or show similar biological properties., (©2020 American Association for Cancer Research.)

Ezrin, one of the ezrin-radixin-moesin (ERM) proteins, is involved in the formation of cell membrane processes and has been implicated in the promotion of cancer proliferation and metastasis. However, the possible role of ezrin in hepatocellular carcinoma (HCC) metastasis and glycolysis reprogramming has remained unclear. In this study, we found that ezrin was upregulated in HCC tissues, and its overexpression was linked with HCC patients' aggressive tumor characteristics and poor prognosis. Functional experiments further revealed that ezrin overexpression promoted HCC cell proliferation, epithelial-to-mesenchymal transition (EMT) progression and angiogenesis. In addition, by measuring glucose consumption, lactate production, ATP levels and the expression of glucose metabolism-related markers in HCC cells, we investigated whether ezrin regulated glucose metabolism. Moreover, 2-deoxy-D-glucose (2-DG) affected ezrin-mediated proliferation, migration and EMT of HCC cells, which suggested that ezrin may, at least in part, promote HCC progression by regulating glycolysis reprogramming. Based on our results, we proposed that ezrin was involved in HCC progression and may be a valid prognostic marker., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro , palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations., (©2020 American Association for Cancer Research.)

Background: Gastric cancer (GC) is a major leading cause of cancer mortality worldwide. Polyadenylate (poly(A))-binding protein (PABP)-interacting protein 1 (Paip1) is a key regulator in the initiation of translation; however, its role in GC remains to be investigated., Purpose: The purpose of this study is to determine Paip1 expression levels and investigate its underlying molecular mechanism in GC., Patients and Methods: In the present study, a total of 90 GC samples and 90 adjacent noncancerous tissues were used to examine the expression of Paip1. In order to gain a deep insight into the molecular mechanism of Paip1 in GC, the Paip1 siRNA sequences were transfected into GC cell lines (MGC-803 and SGC-7901), respectively. Meanwhile, Paip1 plasmid was used to mediate overexpression of Paip1. Cell proliferation were examined via colony formation assay, EdU assay and flow cytometry assay. Cell metastasis were discovered via wound healing assay and Transwell assays. In addition, key EMT makers were detected by Western blotting assay., Results: In this study, Paip1 expression was observed to be upregulated in GC and was associated with shorter overall survival. Knockdown of Paip1 inhibited cell proliferation, migration and caused cell cycle arrest in GC cells, whereas its overexpression reversed these effects. Another mechanistic study showed that Paip1 overexpression promoted EMT progression and regulated its targets expression., Conclusion: High expression of Paip1 plays a significant role in the progression of GC and may be a potential biomarker of poor prognosis as well as a therapeutic target., Competing Interests: The authors report no conflicts of interest in this work.

Purpose: Human hydroxysteroid dehydrogenase-like 2 (HSDL2) is a characterized SDR gene that not only catalyses the oxidation and reduction of multiple substrates but also regulates different metabolic and signalling pathways. Accumulating evidences suggest that HSDL2 play an important role in cancer progression. However, the role of HSDL2 in breast cancer has not yet been determined. Thus, this study aims to explore the relevance of HSDL2 in breast cancer progression., Patients and Methods: The location of HSDL2 protein was detected in MDA-MB-231 breast cancer cells by using immunofluorescence (IF) staining. The expression level of HSDL2 was evaluated by immunohistochemical (IHC) staining in 119 breast cancer tissues and 40 normal breast tissues. Then, the correlations between the overexpression of HSDL2 and clinicopathological features of breast cancer patients were evaluated by using the chi-square test, and the survival rates were calculated by the Kaplan-Meier method. In addition, the role of HSDL2 in breast cancer proliferation was assessed by MTT and colony formation assays, and cell cycle distribution was detected by flow cytometry analysis and Western blot., Results: IF staining and IHC analysis consistently showed that HSDL2 was predominantly expressed in the cytoplasm of breast cancer cells. The positive rate of HSDL2 protein was significantly higher in breast cancer tissues (87.4%, 104/119) than in adjacent normal breast tissues (25%, 10/40) ( p <0.01). A high expression of HSDL2 protein was significantly associated with high histological grades, late clinical stages and low survival rates. Moreover, multivariate analysis indicated that HSDL2 protein was an independent prognostic factor in breast cancer patients. Studies in vitro showed that HSDL2 depletion reduced cell proliferation and induced cell cycle arrest in breast cancer., Conclusion: In conclusion, this study indicated that HSDL2 plays a role in promoting the development of breast cancer. HSDL2 could be a valuable prognostic biomarker and a potential therapeutic target for patients with breast cancer., Competing Interests: The authors report no conflicts of interest in this work.

In the article has been presented an analysis of susceptibility of selected dental materials, made in the CAD/CAM technology. The morphology and structural properties of selected dental materials and their composites were determined by using XRPD (X-ray powder diffraction) techniques, as well as the IR (infrared) spectroscopy. Moreover, an adhesion as well as development of biofilm by oral microorganisms has been studied. It has been shown that a degree of the biofilm development on the tested dental materials depended on microorganism genus and species. Streptococcus mutans has demonstrated the best adhesion to the tested materials in comparison with Candida albicans and Lactobacillus rhamnosus . However, the sintered materials such as IPS e.max® and the polished IPS e.max® have showed the best "anti-adhesive properties" in relation to S. mutans and L. rhamnosus that have not formed the biofilm on the polished IPS e.max® sample. Furthermore, S. mutans have not formed the biofilm on both surfaces. On the contrary to S. mutans and L. rhamnosus , C. albicans has demonstrated the adhesive properties in relation to the above-mentioned surfaces. Moreover, in contrast to S. mutans and C. albicans , L. rhamnosus has not formed the biofilm on the polished IPS Empress material.

Background: Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5'-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers. The objective was to interrogate how Zyflamend activates AMPK by determining the roles of LKB1 and CaMKK2., Methods: AMPK activation was determined in CWR22Rv1 cells treated with a variety of inhibitors of LKB1 and CaMKK2 in the presence and absence of Zyflamend, and in LKB1-null HeLa cells that constitutively express CaMKK2, following transfection with wild type LKB1 or catalytically-dead mutants. Upstream regulation by Zyflamend of LKB1 and CaMKK2 was investigated targeting protein kinase C-zeta (PKCζ) and death-associated protein kinase (DAPK), respectively., Results: Zyflamend's activation of AMPK appears to be LKB1 dependent, while simultaneously inhibiting CaMKK2 activity. Zyflamend failed to rescue the activation of AMPK in the presence of pharmacological and molecular inhibitors of LKB1, an effect not observed in the presence of inhibitors of CaMKK2. Using LKB1-null and catalytically-dead LKB1-transfected HeLa cells that constitutively express CaMKK2, ionomycin (activator of CaMKK2) increased phosphorylation of AMPK, but Zyflamend only had an effect in cells transfected with wild type LKB1. Zyflamend appears to inhibit CaMKK2 by DAPK-mediated phosphorylation of CaMKK2 at Ser511, an effect prevented by a DAPK inhibitor. Alternatively, Zyflamend mediates LKB1 activation via increased phosphorylation of PKCζ, where it induced translocation of PKCζ and LKB1 to their respective active compartments in HeLa cells following treatment. Altering the catalytic activity of LKB1 did not alter this translocation., Discussion: Zyflamend's activation of AMPK is mediated by LKB1, possibly via PKCζ, but independent of CaMKK2 by a mechanism that appears to involve DAPK., Conclusions: Therefore, this is the first evidence that natural products simultaneously and antithetically regulate upstream kinases, known to be involved in cancer, via the activation of AMPK.

Colorectal cancer is characterized by an increase in the utilization of glucose and a diminishment in the oxidation of butyrate, which is a short chain fatty acid. In colorectal cancer cells, butyrate inhibits histone deacetylases to increase the expression of genes that slow the cell cycle and induce apoptosis. Understanding the mechanisms that contribute to the metabolic shift away from butyrate oxidation in cancer cells is important in in understanding the beneficial effects of the molecule toward colorectal cancer. Here, we demonstrate that butyrate decreased its own oxidation in cancerous colonocytes. Butyrate lowered the expression of short chain acyl-CoA dehydrogenase, an enzyme that mediates the oxidation of short-chain fatty acids. Butyrate does not alter short chain acyl-CoA dehydrogenase levels in non-cancerous colonocytes. Trichostatin A, a structurally unrelated inhibitor of histone deacetylases, and propionate also decreased the level of short chain acyl-CoA dehydrogenase, which alluded to inhibition of histone deacetylases as a part of the mechanism. Knockdown of histone deacetylase isoform 1, but not isoform 2 or 3, inhibited the ability of butyrate to decrease short chain acyl-CoA dehydrogenase expression. This work identifies a mechanism by which butyrate selective targets colorectal cancer cells to reduce its own metabolism., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Amino acid composition and isoflavone are alleged contributors to the beneficial effects of soy protein isolate (SPI) on lipid metabolism. Therefore, we investigated the contributing component(s) of SPI in a maternal diet to the regulation of lipid metabolism in offspring. We also determined serum parameters in dams to investigate specific maternal cues that might be responsible for this regulation. Female rats were fed either a casein (CAS), a low-isoflavone SPI, or a casein plus genistein (GEN, 250 mg/kg) diet for two weeks before mating, as well as during pregnancy and lactation. Male offspring (CAS, SPI and GEN groups) were studied 21 days after birth. The SPI group had lower serum triglyceride levels than the other groups. Serum cholesterol was reduced in both the SPI and GEN groups compared with the CAS group. Expressions of target genes of peroxisome proliferator-activated receptor α were altered in the SPI group. Serum aromatic amino acid levels in dams were associated with serum triglyceride in offspring. In conclusion, the maternal consumption of a low-isoflavone SPI diet or a casein diet containing genistein has different effects on the lipid metabolism of their offspring; however, more profound effects were observed in the SPI group. Therefore, the altered lipid metabolism of offspring may be attributed to amino acid composition in maternal dietary protein sources., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Cancer, in part, is driven, by alterations in cellular metabolism that promote cell survival and cell proliferation. Identifying factors that influence this shift in cellular metabolism in cancer cells is important. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been reported to be elevated in colorectal cancer patients. While much is known toward the effect of dietary nutrients on regulating inflammation and the inflammatory response, which includes cytokines such as IL-1β, far less is understood how cytokines impact nutrient fate to alter cancer cell metabolism. Butyrate, a nutrient derived from the fermentation of dietary fiber in the colon, is the preferential exogenous energetic substrate used by non-cancerous colonocytes, but is used less efficiently by colorectal cancer cells. To test whether IL-1β alters colonocyte energy metabolism, we measured butyrate oxidation in HCT116 colorectal cancer cells with and without IL-1β. We hypothesize that IL-1β will push cancerous colonocytes away from the utilization and oxidation of butyrate. In this study, we demonstrate that pretreatment of colorectal cancer cells with IL-1β diminished butyrate oxidation and NADH levels. This effect was blocked with the interleukin receptor antagonist A (IL-1RA). Moreover, IL-1β suppressed basal mitochondrial respiration and lowered the mitochondrial spare capacity. By using inhibitors to block downstream targets of the interleukin-1 receptor pathway, we show that p38 is required for the IL-1β-mediated decrease in butyrate oxidation. These data provide insight into the metabolic effects induced by IL-1β in colorectal cancer, and identify relevant targets that may be exploited to block the effects of this cytokine. J. Cell. Biochem. 118: 1614-1621, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In utero environment is known to affect fetal development. Especially, the distinct fetal programming of carcinogenesis was reported in offspring exposed to maternal diets containing soy protein isolate (SPI) or genistein. Therefore, we investigated whether maternal consumption of low-isoflavone SPI or genistein alters hepatic gene expression and liver development in rat offspring. Female Sprague-Dawley rats were fed a casein diet, a low-isoflavone SPI diet or a casein diet supplemented with genistein (250 mg/kg diet) for 2 weeks before mating and throughout pregnancy and lactation. Male offspring were studied on postnatal day 21 (CAS, SPI and GEN groups). Among 965 differentially expressed hepatic genes related to maternal diet (P<.05), the expression of 590 was significantly different between CAS and SPI groups. Conversely, the expression of 88 genes was significantly different between CAS and GEN groups. Especially, genes involved in drug metabolism were significantly affected by the maternal diet. SPI group showed increased cell proliferation, reduced apoptosis and activation of the mTOR pathway, which may contribute to a higher relative liver weight compared to other groups. We observed higher serum homocysteine levels and lower global and CpG site-specific DNA methylation of Gadd45b, a gene involved in cell proliferation and apoptosis, in SPI group compared to CAS group. Maternal SPI diet also reduced histone H3-Lysine 9 (H3K9) trimethylation and increased H3K9 acetylation in offspring. These results demonstrate that maternal consumption of a low-isoflavone SPI diet alters the hepatic gene expression profile and liver development in offspring possibly by epigenetic processes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Proinflammatory cytokines impact islet β-cell mass and function by altering the transcriptional activity within pancreatic β-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines. Herein, we report that IL-1β, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-κB controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1β. Nitric oxide production, which is markedly elevated in pancreatic β-cells exposed to IL-1β, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1β-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration. Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1β were dependent on NF-κB transcriptional activity. We conclude that IL-1β-induced transcriptional reprogramming via NF-κB reciprocally regulates chemokine and insulin secretion while also negatively regulating β-cell proliferation. These findings are consistent with NF-κB as a major regulatory node controlling inflammation-associated alterations in islet β-cell function and mass., (Copyright © 2015 the American Physiological Society.)

The purpose of this study is to investigate the effects of euphorbiasteroid, a component of Euphorbia lathyris L., on adipogenesis of 3T3-L1 pre-adipocytes and its underlying mechanisms. Euphorbiasteroid decreased differentiation of 3T3-L1 cells via reduction of intracellular triglyceride (TG) accumulation at concentrations of 25 and 50 μM. In addition, euphorbiasteroid altered the key regulator proteins of adipogenesis in the early stage of adipocyte differentiation by increasing the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, levels of adipogenic proteins, including fatty acid synthase, peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein α, were decreased by euphorbiasteroid treatment at the late stage of adipocyte differentiation. The anti-adipogenic effect of euphorbiasteroid may be derived from inhibition of early stage of adipocyte differentiation. Taken together, euphorbiasteroid inhibits adipogenesis of 3T3-L1 cells through activation of the AMPK pathway. Therefore, euphorbiasteroid and its source plant, E. lathyris L., could possibly be one of the fascinating anti-obesity agent., (Copyright © 2015 John Wiley & Sons, Ltd.)

Unlabelled: Whether dietary fiber protects against colorectal cancer is controversial because of conflicting results from human epidemiologic studies. However, these studies and mouse models of colorectal cancer have not controlled the composition of gut microbiota, which ferment fiber into short-chain fatty acids such as butyrate. Butyrate is noteworthy because it has energetic and epigenetic functions in colonocytes and tumor-suppressive properties in colorectal cancer cell lines. We used gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium to demonstrate that fiber does have a potent tumor-suppressive effect but in a microbiota- and butyrate-dependent manner. Furthermore, due to the Warburg effect, butyrate was metabolized less in tumors where it accumulated and functioned as a histone deacetylase (HDAC) inhibitor to stimulate histone acetylation and affect apoptosis and cell proliferation. To support the relevance of this mechanism in human cancer, we demonstrate that butyrate and histone-acetylation levels are elevated in colorectal adenocarcinomas compared with normal colonic tissues., Significance: These results, which link diet and microbiota to a tumor-suppressive metabolite, provide insight into conflicting epidemiologic findings and suggest that probiotic/prebiotic strategies can modulate an endogenous HDAC inhibitor for anticancer chemoprevention without the adverse effects associated with synthetic HDAC inhibitors used in chemotherapy., (©2014 American Association for Cancer Research.)

Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/db+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.

The reaction mechanism for conversion of MnO nanoparticles to Mn-ferrite nanoparticles was studied, which involved sequential consumption of MnO and the growth of ferrite. The method could be applied to other ferrite nanoparticles including cobalt ferrite.

Employing neural stem cells from the brain cortex of E12 rat embryos, we investigated the possible role of phospholipase D (PLD) in the synaptogenesis and neurite formation of neural cells during differentiation. Expression level of PLD1 increased during neuronal differentiation of the neural stem cells, resulting in increased PLD activity. Expression level of synapsin I, a marker of synaptogenesis, also increased as the differentiation of neural stem cells progressed. To figure out the effect of PLD on synapsin I expression, we treated the neural stem cells with phorbol myristate acetate (PMA) to stimulate PLD activity. Increased PLD activity induced by PMA treatment resulted in elevated synapsin I expression and neurite outgrowth during neuronal differentiation. To further confirm the role of PLD in neurite outgrowth, we transfected the dominant-negative form of rat PLD1 cDNA (DN-rPLD1) into neural stem cells to downregulate PLD activity. Overexpression of DN-rPLD1 showed the complete inhibition of neurite outgrowth of neural stem cells under differentiation condition. While transfection of DN-rPLD1 did not affect the synapsin I expression, overexpression of rPLD1 resulted in increased synapsin I expression of the neural cells. These results suggest that PLD1 plays a critical role in neurite outgrowth during differentiation of the neural stem cells. In conclusion, this is the first evidence to show that PLD1 acts as an important regulator of neurite outgrowth in neural stem cell by promoting neuronal differentiation via increase of synapsin I expression.