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Abstract Autophagy maintains cellular homeostasis during low energy states. According to the current understanding, glucose-depleted cells induce autophagy through AMPK, the primary energy-sensing kinase, to acquire energy for survival. However, contrary to the prevailing concept, our study demonstrates that AMPK inhibits ULK1, the kinase responsible for autophagy initiation, thereby suppressing autophagy. We found that glucose starvation suppresses amino acid starvation-induced stimulation of ULK1-Atg14-Vps34 signaling via AMPK activation. During an energy crisis caused by mitochondrial dysfunction, the LKB1-AMPK axis inhibits ULK1 activation and autophagy induction, even under amino acid starvation. Despite its inhibitory effect, AMPK protects the ULK1-associated autophagy machinery from caspase-mediated degradation during energy deficiency, preserving the cellular ability to initiate autophagy and restore homeostasis once the stress subsides. Our findings reveal that dual functions of AMPK, restraining abrupt induction of autophagy upon energy shortage while preserving essential autophagy components, are crucial to maintain cellular homeostasis and survival during energy stress.

ObjectiveAlcohol intake is a major risk factor for various diseases. Elucidating alcohol use disorder (AUD) is important in preventing diseases and promoting health. We aimed to investigate the effect of art therapy on emotional (Minnesota Multiphasic Personality Inventory-2 [MMPI-2]) and physical (natural killer [NK] cell count, expression of stress-associated proteins [SAP], and electroencephalography) changes in patients with AUD.MethodsParticipants were randomly divided into two groups (n = 35), with the experimental group undergoing art therapy involving weekly 60-min group therapy sessions for 10 weeks. Statistical analysis was performed using Ranked ANCOVA and Wilcoxon's signed rank test. Western blotting was performed to analyze serum SAP levels.ResultsWe observed an association between psychological mechanisms and stress proteins. There was an increased number of NK cells in the experimental group after the program. Moreover, compared with the control group, the experimental group showed significant changes in SAP expression. Further, the experimental group showed a positive change in the MMPI-2 profile, as well as a decrease in depression, anxiety, impulsivity, and alcohol dependence.ConclusionsContinuous psychological support could be applied as a stress-control program for preventing stress recurrence and post-discharge relapse. Our findings strengthen the link between biomedical science and mental health in rehabilitation treatment for AUD.

Abstract Background The receptor for advanced glycation end-products (RAGE) is involved in neuroinflammation. This study investigated the changes in RAGE expression following noise-induced hearing loss. Methods Three-week-old female Sprague–Dawley rats were exposed to 115 dB SPL white noise for 4 h daily for 3 d (noise group, n = 16). In parallel, age and sex-matched control rats were raised under standard conditions without noise exposure (control group, n = 16). After 2 h (noise immediate, n = 8) and 4 wk (noise 4-week, n = 8) of noise exposure, the auditory cortex was harvested and cytoplasmic and nuclear fractions were isolated. The gene expression levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and RAGE were evaluated using real-time reverse transcription polymerase chain reaction. The protein expression levels of nuclear RAGE and cytosolic RAGE were evaluated using western blotting. Additionally, matrix metalloproteinase 9 (MMP9) was pharmacologically inhibited in the noise immediate group, and then nuclear and cytosolic RAGE expression levels were evaluated. Results The noise immediate and noise 4-week groups exhibited increased auditory thresholds at 4, 8, 16, and 32 kHz frequencies. The genes encoding the pro-inflammatory cytokines TNF-α, IL6, IL1β, and NF- κB were increased 3.74, 1.63, 6.42, and 6.23-fold in the noise immediate group, respectively (P = 0.047, 0.043, 0.044, and 0.041). RAGE mRNA expression was elevated 1.42-fold in the noise 4-week group (P = 0.032). Cytosolic RAGE expression was increased 1.76 and 6.99-fold in the noise immediate and noise 4-week groups, respectively (P = 0.04 and 0.03). Nuclear RAGE expression was comparable between the noise and control groups. matrix metalloproteinase 9 (MMP9) inhibition reduced cytosolic RAGE expression in the noise immediate group (P = 0.004). Conclusions Noise exposure increased the expression of cytosolic RAGE in the auditory cortex and upregulated pro-inflammatory genes, but this response could be alleviated by MMP9 inhibition.

Abstract Background Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. Methods We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. Results In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. Conclusion Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time.

Abstract Background This study aimed to investigate the changes in molecules related to perineuronal nets (PNNs) and synaptic transporters in the primary auditory cortices of rats with noise-induced hearing loss. Female Sprague–Dawley rats at postnatal day 7 were divided into the noise and control groups. Four hours of 115 dB SPL white noise was delivered for 10 days to the noise group. Thirty days after noise exposure, the primary auditory cortex and the inferior colliculus were harvested. The expression levels of vesicular glutamatergic transporter (VGLUT)1, VGLUT2, vesicular GABA transporter (VGAT), glutamate decarboxylase (GAD)67, brevican, aggrecan, MMP9, and MMP14 were evaluated using real-time reverse transcription polymerase chain reaction or western blot. An immunofluorescence assay was conducted to assess parvalbumin (PV), Wisteria floribunda agglutinin (WFA), and brevican. The immune-positive cells were counted in the primary auditory cortex. Results The expression level of VGLUT1 in the primary auditory cortex was decreased in the noise group. The expression level of VGLUT2 in the inferior colliculus was elevated in the noise group. The expression levels of brevican and PV + WFA in the primary auditory cortex were decreased in the noise group. The expression level of MMP9 in the primary auditory cortex was increased in the noise group. Conclusion Noise-induced hearing loss during the precritical period impacted PNN expression in the primary auditory cortex. Increased MMP9 expression may have contributed to the decrease in brevican expression. These changes were accompanied by the attenuation of glutamatergic synaptic transporters.

Fibroblastic reticular cells (FRC) are important for lymph node (LN) structure and function. Here the authors show that the YAP/TAZ complex downstream of Hippo signalling regulates FRC commitment and maturation, with YAP/TAZ deficiency impairing FRC differentiation, while hyperactivation of YAZ/TAZ inducing myofibroblastic FRCs and LN fibrosis.

Spontaneous regression of lung cancer is exceptionally rare. But there have been several intriguing cases reported in early and even advanced stages of lung cancer. Although the exact mechanism remains to be elucidated, the inflammation and immunologic response have been suggested as one of the means of spontaneous regression. Chronic inflammation is generally known to induce and aggravate tumorigenesis, but the relationship between cancer and inflammation highly depends on the contexts. Here, we present a case of a 60-year-old male ex-smoker who complained of recurrent hemoptysis, cough, and purulent sputum. The initial chest CT scan revealed diffuse bronchial thickening and an endobronchial mass-like lesion in the left lingular segment. The bronchoscopic and pathological findings also suggested a diagnosis of squamous cell carcinoma with severe mucosal inflammation. He was treated with antibiotics for the bronchitis during the first 1 week and his symptoms markedly improved. After 3 weeks, he underwent a follow-up examination. Chest computed tomography and bronchoscopy revealed the significant improvement of the bronchial narrowing and mucosal edema. Biopsy was performed several times around the lesion where the tissue was initially taken. However, the pathological results showed only chronic inflammation of bronchi, not cancer cells. Fortunately, there was no recurrence of lung cancer in follow-up chest computed tomography or bronchoscopy for almost 5 years. In this case, the incidentally diagnosed bronchial squamous cell carcinoma disappeared after severe inflammatory reaction of the bronchial wall. The clinician should remind the risk of early lung cancer accompanied with bronchitis in high-risk patients of lung cancer and also be aware that although it is very rare, the lesions could spontaneously regress.

Nonalcoholic fatty liver disease (NAFLD) is a common risk factor for metabolic syndrome that increases the risk of future cardiovascular disease, stroke, and diabetes. Recently, autophagy has been proposed as a means to prevent NAFLD. We investigated whether substances with autophagy-inducing activity alleviate NAFLD. The Valeriana fauriei (V. fauriei) was selected as a potential autophagy inducer among various natural materials using a Cyto-ID autophagy detection kit. V. fauriei 70 % ethanol extract (VFE) increased LC3II levels in the presence of the lysosomal inhibitor and reduced the GFP/mCherry puncta ratio, suggesting that VFE enhanced autophagy. VFE reduced oleic acid (OA)-induced lipid accumulation and increased the number of autophagosome in hepatocytes. Autophagy induction by VFE is due to inhibition of mTORC1 activity. VFE supplementation reduced fatty liver by downregulating lipogenesis-related genes and increased the autophagy, as revealed by TEM and IHC analysis in the fatty liver. We identified iridoids as main compounds of VFE; didrovaltrate (DI), valeriotriate B (VAL B), valeriotetrate C (VAL C), valtrate (VAL), and valechlorine (VC) were shown to enhance autophagy. These compounds also reduced OA-induced lipid accumulation in an Atg5-dependent manner. Taken together, VFE and its iridoids might be effective in alleviating fatty liver by acting as autophagy enhancers to break down LDs.

The Hippo pathway regulates the differentiation of stem and progenitor cells, but it is unclear how it acts in liver development. Here, the authors knockout Hippo pathway components Lats1 and 2in the liver, causing suppression of hepatocyte differentiation but promoting biliary cell differentiation.

Limonin, the most prevalent limonoid in citrus fruits, is widely used as a dietary supplement because of its biological activities. Although studies have shown that limonin inhibits bone resorption in osteoclasts and improves bone quality in orchidectomised rats, the anti-osteoporosis activity of limonin in ovariectomised (OVX) animal models is still unknown, and its exact molecular mechanisms remain undefined. Therefore, the effect of limonin on osteoblastogenesis in MC3T3-E1 cells and an OVX-induced osteoporosis rat model was investigated. Limonin stimulated alkaline phosphatase (ALP) activity, mineralisation, and increased osteoblast differentiation gene marker expression via extracellular signal-regulated kinase (ERK) and p38 signalling in osteoblastic MC3T3-E1 cells. In animals, limonin decreased OVX-induced body weight increase, affected the trabecular bone structure and biochemical properties, and facilitated bone mineral density and content regulation. These findings demonstrated that limonin has beneficial bone metabolism effects based on bone formation and might have potential as a functional food ingredients and a dietary supplement for osteoporosis.

Previous studies have described the effects of zingerone (ZO) on cisplatin (CXP)-induced injury to the kidneys, liver, and other organs but not to the cochlea. This study aimed to investigate the effects of ZO on CXP-induced ototoxicity. Eight-week-old Sprague–Dawley rats were used and divided into a control group, a CXP group, and a CXP + ZO group. Rats in the CXP group received 5 mg/kg/day CXP intraperitoneally for five days. Rats in the CXP + ZO group received 5 mg/kg/day CXP intraperitoneally for five days and 50 mg/kg/day ZO intraperitoneally for seven days. Auditory brainstem response thresholds (ABRTs) were measured before (day 0) and after (day 10) drug administration. Cochlear histology was examined using hematoxylin and eosin (H&E) staining and cochlear whole mounts. The expression levels of cytochrome P450 (CYP)1A1, CYP1B1, inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NFκB), tumor necrosis factor alpha (TNFα), and interleukin 6 (IL6) were estimated using quantitative reverse transcription-polymerase chain reaction. The expression levels of heme oxygenase 1 (HO1) and caspase 3 were analyzed via Western blotting. The auditory thresholds at 4, 8, and 16 kHz were attenuated in the CXP + ZO group compared with the CXP group. The mRNA expression levels of CYP1A1, CYP1B1, iNOS, NFκB, TNFα, and IL6 were lower in the CXP + ZO group than in the CXP group. The protein expression levels of HO1 and caspase 3 were lower in the CXP + ZO group than in the CXP group. Cotreatment with ZO exerted otoprotective effects against CXP-induced cochlear injury via antioxidative and anti-inflammatory activities involving CYPs, iNOS, NFκB, and TNFα.

Elongation factor Tu guanosine-5’-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of EFTUD2 variants, which may result in misclassification of the variant’s pathogenicity. Given the importance of the functional verification of EFTUD2 variants, we identified a novel splice donor site variant, c.271+1G>A of EFTUD2, whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of EFTUD2 exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of EFTUD2, thereby allowing for in vitro functional verification of splice site variants in EFTUD2.

Premature ovarian failure (POF) is defined as loss of ovarian function in women less than 40 years of age. The causes of POF are diverse and include environmental factors. Di-2-ethylhexyl phthalate (DEHP) is one factor that may cause POF. The ubiquitin-proteasome system maintains intracellular balance by promoting or inhibiting protein degradation. To investigate the differential expressions of deubiquitinating enzyme (DUB) genes in patients with POF, we developed two in vitro POF models by treating A2780 or OVCAR5 with DEHP. Using these models, a multiplex RT-PCR system for DUB genes was applied to identify biomarkers by comparing expression patterns and DUB mRNA levels; multiplex RT-PCR results were validated by qRT-PCR and Western blotting analyses. Observed differential expression levels of several DUB genes including USP12, COPS5, ATXN3L, USP49, and USP34 in A2780 and OVCAR5 cells at the mRNA and protein levels suggest that they should be investigated as potential biomarkers of POF.

Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function.

Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.

This study was designed to evaluate the effect of ovariectomy on nutrikinetics of genistein metabolites. To characterize the time-dependent changes in genistein metabolite concentrations, we identified 13 genistein metabolites using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The nutrikinetics of the individual metabolites at different time points were analyzed. Nutrikinetic analysis showed that genistein, genistein 4'-glucuronide, genistein 7-glucuronide, 3-hydroxygenistein, and hippuric acid showed relatively high bioavailability in the sham group compared to that in the ovariectomy group, suggesting that ovariectomy likely results in lower genistein bioavailability. These results may be related to alteration of gut microbiota by ovariectomy. The relative abundance of species of the Parabacteroides, Dorea, and Butyricimonas genera, and Desulfovibrionaceae_unclassified, Lachnospiraceae_unclassified, and Rikenellaceae_unclassified families increased in the ovariectomy group while the relative abundance of 523_7_unclassified and Y52_unclassified_unclassified increased in the sham group. These results suggest that gut microbiota alteration by ovariectomy may affect genistein bioavailability.

Inula japonica Thunb. (Asteraceae) is a flowering plant that grows mainly in Korea, Japan, and China and its flower extract has diverse biological effects such as anti-inflammatory and antioxidative activities. However, the effects on obesity and enhancement of endurance capacity have not been explored yet. This study aims to reveal the effects of I. japonica flower ethanol extract (IJE) on obesity and endurance capacity in high-fat diet (HFD) fed C57BL/6J mice and the mechanism. IJE inhibited lipid accumulation in 3T3-L1 adipocytes in vitro. Also, IJE-fed mice showed reduced body weight gain, hepatic lipid, and body fat mass, and increased muscle weight. IJE reduced lipid accumulation in the liver and adipose tissue by decreasing lipogenic and adipogenic gene expression. Additionally, consumption of low-dose IJE significantly enhanced endurance capacity via increasing AMP-activated protein kinase activity and mRNA levels of Myh7 and Myh2. Luteolin and 1β-hydroxyalantolactone (1β-HA), compounds of IJE, are involved in anti-adipogenesis in the 3T3-L cells and only luteolin increased the protein levels of MHC during C2C12 myoblast differentiation. Collectively, our results suggest that consumption of IJE not only helps to prevent obesity but also enhances endurance capacity reduced by HFD.

Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.

BackgroundsThe age at menarche has decreased worldwide. Previous studies on Korean adolescents have reported a downward trend in age at menarche. This study aimed to investigate the current trends in age at menarche among Korean adolescents using nationally representative data.Materials and methodsThe study used data from the Korea National Health and Nutrition Examination Survey 2007–2021. A total of 50,730 females born between 1927 and 2004 with information on age at menarche were included. The trend in age at menarche was analyzed according to 15 birth-year groups (with 5-year intervals) using quantile regression analysis.ResultsThe mean age at menarche decreased from 16.92 ± 0.06 years for females born before 1935 to 12.45 ± 0.04 years for females born between 2000 and 2004 (p

Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.

Purpose The association between appendicular skeletal muscle mass (ASM) and cardiometabolic risk has been emphasized. We estimated reference values of the percentage of ASM (PASM) and investigated their association with metabolic syndrome (MS) in Korean adolescents. Methods Data from the Korea National Health and Nutrition Examination Survey performed between 2009 and 2011 were used. Tables and graphs of reference PASM were generated using 1,522 subjects, 807 of whom were boys aged 10 to 18. The relationship between PASM and each component of MS in adolescents was further analyzed in 1,174 subjects, 613 of whom were boys. Moreover, the pediatric simple MS score (PsiMS), the homeostasis model assessment of insulin resistance (HOMA-IR), and the triglyceride-glucose (TyG) index were analyzed. Multivariate linear and logistic regressions adjusting for age, sex, household income, and daily energy intake were performed. Results In boys, PASM increased with age; the trend was different in girls, in whom PASM declined with age. PsiMS, HOMA-IR, and TyG index showed inverse associations with PASM (PsiMS, β=-0.105, P

Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M − H]− ion at m/z 217. While M2 showed an [M − H]− ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.

Objective: The price of pharmaceuticals is important from the economic and industrial perspectives but as well as patients’ access to treatment. This study aimed to analyze the variables affecting the prices of new drugs in South Korea’s pricing system.Methods: Data on 192 new drugs listed in South Korea from 2012 to 2022 were collected from the official website of the Health Insurance Review and Assessment Service. The independent variables included drugs for severe diseases, alternatives, number of patients, number of advanced 7 countries listed, budget impact, and listing period. The dependent variables included annual treatment cost and the price ratio to the advanced 7 country’s average adjusted price. Descriptive statistics of variables, linear correlations between quantitative independent and dependent variables, and associations between independent and dependent variables were analyzed.Results: The mean annual treatment cost and price ratio to the advanced 7 country’s average adjusted price were higher for drugs for severe diseases and those with no alternatives. Annual treatment cost and price ratio to the advanced 7 country’s average adjusted price were negatively correlated with the number of patients and positively correlated with the number of advanced 7 countries listed. Annual treatment cost was affected by the variables drugs for severe diseases, alternatives, number of patients, number of advanced 7 countries listed, and budget impact. The price ratio to the advanced 7 country’s average adjusted price was affected by drugs for severe diseases, alternatives, and the number of patients.Conclusion: This study revealed the effect of different variables on the prices of new drugs in South Korea, allowing for the development of a more effective assessment system to evaluate the prices of new drugs while ensuring profitability for pharmaceutical companies, sustainability of public insurance, and accessibility to drugs by patients.

To generate a stable and effective air–liquid discharge in an open atmosphere, we investigated the effect of the dielectric barrier on the discharge between the pin electrode and liquid surface in an atmospheric-pressure plasma reactor. The atmospheric-pressure plasma reactor used in this study was based on a pin–plate discharge structure, and a metal wire was used as a pin-type power electrode. A plate-type ground electrode was placed above and below the vessel to compare the pin–liquid discharge and pin–liquid barrier discharge (PLBD). The results indicated that the PLBD configuration utilizing the bottom of the vessel as a dielectric barrier outperformed the pin–liquid setup in terms of the discharge stability and that the concentration of reactive species was different in the two plasma modes. PLBD can be used as a digestion technique for determining the phosphorus concentration in natural water sources. The method for decomposing phosphorus compounds by employing PLBD exhibited excellent decomposition performance, similar to the performance of thermochemical digestion—an established conventional method for phosphorus detection in water. The PLBD structure can replace the conventional chemical-agent-based digestion method for determining the total dissolved phosphorus concentration using the ascorbic acid reduction method.

Purpose: Human breast milk (HBM) contains immune components that produced and delivered from the mother along with nutrients necessary for the baby. MicroRNA (miRNA) is a small noncoding RNA molecule, that is used as an ideal biomarker for diagnosis and prognosis of various diseases and are more abundant in HBM. We analyzed and compared the immune components and miRNAs of HBM. Methods: HBM were collected from 20 healthy breastfeeding mothers. We measured the amount of lactoferrin, lysozyme, and immunoglobulin A (IgA) and extracted the miRNAs from each breast milk samples. Next, the top 5 and bottom 5 expressed miRNAs were compared and analyzed based on the amounts of the 3 immune components. Results: The mean levels and ranges of lactoferrin, lysozyme, and IgA were 6.33 (2.24-14.77)x106 ng/mL, 9.90 (1.42-17.59)x107 pg/mL, and 6.64 (0.48-20.01)x105 ng/mL, respectively. The miRNAs concentration per 1 mL of skim milk was 40.54 (14.95-110.01) ng/μL. Comparing the bottom 5 and top 5 groups of each immune component, 19 miRNAs were significantly upregulated (6, 9, and 4 targeting lactoferrin, lysozyme, and IgA, respectively) and 21 were significantly downregulated (4, 9, and 8 targeting lactoferrin, lysozyme, and IgA, respectively). There were no miRNAs that were expressed significantly higher or lower in common to all 3 components. However, 2 and 3 miRNAs were commonly overexpressed and underexpressed, in the top 5 groups of lysozyme and IgA concentrations. Conclusion: We identified the immune components and miRNAs in breast milk and found that each individual has different ingredients. [ABSTRACT FROM AUTHOR]

Objective: Koreans have a lot of interest in improving their quality of life, happiness, selfcare, and health. This study aims to verify the relationship between social support, health selfefficacy, and health-promoting lifestyle among participants engaged in physical activity. Methods: In 2022, a total of 179 participants who engaged in physical activity in Jeju Special Self-Governing Province were measured for social support, health self-efficacy, and health-promoting lifestyle. Data analysis was conducted using SPSS 24.0 and Amos 24.0 statistical programs. Results: Social support had a significant negative effect on health-promoting lifestyle, while it had a significant positive effect on health self-efficacy. Health self-efficacy had a significant positive effect on healthpromoting lifestyle. Health self-efficacy was found to have significant indirect effect on social support and health-promoting lifestyle. Conclusions: The results of this study are expected to increase awareness among physical activity participants of the importance of health-promoting lifestyle, and these findings suggest that campaigns efforts will be necessary for Korea association of health promotion to communicate the importance of health-promoting lifestyle to the general public. [ABSTRACT FROM AUTHOR]