ClinicalOmicsDB: exploring molecular associations of oncology drug responses in clinical trials.

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established ontology for easier navigation. The web application provides users with three options to explore molecular associations of oncology drug responses, focusing on studies, treatments or genes, respectively. Gene set analysis further connects treatment response to pathway activity and tumor microenvironment attributes. The user-friendly web interface of ClinicalOmicsDB streamlines interactive analysis. A Rust-based backend speeds up response time, and application programming interfaces and an R package enable programmatic access. We use three case studies to demonstrate the utility of this resource in human cancer studies. ClinicalOmicsDB is freely available at http://trials.linkedomics.org/.

Effects of resistance training and nutritional support on osteosarcopenia in older, community-dwelling postmenopausal Korean females (ERTO-K study): a study protocol.

BACKGROUND: Osteosarcopenia is geriatric syndrome defined as the concomitant occurrence of osteopenia/osteoporosis, and sarcopenia. Osteosarcopenia is a relatively new concept in geriatric medicine; however, it may increase the risk of fragility fractures, several morbidities and mortalities, and socioeconomic costs. Although resistance exercises and nutritional support-including protein, calcium, and vitamin D-are potential non-pharmacological management procedures, evidence is still lacking. The objective of this study was therefore to evaluate the effect of combined resistance exercise and nutritional support on the quality and quantity of bone and muscle in postmenopausal females with osteosarcopenia. METHODS: This research proposal presents the protocol for a prospective, single-center, single-blinded, two-armed randomized controlled trial. Thirty-four participants with osteosarcopenia will be recruited and randomly divided into intervention and control groups; both groups will receive nutritional supplements (protein, 40 g; vitamin D, 1600 IU; calcium, 600 mg) daily. The intervention group will undergo 24 weeks of resistance exercise of increasing intensity, achieved through a three-phase step-up process. The primary outcomes will be the changes in skeletal muscle index and bone marrow density of the lumbar spine and femoral neck between the baseline and end of intervention (24 weeks). The secondary outcomes will be the body composition, whole body phase angle, physical function assessment, quality of life, psychological assessment, and bone turnover markers of participants, surveyed at multiple time points. DISCUSSION: This randomized controlled trial may reveal the effect of resistance exercise and nutritional support on older postmenopausal women with osteosarcopenia. The results will provide evidence for developing proper non-pharmacological management guidelines for postmenopausal women. TRIAL REGISTRATION: Clinical Research Information Service of Republic of Korea, KCT0008291, Registered on 16 March 2023, https://cris.nih.go.kr/cris/search/detailSearch.do/25262 .

Increased risk of pancreatic, thyroid, prostate and breast cancers in men with a family history of breast cancer: A population-based study.

The association between a family history of breast cancer (FHBC) in female first-degree relatives (FDRs) and cancer risk in men has not been evaluated. This study aimed to compare the risks of overall and site-specific cancers in men with and without FHBC. A population-based study was conducted with 3 329 106 men aged ≥40 years who underwent national cancer screening between 2013 and 2014. Men with and without FHBC in their female FDRs were age-matched in a 1:4 ratio. Men without FHBC were defined as those without a family history of any cancer type in their FDRs. Data from 69 124 men with FHBC and 276 496 men without FHBC were analyzed. The mean follow-up period was 4.7 ± 0.9 years. Men with an FHBC in any FDR (mother or sister) had a higher risk of pancreatic, thyroid, prostate and breast cancers than those without an FHBC (adjusted hazard ratios [aHRs] (95% confidence interval [CI]): 1.35 (1.07-1.70), 1.33 (1.12-1.56), 1.28 (1.13-1.44) and 3.03 (1.130-8.17), respectively). Although an FHBC in any one of the FDRs was not associated with overall cancer risk, FHBC in both mother and sibling was a significant risk factor for overall cancer (aHR: 1.69, 95% CI:1.11-2.57) and increased the risk of thyroid cancer by 3.41-fold (95% CI: 1.10-10.61). FHBC in the mother or sister was a significant risk factor for pancreatic, thyroid, prostate and breast cancers in men; therefore, men with FHBC may require more careful BRCA1/2 mutation-related cancer surveillance.

Engineered CD8+ T cell-derived extracellular vesicles induce enhanced anti-cancer efficacy and targeting to lung cancer cells.

Lung cancer is a common and highly malignant tumor. Although lung cancer treatments continue to advance, conventional therapies are limited and the response rate of patients to immuno-oncology drugs is low. This phenomenon raises an urgent need to develop effective therapeutic strategies for lung cancer. In this study, we genetically modified human primary CD8+ T cells and obtained antitumor extracellular vesicles (EVs) from them. The engineered EVs, containing interlekin-2 and the anti-epidermal growth factor receptor (EGFR) antibody cetuximab on their surfaces, exhibited direct cytotoxicity against A549 human lung cancer cells and increased cancer cell susceptibility to human peripheral blood mononuclear cell-mediated cytotoxicity. In addition, the engineered EVs specifically targeted the lung cancer cells in an EGFR-dependent manner. Taken together, these findings show that surface engineering of cytokines and antibodies on CD8+ T cell-derived EVs not only enhances their antitumor effects but also confers target specificity, suggesting a potential of modifying the immune cell-derived EVs in cancer treatment.

Morpho-physiological and genetic characteristics of a salt-tolerant mutant line in soybean (Glycine max L.).

KEY MESSAGE: One major quantitative trait loci and candidate gene for salt tolerance were identified on chromosome 3 from a new soybean mutant derived from gamma-ray irradiation, which will provide a new genetic resource for improving soybean salt tolerance. Soil salinity is a worldwide problem that reduces crop yields, but the development of salt-tolerant crops can help overcome this challenge. This study was conducted with the purpose of evaluating the morpho-physiological and genetic characteristics of a new salt-tolerant mutant KA-1285 developed using gamma-ray irradiation in soybean (Glycine max L.). The morphological and physiological responses of KA-1285 were compared with salt-sensitive and salt-tolerant genotypes after treatment with 150 mM NaCl for two weeks. In addition, a major salt tolerance quantitative trait locus (QTL) was identified on chromosome 3 in this study using the Daepung X KA-1285 169 F2:3 population, and a specific deletion was identified in Glyma03g171600 (Wm82.a2.v1) near the QTL region based on re-sequencing analysis. A kompetitive allele-specific PCR (KASP) marker was developed based on the deletion of Glyma03g171600 which distinguished the wild-type and mutant alleles. Through the analysis of gene expression patterns, it was confirmed that Glyma03g171700 (Wm82.a2.v1) is a major gene that controls salt tolerance functions in Glyma03g32900 (Wm82.a1.v1). These results suggest that the gamma-ray-induced mutant KA-1285 has the potential to be employed for the development of a salt-tolerant cultivar and provide useful information for genetic research related to salt tolerance in soybeans.

Mutual association between family history of gastric and colorectal cancer and risk of gastric and colorectal cancer.

BACKGROUND AND AIM: We evaluated the associations between gastric cancer (GC) family history (FH) and colorectal cancer (CRC) risk and between CRC FH and GC/gastric adenoma risk. METHODS: We used data of participants who underwent national cancer screening between 2013 and 2014. Participants with GC or CRC FH in first-degree relatives (n = 1 172 750) and those without cancer FH (n = 3 518 250) were matched 1:3 by age and gender. RESULTS: Of the 1 172 750 participants with a FH, 871 104, 264 040, and 37 606 had FHs of only GC, only CRC, and both GC and CRC, respectively. The median follow-up time was 4.8 years. GC and CRC FHs were associated with increased GC and CRC risks, respectively. GC FH was associated with CRC risk (adjusted hazard ratio 1.05; 95% confidence interval [CI] 1.01-1.10), whereas CRC FH was not associated with the risk of GC or gastric adenoma. However, gastric adenoma risk increased 1.62-fold (95% CI 1.40-1.87) in participants with FHs of both GC and CRC, demonstrating a significant difference with the 1.39-fold (95% CI 1.34-1.44) increase in participants with only GC FH. Furthermore, GC risk increased by 5.32 times (95% CI 1.74-16.24) in participants with FHs of both GC and CRC in both parents and siblings. CONCLUSIONS: GC FH was significantly associated with a 5% increase in CRC risk. Although CRC FH did not increase GC risk, FH of both GC and CRC further increased the risk of gastric adenoma. FHs of GC and CRC may affect each other's neoplastic lesion risk.

Physical activity and osteosarcopenia in Korean adults aged 65 years and older: a national cross-sectional study using the KNHANES data.

BACKGROUND: Osteosarcopenia is a syndrome characterized by the co-existence of osteoporosis and sarcopenia. This study aimed to examine the relationship between various types of physical activity and osteosarcopenia in community-dwelling Korean adults aged 65 years or older. METHODS: This cross-sectional study used raw data from the fourth and fifth editions of the Korean National Health and Nutritional Survey Examination, conducted from 2008 to 2011. The researchers exclusively recruited participants aged 65 years or older for the study. These participants were categorized into four distinct groups based on their clinical factors, namely individuals without osteoporosis or sarcopenia, those with osteoporosis alone, those with sarcopenia alone, and individuals with osteosarcopenia. The International Physical Activity Short-Form was used to calculate the weekly time spent walking, moderate-intensity aerobic physical activity, and vigorous aerobic physical activity. Number of days in performing strengthening or stretching exercises were also surveyed. We used logistic regression analyses to examine the association between various physical activities and occurrence of osteosarcopenia. RESULTS: A total of 1,342 participants (639 men and 703 women) were included in the analysis. No significant difference was observed in the amount and level of aerobic physical activity between the groups. The odds ratios below were based on participants without osteoporosis or sarcopenia as the reference category. The un-adjusted odds ratio of participants who performed stretching (male, 0.179, 95% CI 0.078-0.412; female 0.430, 95% CI 0.217-0.853) and strengthening exercises (male, 0.143, 95% CI 0.051-0.402; female, 0.044, 95% CI 0.006-0.342) at least twice per week was significantly lower in participants with osteosarcopenia compared to those without. In the adjusted analysis (adjusted by age, body mass index, house income, educational level, smoking habits, drinking status, and protein intake), only female patients in the osteosarcopenia group had a significantly lower adjusted odds ratio for performing strengthening exercise compared to female participants without osteoporosis or sarcopenia (0.062, 95% CI 0.007-0.538). CONCLUSIONS: After adjusting for confounding factors and protein intake, women aged 65 years and older who suffered osteosarcopenia had considerably lower odds ratio of performing strengthening exercises.

Heterointerface Effect on Two-Step Nucleation Mechanism of Bi Particles.

The nucleation and crystallization of Bi particles on two matrices, crystalline bismuth sulfide (c-Bi2S3) and amorphized bismuth titanium oxide (a-Bi12TiO20), were studied by using in situ transmission electron microscopy (TEM) analysis. The atomic structures of the Bi particles were monitored by acquiring high-resolution TEM images in real time. The Bi particles were grown on c-Bi2S3 and a-Bi12TiO20 via a two-step nucleation mechanism; dense liquid clusters were clearly observed at the initial stage of nucleation, and the coalescence of clusters was frequently observed during the growth. However, the nucleation and crystallization behaviors of Bi particles were governed by the matrix; in particular, the evolution of their morphology and atomic structure was confined on c-Bi2S3 but free from matrix effects on a-Bi12TiO20. The matrix effect on the two-step nucleation mechanism was demonstrated from a thermodynamic point of view.

Quantitative Trait Loci (QTL) Analysis of Seed Protein and Oil Content in Wild Soybean (Glycine soja).

Soybean seeds consist of approximately 40% protein and 20% oil, making them one of the world's most important cultivated legumes. However, the levels of these compounds are negatively correlated with each other and regulated by quantitative trait loci (QTL) that are controlled by several genes. In this study, a total of 190 F2 and 90 BC1F2 plants derived from a cross of Daepung (Glycine max) with GWS-1887 (G. soja, a source of high protein), were used for the QTL analysis of protein and oil content. In the F2:3 populations, the average protein and oil content was 45.52% and 11.59%, respectively. A QTL associated with protein levels was detected at Gm20_29512680 on chr. 20 with a likelihood of odds (LOD) of 9.57 and an R2 of 17.2%. A QTL associated with oil levels was also detected at Gm15_3621773 on chr. 15 (LOD: 5.80; R2: 12.2%). In the BC1F2:3 populations, the average protein and oil content was 44.25% and 12.14%, respectively. A QTL associated with both protein and oil content was detected at Gm20_27578013 on chr. 20 (LOD: 3.77 and 3.06; R2 15.8% and 10.7%, respectively). The crossover to the protein content of BC1F3:4 population was identified by SNP marker Gm20_32603292. Based on these results, two genes, Glyma.20g088000 (S-adenosyl-l-methionine-dependent methyltransferases) and Glyma.20g088400 (oxidoreductase, 2-oxoglutarate-Fe(II) oxygenase family protein), in which the amino acid sequence had changed and a stop codon was generated due to an InDel in the exon region, were identified.

Transcriptome Analysis of Differentially Expressed Genes Associated with Salt Stress in Cowpea (Vigna unguiculata L.) during the Early Vegetative Stage.

Cowpea (Vigna unguiculata (L.), 2n = 22) is a tropical crop grown in arid and semiarid regions that is tolerant to abiotic stresses such as heat and drought. However, in these regions, salt in the soil is generally not eluted by rainwater, leading to salt stress for a variety of plant species. This study was conducted to identify genes related to salt stress using the comparative transcriptome analysis of cowpea germplasms with contrasting salt tolerance. Using the Illumina Novaseq 6000 platform, 1.1 billion high-quality short reads, with a total length of over 98.6 billion bp, were obtained from four cowpea germplasms. Of the differentially expressed genes identified for each salt tolerance type following RNA sequencing, 27 were shown to exhibit significant expression levels. These candidate genes were subsequently narrowed down using reference-sequencing analysis, and two salt stress-related genes (Vigun_02G076100 and Vigun_08G125100) with single-nucleotide polymorphism (SNP) variation were selected. Of the five SNPs identified in Vigun_02G076100, one that caused significant amino acid variation was identified, while all nucleotide variations in Vigun_08G125100 was classified as missing in the salt-resistant germplasms. The candidate genes and their variation, identified in this study provide, useful information for the development of molecular markers for cowpea breeding programs.

Association Between Family History of Gastric Cancer and the Risk of Gastric Cancer and Adenoma: A Nationwide Population-Based Study.

INTRODUCTION: A family history of gastric cancer (GC) is a well-known risk factor for GC. However, the association between family history of GC and the risk of GC and gastric adenoma according to the affected family members is unclear. METHODS: We analyzed the data of participants aged ≥40 years who underwent national GC screening between 2013 and 2014. Participants with and without a family history of GC among first-degree relatives were matched by age and sex in a 1:4 ratio. RESULTS: During a median follow-up of 4.9 years, 0.96% and 0.46% of 896,721 participants with a family history of GC and 0.65% and 0.32% of 3,586,884 participants without a family history of GC developed GC and gastric adenoma, respectively. A family history of GC among any first-degree relative was a risk factor for GC (adjusted hazard ratio [HR] 1.48, 95% confidence interval 1.45-1.52) and gastric adenoma (HR 1.44, 95% confidence interval 1.39-1.50). The HRs for GC and gastric adenoma were higher in participants with a family history of GC in parents and siblings (2.26 and 2.19, respectively) than in those with a family history of GC in parents only (1.40 and 1.41, respectively) or siblings only (1.59 and 1.47, respectively). The HRs for GC in participants with vs without a family history of GC were 1.62, 1.55, and 1.42 in the 40-49, 50-59, and ≥60 years' age groups of participants, respectively. Similarly, the HRs for gastric adenoma increased with decreasing age of participants. DISCUSSION: A family history of GC was a risk factor for both GC and gastric adenoma. The risk of GC and gastric adenoma of the participants was higher when both parents and siblings had GC.

Shrimp miR-965 transfers tumoricidal mitochondria.

BACKGROUND: Micro RNA of Marsupenaeus japonicas has been known to promote apoptosis of tumor cells. However, the detailed mechanisms are not well understood. RESULTS: Using tomographic microscope, which can detect the internal structure of cells, we observed breast tumor cells following treatment of the miRNA. Intriguingly, we found that mitochondria migrate to an adjacent tumor cells through a tunneling nanotube. To recapitulate this process, we engineered a microfluidic device through which mitochondria were transferred. We show that this mitochondrial transfer process released endonuclease G (Endo G) into tumor cells, which we referred to herein as unsealed mitochondria. Importantly, Endo G depleted mitochondria alone did not have tumoricidal effects. Moreover, unsealed mitochondria had synergistic apoptotic effects with subtoxic dose of doxorubicin thereby mitigating cardiotoxicity. CONCLUSIONS: Together, we show that the mitochondrial transfer through microfluidics can provide potential novel strategies towards tumor cell death.

Suppressive effect of α-mangostin for cancer stem cells in colorectal cancer via the Notch pathway.

BACKGROUND: Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs. METHODS: The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model. RESULTS: αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment. CONCLUSION: This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU-induced augmentation of CSCs via the Notch signaling pathway.

A survey of the perceptions of barriers to and facilitators of cardiac rehabilitation in healthcare providers and policy stakeholders.

BACKGROUND: Cardiac rehabilitation (CR) is a prognostic management strategy to help patients with CVD achieve a good quality of life and lower the rates of recurrence, readmission, and premature death from disease. Globally, cardiac rehabilitation is poorly established in hospitals and communities. Hence, this study aimed to investigate the discrepancies in the perceptions of the need for CR programs and relevant health policies between directors of hospitals and health policy personnel in South Korea to shed light on the status and to establish practically superior and effective strategies to promote CR in South Korea. METHODS: We sent a questionnaire to 592 public health policy managers and directors of selected hospitals, 132 of whom returned a completed questionnaire (response rate: 22.3%). The participants were categorized into five types of organizations depending on their practice of PCI (Percutaneous Coronary Intervention), establishment of cardiac rehabilitation, director of hospital, and government's policy makers. Differences in the opinions between directors of hospitals that perform/do not perform PCI, directors of hospitals with/without cardiac rehabilitation, and between hospital directors and health policy makers were analyzed. RESULTS: Responses about targeting diseases for cardiac rehabilitation, patients' roles in cardiac rehabilitation, hospitals' roles in cardiac rehabilitation, and governmental health policies' roles in cardiac rehabilitation were more positive among hospitals that perform PCI than those that do not. Responses to questions about the effectiveness of cardiac rehabilitation and hospitals' roles in cardiac rehabilitation tended to be more positive in hospitals with cardiac rehabilitation than in those without. Hospital directors responded more positively to questions about targeting diseases for cardiac rehabilitation and governmental health policies' roles in cardiac rehabilitation than policy makers, and both hospitals and public organizations provided negative responses to the question about patients' roles in cardiac rehabilitation. Responses to questions about targeting diseases for cardiac rehabilitation, patients' roles in cardiac rehabilitation, and governmental health policies' roles in cardiac rehabilitation were more positive in hospitals that perform PCI than those that do not and public organizations. CONCLUSIONS: Hospitals must ensure timely referral, provide education, and promote the need for cardiac rehabilitation. In addition, governmental socioeconomic support is needed in a varity of aspects.

Clinical evaluation of usefulness and effectiveness of sitting type continuous passive motion machines in patients with total knee arthroplasty: a study protocol for a single-blinded randomized controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) is an important management strategy for patients with knee osteoarthritis (OA) refractory to conservative management. Postoperative range of motion (ROM) exercise is important to recover patients' activities of daily living. Continuous passive motion (CPM) is a machine that provides passive ROM exercises of the knee joint in a pre-defined arc of motion. The short- and long-term effects of CPM exercise are controversial. We hypothesized that the inconsistent results of the CPM exercise are due to poor fitting of CPM machines and measurement errors. This study aims to present a protocol for investigating a new type of CPM machine that could be applied in a sitting position in comparison with the conventional type of CPM machine for patients with unilateral TKAs. METHODS: This study presents the protocol of a prospective, multicenter, single-blinded, three-armed randomized controlled trial (RCT). One hundred and twenty-six patients receiving unilateral TKAs will be recruited at the physical medicine and rehabilitation clinics of two urban tertiary medical hospitals. The patients were randomly divided into three groups with a 1:1:1 allocation. The intervention group will receive two weeks of post-operative rehabilitation using a new type of CPM machine. The control group will receive 2 weeks of post-operative rehabilitation using conventional CPM machines. The third group will receive post-operative rehabilitation with both types of CPM machines. The primary outcome will be the change in the passive ROM of the affected knee joint from baseline to 2 weeks after baseline assessment. The secondary outcomes will be pain and functional measurements, and will include patient-reported outcomes and performance tests surveyed at multiple time points up to 3 months after TKA. DISCUSSION: This is the first RCT to investigate the effect of a new type of CPM machine. The results of this RCT will determine whether the position of the patients during CPM exercise is important in post-operative rehabilitation protocols after TKAs and will provide evidence for the development of proper rehabilitation guidelines after TKAs. TRIAL REGISTRATION: Clinical Research Information Service of Republic of Korea, KCT0005520, Registered on 21 October 2020, https://cris.nih.go.kr/cris/search/detailSearch.do/21750.

A Circular-Based Reference Point Extraction Method for Correcting the Alignment of Round Parts.

For products such as smartphones, the technology gap between companies is gradually narrowing with the advancements in technology. Therefore, product design can be a visible strategy for differentiation. However, it is difficult to apply automated production and defect detection processes to the various designs that are being developed. This study proposes a high-speed circular measurement method for correcting the alignment of round parts, which is difficult in an automated process. For analyzing the performance of the proposed method, its processing speed and accuracy are compared with those of the existing methods. The results of the analysis indicate that the overall performance of the proposed method is better than those of the existing methods.

Hemp-Derived Nanovesicles Protect Leaky Gut and Liver Injury in Dextran Sodium Sulfate-Induced Colitis.

Hemp (Cannabis sativa L.) is used for medicinal purposes owing to its anti-inflammatory and antioxidant activities. We evaluated the protective effect of nanovesicles isolated from hemp plant parts (root, seed, hemp sprout, and leaf) in dextran sulfate sodium (DSS)-induced colitis in mice. The particle sizes of root-derived nanovesicles (RNVs), seed-derived nanovesicles (SNVs), hemp sprout-derived nanovesicles (HSNVs), and leaf-derived nanovesicles (LNVs) were within the range of 100-200 nm as measured by nanoparticle tracking analysis. Acute colitis was induced in C57BL/N mice by 5% DSS in water provided for 7 days. RNVs were administered orally once a day, leading to the recovery of both the small intestine and colon lengths. RNVs, SNVs, and HSNVs restored the tight (ZO-1, claudin-4, occludin) and adherent junctions (E-cadherin and α-tubulin) in DSS-induced small intestine and colon injury. Additionally, RNVs markedly reduced NF-κB activation and oxidative stress proteins in DSS-induced small intestine and colon injury. Tight junction protein expression and epithelial cell permeability were elevated in RNV-, SNV-, and HSNV-treated T84 colon cells exposed to 2% DSS. Interestedly, RNVs, SNVs, HSNVs, and LNVs reduced ALT activity and liver regeneration marker proteins in DSS-induced liver injury. These results showed for the first time that hemp-derived nanovesicles (HNVs) exhibited a protective effect on DSS-induced gut leaky and liver injury through the gut-liver axis by inhibiting oxidative stress marker proteins.

SDG8-Mediated Histone Methylation and RNA Processing Function in the Response to Nitrate Signaling.

Chromatin modification has gained increased attention for its role in the regulation of plant responses to environmental changes, but the specific mechanisms and molecular players remain elusive. Here, we show that the Arabidopsis (Arabidopsis thaliana) histone methyltransferase SET DOMAIN GROUP8 (SDG8) mediates genome-wide changes in H3K36 methylation at specific genomic loci functionally relevant to nitrate treatments. Moreover, we show that the specific H3K36 methyltransferase encoded by SDG8 is required for canonical RNA processing, and that RNA isoform switching is more prominent in the sdg8-5 deletion mutant than in the wild type. To demonstrate that SDG8-mediated regulation of RNA isoform expression is functionally relevant, we examined a putative regulatory gene, CONSTANS, CO-like, and TOC1 101 (CCT101), whose nitrogen-responsive isoform-specific RNA expression is mediated by SDG8. We show by functional expression in shoot cells that the different RNA isoforms of CCT101 encode distinct regulatory proteins with different effects on genome-wide transcription. We conclude that SDG8 is involved in plant responses to environmental nitrogen supply, affecting multiple gene regulatory processes including genome-wide histone modification, transcriptional regulation, and RNA processing, and thereby mediating developmental and metabolic processes related to nitrogen use.

Interferon-γ inhibits retinal neovascularization in a mouse model of ischemic retinopathy.

Interferon-γ (IFNG) is one of the key cytokines that regulates both innate and adaptive immune responses in the body. However, the role of IFNG in the regulation of vascularization, especially in the context of Vascular endothelial growth factor A (VEGFa)-induced angiogenesis is not clarified. Here, we report that IFNG shows potent anti-angiogenic potential against VEGFa-induced angiogenesis. IFNG significantly inhibited proliferation, migration, and tube formation of Human umbilical vein endothelial cells (HUVECs) both under basal and VEGFa-treated conditions. Intriguingly, Knockdown (KD) of STAT1 abolished the inhibitory effect of IFNG on VEGFa-induced angiogenic processes in HUVECs. Furthermore, IFNG exhibited potent anti-angiogenic efficacy in the mouse model of oxygen-induced retinopathy (OIR), an in vivo model for hypoxia-induced retinal neovascularization, without induction of functional side effects. Taken together, these results show that IFNG plays a crucial role in the regulation of VEGFa-dependent angiogenesis, suggesting its potential therapeutic applicability in neovascular diseases.

Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors.

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE2 levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE2 (IC50: 0.24 µM) in A549 cells via inhibition of mPGES-1 (IC50: 0.49 µM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.