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Long-term consumption of erythritol, a widely used sugar substitute, has been associated with increased risks of thrombosis and cardiometabolic diseases. In this study, we investigated the effects and mechanisms of allulose in mitigating these risks compared to erythritol using the clusterProfiler tool in R (version 4.12.6). Since a high-fat diet (HFD) is known to enhance platelet aggregation, we compared the pathways related to these processes between groups of mice treated with allulose and those treated with erythritol. While erythritol exacerbated HFD-induced increased platelet aggregation, allulose treatment significantly reduced it. Further analysis of platelet gene expression in sickle cell disease (SCD) patients to explore the potential of using sugar substitutes revealed that platelet coagulation mechanisms could be exacerbated by HFD. Additionally, the top up- and downregulated pathways in SCD were significantly reduced in the allulose-treated group compared to the erythritol group. Specific mechanisms related to this include the mitochondrial complex I and mitochondrial translational process as potential pathological factors in platelet coagulation related to SCD. Therefore, this study demonstrates that allulose may offer a safer alternative to erythritol in dietary applications, especially in individuals susceptible to thrombotic events, by modulating critical pathways associated with platelet function and mitochondrial activity. [ABSTRACT FROM AUTHOR]

Obesity is known to affect various tissues and contribute to conditions such as neuroinflammation. However, the specific mechanisms and time-dependent progression of these effects across different tissues remain unclear. In this study, we monitored gene expression at intervals to examine the effects of a high-fat diet (HFD) on brain, liver, adipose, and muscle tissues in male C57/BJ mice, with a particular focus on neuroinflammation. Early inflammatory responses exhibit a progression that starts in the liver, extends to adipose tissue, and subsequently involves muscle and brain tissues. Although the brain did not show significant gene expression of inflammatory responses, mechanisms leading to neuroinflammation increased after 24 weeks, possibly through systemic chronic inflammation (SCI). Notably, mitochondrial complex I activity serves as a biomarker to indicate the inflammatory transition from the liver to adipose and other tissues caused by SCI. These similar gene expression dynamics were also observed in the hippocampus of Alzheimer's patients and in an Alzheimer's mouse model treated with a HFD. These results suggest that initially, the brain suppresses inflammatory responses, including interferon-gamma (IFN-γ), more than other tissues in response to a HFD. However, at the onset of SCI, the brain eventually exhibits inflammatory dynamics similar to those of other tissues. This underscores the significance of our findings, indicating that the early kinetics of chronic IFN-γ response and mitochondrial complex I activity inhibition serve as crucial biomarkers, emerging early in various conditions, including obesity and aging. [ABSTRACT FROM AUTHOR]

The rapid proliferation of Internet of Things (IoT) technology has facilitated automation across various sectors. Nevertheless, this advancement has also resulted in a notable surge in cyberattacks, notably botnets. As a result, research on network analysis has become vital. Machine learning-based techniques for network analysis provide a more extensive and adaptable approach in comparison to traditional rule-based methods. In this paper, we propose a framework for analyzing communications between IoT devices using supervised learning and ensemble techniques and present experimental results that validate the efficacy of the proposed framework. The results indicate that using the proposed ensemble techniques improves accuracy by up to 1.7% compared to single-algorithm approaches. These results also suggest that the proposed framework can flexibly adapt to general IoT network analysis scenarios. Unlike existing frameworks, which only exhibit high performance in specific situations, the proposed framework can serve as a fundamental approach for addressing a wide range of issues. [ABSTRACT FROM AUTHOR]

This article, published in the Chemistry of Natural Compounds journal, explores the chemical components found in Smilax sieboldii, a type of climbing shrub. Smilax plants are commonly used in traditional medicine and have been studied for their potential medicinal effects. The researchers identified several bioactive compounds in the plant, including phenolic compounds, flavonoids, and fatty acid esters. Some of these compounds have shown anti-inflammatory, anticancer, and antioxidant properties. The study provides valuable information about the chemical composition of S. sieboldii and its potential medicinal uses. The research was supported by the Korean Forest Service. [Extracted from the article]

The utilization of polymethyl methacrylate (PMMA) bone cement is employed for the purpose of stabilizing fractured vertebral bodies. The existence of a mechanical imbalance in hard polymethylmethacrylate (PMMA) bone cement has the potential to increase the likelihood of a fracture occurring in the neighbouring vertebral body. In order to reduce potential difficulties, the primary goal of this study is to investigate the potential benefits of increasing PMMA bone cement's bioactivity and lowering its elastic modulus. The incorporation of a 10% volume fraction of hyaluronic acid (HyA) and polyethylene glycol (PEG) into the bone cement led to an improvement in the bioactivity and decreasing of elastic modulus of polymethylmethacrylate (PMMA). The integration of HyPE gel phase presents several advantages over pure PMMA bone cement, including enhanced setting parameters, improved degradability, and increased biocompatibility. The gel phase is additionally accountable for a reduction in the elastic modulus of polymethylmethacrylate (PMMA) bone cement. In addition, the existence of a porous structure that arises from the degradation of the HyPE gel phase delivers a significant amount of room, thereby enhancing the process of bone regeneration when implanted in the femur of rabbits. The utilization of HyPE in PMMA has been shown through comprehensive µ-CT analysis to enhance bone formation, thereby promoting osteointegration at the implantation site. Furthermore, the histological analysis demonstrated the existence of osteogenic activity in the PMMA polyethylene glycol supplemented with 10% HyA and 10% PEG after a 2-month period subsequent to implantation. [ABSTRACT FROM AUTHOR]

Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10−5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial–mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells. [ABSTRACT FROM AUTHOR]

Chronic oral inflammation and biofilm-mediated infections drive diseases such as dental caries and periodontitis. This study investigated the anti-inflammatory and antibacterial potential of an ethanol extract from Astilbe chinensis inflorescence (GA-13-6) as a prominent candidate for natural complex substances (NCS) with therapeutic potential. In LPS-stimulated RAW 264.7 macrophages, GA-13-6 significantly suppressed proinflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and nitric oxide (NO), surpassing purified astilbin, a known bioactive compound found in A. chinensis. Furthermore, GA-13-6 downregulated the expression of cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS), indicating an inhibitory effect on the inflammatory cascade. Remarkably, GA-13-6 exhibited selective antibacterial activity against Streptococcus mutans, Streptococcus sanguinis, and Porphyromonas gingivalis, key players in dental caries and periodontitis, respectively. These findings suggest that complex GA-13-6 holds the potential for the treatment or prevention of periodontal and dental diseases, as well as various other inflammation-related conditions, while averting the induction of antibiotic resistance. [ABSTRACT FROM AUTHOR]

Background and Aims: Longitudinal change in income is crucial in explaining cardiovascular health inequalities. However, there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D). Methods: Using a nationally representative sample from the Korean National Health Insurance Service database, 1 528 108 adults aged 30–64 with T2D and no history of CVD were included from 2009 to 2012 (mean follow-up of 7.3 years). Using monthly health insurance premium information, income levels were assessed annually for the baseline year and the four preceding years. Income variability was defined as the intraindividual standard deviation of the percent change in income over 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, heart failure, and stroke) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders. Results: High-income variability was associated with increased CVD risk (HRhighest vs. lowest quartile 1.25, 95% CI 1.22–1.27; Ptrend <.001). Individuals who experienced an income decline (4 years ago vs. baseline) had increased CVD risk, which was particularly notable when the income decreased to the lowest level (i.e. Medical Aid beneficiaries), regardless of their initial income status. Sustained low income (i.e. lowest income quartile) over 5 years was associated with increased CVD risk (HRn = 5 years vs. n = 0 years 1.38, 95% CI 1.35–1.41; Ptrend <.0001), whereas sustained high income (i.e. highest income quartile) was associated with decreased CVD risk (HRn = 5 years vs. n = 0 years 0.71, 95% CI 0.70–0.72; Ptrend <.0001). Sensitivity analyses, exploring potential mediators, such as lifestyle-related factors and obesity, supported the main results. Conclusions: Higher income variability, income declines, and sustained low income were associated with increased CVD risk. Our findings highlight the need to better understand the mechanisms by which income dynamics impact CVD risk among individuals with T2D. Structured Graphical Abstract This study investigates the association between income dynamics over five years and incident composite cardiovascular outcomes in non-elderly individuals with type 2 diabetes. Our graphical abstract highlights significant associations between cardiovascular risk and income metrics, including income variability (standard deviation of percent change), changes in income status (rise and decline), and cumulative number of years in low- or high-income status. [ABSTRACT FROM AUTHOR]

The article "Anthraquinone, Lignan, and Flavonoid Constituents from the Leaves of Sageretia thea" provides information about the chemical constituents of Sageretia thea, a shrub commonly known as 'Sangdong' or 'Chinese sweet plum'. The leaves of this shrub are used to make tea and have been historically used in herbal medicine. The study isolated and determined the chemical structures of several secondary metabolites found in the leaves of S. thea. The article includes detailed information about the compounds, such as their physical properties, chemical formulas, and spectroscopic data. This information may be valuable for researchers studying these compounds. [Extracted from the article]

Fludioxonil (Flu) is a phenylpyrrole fungicide and is currently used in over 900 agricultural products globally. Flu possesses endocrine‐disrupting chemical‐like properties and has been shown to mediate various physiological and pathological changes, such as apoptosis and differentiation, in diverse cell lines. However, the effects of Flu on cardiomyocytes have not been studied so far. The present study investigated the effects of Flu on mitochondria in AC16 human cardiomyocytes and H9c2 rat cardiomyoblasts. Flu decreased cell viability in a water‐soluble tetrazolium assay and mediated morphological changes suggestive of apoptosis in AC16 and H9c2 cells. We confirmed that annexin V positive cells were increased by Flu through annexin V/propidium iodide staining. This suggests that the decrease in cell viability due to Flu may be associated with increased apoptotic changes. Flu consistently increased the expression of pro‐apoptotic markers such as Bcl‐2‐associated X protein (Bax) and cleaved‐caspase 3. Further, Flu reduced the oxygen consumption rate (OCR) in AC16 and H9c2 cells, which is associated with decreased mitochondrial membrane potential (MMP) as observed through JC‐1 staining. In addition, Flu augmented the production of mitochondrial reactive oxygen species, which can trigger oxidative stress in cardiomyocytes. Taken together, these results indicate that Flu induces mitochondrial dysregulation in cardiomyocytes via the downregulation of the OCR and MMP and upregulation of the oxidative stress, consequently resulting in the apoptosis of cardiomyocytes. This study provides evidence of the risk of Flu toxicity on cardiomyocytes leading to the development of cardiovascular diseases and suggests that the use of Flu in agriculture should be done with caution and awareness of the probable health consequences of exposure to Flu. [ABSTRACT FROM AUTHOR]

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Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1β) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production—all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1β) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production—all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

In the aging society, slow bone regeneration poses a serious hindrance to the quality of life. To deal with this problem, in this study, we have combined irisin with the bioglass regular beads to enhance the bone regeneration process. For this purpose, highly porous bioglass was obtained as spherical beads by using sodium alginate. The bioglass was evaluated by various analytical techniques such as SEM, EDS, XRD, and pore size distribution. The results depicted that porous bioglass was prepared correctly and SEM analysis showed a highly porous bioglass was formulated. On this bioglass, irisin was loaded with the assistance of polyvinyl alcohol (PVA) in three concentrations (50 ng/ml, 100 ng/ml, and 150 ng/ml per 1 g of bioglass). SEM analysis showed that pores are covered with PVA. The irisin release profile showed a sustained release over the time period of 7 days. In vitro, biocompatibility evaluation by the MC3T3E1 cells showed that prepared bioglass and irisin loaded bioglass (BGI50, BGI100, and BG150) are highly biocompatible. Alizarin Red staining analysis showed that after 2 weeks BGI50 samples showed highest calcium nodule formation. In vivo in the rabbit femur model was conducted for 1 and 2 months. BGI150 samples showed highest BV/TV ratio of 37.1 after 2 months. The histological data showed new bone formation surrounding the beads and with beads loaded with irisin. Immunohistochemistry using markers OPN, RUNX, COL, and ALP supported the osteogenic properties of the irisin-loaded bioglass beads. The results indicated that irisin-loaded bioglass displayed remarkable bone regeneration. [ABSTRACT FROM AUTHOR]

This article discusses the secondary metabolites found in the leaves and twigs of Acer pseudosieboldianum, also known as the Korean maple. The study identifies and characterizes several compounds, such as gallic acid and chlorogenic acid, that have not been previously reported in the Aceraceae family. The research contributes to our understanding of the plant's chemical composition and potential medicinal properties. The document provides detailed information on the molecular formula, physical properties, and NMR data for each compound. The research was supported by the Gyeonggi Provincial Government and received English language editing assistance. [Extracted from the article]

3D-printed titanium (Ti) cages present an attractive alternative for addressing issues related to osteoporosis-induced fractures, accidental fractures, and spinal fusion surgery due to disc herniation. These Ti-based bone implants possess superior strength compared to other metals, allowing for versatile applications in orthopedic scenarios. However, when used as standalone solutions, certain considerations may arise, such as interaction with soft tissues. Therefore, to overcome these issues, the combination with hydrogel has been considered. In this study, to impart Ti with regenerative abilities a 3D-printed Ti cage was loaded with gelatin and hyaluronic acid (G-H) to improve the cell attachment ability of the Ti-based bone implants. The void spaces within the mesh structure of the 3D Ti cage were filled with G-H, creating a network of micro-sized pores. The filled G-H acted as the bridge for the cells to migrate toward the large inner pores of the 3D Ti cage. Due to the microporous surface and slow release of gelatin and hyaluronic acid, the biocompatibility of the coated Ti cage was increased with an elevation in osteoconduction as depicted by the up-regulation of bone-related gene expressions. The in vivo implantation in the rabbit femur model showed enhanced bone regeneration due to the coated G-H on the Ti cage compared to the pristine hollow Ti cage. The G-H filled the large holes of the 3D Ti cage that acted as a bridge for the cells to travel inside the implant and aided in the fast regeneration of bone. [ABSTRACT FROM AUTHOR]

Security incidents targeting control systems and the industrial internet of things (IIoT) are on the rise as attackers gain a better understanding of the nature of these systems and their increasing connectivity to information technology (IT). Every year, the number of vulnerabilities associated with these incidents increases, making it impractical to apply timely patches for all of them. The current vulnerability assessments, which are the basis for vulnerability patching, have limitations in that they do not adequately reflect the risk of exploitation in the real world after discovery and do not consider operational technology (OT) and industrial control system (ICS) environments other than IT environments. This study proposes to evaluate exploit risk in real-world environments by considering OT/ICS environments and calculating three metrics, including exploit chain risk, exploit code availability, and exploit use probability based on cyber threat information, including IIoT vulnerability data, used in OT/ICS environments. In addition, we construct exploitation scenarios in a control system environment to prioritize vulnerabilities with a high risk of exploitation based on the three metrics. We show that by assessing the risk of attackers' intentions and exploited technologies for attacks against IIoT devices in a control system environment, we can provide defenders with comprehensive attack risk information for proactive defense. [ABSTRACT FROM AUTHOR]

Veratrum spp. have traditionally been used in folk medicine to treat various pathologies. In this study, nine compounds, comprising one simple phenolic compound (1), three stilbenoids (2-4), and five flavonoids (5-9), were isolated from the aerial parts of Veratrum versicolor f. viride Nakai. The structures of these compounds were elucidated by spectroscopic analyses and comparison with reported data. Together, all reported compounds were isolated from V. versicolor f. viride for the first time in the study. Among them, two flavone aglycone tricetins (7 and 9) have never been isolated from the genus Veratrum or the family Melanthiaceae. The ethanol extract and isolated compounds were assessed for their inhibitory effects on elastase, tyrosinase, and melanin synthesis. Compounds 5 and 7 inhibited elastase (IC50: 292.25 ± 14.39 and 800.41 ± 5.86 µM, respectively), whereas compounds 2-5 inhibited tyrosinase with IC50 values in the range of 6.42 ~ 51.19 µM, respectively. In addition, compounds 3-6 and 8 exhibited dose-dependent inhibition (70.4% ~ 91.0%) of melanogenesis at a concentration of 100 µM. [ABSTRACT FROM AUTHOR]

Icariin, a major bioactive compound found in the Epimedium genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we aimed to investigate the regulatory effect of icariin and its active metabolites (icariside II and icaritin) against prime G-protein-coupled receptor targets, considering their association with neuronal disorders. Icariside II exhibited selective agonist activity towards the dopamine D3 receptor (D3R), with half-maximal effective concentrations of 13.29 μM. Additionally, they effectively inhibited the specific binding of radioligands to D3R. Molecular docking analysis revealed that icariside II potentially exerts its agonistic effect through hydrogen-bonding interaction with Asp110 of the D3R, accompanied by negative binding energy. Conversely, icaritin demonstrated selective antagonist effects on the muscarinic acetylcholine M2 receptor (M2R). Radioligand binding assay and molecular docking analysis identified icaritin as an orthosteric ligand for M2R. Furthermore, all three compounds, icariin and its two metabolites, successfully mitigated MK-801-induced schizophrenia-like symptoms, including deficits in prepulse inhibition and social interaction, in mice. In summary, these findings highlight the potential of icariin and its metabolites as promising lead structures for the discovery of new drugs targeting cognitive and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Natural flavone and isoflavone analogs such as 3′,4′,7-trihydroxyflavone (1), 3′,4′,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer's and Parkinson's disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC50 value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC50 value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD4R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD4R antagonist effect, respectively, for neuroprotection. The route of administration should be considered. [ABSTRACT FROM AUTHOR]

Aggregation and non-enzymatic glycation of amyloidogenic peptides, amyloid-beta (Aβ), and insulin are key features of neuropathology. In this study, we evaluate the anti-glycation effect of Cassia seed-derived secondary metabolites on human insulin and bovine serum albumin, as well as their anti-Aβ aggregation and antioxidant effects using in vitro spectrofluorometric method, thioflavin T fluorescence, and peroxynitrite (ONOO‒) scavenging assay. Furthermore, molecular docking simulation was performed to investigate the binding characteristics of test compounds and Aβ42 peptide. Among 38 compounds, anthraquinones 9–12 and 14–18; naphthopyrones 24, 25, 27, and 33–36; and 38 from the naphthalenes and naphthalenic lactone groups showed moderate-to-good inhibition of AGE formation with IC50 values ranging from 7.52 ± 1.19 to 155.86 ± 0.79 µM. Likewise, compounds 5, 24, 15, 16, 27, and 20 showed good inhibition of D-ribose-mediated glycation of human insulin, with an IC50 value range of 46.37 ± 4.06 to 97.69 ± 7.88 µM. In the thioflavin-T assay, compounds 8 and 12 showed promising inhibition of Aβ aggregation, comparable to that of the reference compound morin. Molecular docking simulations confirmed that these active compounds have strong potential to interact with Aβ42 peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ42 aggregation. In addition, compounds 5, 8, 10, 14, and 35 scavenged ONOO− at low concentrations. Overall, Cassia compounds' anti-glycation, anti-Aβ aggregation, and antioxidant effects warrant further in vivo studies to evaluate their potential neuroprotective effects against comorbid AD and diabetes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle–stimulating hormone (FSH), a gonadotropin that rises in post–menopausal females, activates its receptor FSHR in the hippocampus, to drive AD–like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPβ/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPβ/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aβ and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPβ/δ-secretase signalling. Follicle stimulating hormone (FSH) has been shown to Alzheimer's disease like pathology in rodent models. Here the authors show using cellular and animal models that ApoE4 and FSH collectively act to trigger AD-like pathogenesis, by activating C/EBPβ/δ-secretase signalling. [ABSTRACT FROM AUTHOR]

A new flavan-3-ol glycoside, compound 1 (careyarboside A), was isolated from the ethanol extract of the stems of Careya arborea, together with six known compounds. Of these, three phenolic glycosides (leonuriside A, picraquassioside D, and careyarboside B) have never been previously isolated from genus Careya and family Lecythidaceae. Their chemical structures were identified using spectroscopic data, specifically HRESIMS, 1D and 2D NMR data, including 1H-1H COSY, HSQC, and HMBC. In addition, the chemical structures of the known compounds were identified through spectral comparisons with those of published values. [ABSTRACT FROM AUTHOR]

Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ‐secretase) and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded 4 weeks after nerve transection and repair and 2 weeks after daily treatments with CP11 were double those of vehicle‐treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11‐treated mice than vehicle‐treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 h with CP11, neurites were nearly 50% longer than in vehicle‐treated controls and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8‐dihydroxyflavone (7,8‐DHF). Combined treatment with CP11 and 7,8‐DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA‐12, indicating that the enhancement was independent of TrkB signalling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB− neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential. [ABSTRACT FROM AUTHOR]

Smilax sieboldii, a climbing tree belonging to Smilacaceae, has been used in traditional oriental medicine for treating arthritis, tumors, leprosy, psoriasis, and lumbago. To evaluate the anti-obesity effects of S. sieboldii (Smilacaceae), we screened methylene chloride (CH2Cl2), ethyl acetate (EtOAc), aqueous-saturated n-butanol, and ethanol (EtOH) extracts of the whole plant at various concentrations to inhibit adipogenesis in adipocytes. The 3T3-L1 cell line with Oil red O staining with the help of fluorometry was used as an indicator of anti-obesity activity. Bioactivity-guided fractionation of the EtOH extract and subsequent phytochemical investigation of the active CH2Cl2- and EtOAc-soluble fractions resulted in the isolation of 19 secondary metabolites (1–19), including a new α-hydroxy acid derivative (16) and two new lanostane-type triterpenoids (17 and 18). The structures of these compounds were characterized using various spectroscopic methods. All the isolated compounds were screened for adipogenesis inhibition at a concentration of 100 μM. Of these, compounds 1, 2, 4–9, 15, and 19 significantly reduced fat accumulation in 3T3-L1 adipocytes, especially compounds 4, 7, 9, and 19, showing 37.05 ± 0.95, 8.60 ± 0.41 15.82 ± 1.23, and 17.73 ± 1.28% lipid content, respectively, at a concentration of 100 μM. These findings provide experimental evidence that isolates from S. sieboldii extracts exert beneficial effects regarding the regulation of adipocyte differentiation. [ABSTRACT FROM AUTHOR]

Introduction: Growth-associated protein 43 (GAP-43) is known as a neuronal plasticity protein because it is widely expressed at high levels in neuronal growth cones during axonal regeneration. GAP-43 expressed in mature adult neurons is functionally important for the neuronal communication of synapses in learning and memory. Brain-derived neurotrophic factor (BDNF) is closely related to neurodegeneration and synaptic plasticity during the aging process. However, the molecular mechanisms regulating neurodegeneration and synaptic plasticity underlying the pathogenesis and progression of Alzheimer's disease (AD) still remain incompletely understood. Methods: Remarkably, the expressions of GAP-43 and BDNF perfectly match in various neurons in the Human Brain Atlas database. Moreover, GAP-43 and BDNF are highly expressed in a healthy adults' hippocampus brain region and are inversely correlated with the amyloid beta (Ab), which is the pathological peptide of amyloid plaques found in the brains of patients with AD. Results: These data led us to investigate the impact of the direct molecular interaction between GAP-43 and BDNF in hippocampal neuron fate. In this study, we show that GAP-43 and BDNF are inversely associated with pathological molecules for AD (Tau and Ab). In addition, we define the three-dimensional protein structure for GAP-43 and BDNF, including the predictive direct binding sites via analysis using ClusPro 2.0, and demonstrate that the deprivation of GAP-43 and BDNF triggers hippocampal neuronal death and memory dysfunction, employing the GAP-43 or BDNF knock-down cellular models and 5XFAD mice. Conclusion: These results showthatGAP-43 and BDNF are direct binding partners in hippocampal neurons and that their molecular signaling might be potential therapeutic targets for AD. [ABSTRACT FROM AUTHOR]

Nanocomposites have been widely studied for sensor applications because of their high design flexibility. However, the creep behavior of polymeric materials is a crucial issue of nanocomposite‐based strain sensors in terms of sensing accuracy in high‐temperature environments, which acts as a bottleneck for the use of nanocomposites in embedded type sensors for monitoring the curing reactions and structural health of composite. Herein, we suggest a microwave‐assisted cross‐linking method for enhancing the reliability of polymer‐based coaxial‐structured fiber strain sensors in high temperatures. A dry‐jet wet‐spun ultra‐high molecular weight polyethylene core fiber with a microwave post‐treatment in a peroxide bath provided superior strength (2.1 GPa), modulus (69 GPa), and enhanced creep resistance (>94%). By using a creep resistance‐enhanced core fiber, coaxial‐structured fiber strain sensors, which have multi‐layer structured shell parts, could be fabricated via the simple dip‐coating method. The fabricated coaxial‐structured fiber strain sensor showed a high gauge factor (4.12 with strain range of 0%–1%), a low‐temperature sensitivity coefficient (−6.5 × 10−4), and an improved sensing accuracy (<3% error at 80 °C) in high‐temperature environments. From these results, it can be confirmed that the microwave‐assisted cross‐linking method is very promising for use in nanocomposite‐based strain sensors for various application fields. [ABSTRACT FROM AUTHOR]

Objective: There is limited evidence on the association of sustained low-income status, income changes, and all-cause mortality risk in individuals with type 2 diabetes (T2D).Research Design and Methods: Using the Korean Health Insurance Service database, we studied 1,923,854 adults with T2D (aged ≥30 years) without cardiovascular disease and cancer, who were enrolled from 2009 through 2012 and followed to the end of 2020 (median 10.8 years of follow-up). We defined income levels based on the amount of health insurance premiums and categorized them into quartiles, the first being the low-income group, and assessed the income status annually in the preceding 5 years. Cox proportional hazards models were used to quantify the association of low-income status and income changes with mortality, with adjustment for sociodemographic factors, comorbidities, and diabetes duration and treatment.Results: Participants who consecutively had low income showed a higher risk of mortality (hazard ratio [HR] 1.19; 95% CI 1.16-1.22), compared with those who had never been in the low-income group. This association was much stronger for consecutive recipients of Medical Aid, reflecting very-low-income status (HR 2.26; 95% CI 2.16-2.36), compared with those who had never been Medical Aid beneficiaries. Sustained low- and very-low-income status was associated with increased risk of mortality, specifically for younger adults (aged<40 years) and males. Those who experienced declines in income between the first (preceding 5 years) and the last (baseline) time points had an increased risk of mortality, regardless of baseline income status.Conclusions: Among Korean adults with T2D, sustained low-income status and declines in income were associated with increased risk of mortality. [ABSTRACT FROM AUTHOR]

The application of polymer-based composite materials as bearing liner materials in eco-friendly water lubrication has received considerable attention owing to their superior tribological behaviors, corrosion resistance, and high damping characteristics, and their design flexibility can improve the bearing performances in response to the distribution of lubricant film pressure based on the regulation of elastic constants. However, the low viscosity and high density of water essentially cause thin-filmed lubrication accompanied by a low load-carrying capacity. Particularly, a high rotational speed enhancing the wedge effect induces turbulence and considerable inertial effect. Moreover, substantial elastic deformation of the composite bearing liners alters the formation of the lubricant film. In this study, we analyze a water-lubricated composite journal bearing system incorporating the turbulence, inertial effect, and elastic deformation of the bearing liner. Reynolds equation was modified considering the turbulence and inertial effect. The elastic deformation of the composite bearing liner was determined by solving the constitutive equation. The Reynolds equation and the constitutive equation were solved via the finite differencemethod and finite elementmethod, respectively. In addition, the analytical relation for the elastic deformation was derived that suitably eliminated the requirement of solving the constitutive equation. With the introduction of the primary parameters, Sommerfeld number, Reynolds number, and deformation coefficient, the relation of the normalized minimum film thickness with respect to the parameters was modeled based on the Gaussian regression model. Accordingly, we proposed the new optimal maximumload-carrying capacity boundaries that narrowed down the operating region compared to conventional boundaries. [ABSTRACT FROM AUTHOR]

Pueraria lobata leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients of P. lobata leaves and to elucidate their function in monoamine oxidase (MAO) activation and Aβ self-aggregation using in vitro and in silico approaches. To the best of our knowledge, this is the first study to elucidate coumestrol as a selective and competitive MAO-A inhibitor. We identified that coumestrol, a coumestan-derivative, exhibited a selective inhibitory effect against MAO-A (IC50 = 1.99 ± 0.68 µM), a key target protein for depression. In a kinetics analysis with 0.5 µg MAO-A, 40–160 µM substrate, and 25 °C reaction conditions, coumestrol acts as a competitive MAO-A inhibitor with an inhibition constant of 1.32 µM. During an in silico molecular docking analysis, coumestrol formed hydrogen bonds with FAD and pi–pi bonds with hydrophobic residues at the active site of the enzyme. Moreover, based on thioflavin-T-based fluorometric assays, we elucidated that coumestrol effectively prevented self-aggregation of amyloid beta (Aβ), which induces an inflammatory response in the central nervous system (CNS) and is a major cause of Alzheimer's disease (AD). Therefore, coumestrol could be used as a CNS drug to prevent diseases such as depression and AD by the inhibition of MAO-A and Aβ self-aggregation. [ABSTRACT FROM AUTHOR]

Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU's antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8–100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications. [ABSTRACT FROM AUTHOR]

Biochar application has been considered as a promising solution to address the effects of modern agriculture on climate change. However, there is a lack of research on the biochar application of greenhouse gas emissions based on poor soils in Korean agricultural land. Therefore, this study aimed to evaluate the effects of biochar application according to different soil characteristics on soil organic carbon (SOC) improvement and greenhouse gas reduction. The incubation experiments were conducted for 49 days and used different feedstock (barley straw and poultry manure) and biochar application rates (0, 5, 10, and 20-ton ha−1) in four soil characteristics (upland, U; greenhouse, G; converted land, C; reclaimed land, R). The results of this study showed that the SOC increased significantly in all soils after biochar application. The increasing SOC rate was the highest in poor soil. Biochar 20-ton ha−1 treatment significantly reduced N2O emissions by 33.2% compared with the control. Barley straw biochar significantly reduced N2O emissions from all soils. Barley straw biochar decreased approximately 74.5% of N2O emissions compared with poultry manure biochar. Poultry manure biochar improved SOC and reduced N2O emissions in poor soil. However, in poultry manure biochar treatment in U and G soil, N2O emissions increased. In conclusion, barley straw biochar application was found to suppress N2O emissions and improve the SOC in all soil characteristics of agricultural land. In addition, the soil carbon storage effect and N2O reduction effect of biochar were the highest in poor soil. Thus, the biochar application can be a potential agricultural practice for improving soil quality and decreasing N2O emissions in domestic agricultural soil. [ABSTRACT FROM AUTHOR]

As the architecture of deep learning-based speech recognizers has recently changed to the end-to-end style, increasing the effective amount of training data has become an important issue. To tackle this issue, various data augmentation techniques to create additional training data by transforming labeled data have been studied. We propose a method called FrameAugment to augment data by changing the speed of speech locally for selected sections, which is different from the conventional speed perturbation technique that changes the speed of speech uniformly for the entire utterance. To change the speed of the selected sections of speech, the number of frames for the randomly selected sections is adjusted through linear interpolation in the spectrogram domain. The proposed method is shown to achieve 6.8% better performance than the baseline in the WSJ database and 9.5% better than the baseline in the LibriSpeech database. It is also confirmed that the proposed method further improves speech recognition performance when it is combined with the previous data augmentation techniques. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease with motor disorders as the key clinical features. BDNF/TrkB neurotrophic signalings are progressively reduced, whereas δ-secretase, a protease that cleaves α-synuclein (α-Syn) at N103 and promotes its aggregation and neurotoxicity, is gradually escalated in PD patient brains, associated with dopaminergic neuronal loss in the Substantia Nigra. Here, we show that stimulation of deficient BDNF/TrkB signalings with its small molecular agonist CF3CN displays the promising therapeutic effect, and blockade of δ-secretase with an optimal specific inhibitor #11A exhibits marked therapeutic effect, and combination of both demonstrates additive restorative efficacy in MPTP-induced human SNCA transgenic PD mice. Upon oral administration, CF3CN robustly activates TrkB-mediated neurotrophic pathway in the brains of SNCA mice and decreases α-Syn N103 cleavage by δ-secretase, and #11A strongly blocks δ-secretase and reduces α-Syn N103 fragmentation, increasing TH-positive dopaminergic neurons. The mixture of CF3CN and #11A shows the maximal TH and dopamine levels with demonstrable BDNF as compared to negligible BDNF in vehicle-treated MPTP/SNCA mice, leading to the climaxed motor functions. Notably, both compounds possess the appropriate in vivo PK profiles. Hence, our findings support that CF3CN and #11A are promising therapeutic pharmaceutical agents for treating PD. [ABSTRACT FROM AUTHOR]

Perturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability. Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage. [ABSTRACT FROM AUTHOR]

Angiogenesis plays important roles in pathological conditions such as cancer and inflammation as well as normal tissue development and homeostasis. Here, we investigated the effects and molecular mechanisms of α-viniferin, an oligostilbene isolated from Caragana sinica, on human umbilical vein endothelial cell responses in vitro and angiogenic sprouting in aortic rings ex vivo. α-viniferin treatment inhibited mitogen-induced HUVEC proliferation by retinoblastoma protein hypophosphorylation. In addition, α-viniferin suppressed mitogen-induced HUVEC adhesion, migration, invasion, and microvessel outgrowth. These anti-angiogenic activities of α-viniferin might be mediated through downregulation of cell cycle-related proteins, vascular endothelial growth factor receptor-2 (VEGFR-2), and matrix metalloproteinase-2. Furthermore, inactivation of VEGFR-2/p70 ribosomal S6 kinase signaling pathway was found to be involved in α-viniferin-mediated modulation of endothelial cell responses. Our results demonstrate the pharmacological functions and molecular mechanisms of α-viniferin in regulating angiogenesis, suggesting the therapeutic potential of α-viniferin to treat and prevent various angiogenesis-related diseases. [ABSTRACT FROM AUTHOR]

Hemp (Cannabis sativa L.) contains a variety of secondary metabolites, including cannabinoids, such as psychoactive (−)-trans-Δ⁹-tetrahydrocannabinol. The present study was conducted to identify the major phenolic components contained in hemp root, which has been relatively under-researched compared to other parts of hemp. The aqueous ethanol extract of hemp roots was fractionated into methylene chloride (MC), ethyl acetate (EA), and water (WT) fractions, and high-performance liquid chromatography with photodiode array detection (HPLC-DAD) analysis was performed. The main ultraviolet (UV)-absorbing phenolic compound contained in the EA fraction was identified as p-coumaric acid by comparing the retention time and UV absorption spectrum with a standard. Silica gel column chromatography was performed to isolate a hydrophobic derivative of p-coumaric acid contained in the MC fraction. Nuclear magnetic resonance (NMR) analysis identified the isolated compound as ethyl p-coumarate. For comparative purposes, ethyl p-coumarate was also chemically synthesized by the esterification reaction of p-coumaric acid. The content of p-coumaric acid and ethyl p-coumarate in the total extract of hemp root was estimated to be 2.61 mg g−1 and 6.47 mg g−1, respectively, by HPLC-DAD analysis. These values correspond to 84 mg Kg−1 dry root and 216 mg Kg−1 dry root, respectively. In conclusion, this study identified p-coumaric acid and ethyl p-coumarate as the main phenolic compounds contained in the hemp roots. [ABSTRACT FROM AUTHOR]

Axon regeneration after peripheral nerve injury is slow and inefficient, leading to generally poor functional recovery. Activity-dependent experimental therapies that increase expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors enhance regeneration, suggesting that treatments with BDNF might also be effective. However, recombinant human BDNF (rhBDNF), as well as 7,8-dihydroxyflavone (7,8-DHF), a small molecular BDNF mimetic, may have limited treatment applications because of their modest oral bioavailability and pharmacokinetic profile. R13 is a 7,8-DHF prodrug. Upon oral administration, it is converted in the liver to 7,8-DHF. In immunoblots from tissues at the site of nerve injury, a single oral treatment with R13 to mice following sciatic nerve transection and repair produced a rapid and prolonged increase in immunoreactivity to phosphorylated TrkB, prolonged phosphorylation of mitogen activated protein kinase (MAPK/Erk1/2), and a rapid but transient increase in phosphorylated AKT (protein kinase B). Intramuscular injections of fluorescent retrograde tracers into the gastrocnemius and tibialis anterior muscles 4 weeks after nerve injury resulted in significantly greater numbers of labeled motoneurons and dorsal root ganglion neurons in R13-treated mice than in vehicle-treated controls. Direct electromyographic (EMG) responses (M waves) were significantly larger in R13-treated mice 4 weeks after injury than vehicle-treated controls or mice treated with oral 7,8-DHF. Oral treatments with the prodrug, R13, are a potent therapy for stimulating axon regeneration and functional recovery after peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3–7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer’s disease. Blocking FSH action in these mice abrogates the Alzheimer’s disease-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer’s disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer’s disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.Follicle-stimulating hormone acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Netrin‐1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age‐dependent protease that cuts human alpha‐synuclein (α‐Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α‐SNCA transgenic mice in an age‐dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin‐1 levels. Netrin‐1 deprivation in primary cultures induces AEP and caspase‐3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin‐1 deprivation‐elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP‐truncated UNC5C intracellular fragment strongly elicits α‐Syn aggregation and dopaminergic loss, locomotor deficits in α‐SNCA transgenic mice. Hence, the findings demonstrate that netrin‐1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis. [ABSTRACT FROM AUTHOR]

The anti-adipogenic activities of all the isolated compounds (except compound B 3 b owing to insufficient material) were evaluated by assessing the fat accumulation in treated 3T3-L1 cells using Oil Red O staining. 3T3-L1 cells were treated with various concentrations of the test compounds from the start of adipocyte differentiation (day 0) until day 8. Effect of compounds isolated from the stems of I. cambodianum on lipid accumulation during adipocyte differentiation in 3T3-L1 cells. Six compounds were isolated from the stems of I I. cambodianum i and identified as callitrisic acid (4 I epi i -dehydroabietic acid, B 1 b ), augustanoic acid A ( B 2 b ), epipalustric acid ( B 3 b ), 4-allyl-4-(3-methylbut-2-enyl)-1,2-methylenedioxycyclohexa-2,6-dien-5-one ( B 4 b ), 4 I epi i -dehydroabietinol ( B 5 b ), and augustanoic acid E ( B 6 b ). [Extracted from the article]

Psychosis can include schizophrenia, mood disorders with psychotic features, delusional disorder, active delirium, and neurodegenerative disorders accompanied by various psychotic symptoms. Late-onset psychosis requires careful intervention due to the greater associated risks of secondary psychosis; higher morbidity and mortality rates than early-onset psychosis; and complicated treatment considerations due to the higher incidence of adverse effects, even with the black box warning against antipsychotics. Pharmacological treatment, including antipsychotics, should be carefully initiated with the lowest dosage for short-term efficacy and monitoring of adverse side effects. Further research involving larger samples, more trials with different countries working in consortia, and unified operational definitions for diagnosis will help elaborate the clinical characteristics of late-onset psychosis and lead to the development of treatment approaches. [ABSTRACT FROM AUTHOR]

Cognitive problems in depression are a major factor affecting functional recovery, improvement of quality of life, therapeutic response, and overall prognosis. Cognitive dysfunction tends to be persistently observed during the active episode of depression and after remission. To achieve functional recovery, cognitive dysfunction is an essential target for depression treatment. To improve cognitive function in treatment of depression, early recognition and assessment with personalized management are necessary. In this review, the importance of cognitive dysfunction in the treatment of depression and potential pathophysiological mechanisms are summarized. The monoamine system, systematic inflammation, and hypothalamic–pituitary–adrenal axis are all related to the pathogenesis of cognitive dysfunction in depression. Clinicians should consider individualized factors that can affect cognitive problem, including age, duration of illness, the number of episodes, previous treatment response, baseline cognitive reservoir, subtype of depression, and presence of childhood trauma. Comorbid physical and psychiatric conditions also need to be evaluated. [Psychiatr Ann. 2022;52(3):95–99.] [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (= 4,2′,4′-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions. In the present study, we re-examined the potential of ILG to inhibit human monoamine oxidase (hMAO) in vitro and established its mechanism of inhibition through a kinetics study and molecular docking examination. ILG showed competitive inhibition of hMAO-A and mixed inhibition of hMAO-B with IC50 values of 0.68 and 0.33 µM, respectively, which varied slightly from the reported IC50 values. Since ILG has been reported to reduce dopaminergic neurodegeneration and psychostimulant-induced toxicity (both of which are related to dopamine and vasopressin receptors), we investigated the binding affinity and modulatory functions of ILG on dopamine and vasopressin receptors. ILG was explored as an antagonist of the D1 receptor and an agonist of the D3 and V1A receptors with good potency. An in silico docking investigation revealed that ILG can interact with active site residues at target receptors with low binding energies. These activities of ILG on hMAO and brain receptors suggest the potential role of the compound to ameliorate dopaminergic deficits, depression, anxiety, and associated symptoms in Parkinson's disease and other neuronal disorders. [ABSTRACT FROM AUTHOR]