Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression.

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

Is Renal Denervation Effective in Treating Resistant Hypertension?

Resistant hypertension is diagnosed in patients whose blood pressure target is unmet despite the use of three or more antihypertensive medications. Systemic sympathetic hyperactivation is associated with the development of resistant hypertension. As the kidney is largely pervasive of the sympathetic nervous system renal denervation procedure was developed to control blood pressure by attenuating the renal and systemic sympathetic hyperactivity. Renal denervation is a minimally invasive procedure that uses radiofrequency or ultrasound energy waves to reduce the activity of the renal artery nerves. Previous clinical trials have shown conflicting results regarding the efficacy of the procedure. Symplicity HTN-1 and -2 trials showed effective blood pressure lowering results in the renal denervation group with a good safety profile. However, the Symplicity HTN-3 trial showed no difference in blood pressure lowering effect between the renal denervation and control Sham procedure groups. Notwithstanding, some recent clinical trials with Sham control and meta-analysis showed clinical benefits of renal denervation. Other clinical benefits of renal denervation include glucose control, cardiovascular protective effect, reduction of obstructive sleep apnea, and neuralgia control. A subset of patients with satisfactory blood pressure control response to the procedure may experience improved glucose control due to the overall reduced sympathetic activity and insulin resistance. Sympathetic activity control after renal denervation has cardioprotective effects, especially for those with arrhythmia and left ventricular hypertrophy. Also, renal denervation could be helpful in renalorigin pain control. Renal denervation is an effective, safe, non-invasive procedure with many clinical benefits beyond blood pressure control. Further development in the procedure technique and selection of target patients are needed for wider clinical use of renal denervation in resistant hypertension.

Development of AI-generated medical responses using the ChatGPT for cancer patients.

BACKGROUND AND OBJECTIVE: To develop a healthcare chatbot service (AI-guided bot) that conducts real-time conversations using large language models to provide accurate health information to patients. METHODS: To provide accurate and specialized medical responses, we integrated several cancer practice guidelines. The size of the integrated meta-dataset was 1.17 million tokens. The integrated and classified metadata were extracted, transformed into text, segmented to specific character lengths, and vectorized using the embedding model. The AI-guide bot was implemented using Python 3.9. To enhance the scalability and incorporate the integrated dataset, we combined the AI-guide bot with OpenAI and the LangChain framework. To generate user-friendly conversations, a language model was developed based on Chat-Generative Pretrained Transformer (ChatGPT), an interactive conversational chatbot powered by GPT-3.5. The AI-guide bot was implemented using ChatGPT3.5 from Sep. 2023 to Jan. 2024. RESULTS: The AI-guide bot allowed users to select their desired cancer type and language for conversational interactions. The AI-guided bot was designed to expand its capabilities to encompass multiple major cancer types. The performance of the AI-guide bot responses was 90.98 ± 4.02 (obtained by summing up the Likert scores). CONCLUSIONS: The AI-guide bot can provide medical information quickly and accurately to patients with cancer who are concerned about their health.

Family-based genome-wide association analysis of novelty seeking in a Korean schizophrenic population: A pilot study.

Schizophrenia (SPR) is the most devastating mental illness that causes severe deterioration in social and occupational functioning, but, the etiology remains unknown. The objective of this study is to explore the genetic underpinnings of novelty seeking behavior in schizophrenic family within the Korean population. By conducting a family-based genome-wide association study, we aim to identify potential genetic markers and variations associated with novelty seeking traits in the context of SPR. We have recruited 27 probands (with SPR) with their parents and siblings whenever possible. DNA was extracted from blood sampling of 58 individuals in 27 families and analyzed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (qFAM) was used to derive SNP association values across all chromosomes. Although none of the final 800,000 SNPs reached the genome-wide significant threshold of 8.45 × 10-7, the most significant 4 SNPs were within the 10-5 to 10-7. This study identifies genetic associations between novelty seeking behavior and SPR within families. RAPGEF5 emerges as a significant gene, along with other neuropsychiatric-related genes. Noteworthy genes like DRD4 and COMT did not show associations, possibly due to the focus on schizophrenic family. While shedding light on this complex relationship, larger studies are needed for robust conclusions and deeper mechanistic insights.

Mortality of elderly patients with acute kidney injury undergoing continuous renal replacement therapy: is age a risk factor?

BACKGROUND: Whether advanced age is associated with poor outcomes of elderly patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is controversial. This study aimed to evaluate age effect and predictors for mortality in elderly AKI patients undergoing CRRT. METHODS: Data of 480 elderly AKI patients who underwent CRRT were retrospectively analyzed. Subjects were stratified into two groups according to age: younger-old (age, 65-74 years; n = 205) and older-old (age, ≥75 years; n = 275). Predictors for 28-day and 90-day mortality and age effects were analyzed using multivariable Cox regression analysis and propensity score matching. RESULTS: Urine output at the start of CRRT (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.99-1.00; p = 0.04), operation (aHR, 0.53; 95% CI, 0.30-0.93; p = 0.03), and use of an intra-aortic balloon pump (aHR, 3.60; 95% CI, 1.18-10.96; p = 0.02) were predictors for 28-day mortality. Ischemic heart disease (aHR, 1.74; 95% CI, 1.02-2.98; p = 0.04) and use of a ventilator (aHR, 0.56; 95% CI, 0.36-0.89; p = 0.01) were predictors for 90-day mortality. The older-old group did not exhibit a higher risk for 28- day or 90-day mortality than the younger-old group in multivariable or propensity score-matched models. CONCLUSION: Advanced age was not a risk factor for mortality among elderly AKI patients undergoing CRRT, suggesting that advanced age should not be considered for therapeutic decisions in critically ill elderly patients with AKI requiring CRRT.

[MR Imaging Features of Pediatric Bone Marrow]. / 소아 골수의 MR 영상 소견.

MRI plays a crucial role in bone marrow (BM) assessment, and has very high sensitivity in diagnosing marrow disorders. However, for radiologists who may not frequently encounter pediatric imaging, distinguishing pathologic BM lesion from normal BM can be challenging. Conditions involving the BM in pediatric patients, such as leukemia and metastatic neuroblastoma, often manifest with diverse musculoskeletal symptoms and may be diagnosed using musculoskeletal MRI examinations. Accurate interpretation of pediatric MRI requires not only an understanding of the normal composition of BM but also an awareness of agerelated developmental changes in the marrow and familiarity with conditions that commonly involve pediatric BM. We aim to describe the composition of normal BM and outline the normal and abnormal MRI findings in pediatric BM. Additionally, we aim to present clinical cases of malignant BM disorders including leukemia, neuroblastoma metastasis, and other malignant BM disorders.

Millingtonia hortensis L.f. ethanol extract exerts in vivo and in vitro anti-inflammatory activities through inhibition of Syk kinase in NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Millingtonia hortensis L.f., commonly known as tree jasmine or Indian cork tree, is native to South Asia and Southeast Asia. Traditionally, its stem bark, leaves, and roots are employed for pulmonary, gastrointestinal, and antimicrobial purposes, while the flowers are used in treating asthma and sinusitis. AIM OF THE STUDY: The underlying anti-inflammatory mechanisms of M. hortensis remain relatively unexplored. Therefore, we studied the anti-inflammatory effects of M. hortensis and the molecular mechanisms of its ethanol extracts (Mh-EE) both in vitro and in vivo. MATERIALS AND METHODS: Nitric oxide (NO) production was assessed using Griess reagent, while cell viability of RAW264.7 cell and HEK293T cells were determined via the MTT assay. Constituent analysis of Mh-EE using GC/MS-MS and HPLC, and mRNA expression of inflammatory cytokines was measured through PCR and RT-PCR. Protein levels were analyzed using western blotting. The thermal stability of Mh-EE was evaluated by CESTA. Lastly, a gastritis in vivo model was induced by HCl/EtOH, and protein expression levels were measured using western blotting. RESULTS: Mh-EE significantly reduced NO production in LPS-induced RAW264.7 cells without substantially affecting cell viability. Additionally, Mh-EE decreased the expression of proinflammatory factors, such as iNOS, IL-1ß and COX2. Furthermore, Mh-EE downregulated TLR4 expression, altered MyD88 recruitment, and suppressed phosphorylation of Syk, IKKα, IκBα and AKT. Simultaneously, Mh-EE also attenuated NF-κB signaling in HCl/EtOH-induced mice. CONCLUSIONS: Mh-EE exerts anti-inflammatory effects by suppressing p-Syk in the NF-κB pathway, and it has potential as a novel treatment agent for inflammatory diseases.

In vitro Fertilization Outcomes of Frozen-thawed Embryo Transfer with Hatched Blastocysts versus with Hatching Blastocysts.

This study aimed to elucidate the effect of hatching status on in vitro fertilization (IVF) outcomes in frozen-thawed blastocyst transfer cycles. Frozen-thawed embryo transfer (FET) cycles performed at a single fertility center between 2016 and 2021 were retrospectively assessed. Analyses were restricted to 6,821 frozen-thawed blastocyst transfers in women aged 24-47 years. For optimal comparability, double embryo transfer (ET) cycles consisting of one hatching and one hatched blastocyst were excluded. The implantation and pregnancy rates were evaluated and compared between the hatching and hatched blastocyst transfer groups based on patients' age (<38 vs. ≥38 years), blastocyst grade (good vs. bad grade), and the number of transferred embryos (single ET vs. double ET). Hatched blastocyst transfer was associated with higher implantation and clinical pregnancy rates in the single ET group (15.7% and 15.6%, respectively; p<0.001). The transfer of two hatched blastocysts had higher implantation and clinical pregnancy rates compared to the transfer of two hatching blastocysts (19.5% and 20.4%, respectively; p<0.001) in the double ET group. In the hatched blastocyst transfer group, the clinical pregnancy and implantation rates were higher, regardless of each woman's age and embryo quality. The IVF treatment outcomes were improved when the blastocysts were hatched during FET cycles. Hence, hatched blastocyst transfer in FET cycles could be considered a superior method in IVF practice.

Interface of gallium-based liquid metals: oxide skin, wetting, and applications.

Gallium-based liquid metals (GaLMs) are promising for a variety of applications-especially as a component material for soft devices-due to their fluidic nature, low toxicity and reactivity, and high electrical and thermal conductivity comparable to solid counterparts. Understanding the interfacial properties and behaviors of GaLMs in different environments is crucial for most applications. When exposed to air or water, GaLMs form a gallium oxide layer with nanoscale thickness. This "oxide nano-skin" passivates the metal surface and allows for the formation of stable microstructures and films despite the high-surface tension of liquid metal. The oxide skin easily adheres to most smooth surfaces. While it enables effective printing and patterning of the GaLMs, it can also make the metals challenging to handle because it adheres to most surfaces. The oxide also affects the interfacial electrical resistance of the metals. Its formation, thickness, and composition can be chemically or electrochemically controlled, altering the physical, chemical, and electrical properties of the metal interface. Without the oxide, GaLMs wet metallic surfaces but do not wet non-metallic substrates such as polymers. The topography of the underlying surface further influences the wetting characteristics of the metals. This review outlines the interfacial attributes of GaLMs in air, water, and other environments and discusses relevant applications based on interfacial engineering. The effect of surface topography on the wetting behaviors of the GaLMs is also discussed. Finally, we suggest important research topics for a better understanding of the GaLMs interface.

Characteristics of patients and facility of peritoneal dialysis in Korea: Results from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea.

BACKGROUND: Varying peritoneal dialysis (PD)-related clinical outcomes have been reported in different countries. As a participant of the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), this study investigated the characteristics of Korean PD patients, PD facilities and the incidence rates of clinical outcomes including mortality and PD-related outcomes. METHODS: From July 2019 to December 2021, a total of 766 Korean PD patients were included for analysis. Poisson regression analysis was used to explore the incidence rates of various clinical events including mortality, modality transfer, exit site or catheter tunnel infection and peritonitis. RESULTS: Among the 766 patients (median age 55.5 years, males 59.5%), 276 were incident and 490 were prevalent PD patients. The incidence rates of events were as follows: all-cause mortality (0.048), modality transfer (0.051), exit site or catheter tunnel infection (0.054) and peritonitis (0.136) events per person year. The most common causative organism for exit site or tunnel infection was staphylococcus species (47%) and that for peritonitis was streptococcus (28%) followed by staphylococcus (27%) species. CONCLUSIONS: Up to now, PDOPPS Korea has recruited 766 Korean PD patients and started documentation of major PD-related outcomes which occurred during the follow-up period. The overall incidence rates of clinical outcomes in Korean PD patients were relatively favourable. There was no statistically significant difference in the incidence rates of clinical outcomes according to both facility and patient factors.

Alteration of Keratinized Mucosa Dimensions in the Early Healing Period after Implant Placement: A 6-month Prospective Study.

PURPOSE: This study aimed to assess the alteration in keratinized mucosa (KM) dimensions in the early healing period after implant placement, and the influence of variables obtained during implant surgery on KM alteration. MATERIALS AND METHODS: Study participants were consecutively recruited from patients who had received implants following a non-submerged surgical protocol. The implant had to be installed in the extraction socket that had healed for more than 6 months without any soft or hard tissue augmentation. Keratinized mucosa width (KMW), keratinized mucosa thickness (KMT), soft tissue level (STL), and probing pocket depth (PPD) were measured at implant placement and 3 and 6 months after implant surgery. The influence of variables obtained during implant surgery on the 6-month KMW alteration was assessed. RESULTS: A total of 66 implants in 55 patients who completed the follow-up examination after 6 months were included in this study. KMW, KMT, and STL significantly decreased at 3- and 6-months examination by 0.7-1.2 mm. KMW was reduced by 24.6%. Mesial PPD significantly increased between the 3- and 6-months follow-up. In the multivariate generalized estimating estimations analysis, the implant diameter negatively influenced the 6-month KMW alteration, but the KMW at implant surgery positively influenced the 6-month KMW alteration. CONCLUSIONS: The KMW decreased significantly at 3 and 6 months after implant placement. If the initial KMW was wider, the KMW was reduced more at 6 months after implant placement. Therefore, it is important to carefully monitor KMW alterations during the early healing period to ensure optimal esthetics and peri-implant tissue health.

Mexenone protects mice from LPS-induced sepsis by EC barrier stabilization.

Blood vessels permit the selective passage of molecules and immune cells between tissues and circulation. Uncontrolled inflammatory responses from an infection can increase vascular permeability and edema, which can occasionally lead to fatal organ failure. We identified mexenone as a vascular permeability blocker by testing 2,910 compounds in the Clinically Applied Compound Library using the lipopolysaccharide (LPS)-induced vascular permeability assay. Mexenone suppressed the LPS-induced downregulation of junctional proteins and phosphorylation of VE-cadherin in Bovine Aortic Endothelial Cells (BAECs). The injection of mexenone 1 hr before LPS administration completely blocked LPS-induced lung vascular permeability and acute lung injury in mice after 18hr. Our results suggest that mexenone-induced endothelial cell (EC) barrier stabilization could be effective in treating sepsis patients.

Antioxidant Activities in Kenaf (Hibiscus cannabinus) Shoots during Growth Stages and Destination of Chlorogenic Acid and Kaempferol Glycosides.

Apart from being utilized as a commercial fiber at maturity, kenaf shoots have potential as a food and feed source because of their diverse bioactivities. Previous studies have focused on mature stems because of their high biomass, whereas the antioxidant activities (AA) and the destination of AA contributors of kenaf stems and their high-yielding byproduct leaves during the growth stage have rarely been studied. Therefore, we investigated changes in AA and its relative components in kenaf leaves and stems during the four vital growth stages. Higher ABTS radical cation and DPPH radical scavenging abilities and ferric reducing antioxidant power, total phenolic content, total flavonoid content, and total polysaccharide content were observed at all leaf stages and in the late stem stages. Chlorogenic acid (CGA) and kaempferol glycosides, especially kaempferitrin (Kfr), were identified as representative phenolic acids and flavonoids in both kenaf leaves and stems. The content of CGA in both leaves and stems increased corresponding to the plant's growth stage, whereas kaempferol glycosides were enhanced in leaves but declined in stems. The highest correlation was observed between TPC and AA in all organs. Further evaluation of CGA and Kfr verified that CGA was the predominant contributor to AA, surpassing Kfr. These findings suggest that kenaf leaves increase antioxidant levels as they grow and can be a useful source of stem harvesting byproducts.

Effects of high-intensity interval robot-assisted gait training on cardiopulmonary function and walking ability in chronic stroke survivors: A multicenter single-blind randomized controlled trial.

BACKGROUND: Chronic stroke can impair cardiopulmonary function, mobility, and daily activities. This study assessed the impact of robot-assisted gait training (RAGT) on such impairments. OBJECTIVE: To investigate the effects of robot-assisted gait training on cardiopulmonary function, walking ability, lower extremity function and strength, activities of daily living (ADLs), and blood test results among individuals with chronic stroke. METHODS: A multicenter, prospective, single-blinded, randomized controlled trial with 22 chronic stroke participants compared RAGT against a control exercise regimen. RAGT involved three days weekly sessions of high-intensity interval training for 8 weeks (24 sessions) with a Morning Walk® device. The control group also performed home exercises. (24 sessions) Measures included VO2max, Functional Ambulatory Category, 2-minute walk test, 10-meter walk test, Motricity Index-Lower, Korean version of the Fugl-Meyer Assessment Scale, Modified Barthel Index, Berg Balance Scale, muscle strength, InBody body composition, and blood tests (cholesterol, lipid, glucose). RESULTS: RAGT significantly improved VO2max, gait, balance, and lower limb strength compared with controls, with significant improvements in 2-minute walk test, 10-meter walk test, Motricity Index-Lower, and Fugl-Meyer Assessment outcomes. No changes were seen in muscle mass or blood markers. CONCLUSION: RAGT enhances cardiopulmonary function and ambulatory capacity in chronic stroke patients, underscoring its potential in stroke rehabilitation.

Conversion of gingerols to shogaols in ginger (Zingiber officinale roscoe) by puffing.

Effect of puffing on conversion of gingerols to shogaols, physicochemical properties as well as antioxidant and anti-inflammatory activities of puffed ginger was investigated. Puffing significantly increased extraction yield and the highest value was 12.52% at 980 kPa. The significant decrease in gingerols and increase in shogaols were occurred after puffing, respectively. Especially, 6-shogaol was dramatically increased from 4.84 to 99.10 mg/g dried ginger. Puffed ginger exhibited the higher antioxidant activities (analyzed by DPPH, ABTS, TPC, and TFC) than those of control, and they were significantly increased with increasing puffing pressure. In case of anti-inflammatory activity, puffed ginger did not inhibit NO production, but significantly inhibited TNF-α and IL-6 productions. Among gingerols and shogaols, 6-shogaol showed significantly strong correlations with both antioxidant and anti-inflammatory activities. Consequently, puffed ginger can be applied to functional food industry, which dramatically increased the contents of 6, 8, 10-shogaols, the main bioactive compounds in ginger.

Safe and successful pregnancy following breast cancer treatment in young patients 35 years old or under without invasive fertility preservation: a retrospective study.

Purpose: Recent advances in the treatment of breast cancer have led to the improvement of breast cancer patient's survival. With the prolonged survival of these patients, pregnancy became an important issue, especially in young cancer patient aged 35 years or under. Increased hormone levels during pregnancy, however, raise concerns about elevating the risk of cancer recurrence. The aim of this study was to validate the notion of increased risk associated with pregnancy after breast cancer treatment in young patients. Methods: From January 2009 to December 2020, newly diagnosed breast cancer patients 35 years old or under who underwent optimal surgery in Korea University Guro Hospital were enrolled in this study. Patients were categorized into 3 groups: nulliparous, pregnancy prior to treatment of breast cancer, and patients with pregnancy after breast cancer treatment. Their overall survival and disease-free survival were evaluated. Results: A total of 107 patients were enrolled in this study. Thirteen patients (12.1%) conceived and successfully delivered. The mean follow-up period after surgery was 58.9 (± 33.5) months. There was no significant difference in overall survival (P = 0.608) and disease-free survival (P = 0.591) among different groups. Conclusion: In young patients, pregnancy after treatment for breast cancer did not affect their overall survival or diseasefree survival as compared to nullipara or previously delivered groups. Therefore, pregnancy counseling should not be prevented in young breast cancer patients 35 years old or under.

Light-Induced Antioxidant Phenolic Changes among the Sprouts of Lentil Cultivar.

Lentil is a leguminous crop with a high content of health-beneficial polyphenols. Lentil sprouts are popularly consumed in fresh vegetable markets, although their phytochemical qualities are not well understood. In this study, we investigated the accumulation of phenolics in lentil sprouts in response to photosynthetic and stress light qualities, including fluorescent light (FL), red LED (RL), blue LED (BL), ultraviolet A (UV-A), and ultraviolet B (UV-B). Three lentil cultivars, Lentil Green (LG), French Green (FG), and Lentil Red (LR), were used to evaluate sprouts grown under each light condition. The adequate light intensities for enhancing the antioxidant activity of lentil sprouts were found to be 11 W/m2 under photosynthetic lights (FL, RL, BL), and 1 W/m2 under stress lights (UV-A, UV-B). Subsequently, HPLC-ESI/Q-TOF MS analysis was conducted for the quantitative analysis of the individual phenolics that were accumulated in response to light quality. Four main phenolic compounds were identified: ferulic acid, tricetin, luteolin, and kaempferol. Notably, tricetin accumulation was significantly enhanced under BL across all three lentil cultivars examined. Furthermore, the study revealed that the other phenolic compounds were highly dependent on FL, BL, or UV-B exposure, exhibiting cultivar-specific variations. Additionally, the antioxidant activities of lentil extracts indicated that BL was most effective for LG and FG cultivars, whereas FL was most effective for enhancing antioxidant activity of LR cultivars as the sprouts grew.

Congenital Intracranial Vascular Malformations in Children : Radiological Overview.

Prompt medical attention is crucial for congenital intracranial vascular malformations in children and newborns due to potential severe outcomes. Imaging is pivotal for accurate identification, given the diverse risks and treatment strategies. This article aims to enhance the identification and understanding of congenital intracranial vascular abnormalities including arteriovenous malformation, arteriovenous fistula, cavernous malformation, capillary telangiectasia, developmental venous anomaly, and sinus pericranii in pediatric patients.

Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it kills cancer cells while sparing normal cells. However, many cancers, including pancreatic ductal adenocarcinoma (PDAC), exhibit intrinsic or acquired resistance to TRAIL, and the molecular mechanisms underlying TRAIL resistance in cancers, particularly in PDAC, remain unclear. In this study, we demonstrated that glutamine (Gln) endows PDAC cells with resistance to TRAIL through KDM4C-mediated epigenetic regulation of cFLIP. Inhibition of glutaminolysis significantly reduced the cFLIP level, leading to TRAIL-mediated formation of death-inducing signaling complexes. Overexpression of cFLIP dramatically rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Alpha-Ketoglutarate (aKG) supplementation significantly reversed the decrease in the cFLIP level induced by glutaminolysis inhibition and rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Knockdown of glutamic-oxaloacetic transaminase 2, which facilitates the conversion of oxaloacetate and glutamate into aspartate and aKG, decreased aKG production and the cFLIP level and activated TRAIL-induced apoptosis. AKG-mediated epigenetic regulation was necessary for maintaining a high level of cFLIP. Glutaminolysis inhibition increased the abundance of H3K9me3 in the cFLIP promoter, indicating that Gln-derived aKG production is important for Jumonji-domain histone demethylase (JHDM)-mediated cFLIP regulation. The JHDM KDM4C regulated cFLIP expression by binding to its promoter, and KDM4C knockdown sensitized PDAC cells to TRAIL-induced apoptosis. The present findings suggest that Gln-derived aKG production is required for KDM4C-mediated epigenetic regulation of cFLIP, which leads to resistance to TRAIL.

Microneedles: A novel clinical technology for evaluating skin characteristics.

BACKGROUND: Current methods for evaluating efficacy of cosmetics have limitations because they cannot accurately measure changes in the dermis. Skin sampling using microneedles allows identification of skin-type biomarkers, monitoring treatment for skin inflammatory diseases, and evaluating efficacy of anti-aging and anti-pigmentation products. MATERIALS AND METHODS: Two studies were conducted: First, 20 participants received anti-aging treatment; second, 20 participants received anti-pigmentation treatment. Non-invasive devices measured skin aging (using high-resolution 3D-imaging in the anti-aging study) or pigmentation (using spectrophotometry in the anti-pigmentation study) at weeks 0 and 4, and adverse skin reactions were monitored. Skin samples were collected with biocompatible microneedle patches. Changes in expression of biomarkers for skin aging and pigmentation were analyzed using qRT-PCR. RESULTS: No adverse events were reported. In the anti-aging study, after 4 weeks, skin roughness significantly improved in 17 out of 20 participants. qRT-PCR showed significantly increased expression of skin-aging related biomarkers: PINK1 in 16/20 participants, COL1A1 in 17/20 participants, and MSN in 16/20 participants. In the anti-pigmentation study, after 4 weeks, skin lightness significantly improved in 16/20 participants. qRT-PCR showed significantly increased expression of skin-pigmentation-related biomarkers: SOD1 in 15/20 participants and Vitamin D Receptor (VDR) in 15/20 participants. No significant change in TFAP2A was observed. CONCLUSION: Skin sampling and mRNA analysis for biomarkers provides a novel, objective, quantitative method for measuring changes in the dermis and evaluating the efficacy of cosmetics. This approach complements existing evaluation methods and has potential application in assessing the effectiveness of medical devices, medications, cosmeceuticals, healthy foods, and beauty devices.