Unveiling the Incidence and Graft Survival Rate in Kidney Transplant Recipients With De Novo Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis.

De novo thrombotic microangiopathy (TMA) is a rare and challenging condition in kidney transplant recipients, with limited research on its incidence and impact on graft survival. This study conducted a systematic review and meta-analysis of 28 cohorts/single-arm studies and 46 case series/reports from database inception to June 2022. In meta-analysis, among 14,410 kidney allograft recipients, de novo TMA occurred in 3.20% [95% confidence interval (CI): 1.93-4.77], with systemic and renal-limited TMA rates of 1.38% (95% CI: 06.5-2.39) and 2.80% (95% CI: 1.27-4.91), respectively. The overall graft loss rate of de novo TMA was 33.79% (95% CI: 26.14-41.88) in meta-analysis. This study provides valuable insights into the incidence and graft outcomes of de novo TMA in kidney transplant recipients.

Origin of unique electronic structures of single-atom alloys unraveled by interpretable deep learning.

We uncover the origin of unique electronic structures of single-atom alloys (SAAs) by interpretable deep learning. The approach integrates tight-binding moment theory with graph neural networks to accurately describe the local electronic structure of transition and noble metal sites upon perturbation. We emphasize the complex interplay of interatomic orbital coupling and on-site orbital resonance, which shapes the d-band characteristics of an active site, shedding light on the origin of free-atom-like d-states that are often observed in SAAs involving d10 metal hosts. This theory-infused neural network approach significantly enhances our understanding of the electronic properties of single-site catalytic materials beyond traditional theories.

Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion.

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

Prescription Pattern in Angiotensin Receptor Neprilysin Inhibitor is Associated with Heart Failure Events.

Background: Angiotensin receptor neprilysin inhibition (ARNI) is superior to enalapril in reducing the risk of cardiovascular death and heart failure hospitalization (HFH). However, whether prescription pattern is associated with heart failure outcome is unknown. Methods: This is a retrospective study of 153 patients who received ARNI in a tertiary medical center in Taiwan. We analyzed the impact of dose up-titration and prescription timing including during initial admission, within 3 months after initial HFH discharge, and at outpatient clinics without prior HFH. The primary endpoint was the composite of cardiovascular death and HFH. Results: After a mean follow-up period of 287 ± 197 days, the primary endpoint occurred in 43 (28.1%) subjects. Patients without and with a primary endpoint significantly differed in terms of history of valvular heart disease (VHD, p = 0.006), ventricular tachyarrhythmia (VT, p = 0.043), percutaneous coronary intervention (p = 0.007), coronary artery bypass grafting (p = 0.002), chronic kidney disease (p = 0.002), age (p = 0.002), diastolic blood pressure (p = 0.025), and prescription timing (p = 0.002). Kaplan-Meier analysis showed ARNI up-titration and prescription timing had a significant association with primary endpoint-free survival (Breslow test; p = 0.032, and log-rank test; p = 0.001, respectively). Cox regression analysis showed that independent predictors for the primary endpoint were ARNI up-titration [hazard ratio (HR): 0.41, p = 0.024], non-hospital ARNI versus hospital ARNI (HR: 0.41, p = 0.009), VHD (HR: 2.71, p = 0.013), VT (HR: 3.09, p = 0.02), and age (HR: 1.03, p = 0.033). Conclusions: The prescription pattern of ARNI could be associated with heart failure events.

Comparison of effectiveness and safety between ticagrelor and clopidogrel in patients with acute coronary syndrome and on dialysis in Taiwan.

AIMS: This study aimed to evaluate and compare the effectiveness and safety between clopidogrel and ticagrelor in acute coronary syndrome (ACS) with renal dysfunction. METHODS: We conducted a retrospective cohort study on patients on chronic dialysis and whose admission diagnosis between 1 July 2013 and 31 December 2016 included ACS. The primary effectiveness endpoint was a major adverse cardiovascular event (MACE), and the primary safety endpoint was a major bleeding event. The application of propensity scores through the inverse probability of treatment weighting (IPTW) was applied to the study groups. Cox regression was used to estimate hazard ratios (aHRs) of study endpoints. In addition, the competing risk was adjusted using the Fine and Gray competing risk model. RESULTS: There were 1915 patients in the clopidogrel group and 270 patients in the ticagrelor group. At 12 months, the ticagrelor group had higher risks for MACE (aHR with IPTW: 1.29; 95% CI 1.16-1.44); death (aHR with IPTW: 1.65; 95% CI 1.47-1.86) and cardiac death (subdistribution HR [SHR] with IPTW: 1.64; 95% CI 1.41-1.91), compared with those in the clopidogrel group. For major bleeding event, the risk was significantly higher with ticagrelor than with clopidogrel (SHR with IPTW: 1.49; 95% CI 1.34-1.65). In terms of the risk for any bleeding event, there was no significant difference between the two groups (SHR with IPTW: 1.05; 95% CI 0.95-1.17). CONCLUSIONS: Compared with clopidogrel, ticagrelor was associated with higher MACE, death, cardiac death and major bleeding risk within 12 months in patients with ACS and on dialysis.

Zoledronic acid blocks the interaction between breast cancer cells and regulatory T-cells.

BACKGROUND: Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits osteoclastogenesis. Emerging evidence suggests that ZA has anti-tumor and anti-metastatic properties for breast cancer cells. In a mouse model of ZA-related osteonecrosis of the jaw, ZA administration was found to suppress regulatory T-cells (Tregs) function. Our previous reports also demonstrated ZA acted as an immune modulator to block Tregs. Manipulation of Tregs represents a new strategy for cancer treatment. However, the relationship among ZA, Tregs, and cancer cells remains unclear. In this study, we investigated the effects of ZA on the interaction of breast cancer cells and Tregs. METHODS: The anti-tumor effect of ZA on triple negative breast cancer cell lines were validated by XTT, wound healing and apoptosis analysis. A flow cytometry-based assay was used to analyze the immunosuppressive effect of Tregs treated with media conditioned by breast cancer cells, and a transwell assay was used to evaluate the chemotactic migration of Tregs. Differential gene expression profile on MDA-MB-231 treated with ZA (25 µM) was analyzed by. microarrays to describe the molecular basis of actions of ZA for possible direct anti-tumor effects. Enzyme-linked immunosorbent assays and quantitative real-time PCR were used to investigate the effect of ZA on the expression of cytokines/factors by breast cancer cells. RESULTS: ZA was found to inhibit the proliferation and migration of breast cancer cells. Media conditioned by the MDA-MB-231 cells promoted the expansion, chemotactic migration, and immunosuppressive activity of Tregs, and these effects were attenuated in a dose-dependent manner by ZA treatment, and the attenuation was due to reduced expression of selected breast cancer cell factors (CCL2, CCL5, and IDO). CONCLUSIONS: ZA can significantly affect the interaction between breast cancer cells and Tregs. Our findings indicate that ZA is a potential therapeutic agent that can be used to reduce cancer aggressiveness by abolishing the supportive role of Tregs.

Acute Heat Stress Changes Protein Expression in the Testes of a Broiler-Type Strain of Taiwan Country Chickens.

Heat stress leads to decreased fertility in roosters. This study investigated the global protein expression in response to acute heat stress in the testes of a broiler-type strain of Taiwan country chickens (TCCs). Twelve 45-week-old roosters were randomly allocated to the control group maintained at 25°C, and three groups subjected to acute heat stress at 38°C for 4 h, with 0, 2, and 6 h of recovery, respectively. Testis samples were collected for hematoxylin and eosin staining, apoptosis assay, and protein analysis. The results revealed 101 protein spots that differed significantly from the control following exposure to acute heat stress. The proteins that were differentially expressed participated mainly in protein metabolism and other metabolic processes, responses to stimuli, apoptosis, cellular organization, and spermatogenesis. Proteins that negatively regulate apoptosis were downregulated and proteins involved in autophagy and major heat shock proteins (HSP90α, HSPA5, and HSPA8) were upregulated in the testes of heat-stressed chickens. In conclusion, acute heat stress causes a change in protein expression in the testes of broiler-type B strain TCCs and may thus impair cell morphology, spermatogenesis, and apoptosis. The expression of heat shock proteins increased to attenuate the testicular injury induced by acute heat stress.

Annotation of differential protein expression in the hypothalami of layer-type Taiwan country chickens in response to acute heat stress.

The hypothalamus is the coordinating center for maintaining temperature homeostasis. In this study, global protein expression in the hypothalami of layer-type Taiwan country chickens in response to acute heat stress was investigated. Twelve 30-week-old female TCCs were divided into three acute heat-stressed groups, namely acute heat stress at 36 °C for 4 h with 0 h (without recovery, H4R0), 2 h (H4R2), or 6 h (H4R6) of recovery. A control group was maintained at 25 °C. Hypothalamus samples were collected at the end of each time point for proteomic analysis. The analysis results revealed that 134 protein spots representing 118 distinct proteins exhibited differential expressions after acute heat stress treatment. Results of gene ontology analysis showed that most of the differentially expressed proteins are involved in carbohydrate metabolism, cellular processes, actin cytoskeleton organization, and responses to stimuli. Functional pathway analysis results suggested that the proteins are associated with networks of carbon metabolism, glycolysis, and gluconeogenesis. Upregulation of the expression of triosephosphate isomerase, phosphoglycerate kinase, pyruvate kinase, alpha-enolase, glycogen phosphorylase (brain form), phosphoglucomutase, L-lactate dehydrogenase A chain and downregulation of 6-phosphogluconolactonase expression indicated an increase in the glycolytic activity and glucose supply for ATP production in the hypothalami in response to heat stress. By contrast, upregulated expressions of heat shock protein 90 alpha, glutathione S-transferase 2s, peroxiredoxin-1, and dihydropyrimidinase-like 2 suggested that acute heat stress adversely affects the hypothalamus; thus, it induces mechanisms that prevent oxidative damage and endoplasmic reticulum stress. In conclusion, acute heat stress induces differential protein expression in the hypothalami of the L2 strain Taiwan country chickens, which may manifest detrimental effects. Furthermore, differential expression is a critical response in the hypothalamus for the regulation of thermotolerance.

Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid.

BACKGROUND: CD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA. METHODS: Flow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells. RESULTS: Proliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect. CONCLUSIONS: Our findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.

[Community Integrated Support Centers: The Experience of Hachioji, Tokyo, Japan].

The proportion of elderly in Taiwan reached 11.99% of the population in 2014. Further, Taiwan is expected to become a super-aged society, as defined by the United Nations, in 2025. Elderly and long-term care needs have increased dramatically and long-term care (LTC) has become an increasingly important focus of policymaking. Japan, already a super-aged society, enacted LTC insurance in 2000 and has since implemented comprehensive LTC services nationwide. This article describes the evolution of the LTC insurance plan in Japan and the function of the Community Inclusive Care System. The latter integrates medical care, homecare services, LTC services, living support, and Community Integrated Support Centers with public-health nurses, social workers, and care managers in order to facilitate the construction of services that enhance aging in place. The authors hope that learning from Japan's experience in developing LTC will facilitate the future development of LTC services in Taiwan.

A room temperature nitric oxide gas sensor based on a copper-ion-doped polyaniline/tungsten oxide nanocomposite.

The parts-per-billion-level nitric oxide (NO) gas sensing capability of a copper-ion-doped polyaniline/tungsten oxide nanocomposite (Cu(2+)/PANI/WO3) film coated on a Rayleigh surface acoustic wave device was investigated. The sensor developed in this study was sensitive to NO gas at room temperature in dry nitrogen. The surface morphology, dopant distribution, and electric properties were characterized using scanning electron microscopy, energy-dispersive X-ray spectroscopy mapping, and Hall effect measurements, respectively. The Cu(2+)/PANI/WO3 film exhibited high NO gas sensitivity and selectivity as well as long-term stability. At 1 ppb of NO, a signal with a frequency shift of 4.3 ppm and a signal-to-noise ratio of 17 was observed. The sensor exhibited distinct selectivity toward NO gas with no substantial response to O2, NH3 and CO2 gases.

Alternative therapy for acute appendicitis with appendicolith using traditional Chinese medicine: A case report.

INTRODUCTION: Treating older patients with acute appendicitis with multiple underlying diseases is a challenging situation in the clinical setting. Throughout the history of East Asian medicine, many texts have noted the use of herbal decoctions to successfully treat symptoms associated with appendicitis, thereby providing an alternative management strategy for treating frail patients with acute appendicitis. CASE PRESENTATION: This report presents the case of a 93-year-old male diagnosed with acute appendicitis with appendicolith who was unsuitable for surgical intervention due to poor lung condition and prolonged prothrombin time caused by Apixaban. By receiving complementary therapy consisting of traditional Chinese medicine (TCM) and antibiotics, he recovered successfully. DISCUSSION: In the early stage of acute appendicitis, infection control and gastrointestinal mobility are the most important factors to consider. Scientific research has demonstrated that many herbs used in TCM formulas possess anti-inflammatory, anti-oxidative and immune attenuation effects. For many patients who are unsuitable for surgical intervention due to unfavorable conditions, such as the prolonged prothrombin time presented in this case, complementary treatment with TCM offers adjuvant therapeutical effects associated with infection control, and improvement of the gastrointestinal environment and function of elderly patients.

Alternative therapy for lymphoma with febrile neutropenia using traditional Chinese medicine: A case report.

INTRODUCTION: Febrile neutropenia is a common complication in patients undergoing chemotherapy for hematologic malignancies and is associated with significant morbidity and mortality. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis is consistently associated with a notable reduction in the risk of febrile neutropenia. However, the use of G-CSF in patients who are already neutropenic from chemotherapy remains controversial. Studies have shown that 12.9 % of cancer patients incorporate traditional Chinese medicine (TCM) to alleviate chemotherapy side effects in Taiwan; thereby providing an alternative management strategy for febrile neutropenia in cancer patients. CASE PRESENTATION: This is an 18-year-old female with newly diagnosed precursor T-lymphoblastic lymphoma. After chemotherapy, the patient developed febrile neutropenia. Despite the use of antibiotics and G-CSF, the febrile neutropenia persisted for two months. Approximately ten days after the initiation of traditional Chinese medicine decoction with the strategy of tonifying the spleen and stomach, clearing yin fire, and uplifting yang, her absolute neutrophil count (ANC) had gradually increased. Additionally, after two weeks of treatment, her fever subsided. The patient continued with chemotherapy and was discharged in stable condition. DISCUSSION: Antibiotic use aligns with the TCM perspective of an "attack" approach. Conversely, our TCM decoction was designed to raise the ANC by tonifying the spleen and stomach, clearing Yin Fire, and uplifting Yang. Li Dongyuan, one of the four great masters of the Jin Yuan Dynasty, created the formula: Bupiwei Shengyang Sanhuo Decoction that is notable in this regard. The herbs in our decoction have shown hematopoietic and myelosuppression-alleviating effect. For many patients who do not respond adequately to G-CSF alone, integrative treatments involving both TCM and Western medicine can offer additional therapeutic benefits by increasing blood cell counts.

Unraveling Reactivity Origin of Oxygen Reduction at High-Entropy Alloy Electrocatalysts with a Computational and Data-Driven Approach.

High-entropy alloys (HEAs), characterized as compositionally complex solid solutions with five or more metal elements, have emerged as a novel class of catalytic materials with unique attributes. Because of the remarkable diversity of multielement sites or site ensembles stabilized by configurational entropy, human exploration of the multidimensional design space of HEAs presents a formidable challenge, necessitating an efficient, computational and data-driven strategy over traditional trial-and-error experimentation or physics-based modeling. Leveraging deep learning interatomic potentials for large-scale molecular simulations and pretrained machine learning models of surface reactivity, our approach effectively rationalizes the enhanced activity of a previously synthesized PdCuPtNiCo HEA nanoparticle system for electrochemical oxygen reduction, as corroborated by experimental observations. We contend that this framework deepens our fundamental understanding of the surface reactivity of high-entropy materials and fosters the accelerated development and synthesis of monodisperse HEA nanoparticles as a versatile material platform for catalyzing sustainable chemical and energy transformations.

Privacy preservation for federated learning in health care.

Artificial intelligence (AI) shows potential to improve health care by leveraging data to build models that can inform clinical workflows. However, access to large quantities of diverse data is needed to develop robust generalizable models. Data sharing across institutions is not always feasible due to legal, security, and privacy concerns. Federated learning (FL) allows for multi-institutional training of AI models, obviating data sharing, albeit with different security and privacy concerns. Specifically, insights exchanged during FL can leak information about institutional data. In addition, FL can introduce issues when there is limited trust among the entities performing the compute. With the growing adoption of FL in health care, it is imperative to elucidate the potential risks. We thus summarize privacy-preserving FL literature in this work with special regard to health care. We draw attention to threats and review mitigation approaches. We anticipate this review to become a health-care researcher's guide to security and privacy in FL.

Induction of Petite Colonies in Candida glabrate via Rose Bengal-Mediated Photodynamic Therapy.

Facing a 40% mortality rate in candidemia patients, drug-resistant Candida and their petite mutants remain a major treatment challenge. Antimicrobial photodynamic therapy (aPDT) targets multiple fungal structures, unlike antibiotics/antifungals, potentially thwarting resistance. Traditional methods for inducing petite colonies rely on ethidium bromide or fluconazole, which can influence drug susceptibility and stress responses. This study investigated the application of green light (peak 520 nm) and rose bengal (RB) photosensitizer to combat a drug-resistant Candida glabrata isolate. The findings revealed that aPDT treatment significantly inhibited cell growth (≥99.9% reduction) and effectively induced petite colony formation, as evidenced by reduced size and loss of mitochondrial redox indicator staining. This study provides initial evidence that aPDT can induce petite colonies in a multidrug-resistant C. glabrata strain in vitro, offering a potentially transformative approach for combating resistant fungal infections.

Assessing sugar-sweetened beverage consumption in early pregnancy using a substance abuse framework.

Sugar-sweetened beverages (SSB) are previously reported to jeopardize maternal fetal health, most well-known for gestational diabetes, childhood obesity, and cognitive impairment. Although warnings and diet recommendations urge pregnant women to consume less SSB, there is no noticeable difference in their behavior. How and why reproductive women change their SSB consumption patterns were not investigated previously. Our study aims to investigate beverage consumption patterns and how these patterns change in pregnancy in the context of substance use disorder (SUD). We invited all pregnant women visiting the clinic to answer a structured 20-min questionnaire every trimester during the regular antennal visit. At the end of the study, 337 pregnant women aged over 20 participated. A total of 301 responses entered for final analysis, with a response rate of 89.3%. Our finding showed those with high DSM-5-TR scores reduced SSB intake after becoming pregnant, while those with mild or low DSM-5-TR scores increased SSB intake after becoming pregnant. The top 3 factors related to their SSB consumption were "use despite of known health hazard (n = 133)", "increased desire to drink (n = 88)", and "excessive time spent on seeking SSB (n = 85)". The least reported factors were in the domains of social impairment (ranging from n = 3 to n = 26), pharmacologic effects (i.e., tolerance (n = 24) and withdrawal (n = 70). When participants reduced SSB consumption after becoming pregnant, their choice of beverages largely shifted to sugarless beverage but not much plain water. The result provided new insights in deciphering pregnant women's psychomotor factors for SSB intake, which served as useful references for making clinical or even public health recommendations.

Interpretable design of Ir-free trimetallic electrocatalysts for ammonia oxidation with graph neural networks.

The electrochemical ammonia oxidation to dinitrogen as a means for energy and environmental applications is a key technology toward the realization of a sustainable nitrogen cycle. The state-of-the-art metal catalysts including Pt and its bimetallics with Ir show promising activity, albeit suffering from high overpotentials for appreciable current densities and the soaring price of precious metals. Herein, the immense design space of ternary Pt alloy nanostructures is explored by graph neural networks trained on ab initio data for concurrently predicting site reactivity, surface stability, and catalyst synthesizability descriptors. Among a few Ir-free candidates that emerge from the active learning workflow, Pt3Ru-M (M: Fe, Co, or Ni) alloys were successfully synthesized and experimentally verified to be more active toward ammonia oxidation than Pt, Pt3Ir, and Pt3Ru. More importantly, feature attribution analyses using the machine-learned representation of site motifs provide fundamental insights into chemical bonding at metal surfaces and shed light on design strategies for high-performance catalytic systems beyond the d-band center metric of binding sites.

Prognostic serum biomarkers in cancer patients with COVID-19: A systematic review.

PURPOSE: Cancer patients with COVID-19 likely express biomarker changes in circulation. However, the biomarkers used in SARS-CoV-2 infected cancer patients for COVID-19 severity and prognosis are largely unclear. Therefore, this systematic review aims to determine what biomarkers were measured in cancer patients with COVID-19 and their prognostic utility. METHODS: A systematic literature review in PubMed, Embase, and Scopus was performed on June 16th, 2021. The search keywords coronavirus, neoplasm, biomarkers, and disease progression were used to filter out 17 eligible studies, which were then carefully evaluated. RESULTS: A total of 4,168 patients, 16 types of cancer, and 60 biomarkers were included. Seven up-regulated markers, including CRP, d-dimer, ferritin, IL-2R, IL-6, LDH, and PCT, were identified in eligible studies. Albumin and hemoglobin were significantly down-regulated in cancer patients with COVID-19. Moreover, we observed that the SARS-CoV-2 infected cancer patients with lower CRP, ferritin, and LDH levels successfully survived from COVID-19 treatments. CONCLUSION: Several important clinical biomarkers, such as CRP, ferritin, and LDH, may serve as the prognostic markers to predict the outcomes following COVID-19 treatment and monitor the deterioration of COVID-19 in cancer patients.

Prinsepiae Nux Extract Activates NRF2 Activity and Protects UVB-Induced Damage in Keratinocyte.

Ultraviolet B (UVB) is one of the most important environmental factors that cause extrinsic aging through increasing intracellular reactive oxygen species (ROS) production in the skin. Due to its protective roles against oxidative stress, nuclear factor erythroid-2-related factor (NRF2) has been traditionally considered as a target for skin aging prevention. Here, we identified the extract of Prinsepiae Nux, a top-grade drug listed in Shen Nong Ben Cao Jing, as a potent NRF2 activator by high-throughput screening. A bioassay-guided fractionation experiment revealed that NRF2-activating components were concentrated in the 90% methanol (MP) fraction. MP fraction significantly increased the expression of NRF2 and HO-1 protein and upregulated HO-1 and NQO1 mRNA expression in HaCaT cells. Moreover, MP fraction pre-treatment dramatically reversed UVB-induced depletion of NRF2 and HO-1, accumulation of intracellular ROS, NF-κB activation, and the upregulation of pro-inflammatory genes. Finally, the qualitative analysis using UPLC-tandem mass spectroscopy revealed the most abundant ion peak in MP fraction was identified as α-linolenic acid, which was further proved to activate NRF2 signaling. Altogether, the molecular evidence suggested that MP fraction has the potential to be an excellent source for the discovery of natural medicine to treat/prevent UVB-induced skin damage.