👤 Haeyoun Kang

Previous studies have reported that 40 Hz visual stimulation (acute white light exposure) reduced Aβ levels in Alzheimer's disease (AD) mouse model. However, whether different light colors distinctly regulate AD pathologies has not been well characterized. In the present study, an optimized organic light-emitting diode (OLED)-based visual stimulation platform was developed to provide uniform illumination without blind spots, and the color-dependent effects on cognitive function and amyloid-β (Aβ) pathology were investigated in 5xFAD mice, an Aβ-overexpressing AD model. Acute exposure to white or red OLED light (1 h/day for 2 days) significantly improved cognitive function, reduced hippocampal Aβ plaque accumulation via increasing ADAM17 activity, and downregulated proinflammatory cytokine IL-1β levels in 3-month-old 5xFAD mice, whereas green or blue OLED light did not produce these effects. In addition, chronic white and red OLED stimulation (1 h/day for 2 weeks) was shown to enhance recognition memory; however, only red light further diminished Aβ plaque deposition by upregulating ADAM17 activity and suppressing BACE-1 activity without altering neuroinflammation in 6-month-old 5xFAD mice. Moreover, acute white and red OLED exposure (1 h, single session) was observed to enhance c-fos expression, which is associated with neural activation along the visual pathway, thereby suggesting a mechanistic link between light stimulation and cognitive enhancement. Taken together, these findings demonstrate that color-dependent visual stimulation may serve as a promising electroceutical strategy for AD, with red light uniquely combining memory enhancement, Aβ reduction via ADAM17 upregulation and BACE1 suppression, and anti-inflammatory effects. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition and neurofibrillary tangles, which collectively drive neuroinflammation, synaptic dysfunction, and cognitive decline. Here, we investigated whether a peptide epitope vaccine targeting the Aβ1-10 sequence could mitigate Aβ-induced pathology in AD mouse model. Three Aβ1-10 peptides, i.e. Aβ1-10-N, Aβ1-10-D1H, and Aβ1-10-S8R were synthesized, and Aβ1-10-S8R was further conjugated to ovalbumin (OVA) or keyhole limpet hemocyanin (KLH) to enhance immunogenicity. Among seven treatment groups, Aβ1-10-D1H and Aβ1-10-S8R, particularly when conjugated to OVA or KLH, effectively suppressed Aβ, amyloid-beta precursor protein (APP), and beta-secretase 1 (BACE-1) expression, decreased inflammatory cytokine production by astrocytes and microglia, and increased the levels of key synaptic markers (synaptophysin, synaptosomal-associated protein 23 [SNAP-23], postsynaptic density protein 95 [PSD-95]). Carrier protein conjugation also elevated immunoglobulin G (IgG) levels in the spleen, indicative of a robust humoral response. Taken together, these findings demonstrate that Aβ1-10-based immunization, especially with OVA or KLH conjugation, reduces Aβ-driven neuroinflammation, synaptic dysfunction, and memory deficits, suggesting a promising immunotherapeutic strategy for AD. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6-TG directly interacts with RAGE, modulating BACE1 expression through the JAK2-STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. The findings illuminate the therapeutic potential of 6-TG in ameliorating AD manifestations and advocate for small molecule strategies to increase brain sRAGE levels, offering a strategic alternative to the challenges posed by the complexity of AD. Show less

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less

Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes. First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response. Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission ( This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway. Show less

Nonalcoholic fatty liver disease is a hepatic condition characterized by excessive fat accumulation in the liver with advanced stage nonalcoholic steatohepatitis (NASH), potentially leading to liver fibrosis, cirrhosis, and cancer. Currently, the identification and classification of NASH require invasive liver biopsy, which has certain limitations. Mass spectrometry-based proteomics can detect crucial proteins and pathways implicated in NASH development and progression. We collected the liver and serum samples from choline-deficient, L-amino acid-defined high-fat diet fed NASH C57BL/6J mice and human serum samples to examine proteomic alterations and identify early biomarkers for NASH diagnosis. In-depth targeted multiple reaction monitoring scanning and immunoblotting assays were used to verify the biomarker candidates from mouse liver and serum samples, and enzyme-linked immunosorbent assay (ELISA) was employed to analyze human serum samples. The multiple reaction monitoring analysis of NASH liver revealed 50 proteins with altered expression (21 upregulated and 29 downregulated) that are involved in biological processes such as detoxification, fibrosis, inflammation, and fatty acid metabolism. Ingenuity pathway analysis identified impaired protein synthesis, cellular stress and defense, cellular processes and communication, and metabolism in NASH mouse liver. Immunoblotting analysis confirmed that the expression of proteins associated with fatty acid metabolism (Aldo B and Fasn) and urea cycle (Arg1, Cps1, and Otc) was altered in the mouse liver and serum. Further analysis on human serum samples using ELISA confirmed the increased expression of multiple proteins, including Aldo B, Asl, and Lgals3, demonstrating values of 0.917, 0.979, and 0.965 of area under the curve in NASH diagnosis. These findings offer valuable insights into the molecular mechanisms of NASH and possible diagnostic biomarkers for early detection. Show less

Osteoarthritis (OA) is a multifactorial disease influenced by both genetic and environmental factors. Recent studies suggest that genetic variants involved in nutrient metabolism may interact with dietary factors to modulate OA risk. Understanding these gene-nutrient interactions could inform personalized prevention strategies for OA. We conducted a cross-sectional study involving 500 participants to explore associations between specific genetic variants and OA susceptibility, considering dietary intake. Genotyping focused on polymorphisms in the FADS1 gene (rs174537) related to omega-3 fatty acid metabolism, the VDR gene (rs2228570) involved in vitamin D metabolism, and the IL-6 gene (rs1800795), a marker of inflammation. Dietary intake of omega-3 fatty acids, vitamin D, and antioxidants was assessed using validated food frequency questionnaires. Gene-nutrient interactions were evaluated using multivariable logistic regression models, adjusting for potential confounders. Individuals carrying the G allele of FADS1 who reported low omega-3 fatty acid intake exhibited a significantly increased risk of OA [Odds Ratio (OR) = 1.45; 95% Confidence Interval (CI): 1.10-1.90; Show less

The "cold" tumor microenvironment of oral squamous cell carcinoma (OSCC), where tumor-associated lymphatic vessels play a critical role in the transport of immune cells, is associated with a poor prognosis. However, the effect of tumor-induced lymphangiogenesis on CD8+ T cell infiltration and its role in the formation of the tumor immune microenvironment remain unclear. We analyzed the prognostic significance of several lymphangiogenesis factors in OSCC with The Cancer Genome Atlas dataset, and confirmed the impact of fibroblast growth factor-2 (FGF-2) on prognosis in tissue specimens. Subsequently, we investigated the effects of FGF-2 on the proliferation, migration, and tube formation capacities of lymphatic endothelial cells, and CD8+ T cell infiltration through in vivo and in vitro experiments. Survival analysis was performed by Kaplan-Meier analysis and log-rank tests. The hazard ratio was calculated by Cox proportional hazards model. Patients with high FGF-2 levels and increased numbers of peritumoral lymphatic vessels were associated with a worse prognosis. Furthermore, we demonstrated that tumor cell-derived FGF-2 promoted lymphangiogenesis by regulating the FGFR1/PTEN/AKT axis and increased the secretion of CXCL9 to recruit and egress CD8+ T cells via neo-lymphatic vessels. PD-166866, an inhibitor of FGFR1, suppressed lymphangiogenesis and the secretion of CXCL9 to increase CD8+ T cell infiltration and inhibit tumor progression. Our data suggest that FGF-2 is a significant prognostic factor that induces lymphangiogenesis and affects intratumoral CD8+ T cells, contributing to the formation of a "cold" tumor microenvironment in OSCC. FGF-2/FGFR1 could serve as an effective target for improving the prognosis of OSCC. Show less

Protein-protein interactions (PPIs) mediate many fundamental cellular processes. Control of PPIs through optically or chemically responsive protein domains has had a profound impact on basic research and some clinical applications. Most chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, whilst the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a homodimeric oxidoreductase from mycobacteria (MSMEG₂₀₂₇₎ by its native cofactor, F Show less

Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) PIK3CA-mutated advanced BC. In addition, the FDA approved capivasertib (Trucap, AstraZeneca) for HR+HER2- locally advanced or metastatic BC patients with one or more AKT1, PIK3CA, or PTEN alterations. Finally, the FDA recently approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal patients with ER+ HER2- ESR1-mutated advanced or metastatic BC with disease progression following at least one line of endocrine therapy. This study presents a single institutional retrospective review of genomic reports of patients with BC. Analysis of genomic reports of 1361 BC sequencing reports was performed for 1010 patients with BC from 2013 to 2023 (23% of patients had multiple reports). Eligible patients had at least one primary or metastatic tumor. Multiple sequencing platforms were used for FFPE specimens including Tempus xT targeted next-generation sequencing (NGS), Foundation One Medicine, HopeSeq, Ashion Analytics GEM ExTra, and Exact Sciences Oncomap. Liquid biopsies were performed by Guardant, Tempus, and Foundation One Medicine. Chart reviews were performed to collect patient characteristics. BRCA1/2-mutated, metastatic BC patients who initiated treatment with olaparib or talazoparib, and PIK3CA-mutated, HR+ metastatic BC patients who initiated treatment with alpelisib were reported. In addition, patients with ESR1 or AKT1/PIK3CA/PTEN mutations were identified. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed for BRCA1/2 and PIK3CA-mutated patients who received PARPi or alpelisib. Survival curves were generated using the Kaplan Meier method. A cohort of 1010 BC patients with 1361 genomic reports was identified. A total of 935/1361 (69%) specimens were formalin-fixed paraffin-embedded (FFPE) tumor biopsies and 426/1361 (31%) were liquid biopsies. Receptor status included 65% HR+HER2-, 8% HR+HER2+, 4% HR-HER2+, and 23% TNBC. Racial and ethnic distribution of these patients included 50% non-Hispanic White, 26% Hispanic, 17% Asian, 6% African American, 1% other (Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, or unknown). Sequencing platforms included 30% Tempus xT, 31% Foundation One, 10% HopeSeq, 20% GEM ExTra, and 9% Exact Sciences. Liquid biopsies included 79% Guardant, 20% Tempus, and 1% Foundation One. Of 1010 patients, the most common mutations were TP53 (44%), PIK3CA (38%), ESR1 (14%), PTEN (12%), CCND1 (11%), FGFR1 (10%), CDH1 (10%), ERBB2 (9%), MYC (9%), FGF3 (8%), GATA3 (8%), FGF19 (8%), FGF4 (7%), ARID1A (6%), RB1 (5%), BRCA2 (5%), MAP3K1 (4%), AKT1 (4%), NF1 (4%), MLL3 (4%), ZNF703 (4%), CDKN2A (4%), BRCA1 (4%), MCL1 (3%), ATM (3%), PALB2 (1%), and CHEK2 (1%). The majority of reports with tumor mutation burden (TMB) results (97%) had low or intermediate TMB. A total of 784 actionable mutations in 1010 patients were reported, including 381/1010 (38%) PIK3CA; 144/1010 (14%) ESR1; 122/1010 (12%) PTEN; 48/1010 (5%) BRCA2; 36/1010 (4%) BRCA1; 41/1010 (4%) AKT1; and 12/1010 (1%) PALB2. Of the 96/1010 (10%) patients with BRCA1, BRCA2, or PALB2 mutations not including variants of uncertain significance (VUS), 33/96 (34.4%) received olaparib and 3/96 (3%) received talazoparib in the metastatic setting, and 28 were eligible for response (one had toxicity, two were lost to follow-up, and two went to hospice). Median PFS was 9.0 months and median OS was 21.8 months for patients receiving PARPi. Of the 381/1010 (38%) patients with PIK3CA mutations, 84/381 (22%) received alpelisib and 41 were eligible for response (22 had toxicity, 13 were discontinued, six were lost to follow-up, and two went to hospice). Median PFS was 7.9 months and median OS was 31.2 months for patients receiving alpelisib. A total of 544/1010 (54%) patients had AKT1, PIK3CA, or PTEN mutations which are now FDA approved for capivasertib in HR+HER2- metastatic BC patients. In addition, 144/1010 (14%) patients had ESR1 mutations which are FDA approved for elacestrant in HR+HER2- metastatic BC patients. In this study, a total of 784 clinically actionable mutations were reported for 1010 patients with genomic sequencing. Of these, 96/1010 (10%) patients had at least one actionable mutation in homologous recombination repair genes (BRCA1, BRCA2, PALB2) and 36/96 (37.5%) patients received PARP inhibitors (33 olaparib and three talazoparib). In addition, 381/1010 (38%) patients had at least one clinically actionable PIK3CA mutation, and 84/381 (22%) received alpelisib. Additionally, 544/1010 (54%) of patients had either AKT1 (41/1010), PIK3CA (381/1010), or PTEN (122/1010) alterations that were FDA approved in November 2023 for capivasertib in the treatment of HR+HER2- metastatic BC (MBC) patients. Furthermore, 144/1010 (14%) patients in this study had at least one ESR1 mutation, a clinically actionable mutation that was FDA approved in January 2023 for elacestrant in the treatment of ER+HER2- MBC patients (44% detected by liquid biopsy). Future studies are needed to determine the efficacy of elacestrant and capivasertib for patients with these mutations, and to tailor strategies for optimal patient quality of life and cancer outcome. Show less

Colorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes ( Show less

Jeju native pig (JNP) is an indigenous breed originating from Korea, characterized by short black hair, small stature, and superior meat quality compared with commercial breeds. This study investigated meat quality and transcriptome differences in the Show less

Incontinence-associated dermatitis (IAD) is a common nursing challenge in clinical practice, imposing a significant burden on both patients and healthcare providers. Studies have reported that nurses' preventive attitudes toward IAD significantly influence its prevalence, and there may be a potential association between achievement motivation and these attitudes. Previous research on nurses' preventive attitudes toward IAD has primarily focused on overall levels, overlooking potential heterogeneity within the population. This study aimed to investigate the heterogeneity in clinical nurses' preventive attitudes toward IAD using a person-centered approach and to identify the influencing factors for different subgroups. A secondary aim was to utilize Self-Determination Theory (SDT) to elucidate the relationship between the identified attitude profiles and nurses' achievement motivation, thereby providing targeted strategies to enhance their preventive attitudes. This study selected 1058 clinical nurses from a tertiary hospital in Fujian, China, as research participants from September to October 2024. The study utilized the following instruments: a general information questionnaire, the Attitude Toward the Prevention of Incontinence-Associated Dermatitis Instrument, and the Achievement Motivation Scale. Latent profile analysis (LPA) was employed to identify the latent profiles of nurses' attitudes toward IAD prevention. At the same time, Two subgroups of nurses' attitudes toward IAD prevention were identified: the low-level group (63.42%) and the high-level, low-personal-responsibility group (36.57%). A significant correlation was found between nurses' attitudes toward IAD prevention and achievement motivation. Nurses with a more positive preventive attitude scored higher on the motivation for success dimension, while those with a less positive attitude scored higher on the motivation to avoid failure dimension. Factors influencing nurses' attitudes toward IAD prevention included position, department, number of participants in wound/ostomy/incontinence care training, satisfaction with the work atmosphere, and achievement motivation scores. This study revealed heterogeneity in nurses' attitudes toward IAD prevention. Nurses with positive attitudes tended to adopt a success-driven approach, while those with relatively negative attitudes leaned toward a failure-avoidance strategy, reflecting two fundamentally distinct coping mechanisms. Nursing managers should address these individual differences by targeting achievement motivation as an intervention point. Management strategies should be tailored to the distinct profiles; for instance, interventions for the "low-level group" should prioritize building competence through structured training, while strategies for the "high-level, low-personal-responsibility group" should focus on enhancing autonomy and personal accountability. By adopting such targeted approaches, managers can more effectively enhance nurses' preventive attitudes, thereby improving care quality and reducing IAD incidence. Show less

We assessed the coverage of molecular drug susceptibility testing (mDST) among patients with pulmonary multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in South Korea and identified factors influencing the lack of mDST implementation. This retrospective study included patients with pulmonary MDR/RR-TB who initiated tuberculosis (TB) treatment between January 2015 and September 2021. Data were obtained from the K-TB-N cohort, an integrated national TB database linking three datasets. We assessed mDST coverage, temporal trends and factors associated with the lack of mDST implementation. mDST was defined as the use of the Xpert MTB/RIF assay or line probe assay (LPA) for isoniazid and rifampicin (first-line LPA). In total, 4637 patients were included in the analysis. Of the 4637 patients, 1342 (28.9%) did not undergo mDST; whereas, 3295 (71.1%) underwent mDST. Over the study period, a statistically significant annual increase in mDST coverage was observed, escalating from 49.1% in 2015 to 96.9% in 2021 (p<0.001). Throughout the study, the coverage of the Xpert MTB/RIF assay remained lower than that of LPA (22.1% vs 64.2%, p<0.001). Multivariable logistic regression analysis identified several factors independently associated with a decreased likelihood of mDST being conducted, including TB treatment initiation in secondary general hospitals, small hospitals or primary clinics, as well as in non-public-private mix (PPM) participating institutions. In addition, transfers between PPM-participating and non-participating institutions during the treatment period and sputum acid-fast bacilli smear-negative status were significantly associated with lower mDST uptake. Although the increasing mDST coverage is a positive development, further efforts are needed to achieve nationwide and universal implementation, particularly for the Xpert MTB/RIF assay, in South Korea. Show less

Traumatic brain injury (TBI) represents a major cause of mortality and disability worldwide, particularly affecting young adults and elderly populations. This study investigates the neuroprotective potential of orlistat (ORL), a gastrointestinal lipase inhibitor, in a murine TBI model. Behavioral, histological, and molecular analyses demonstrated that ORL significantly attenuated TBI-induced neurological damage. Microglial depletion experiments revealed that ORL's neuroprotective effects were largely mediated through microglial modulation. In vitro and in vivo studies showed that ORL suppressed microglial activation, phagocytosis, and migration. Single-cell RNA sequencing identified upregulation of lipoprotein lipase (LPL) in a TBI-induced microglial subpopulation. Molecular docking predicted ORL-LPL binding, suggesting direct enzymatic inhibition. Transcriptomic and metabolomic analyses further revealed ORL's modulation of microglial metabolic pathways and inflammatory responses. Our findings position ORL as a promising repurposed therapeutic for TBI through its novel mechanism of targeting microglial LPL-mediated neuroinflammation. Show less

Microtubule associated series/threonine kinase-3 (MAST3) is a member of microtubule associated serine/threonine kinase family (MAST1-4, MAST-like), and the expression and underlying molecular mechanism of MAST3 in human tumors, including breast cancer, is not yet elucidated. We employed immunohistochemistry to assess the significant expression of MAST3 in breast cancer tissue samples. Additionally, we utilized an overexpression vector and shRNA to bi-directionally regulate MAST3 expression, aiming to observe the impact of MAST3 on the proliferation, migration, and invasion capabilities of breast cancer cells. Furthermore, we employed immunoprecipitation, immunoblotting, luciferase reporter genes and real-time quantitative PCR to investigate the interaction between MAST3 and YAP, as well as the regulatory effects on the expression of Hippo pathway-related target genes. Low MAST3 expression was observed both in breast cancer cells and tissues, which was significantly associated with advanced tumor T stage, lymph node metastasis, and poor patient prognosis. Functional experiments found that overexpression of MAST3 can gradually inhibit the proliferation and invasion of breast cancer cells, knocking-out MAST3 showed the opposite functional effect. Immunoprecipitation showed that MAST3 interacts with the key effector factor, yes-associated protein (YAP), in the Hippo pathway. The combination of MAST3-YAP promoted the phosphorylation of YAP, which led to its degradation through the ubiquitin-proteasome pathway and reduced nuclear translocation. MAST3 was identified as a novel tumor suppressor protein in breast cancer, which directly regulates the expression of YAP through the non-dependent mammalian sterile-20-like (MST)-large tumor suppressor (LATS) classical signaling pathway, providing a theoretical and experimental basis for the development of small-molecule tumor inhibitors in breast cancer. Show less

Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4 pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation, thereby slowing the course of CAVD. Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification. Show less

Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target Show less

Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pathway, yet its mechanisms for reducing inflammation remain largely unexplored. To investigate AAV2-shmTOR's impact on atypical inflammation in these conditions, we employed an Show less

Endometrial receptivity is a critical determinant of successful embryo implantation and is intricately linked to the pathophysiology of infertility. This study aimed to elucidate the role of exosomal miR-203a-3p in regulating endometrial receptivity, thereby providing insights into potential therapeutic strategies for infertility treatment. Transcriptomic profiling of exosomes was performed to identify factors associated with endometrial receptivity. miR-203a-3p, exhibiting high expression levels in exosomes, was selected for further investigation. Human endometrial tissues from different menstrual phases and patient groups were analyzed for miR-203a-3p expression. Functional studies using miR-203a-3p mimics and engineered exosomes were conducted in non-receptive AN3-CA cells. During the secretory phase, miR-203a-3p expression was markedly higher in the endometria of fertile women than in those of infertile women. Overexpression of miR-203a-3p, which directly targeted Snail family transcriptional repressor (SNAI1), resulted in increased E-cadherin expression and enhanced spheroid attachment in non-receptive AN3-CA cells. Consistently, delivery of miR-203a-3p mimics via engineered exosomes increased E-cadherin expression by suppressing SNAI1 and enhanced spheroid adhesion in AN3-CA cells. Our data highlight the importance of the miR-203a-3p/SNAI1/E-cadherin axis in governing endometrial receptivity. Exosome-mediated delivery of miR-203a-3p mimics may represent a promising therapeutic strategy for improving embryo implantation and treating infertility. Show less

The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevated COX2 expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect of COX2-expressing CAFs (COX2 We induced COX2 Our in vitro findings demonstrate that COX2 This study advances our understanding of the potential mechanisms by which COX2 Show less

We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis. We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated. TCERG1 expression was significantly higher in somatotroph adenomas than in normal pituitaries (log2 fold change 0.59, adjusted P = 0.0002 Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a biomarker for tumor aggressiveness. Show less

The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism. Show less

Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise. Show less

Renal interstitial fibrosis (RIF) is a progressive, irreversible terminal kidney disease with a poor prognosis and high mortality. Angiopoietin-like 4 (ANGPTL4) is known to be associated with fibrosis in various organs, but its impact on the RIF process remains unclear. This study aimed to elucidate the role and underlying mechanisms of ANGPTL4 in the progression of RIF. In vivo, a chronic kidney disease (CKD) rat model of renal interstitial fibrosis was established via intragastric administration of adenine at different time points (4 and 6 weeks). Blood and urine samples were collected to assess renal function and 24-h urinary protein levels. Kidney tissues were subjected to HE and Masson staining for pathological observation. Immunohistochemistry and real-time quantitative PCR (qRT‒PCR) were performed to evaluate the expression of ANGPTL4 and hypoxia-inducible factor-1α (HIF-1α), followed by Pearson correlation analysis. Subsequently, kidney biopsy tissues from 11 CKD patients (6 with RIF and 5 without RIF) were subjected to immunohistochemical staining to validate the expression of ANGPTL4. In vitro, a fibrosis model of human renal tubular epithelial cells (HK2) was established through hypoxic stimulation. Subsequently, an HIF-1α inhibitor (2-MeOE2) was used, and ANGPTL4 was manipulated using siRNA or plasmid overexpression. Changes in ANGPTL4 and fibrosis markers were analyzed through Western blotting, qRT‒PCR, and immunofluorescence. ANGPTL4 was significantly upregulated in the CKD rat model and was significantly positively correlated with renal injury markers, the fibrotic area, and HIF-1α. These results were confirmed by clinical samples, which showed a significant increase in the expression level of ANGPTL4 in CKD patients with RIF, which was positively correlated with HIF-1α. Further in vitro studies indicated that the expression of ANGPTL4 is regulated by HIF-1α, which in turn is subject to negative feedback regulation by ANGPTL4. Moreover, modulation of ANGPTL4 expression influences the progression of fibrosis in HK2 cells. Our findings indicate that ANGPTL4 is a key regulatory factor in renal fibrosis, forming a loop with HIF-1α, potentially serving as a novel therapeutic target for RIF. Show less