Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss.

Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.

Development of advanced cardiac progenitor cell culture system through fibronectin and vitronectin derived peptide coated plate.

Cardiovascular disease remains a global health concern. Stem cell therapy utilizing human cardiac progenitor cells (hCPCs) shows promise in treating cardiac vascular disease. However, limited availability and senescence of hCPCs hinder their widespread use. To address these challenges, researchers are exploring innovative approaches. In this study, a bioengineered cell culture plate was developed to mimic the natural cardiac tissue microenvironment. It was coated with a combination of extracellular matrix (ECM) peptide motifs and mussel adhesive protein (MAP). The selected ECM peptide motifs, derived from fibronectin and vitronectin, play crucial roles in hCPCs. Results revealed that the Fibro-P and Vitro-P coated plates significantly improved hCPC adhesion, proliferation, migration, and differentiation compared to uncoated plates. Additionally, long-term culture on the coated plates delayed cellular senescence and maintained hCPC stemness. These enhancements were attributed to the activation of integrin downstream signaling pathways. The findings suggest that the engineered ECM peptide motif-MAP-coated plates hold potential for enhancing the therapeutic efficacy of stem cell-based therapies in cardiac tissue engineering and regenerative medicine.

A novel marine-derived mitophagy inducer ameliorates mitochondrial dysfunction and thermal hypersensitivity in paclitaxel-induced peripheral neuropathy.

BACKGROUND AND PURPOSE: Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model. EXPERIMENTAL APPROACH: Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae. KEY RESULTS: PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction. CONCLUSION AND IMPLICATIONS: This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.

Use of a sample injection loop for an accurate measurement of particle number concentration by flow cytometry.

Flow cytometry plays a pivotal role in biotechnology by providing quantitative measurements for a wide range of applications. Nonetheless, achieving precise particle quantification, particularly without relying on counting beads, remains a challenge. In this study, we introduce a novel exhaustive counting method featuring a sample loop-based injection system that delivers a defined sample volume to a detection system to enhance quantification in flow cytometry. We systematically assess the performance characteristics of this system with micron-sized polystyrene beads, addressing issues related to sample introduction, adsorption, and volume measurement. Results underscore the excellent analytical performance of the proposed method, characterized by high linearity and repeatability. We compare our approach to counting bead-based measurements, and while an approximate bias value was observed, the measured values were found to be similar between the methods, demonstrating its comparability and reliability. This method holds great promise for improving the accuracy and precision of particle quantification in flow cytometry, with implications for various fields including healthcare and environmental monitoring.

Promising properties of cytochrome P450 BM3 reconstituted from separate domains by split intein.

Recombinant cytochrome P450 monooxygenases possess significant potential as biocatalysts, and efforts to improve heme content, electron coupling efficiency, and catalytic activity and stability are ongoing. Domain swapping between heme and reductase domains, whether natural or engineered, has thus received increasing attention. Here, we successfully achieved split intein-mediated reconstitution (IMR) of the heme and reductase domains of P450 BM3 both in vitro and in vivo. Intriguingly, the reconstituted enzymes displayed promising properties for practical use. IMR BM3 exhibited a higher heme content (>50 %) and a greater tendency for oligomerization compared to the wild-type enzyme. Moreover, these reconstituted enzymes exhibited a distinct increase in activity ranging from 165 % to 430 % even under the same heme concentrations. The reproducibility of our results strongly suggests that the proposed reconstitution approach could pave a new path for enhancing the catalytic efficiency of related enzymes.

Probiotic Pediococcus acidilactici Strains Exert Anti-inflammatory Effects by Regulating Intracellular Signaling Pathways in LPS-Induced RAW 264.7 Cells.

This study investigated the anti-inflammatory effects of Pediococcus acidilactici strains isolated from fermented vegetables on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In addition, the probiotic characteristics and safety were evaluated. Our results show that Ped. acidilactici strains possess high survivability in simulated gastrointestinal environments and strong attachment to HT-29 cells. All Ped. acidilactici strains exhibited γ-hemolysis and resistance to gentamicin, kanamycin, and streptomycin, a characteristic commonly observed in lactic acid bacteria. Treatment with Ped. acidilactici inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2, leading to a subsequent reduction in nitric oxide and prostaglandin E2 production. Furthermore, the strains downregulated interleukin (IL)-1ß and IL-6 mRNA levels, ultimately suppressing their production. We demonstrated that Ped. acidilactici strains could modulate the activation of nuclear factor-κB, mitogen-activated protein kinase, and activator protein-1, which are known to regulate inflammatory responses. Consequently, the anti-inflammatory properties of Ped. acidilactici strains in this study support their potential application as therapeutic agents for inflammatory diseases, providing molecular insights into next-generation functional probiotic products.

Overview of Dairy-based Products with Probiotics: Fermented or Non-fermented Milk Drink.

Probiotic products have long been recognized for their health benefits. Additionally, milk has held a longstanding reputation as a dairy product that offers high-quality proteins and essential micronutrients. As awareness of the impact of food on health grows, interest in functional products such as probiotic dairy products is on the rise. Fermentation, a time-honored technique used to enhance nutritional value and food preservation, has been used for centuries to increase nutritional value and is one of the oldest food processing methods. Historically, fermented dairy products have been used as convenient vehicle for the consumption of probiotics. However, addressing the potential drawbacks of fermentation has recently led to increase in research on probiotic dairy drinks prepared without fermentation. These non-fermented dairy drinks have the advantage of maintaining the original flavors of milk drinks, containing potential health functional probiotics, and being an alternative dairy product that is helpful for probiotics intake. Currently, research on plant-based dairy products is rapidly increasing in the market. These developments might suggest the potential for novel forms of non-fermented dairy beverages with substantial prospects in the food market. This review aims to provide an overview of milk-based dairy beverages, both fermented and non-fermented, and discuss the potential of non-fermented dairy products. This exploration paves the way for innovative approaches to deliver probiotics and nutrition to consumers.

Foliar applications of a Malvaceae-derived protein hydrolysate and its fractions differentially modulate yield and functional traits of tomato under optimal and suboptimal nitrogen application.

BACKGROUND: Protein hydrolysates (PHs) can enhance plant nitrogen nutrition and improve the quality of vegetables, depending on their bioactive compounds. A tomato greenhouse experiment was conducted under both optimal (14 mM) and suboptimal (2 mM) nitrogen (N-NO3) conditions. Tomatoes were treated with a new Malvaceae-derived PH (MDPH) and its molecular fractions (MDPH1, >10 kDa; MDPH2, 1-10 kDa and MDPH3, <1 kDa). RESULTS: Under optimal N conditions, the plants increased biomass and fruit yield, and showed a higher photosynthetic pigment content in leaves in comparison with suboptimal N, whereas under N-limiting conditions, an increase in dry matter, soluble solid content (SSC) and lycopene, a reduction in firmness, and changes in organic acid and phenolic compounds were observed. With 14 mM N-NO3, MDPH3 stimulated an increase in dry weight and increased yield components and lycopene in the fruit. The MDPH2 fraction also resulted in increased lycopene accumulation in fruit under 14 mM N-NO3. At a low N level, the PH fractions showed distinct effects compared with the whole MDPH and the control, with an increase in biomass for MDPH1 and MDPH2 and a higher pigment content for MDPH3. Regardless of N availability, all the fractions affected fruit quality by increasing SSC, whereas MDPH2 and MDPH3 modified organic acid content and showed a higher concentration of flavonols, lignans, and stilbenes. CONCLUSION: The molecular weight of the peptides modifies the effect of PHs on plant performance, with different behavior depending on the level of N fertilization, confirming the effectiveness of fractioning processes. © 2024 Society of Chemical Industry.

Angiotensin Receptor Blockers and the Risk of Suspected Drug-Induced Liver Injury: A Retrospective Cohort Study Using Electronic Health Record-Based Common Data Model in South Korea.

INTRODUCTION: Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI. OBJECTIVE: We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan. METHODS: Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R. RESULTS: In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12]). CONCLUSIONS: We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice.

Prenatal treatment with corticosterone via maternal injection induces learning and memory impairments via delaying postsynaptic development in hippocampal CA1 neurons of rats.

Previously, we reported that prenatal exposure to high corticosterone induced attention-deficit hyperactivity disorder (ADHD)-like behaviors with cognitive deficits after weaning. In the present study, cellular mechanisms underlying cortisol-induced cognitive dysfunction were investigated using rat pups (Corti.Pups) born from rat mothers that were repetitively injected with corticosterone during pregnancy. In results, Corti.Pups exhibited the failure of behavioral memory formation in the Morris water maze (MWM) test and the incomplete long-term potentiation (LTP) of hippocampal CA1 neurons. Additionally, glutamatergic excitatory postsynaptic currents (EPSCs) were remarkably suppressed in Corti.Pups compared to normal rat pups. Incomplete LTP and weaker EPSCs in Corti.Pups were attributed to the delayed postsynaptic development of CA1 neurons, showing a higher expression of NR2B subunits and lower expression of PSD-95 and BDNF. These results indicated that the prenatal treatment with corticosterone to elevate cortisol level might potently downregulate the BDNF-mediated signaling critical for the synaptic development of hippocampal CA1 neurons during brain development, and subsequently, induce learning and memory impairment. Our findings suggest a possibility that the prenatal dysregulation of cortisol triggers the epigenetic pathogenesis of neurodevelopmental psychiatric disorders, such as ADHD and autism.

Exercise affects high-fat diet-stimulated breast cancer metastasis through irisin secretion by altering cancer stem cell properties.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Construction and characterization of a functional variant hFGF7 with enhanced properties by circular permutation.

Human fibroblast growth factor 7 (hFGF7) is a member of the paracrine-acting FGF family and mediates various reactions such as wound healing, tissue homeostasis, and liver regeneration. These activities make it a plausible candidate for pharmaceutical applications as a drug. However, the low expression level and stability of the recombinant hFGF7 were known to be major hurdles for further applications. Here, the expression level and stability of hFGF7 were attempted to improve by changing the order of amino acids through circular permutation (CP), thereby expecting an alternative fate according to the N-end rule. CP-hFGF7 variants were constructed systematically by using putative amino acid residues in the loop region that avoided the disruption of the structural integrity especially in the functional motif. Among them, cp-hFGF7115-114 revealed a relatively higher expression level in the soluble fraction than the wild-type hFGF7 and was efficiently purified (7 mg L-1) to apparent homogeneity. The activity and stability of the purified variant cp-hFGF7115-114 were comparable or superior to that of the wild-type hFGF7, thereby strongly suggesting that CP could be an alternative tool for the functional expression of hFGF7 in Escherichia coli.

Relationship between Eating Alone and Handgrip Strength in Korean Older Adults.

Sarcopenia is defined as an age-related decline in muscle mass, muscle strength, and physical performance. Eating alone has been linked to various health issues in older adults. This study investigated the relationship between eating alone and handgrip strength (HGS) in older adults using data from 7278 individuals (≥65 years) who participated in the 2014-2019 Korea National Health and Nutrition Examination Survey. HGS was measured using a digital grip strength dynamometer, relative HGS was calculated by dividing HGS by body mass index, and dynapenia was defined as an HGS < 28 kg for men and <18 kg for women. Multivariable logistic regression analysis showed that women who ate two meals alone were more likely to exhibit dynapenia than those who never ate alone (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.03-1.77). If the groups that never ate alone or ate one meal alone were combined as the reference group, the probability of dynapenia was higher in the combined groups that ate two or three meals alone (OR, 1.25; 95% CI, 1.04-1.50). No association was observed between eating alone and dynapenia in men. This suggests that eating alone is a modifiable related factor of dynapenia in older women.

Generation of an induced pluripotent stem cell line (PNUYHi002-A) from a patient with Alzheimer's disease carrying PRNP M232R variant.

We generated a human induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells isolated from a 59-year-old male patient with Alzheimer's disease (AD). The iPSC line was meticulously characterized to confirm its pluripotency, absence of transgenes, and normal karyotype. The unexpected discovery of the M232R variant in PRNP makes this cell line a valuable resource for investigating AD pathogenesis.

Individualized estimation of arterial carbon dioxide partial pressure using machine learning in children receiving mechanical ventilation.

BACKGROUND: Measuring arterial partial pressure of carbon dioxide (PaCO2) is crucial for proper mechanical ventilation, but the current sampling method is invasive. End-tidal carbon dioxide (EtCO2) has been used as a surrogate, which can be measured non-invasively, but its limited accuracy is due to ventilation-perfusion mismatch. This study aimed to develop a non-invasive PaCO2 estimation model using machine learning. METHODS: This retrospective observational study included pediatric patients (< 18 years) admitted to the pediatric intensive care unit of a tertiary children's hospital and received mechanical ventilation between January 2021 and June 2022. Clinical information, including mechanical ventilation parameters and laboratory test results, was used for machine learning. Linear regression, multilayer perceptron, and extreme gradient boosting were implemented. The dataset was divided into 7:3 ratios for training and testing. Model performance was assessed using the R2 value. RESULTS: We analyzed total 2,427 measurements from 32 patients. The median (interquartile range) age was 16 (12-19.5) months, and 74.1% were female. The PaCO2 and EtCO2 were 63 (50-83) mmHg and 43 (35-54) mmHg, respectively. A significant discrepancy of 19 (12-31) mmHg existed between EtCO2 and the measured PaCO2. The R2 coefficient of determination for the developed models was 0.799 for the linear regression model, 0.851 for the multilayer perceptron model, and 0.877 for the extreme gradient boosting model. The correlations with PaCO2 were higher in all three models compared to EtCO2. CONCLUSIONS: We developed machine learning models to non-invasively estimate PaCO2 in pediatric patients receiving mechanical ventilation, demonstrating acceptable performance. Further research is needed to improve reliability and external validation.

Ultraviolet Light-Assisted Decontamination of Chemical Warfare Agent Simulant 2-Chloroethyl Phenyl Sulfide on Metal-Loaded TiO2 /Ti Surfaces.

The application of ultraviolet (UV) light for the decontamination of chemical warfare agents (CWAs) has gained recognition as an effective method, especially for treating hard-to-reach areas where wet chemical methods are impractical. In this study, TiO2 /Ti was employed as a model catalyst, which was contaminated with 2-chloroethyl phenyl sulfide (CEPS), and subjected to photocatalytic decontamination using both UVB and UVC light. Additionally, photocatalytic decontamination efficiency by introducing Au, Pt, and Cu onto the TiO2 /Ti surface was explored. During the photodecomposition process under UVC light, at least eight distinct secondary byproducts were identified. It was observed that the introduction of overlayer metals did not significantly enhance the photodecomposition under UVC light instead overlaid Au exhibited substantially improved activity under UVB light. Whereas, photodecomposition process under UVB light, only five secondary products were detected, including novel compounds with sulfoxide and sulfone functional groups. This novel study offers valuable insights into the generation of secondary products and sheds light on the roles of overlayer metals and photon wavelength in the photodecontamination process of CWA.

Matrin3 mediates differentiation through stabilizing chromatin loop-domain interactions and YY1 mediated enhancer-promoter interactions.

Although emerging evidence indicates that alterations in proteins within nuclear compartments elicit changes in chromosomal architecture and differentiation, the underlying mechanisms are not well understood. Here we investigate the direct role of the abundant nuclear complex protein Matrin3 (Matr3) in chromatin architecture and development in the context of myogenesis. Using an acute targeted protein degradation platform (dTAG-Matr3), we reveal the dynamics of development-related chromatin reorganization. High-throughput chromosome conformation capture (Hi-C) experiments revealed substantial chromatin loop rearrangements soon after Matr3 depletion. Notably, YY1 binding was detected, accompanied by the emergence of novel YY1-mediated enhancer-promoter loops, which occurred concurrently with changes in histone modifications and chromatin-level binding patterns. Changes in chromatin occupancy by Matr3 also correlated with these alterations. Overall, our results suggest that Matr3 mediates differentiation through stabilizing chromatin accessibility and chromatin loop-domain interactions, and highlight a conserved and direct role for Matr3 in maintenance of chromosomal architecture.

A Narrative Review on the Advance of Probiotics to Metabiotics.

Recently, the term metabiotics has emerged as a new concept of probiotics. This concept entails combining existing probiotic components with metabolic by-products improve specific physiological functionalities. Representative ingredients of these metabiotics include short-chain fatty acids (SCFAs), bacteriocins, polysaccharides, and peptides. The new concept is highly regarded as it complements the side effects of existing probiotics and is safe and easy to administer. Known health functions of metabiotics are mainly immune regulation, anti-inflammatory, anticancer, and brain-neurological health. Research has been actively conducted on the health benefits related to the composition of intestinal microorganisms. Among them, the focus has been on brain neurological health, which requires extensive research. This study showed that neurological disorders, such as depression, anxiety, autism spectrum disorder, Alzheimer's disease, and Parkinson's disease, can be treated and prevented according to the gut-brain axis theory by changing the intestinal microflora. In addition, various studies are being conducted on the immunomodulatory and anticancer effects of substances related to metabiotics of the microbiome. In particular, its efficacy is expected to be confirmed through human studies on various cancers. Therefore, developing various health functional effects of the next-generation probiotics such as metabiotics to prevent or treatment of various diseases is anticipated.