Improvement of sleep duration and quality through GABAA receptor by whey protein hydrolysate containing DIQK as the active main compound.

This study characterized the sleep activity, sleep mechanism, and active peptides of whey protein hydrolysates selected through behavioral analysis of fruit-flies (Drosophila melanogaster). Sleep-inducing whey protein (WP) hydrolysate was selected through fruit fly behavior analysis, and sleep activity was measured using a pentobarbital model and electroencephalographic analysis. The mechanism of action was confirmed using a γ-aminobutyric acid (GABA) receptor antagonist, and the active peptide was identified using liquid chromatography-mass spectroscopy. Whey protein hydrolysate, prepared using Alcalase and Prozyme (WP-AP), increased sleep time in a dose-dependent manner. WP-AP significantly increased not only sleep time but also slow-wave sleep and showed an insomnia-alleviating effect in a caffeine-induced insomnia mouse model. In addition, the gene and protein expression levels of GABA sub-type A (GABAA) receptors increased in the brains of mice orally administered with WP-AP. Through peptide analysis, the mixture of DIQK, VPPF peptide, and GABA contained in WP-AP was estimated to exhibit sleep activity, and due to its high content, DIQK was speculated to be the main sleep -inducing ingredient. These results indicate that WP-AP has the potential to be used as a new ingredient to improve sleep quality.

Difference in formation of a dental multi-species biofilm according to substratum direction.

OBJECTIVES: The aim of this study was to investigate the difference in dental biofilm formation according to substratum direction, using an artificial biofilm model. METHODS: A three-species biofilm, consisting of Streptococcus mutans, Streptococcus oralis, and Actinomyces naeslundii, was formed on saliva-coated hydroxyapatite (sHA) discs oriented in three directions: downward (the discs placed in the direction of gravity), vertical (the discs placed parallel to the direction of gravity), and upward (the discs placed in opposite direction of gravity). The biofilms at 22 h and 46 h of age were analyzed using microbiological and biochemical methods, fluorescence-based assays, and scanning electron microscopy to investigate difference in bacterial adhesion, early and mature biofilm formation. RESULTS: The biofilms formed in the upward direction displayed the most complex structure, with the highest number and biovolume of bacteria, as well as the lowest pH conditions at both time points. The vertical and downward directions, however, had only scattered and small bacterial colonies. In the 22-h-old biofilms, the proportion of S. oralis was similar to, or slightly higher than, that of S. mutans in all directions of substratum surfaces. However, in the 46-h-old biofilms, S. mutans became the dominant bacteria in all directions, especially in the vertical and upward directions. CONCLUSIONS: The direction of the substratum surface could impact the proportion of bacteria and cariogenic properties of the multi-species biofilm. Biofilms in an upward direction may exhibit a higher cariogenic potential, followed by those in the vertical and downward directions, which could be related to gravity.

Prediction of Overall Disease Burden in (y)pN1 Breast Cancer Using Knowledge-Based Machine Learning Model.

BACKGROUND: We aimed to construct an expert knowledge-based Bayesian network (BN) model for assessing the overall disease burden (ODB) in (y)pN1 breast cancer patients and compare ODB across arms of ongoing trials. METHODS: Utilizing institutional data and expert surveys, we developed a BN model for (y)pN1 breast cancer. Expert-derived probabilities and disability weights for radiotherapy-related benefit (e.g., 7-year disease-free survival [DFS]) and toxicities were integrated into the model. ODB was defined as the sum of disability weights multiplied by probabilities. In silico predictions were conducted for Alliance A011202, PORT-N1, RAPCHEM, and RT-CHARM trials, comparing ODB, 7-year DFS, and side effects. RESULTS: In the Alliance A011202 trial, 7-year DFS was 80.1% in both arms. Axillary lymph node dissection led to higher clinical lymphedema and ODB compared to sentinel lymph node biopsy with full regional nodal irradiation (RNI). In the PORT-N1 trial, the control arm (whole-breast irradiation [WBI] with RNI or post-mastectomy radiotherapy [PMRT]) had an ODB of 0.254, while the experimental arm (WBI alone or no PMRT) had an ODB of 0.255. In the RAPCHEM trial, the radiotherapy field did not impact the 7-year DFS in ypN1 patients. However, there was a mild ODB increase with a larger irradiation field. In the RT-CHARM trial, we identified factors associated with the major complication rate, which ranged from 18.3% to 22.1%. CONCLUSIONS: The expert knowledge-based BN model predicted ongoing trial outcomes, validating reported results and assumptions. In addition, the model demonstrated the ODB in different arms, with an emphasis on quality of life.

Defect Passivation of 2D Semiconductors by Fixating Chemisorbed Oxygen Molecules via h-BN Encapsulations.

Hexagonal boron nitride (h-BN) is a key ingredient for various 2D van der Waals heterostructure devices, but the exact role of h-BN encapsulation in relation to the internal defects of 2D semiconductors remains unclear. Here, it is reported that h-BN encapsulation greatly removes the defect-related gap states by stabilizing the chemisorbed oxygen molecules onto the defects of monolayer WS2 crystals. Electron energy loss spectroscopy (EELS) combined with theoretical analysis clearly confirms that the oxygen molecules are chemisorbed onto the defects of WS2 crystals and are fixated by h-BN encapsulation, with excluding a possibility of oxygen molecules trapped in bubbles or wrinkles formed at the interface between WS2 and h-BN. Optical spectroscopic studies show that h-BN encapsulation prevents the desorption of oxygen molecules over various excitation and ambient conditions, resulting in a greatly lowered and stabilized free electron density in monolayer WS2 crystals. This suppresses the exciton annihilation processes by two orders of magnitude compared to that of bare WS2. Furthermore, the valley polarization becomes robust against the various excitation and ambient conditions in the h-BN encapsulated WS2 crystals.

Assessment of lymph node area coverage with total marrow irradiation and implementation of total marrow and lymphoid irradiation using automated deep learning-based segmentation.

BACKGROUND: Total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) have the advantages. However, delineating target lesions according to TMI and TMLI plans is labor-intensive and time-consuming. In addition, although the delineation of target lesions between TMI and TMLI differs, the clinical distinction is not clear, and the lymph node (LN) area coverage during TMI remains uncertain. Accordingly, this study calculates the LN area coverage according to the TMI plan. Further, a deep learning-based model for delineating LN areas is trained and evaluated. METHODS: Whole-body regional LN areas were manually contoured in patients treated according to a TMI plan. The dose coverage of the delineated LN areas in the TMI plan was estimated. To train the deep learning model for automatic segmentation, additional whole-body computed tomography data were obtained from other patients. The patients and data were divided into training/validation and test groups and models were developed using the "nnU-NET" framework. The trained models were evaluated using Dice similarity coefficient (DSC), precision, recall, and Hausdorff distance 95 (HD95). The time required to contour and trim predicted results manually using the deep learning model was measured and compared. RESULTS: The dose coverage for LN areas by TMI plan had V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% median values of 46.0%, 62.1%, and 73.5%, respectively. The lowest V100% values were identified in the inguinal (14.7%), external iliac (21.8%), and para-aortic (42.8%) LNs. The median values of DSC, precision, recall, and HD95 of the trained model were 0.79, 0.83, 0.76, and 2.63, respectively. The time for manual contouring and simply modified predicted contouring were statistically significantly different. CONCLUSIONS: The dose coverage in the inguinal, external iliac, and para-aortic LN areas was suboptimal when treatment is administered according to the TMI plan. This research demonstrates that the automatic delineation of LN areas using deep learning can facilitate the implementation of TMLI.

Diagnostic performance and image quality of an image-based denoising algorithm applied to radiation dose-reduced CT in diagnosing acute appendicitis.

PURPOSE: To evaluate diagnostic performance and image quality of ultralow-dose CT (ULDCT) in diagnosing acute appendicitis with an image-based deep-learning denoising algorithm (IDLDA). METHODS: This retrospective multicenter study included 180 patients (mean ± standard deviation, 29 ± 9 years; 91 female) who underwent contrast-enhanced 2-mSv CT for suspected appendicitis from February 2014 to August 2016. We simulated ULDCT from 2-mSv CT, reducing the dose by at least 50%. Then we applied an IDLDA on ULDCT to produce denoised ULDCT (D-ULDCT). Six radiologists with different experience levels (three board-certified radiologists and three residents) independently reviewed the ULDCT and D-ULDCT. They rated the likelihood of appendicitis and subjective image qualities (subjective image noise, diagnostic acceptability, and artificial sensation). One radiologist measured image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). We used the receiver operating characteristic (ROC) analyses, Wilcoxon's signed-rank tests, and paired t-tests. RESULTS: The area under the ROC curves (AUC) for diagnosing appendicitis ranged 0.90-0.97 for ULDCT and 0.94-0.97 for D-ULDCT. The AUCs of two residents were significantly higher on D-ULDCT (AUC difference = 0.06 [95% confidence interval, 0.01-0.11; p = .022] and 0.05 [0.00-0.10; p = .046], respectively). D-ULDCT provided better subjective image noise and diagnostic acceptability to all six readers. However, the response of board-certified radiologists and residents differed in artificial sensation (all p ≤ .003). D-ULDCT showed significantly lower image noise, higher SNR, and higher CNR (all p < .001). CONCLUSION: An IDLDA can provide better ULDCT image quality and enhance diagnostic performance for less-experienced radiologists.

Lactobacillus brevis-Fermented Gamma-Aminobutyric Acid Ameliorates Depression- and Anxiety-Like Behaviors by Activating the Brain-Derived Neurotrophic Factor-Tropomyosin Receptor Kinase B Signaling Pathway in BALB/C Mice.

This study investigated the effects of Lactobacillus brevis-fermented gamma-aminobutyric acid (LB-GABA) on depressive and anxiety-like behaviors with the underlying molecular mechanism in a chronic stress model of BALB/c mice. LB-GABA attenuates both neuronal cell death and the increase of monoamine oxidase activity induced by hydrogen peroxide. Behavioral tests revealed that GABA significantly increased sucrose preference and reduced immobility time in both tail suspension and forced swimming tests. LB-GABA increased exploration of the open arms in the elevated plus maze and restored activity in the open field. Moreover, LB-GABA lowered stress hormone and inflammatory mediator levels. Mechanistically, LB-GABA increased protein levels of BDNF and TrkB, activating downstream targets (AKT, ERK, and CREB), crucial for neuronal survival and plasticity. Furthermore, LB-GABA protected hippocampal neurons from stress-induced cell death and increased serotonin and dopamine levels. Overall, LB-GABA has the potential to alleviate stress-induced depression and anxiety-like symptoms and neuroinflammation by activating the BDNF-TrkB signaling pathway.

Diagnosis of atrial fibrillation based on AI-detected anomalies of ECG segments.

Early detection of atrial fibrillation (AF) is crucial for its effective management and prevention. Various methods for detecting AF using deep learning (DL) based on supervised learning with a large labeled dataset have a remarkable performance. However, supervised learning has several problems, as it is time-consuming for labeling and has a data dependency problem. Moreover, most of the DL methods do not provide any clinical evidence to physicians regarding the analysis of electrocardiography (ECG) for classification or detection of AF. To address these limitations, in this study, we proposed a novel AF diagnosis system using unsupervised learning for anomaly detection with three segments, PreQ, QRS, and PostS, based on the normal ECG. Two independent datasets, PTB-XL and China, were used in three experiments. We used a long short-term memory (LSTM)-based autoencoder to train the segments of the normal ECG. Based on the threshold of anomaly scores using mean squared error (MSE), it distinguished between normal and AF segments. In Experiment A, the best score was that of PreQ, which detected AF with an AUROC score of 0.96. In Experiment B and C for cross validation of each dataset, the best scores were also of PreQ, with AUROC scores of 0.9 and 0.95, respectively. To verify the significance of the anomaly score in distinguishing between AF and normal segments, we utilized an XG-Boosted model after generating anomaly scores in the three segments. The XG-Boosted model achieved an AUROC score of 0.98 and an F1 score of 0.94. AF detection using DL has been controversial among many physicians. However, our study differentiates itself from previous studies in that we can demonstrate evidence that distinguishes AF from normal segments based on the anomaly score.

Association between environmental mercury exposure and allergic disorders in Korean children: Korean National Environmental Health Survey (KoNEHS) cycles 3-4 (2015-2020).

Although previous studies have suggested potential adverse effects of mercury on a child's immune system, the associations have been inconsistent. We aimed to determine the association between urinary mercury levels and allergic diseases in Korean children with high mercury exposure. Data from 853 and 710 children aged 6-11 years in the Korean National Environmental Health Survey (KoNEHS) cycle 3 (2015-2017) and cycle 4 (2018-2020) were analyzed. We examined the association between mercury exposure and the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), and allergic multimorbidity. After adjusting for all covariates, the urinary mercury level was positively associated with AD in the 2015-2017 study (OR = 1.34, 95% CI = 1.01, 1.79) and AR in 2018-2020 study (OR = 1.46, 95% CI = 1.01, 2.10). Pooled effects showed OR of 1.34 (95% CI = 1.01, 1.79) for AD and 1.47 (95% CI = 1.01, 2.12) for allergic multimorbidity. The association with allergic multimorbidity was greater in boys (OR = 1.88, 95% CI = 1.01, 3.49) than in girls (OR = 1.25, 95% CI = 0.73, 2.14). These results suggest that environmental mercury exposure may exacerbate symptoms of atopic dermatitis and allergic multimorbidity in children.

Estimating the risk and benefit of radiation therapy in (y)pN1 stage breast cancer patients: A Bayesian network model incorporating expert knowledge (KROG 22-13).

BACKGROUND: We aimed to evaluate the risk and benefit of (y)pN1 breast cancer patients in a Bayesian network model. METHOD: We developed a Bayesian network (BN) model comprising three parts: pretreatment, intervention, and risk/benefit. The pretreatment part consisted of clinical information from a tertiary medical center. The intervention part regarded the field of radiotherapy. The risk/benefit component encompasses radiotherapy (RT)-related side effects and effectiveness, including factors such as recurrence, cardiac toxicity, lymphedema, and radiation pneumonitis. These factors were evaluated in terms of disability weights and probabilities from a nationwide expert survey. The overall disease burden (ODB) was calculated as the sum of the probability multiplied by the disability weight. A higher value of ODB indicates a greater disease burden for the patient. RESULTS: Among the 58 participants, a BN model utilizing discretization and clustering techniques revealed five distinct clusters. Overall, factors associated with breast reconstruction and RT exhibited high discrepancies (24-34 %), while RT-related side effects demonstrated low discrepancies (3-11 %) among the experts. When incorporating recurrence and RT-related side effects, the mean ODB of (y)pN1 patients was 0.258 (range, 0.244-0.337), with a higher tendency observed in triple-negative breast cancer (TNBC) or mastectomy cases. The ODB for TNBC patients undergoing mastectomy without postmastectomy radiotherapy was 0.327, whereas for non-TNBC patients undergoing breast conserving surgery with RT, the disease burden was 0.251. There was an increasing trend in ODB as the field of RT increased. CONCLUSION: We developed a Bayesian network model based on an expert survey, which helps to understand treatment patterns and enables precise estimations of RT-related risk and benefit in (y)pN1 patients.

Pre-mixing of omega-3 fatty acid-containing liposomes enhances the drug release rate and therapeutic efficacy of anticancer drugs loaded in liposomes.

The therapeutic efficacy of anticancer drugs loaded in liposomes composed of rigid phosphatidylcholine (PC) is hindered by the limited release of these drugs at the tumor site, which in turn hampers delivery of the drug to its intracellular target. In an attempt to improve the therapeutic efficacy of liposomal anticancer drugs, we here explored the use of empty liposomes as "trigger" vehicles to induce drug release from drug-loaded liposomes through liposome-liposome interactions. Empty liposomes containing PC in which omega-3 fatty acids comprised both fatty acid strands (Omega-L) showed a triggering effect on drug release from doxorubicin (DOX)-loaded liposomes (Caelyx). The effectiveness of this triggered-release effect was dependent on the Omega-L composition as well as the mixing ratio of Omega-L to Caelyx. Cryo-TEM and differential calorimetry studies revealed that the Omega-L effect was associated with liposome-liposome interactions that led to loosened membrane packing and increased fluidity of Caelyx. In cultured cells, the intracellular/intranuclear DOX uptake and anticancer efficacy of Caelyx was greatly improved by Omega-L pre-mixing. Intravenous injection of rats with Caelyx, premixed with Omega-L, decreased the area under the plasma concentration-time curve from time zero to time infinity and increased clearance without significantly changing the mean residence time or terminal half-life of DOX compared with Caelyx alone. Ex vivo bioimaging showed that DOX fluorescence in tumors, but not in other organs, was significantly increased by Omega-L premixing. In the mouse xenograft model, premixing of Omega-L with Caelyx suppressed tumor growth 2.5-fold compared with Caelyx. Collectively, the data provide preliminary evidence that the Omega-L-triggered drug release that occurs before and after dosing, particularly at tumor site, improved the therapeutic efficacy of Caelyx. The simple approach described here could enhance the therapeutic value of Caelyx and other anticancer drug-loaded liposomes.

Neuroprotective effect of whey protein hydrolysate containing leucine-aspartate-isoleucine-glutamine-lysine on HT22 cells in hydrogen peroxide-induced oxidative stress.

This study aimed to investigate the neuroprotective effects of whey protein hydrolysate (WPH) containing the pentapeptide leucine-aspartate-isoleucine-glutamine-lysine (LDIQK). Whey protein hydrolysate (50, 100, and 200 µg/mL) demonstrated the ability to restore the viability of HT22 cells subjected to 300 µM hydrogen peroxide (H2O2)-induced oxidative stress. Furthermore, at a concentration of 200 µg/mL, it significantly reduced the increase in reactive oxygen species production and calcium ion (Ca2+) influx induced by H2O2 by 46.1% and 46.2%, respectively. Similarly, the hydrolysate significantly decreased the levels of p-tau, a hallmark of tauopathy, and BCL2 associated X (BAX), a proapoptosis factor, while increasing the protein levels of choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, brain-derived neurotrophic factor (BDNF), a nerve growth factor, and B-cell lymphoma 2 (BCL2, an antiapoptotic factor. Furthermore, it increased nuclear factor erythroid 2-related factor 2 (Nrf2)-hemoxygenase-1(HO-1) signaling, which is associated with the antioxidant response, while reducing the activation of mitogen-activated protein kinase (MAPK) signaling pathway components, namely phosphor-extracellular signal-regulated kinases (p-ERK), phosphor-c-Jun N-terminal kinases (p-JNK), and p-p38. Column chromatography and tandem mass spectrometry analysis identified LDIQK as a compound with neuroprotective effects in WPH; it inhibited Ca2+ influx and regulated the BAX/BCL2 ratio. Collectively, WPH containing LDIQK demonstrated neuroprotective effects against H2O2-induced neuronal cell damage, suggesting that WPH or its active peptide, LDIQK, may serve as a potential edible agent for improving cognitive dysfunction.

Protective Effects of Whey Protein Hydrolysate, Treadmill Exercise, and Their Combination against Scopolamine-Induced Cognitive Deficit in Mice.

In this study, the potential of whey protein hydrolysate (WPH) and treadmill exercise to prevent cognitive decline was investigated, along with their neuroprotective mechanisms. Cognitive dysfunction was induced in mice with 1 mg/kg of scopolamine, followed by the administration of WPH at 100 and 200 mg/kg and/or treadmill exercise at 15 m/min for 30 min five days per week. Both WPH administration and treadmill exercise significantly improved the memory of mice with scopolamine-induced cognitive impairment, which was attributed to several key mechanisms, including a reduction in oxidative stress based on decreased levels of reactive oxygen species and malondialdehyde in the brain tissue and an increase in acetylcholine by increasing choline acyltransferase and decreasing acetylcholine esterase levels. Exercise and WPH also exerted neuroprotective effects by inhibiting the hyperphosphorylation of tau proteins, enhancing the expression of the brain-derived neurotrophic factor, and inhibiting apoptosis by reducing the Bax/Bcl2 ratio in conjunction with the downregulation of the mitogen-activated protein kinase pathway. Moreover, the impact of WPH and treadmill exercise extended to the gut microbiome, suggesting a potential link with cognitive improvement. These findings suggest that both WPH intake and treadmill exercise are effective strategies for mitigating cognitive impairment, providing promising avenues for treating neurodegenerative diseases.

Enzyme Activity and Lipogenesis Inhibition by Fermented Grain Using Natural Enzymes.

This study aims to compare the effects of three enzyme-rich foods, including one fermented (grain enzyme) and two non-fermented foods (enzyme foods 1 and 2), by investigating their antioxidant, anti-inflammatory, and anti-adipogenic properties. Grain enzyme exhibited the highest radical scavenging activity and was rich in antioxidant components, including total polyphenol and total flavonoid contents. Grain enzyme and enzyme foods 1 and 2 inhibited nitric oxide production by 27, 34, and 17%, respectively, at a concentration of 200 µg/mL in LPS-stimulated macrophages. Among the tested enzymes, grain enzyme demonstrated the strongest inhibition on the expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-1ß, while Enzyme Food 2 exhibited the most significant suppression of IL-6 mRNA levels. Furthermore, Grain Enzyme demonstrated a stronger inhibitory effect compared to Enzyme Food 1 and 2. Grain Enzyme decreased the mRNA expression of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer-binding protein (C/EBP)α, and fatty acid-binding protein (FABP)4 by 28, 21, and 30%, respectively, at a concentration of 400 µg/mL. In summary, fermented grain enzymes outperformed non-fermented enzymes in suppressing inflammation and adipogenesis. This study highlights the anti-inflammatory and anti-adipogenic effects of grain enzyme, suggesting its potential as a valuable dietary supplement for managing metabolic disorders.

Developing prompts from large language model for extracting clinical information from pathology and ultrasound reports in breast cancer.

PURPOSE: We aimed to evaluate the time and cost of developing prompts using large language model (LLM), tailored to extract clinical factors in breast cancer patients and their accuracy. MATERIALS AND METHODS: We collected data from reports of surgical pathology and ultrasound from breast cancer patients who underwent radiotherapy from 2020 to 2022. We extracted the information using the Generative Pre-trained Transformer (GPT) for Sheets and Docs extension plugin and termed this the "LLM" method. The time and cost of developing the prompts with LLM methods were assessed and compared with those spent on collecting information with "full manual" and "LLM-assisted manual" methods. To assess accuracy, 340 patients were randomly selected, and the extracted information by LLM method were compared with those collected by "full manual" method. RESULTS: Data from 2,931 patients were collected. We developed 12 prompts for Extract function and 12 for Format function to extract and standardize the information. The overall accuracy was 87.7%. For lymphovascular invasion, it was 98.2%. Developing and processing the prompts took 3.5 hours and 15 minutes, respectively. Utilizing the ChatGPT application programming interface cost US $65.8 and when factoring in the estimated wage, the total cost was US $95.4. In an estimated comparison, "LLM-assisted manual" and "LLM" methods were time- and cost-efficient compared to the "full manual" method. CONCLUSION: Developing and facilitating prompts for LLM to derive clinical factors was efficient to extract crucial information from huge medical records. This study demonstrated the potential of the application of natural language processing using LLM model in breast cancer patients. Prompts from the current study can be re-used for other research to collect clinical information.

Yeast-Hydrolysate-Derived 1-Methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic Acid Inhibits Fat Accumulation during Adipocyte Differentiation.

This study aimed to investigate the impact of yeast hydrolysate (YH) on lipogenesis, elucidate its mechanistic action, and identify the active compounds responsible for its anti-adipogenic effects. YH (2 mg/mL) significantly reduced Oil Red O-stained lipids. YH (2 mg/mL) also downregulated C/EBPß and upregulated KLF2, both of which are early adipogenic factors. Moreover, YH (2 mg/mL) decreased C/EBPα, PPARγ, FABP4, FAS, ACC, and HMGCR mRNA expression. Additionally, YH significantly downregulated SEBP1c and SREBP2 and their target genes, which govern fatty acid and cholesterol metabolism; however, 2 mg/mL YH had a greater suppressive effect on SREBP1c than on SREBP2. YH (2 mg/mL) also significantly reduced the mRNA level of G6PD and malic enzyme, which are enzymes that synthesize NADPH for lipid synthesis, compared with the control. Furthermore, 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (MTCA) was identified as the active compound with anti-adipogenic effects using solvent fractionation and chromatographic analysis of YH, and 1.1 µg/mL MTCA significantly downregulated SREBP1c/SREBP2 mRNAs by 47.8% and 69.2%, respectively, along with the target genes FAS, ACC, and HMGCR by 79.0%, 77.0%, and 40.9%, respectively. Collectively, YH effectively suppressed adipogenic lipid storage by downregulating SREBP- and NADPH-synthesizing genes. These findings suggest that YH containing MTCA has the potential to act as an anti-obesity agent.

Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats.

Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofacitinib after its intravenous (10 mg/kg) or oral (20 mg/kg) administration in poloxamer-407-induced hyperlipidemic (PHL) rats. The area under the plasma concentration-time curve from zero to infinity (AUC0-∞) after intravenous administration of tofacitinib was 73.5% higher in PHL than in control rats, owing to slower time-averaged nonrenal clearance (CLNR) in the former. Evaluation of in vitro metabolism showed that the intrinsic clearance (CLint) of tofacitinib was 38.6% lower in PHL than in control rats, owing to the decreased protein expression of hepatic cytochrome P450 (CYP) 3A1/2 and CYP2C11 in PHL rats. Similar results were observed in PHL rats after oral administration of tofacitinib. These results were likely due to the decreased CLNR, CLint, and P-glycoprotein (P-gp) expression in the intestines of PHL compared to control rats. Overall, these findings indicated that hyperlipidemia slowed the metabolism of tofacitinib, increasing its plasma concentrations, and that this reduced metabolism was due to alterations in expression of the proteins CYP3A1/2, CYP2C11, and P-gp in the liver and/or intestines of PHL rats.

Factors affecting optical coherence tomography angiography signal strength index in patients receiving intravitreal injection treatment.

PURPOSE: To investigate the clinical factors affecting optical coherence tomography angiography (OCTA) signal strength index (SSI) and its change after intravitreal injection treatment in patients with retinal disorders. METHODS: OCTA data from 186 eyes of 166 patients with various retinal disorders including age-related macular degeneration, diabetic macular edema (DME), and retinal vein occlusions who received intravitreal injections were analyzed. The associations between SSI and clinical factors, including age, best-corrected visual acuity (BCVA), media opacity severity, and central macular thickness (CMT), were evaluated both before and after injection. RESULTS: After injection, BCVA improved and CMT decreased significantly, and SSI increased significantly (p = 0.030). BCVA showed a significant positive correlation with media opacity severity before and after injection and with CMT only before injection. In the multivariate analysis, age, presence of DME, BCVA, and media opacity severity were negatively associated with SSI both before and after injection, while CMT was negatively associated with SSI only before injection. After injection, a negative correlation was found between SSI change and both BCVA and CMT change. CONCLUSION: Our findings suggest that OCTA SSI is influenced by various clinical factors, including age, visual acuity, media opacity severity, and macular thickening, especially in cases of DME. The results also indicate that SSI may decrease in patients with macular disorders due to the presence of macular edema and the associated decrease in visual acuity. Therefore, it is crucial to consider these factors when interpreting OCTA data and ensure an adequate level of SSI.

Schisandra chinensis-derived gomisin C suppreses lipid accumulation by JAK2-STAT signaling in adipocyte.

Gomisin C is a lignan isolated from the fruit of Schisandra chinensis. The current study aimed to investigate the effect of gomisin C on lipid accumulation in adipocytes and its underlying mechanism. Gomisin C effectively inhibited lipid accumulation by downregulating adipogenic factors such as PPARγ and C/EBPα. Gomisin C-mediated suppression of lipid accumulation occurred in the early adipogenic stage; C/EBPß was downregulated by 55%, while KLF2 was upregulated by 1.5-fold. Gomisin C significantly reduced the production of reactive oxygen species but upregulated antioxidant enzymes, including catalase, SOD1, and Gpx at the mRNA level. Gomisin C regulated NRF2-KEAP1 pathway by increasing NRF2 and decreasing KEAP1, in protein abundance. Furthermore, gomisin C suppressed the JAK2-STAT signaling pathway by decreasing phosphorylation. Taken together, gomisin C reduced early adipogenesis and ROS production by inhibiting the JAK2-STAT signaling pathway but activating the NRF2-KEAP1 signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01263-8.