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Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary’s Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (β = 0.003, p

Alzheimer's disease (AD) is characterized by the aggregation of disordered proteins, such as amyloid beta (Aβ) and tau, leading to neurotoxicity and disease progression. Despite numerous efforts, effective inhibitors of Aβ and tau aggregates have not been developed. Thus, we aimed to screen natural small molecules from crude extracts that target various pathologies and are prescribed for patients with neurological diseases. In this study, we screened 162 natural small molecules prescribed for neurological diseases and identified genipin and pyrogallol as hit compounds capable of simultaneously regulating the aggregation of Aβ and tau K18. Moreover, we confirmed the dual modulatory effects of these compounds on the reduction of amyloid-mediated neurotoxicity in vitro and the disassembly of preformed Aβ42 and tau K18 fibrils. Furthermore, we observed the alleviatory effects of genipin and pyrogallol against AD-related pathologies in triple transgenic AD mice. Molecular dynamics and docking simulations revealed the molecular interaction dynamics of genipin and pyrogallol with Aβ42 and tau K18, providing insights into their suppression of aggregation. Our findings suggest the therapeutic potential of genipin and pyrogallol as dual modulators for the treatment of AD by inhibiting aggregation or promoting dissociation of Aβ and tau.

Objectives In order to recycle and resource waste glass, the feasibility of foam glass as filter media was evaluated, and column experiments using foam glass media were conducted to confirm the applicability as filter media in rain garden. Through this experiment, various design factors to be considered can be derived in application of foam glass media in the rain garden. Methods Sieve analysis and SEM/EDS analysis were conducted to confirm the physicochemical properties of the foam glass. Column experiments filled with only foam glass and mixtures of sand and foam glass were conducted to simulate rain garden to evaluate the removal efficiency of suspended solids and turbidity using the foam glass media, head difference (Δh) and hydraulic conductivity (K) changes, and calculation of filtered suspended solids loading using both discrete and cumulative mass approach. Finally, comparison of filtration performance with various filter media used in LID facilities was performed to evaluate the feasibility of foam glass media in rain garden. Results and Discussion Since foam glass media has a lower density than water, homogeneous particle size, and smooth surface with pores of various sizes, foam glass media effectively induces internal capture and external adsorption of suspended solids. Foam glass media has been applied to high suspended solids and turbidity removal efficiency. As the suspended solids inflow load increased, clogging occurred in the pores and the removal efficiency gradually decreased, but the foam glass media with lower density than water was continuously disturbed and rearranged due to the head difference energy, and some clogging were alleviated by rearrangement of pores and channels. The load of suspended solids in precipitated, adsorbed, and retained on the foam glass was calculated using the effluent sample (discrete) collected at regular time intervals and the continuously accumulated sample (cumulative) from the output. The filtered suspended solids load calculated using the cumulative mass approach was higher due to the estimation of the amounts of suspended solids remaining in the filtration column is lower because the samples (discrete) collected at regular time intervals from the output do not reflect the amount of suspended solids that change over time. Thus, the amounts of suspended solids removed through the filtration process can be much more accurately estimated using the cumulative samples. Finally, when comparing the removal efficiency with other filter media, foam glass can be used as excellent filter media with higher removal efficiency and greater lifespan. Conclusion Foam glass media with smooth surface, pores of various sizes, and lower density than water can rearrange and regenerate pores to alleviate some clogging, resulting in high suspended solids and turbidity removal efficiency for a long period of time. Considering that the amount of suspended solids filtered is determined by various factors such as particle size and distribution, porosity, depth, linear velocity, and inflow load of the suspended solids, the feasibility test using foam glass media through long-term field experiments is warranted. The amounts of suspended solids removed through the filtration process can be much more accurately estimated using the cumulative samples.

Background Several studies have reported associations between obesity and autonomic dysfunction. However, little research has investigated the effect of bariatric surgery on heart rate recovery (HRR) in the treadmill test and heart rate variability (HRV) in 24-hour Holter monitoring. We investigated the effects of bariatric surgery on HRR and HRV, which are parameters related to autonomic dysfunction. Methods We retrospectively investigated patients who underwent bariatric surgery in 2019. The treadmill test, 24-hour Holter monitoring, and echocardiography were performed before and 6 months after surgery. We compared the changes in HRR in the treadmill test and HRV parameters such as the time domain and spectral domain in 24-hour Holter monitoring before and after surgery. Results Of the 40 patients who underwent bariatric surgery, 25 patients had the treadmill test or 24-hour Holter monitoring both before and after surgery. Body weight and body mass index significantly decreased after surgery (112.86±24.37 kg vs. 89.10±20.26 kg, p

Abstract Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

Abstract Medial opening wedge high tibial osteotomy (MOWHTO) is a widely used surgical treatment option for medial compartmental osteoarthritis with varus deformity. It is important that proper lower limb alignment is achieved. However, there has been no consensus about an optimal alignment in MOWHTO. Most studies suggest that achieving valgus alignment is necessary, and recent studies support slight valgus mechanical alignment of less than 3° of mechanical femorotibial angle. Overcorrection and undercorrection is not recommended for achieving good surgical outcomes. To prevent undercorrection and overcorrection in MOWHTO, the method of placing the weight-bearing line in the target range must be precise. There are several ways to place a weight-bearing line within the target range. While the most important factor for a successful MOWHTO is achieving an ideal mechanical axis correction, there are a few other factors to consider, including joint line obliquity, posterior tibial slope, ligament balancing, and patellar height. Several factors exist that lead to undercorrection and overcorrection. Preoperative amount of varus deformity, lateral hinge fracture, and fixation failure can result in undercorrection, while medial soft tissue laxity and the amount of correction angle and target point beyond hypomochlion can result in overcorrection. This study aimed to review the literature on optimal alignment in MOWHTO and report on the factors to be considered to prevent correction errors and how to achieve an optimal alignment.

Abstract Background Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. Methods Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real‐time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co‐immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. Results Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (−49.86 ± 12.03%, P 3.12‐fold ± 0.13, P 3.3‐fold, P

Abstract Alzheimer’s disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

A prominent characteristic of Alzheimer's disease (AD) is the deposition of both amyloid-β (Aβ) peptide and tau protein in the brain. Aβ and tau not only induce toxicity through self-aggregation but also induce more potent toxicity through the synergistic action of Aβ and tau. In particular, neurotoxic aggregates of Aβ and tau directly affect several AD pathologies including neuroinflammation and cognitive decline. Therefore, there is increasing interest in strategies to modulate the aggregation and dissociation of Aβ and tau for treatment of AD. Our recent study found that Uncaria rhynchophylla (UR) has a therapeutic effect on AD via the inhibition of Aβ aggregation and attenuating Aβ-mediated pathogenesis of AD. However, no studies have investigated whether UR has anti- and disaggregation effects on both Aβ and tau. In this study, we showed the significant effects of UR on aggregation and dissociation of Aβ42 and tau K18 using a thioflavin T (ThT) assay. In addition, histological study revealed an inhibitory effect of UR on the accumulation of Aβ and tau and AD-related pathologies in 3xTg mice with both Aβ and tau pathology. Furthermore, we found that rhynchophylline and corynoxeine, bioactive components of UR, could modulate the aggregation and dissociation of both Aβ and tau using molecular docking simulation, isothermal titration calorimetry, and ThT assays. In conclusion, our results demonstrate that UR can inhibit the aggregation of Aβ and tau and promote the degradation of their aggregates in AD.

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by irreversible cognitive declines. Senile plaques formed by amyloid-β (Aβ) peptides and neurofibrillary tangles, consisting of hyperphosphorylated tau protein accumulation, are prominent neuropathological features of AD. Impairment of adult neurogenesis is also a well-known pathology in AD. Adult neurogenesis is the process by which neurons are generated from adult neural stem cells. It is closely related to various functions, including cognition, as it occurs throughout life for continuous repair and development of specific neural pathways. Notably, subventricular zone (SVZ) neurogenesis, which occurs in the lateral ventricles, transports neurons to several brain regions such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. These migrating neurons can affect cognitive function and behavior in different neurodegenerative diseases. Despite several studies indicating the importance of adult SVZ neurogenesis in neurodegenerative disorders, the pathological alterations and therapeutic implications of impaired adult neurogenesis in the SVZ in AD have not yet been fully explained. In this review, we summarize recent progress in understanding the alterations in adult SVZ neurogenesis in AD animal models and patients. Moreover, we discuss the potential therapeutic approaches for restoring impaired adult SVZ neurogenesis. Our goal is to impart to readers the importance of adult SVZ neurogenesis in AD and to provide new insights through the discussion of possible therapeutic approaches.

Abstract Adenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P

Exposure to air pollutants, such as PM2.5 and ozone, has a serious adverse effect on health, with more than 4 million deaths, including early deaths. Air pollution in ports is caused by exhaust gases from various elements, including ships, and to reduce this, the International Maritime Organization (IMO) is also making efforts to reduce air pollution by regulating the sulfur content of fuel used by ships. Nevertheless, there is a lack of measures to identify and minimize the effects of air pollution. The Community Multiscale Air Quality (CMAQ) model is the most used to understand the effects of air pollution. In this paper, we propose a hybrid model combining the CMAQ model and RNN-LSTM, an artificial neural network model. Since the RNN-LSTM model has very good predictive performance, combining these two models can improve the spatial distribution prediction performance of a large area at a relatively low cost. In fact, as a result of prediction using the hybrid model, it was found that IOA improved by 0.235~0.317 and RMSE decreased by 4.82~8.50 μg/m3 compared to the case of using only CMAQ. This means that when PM2.5 is predicted using the hybrid model, the accuracy of the spatial distribution of PM2.5 can be improved. In the future, if real-time prediction is performed using the hybrid model, the accuracy of the calculation of exposure to air pollutants can be increased, which can help evaluate the impact on health. Ultimately, it is expected to help reduce the damage caused by air pollution through accurate predictions of air pollution.

Abstract Background Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Alzheimer’s disease (AD) is a neurodegenerative disease accompanied by cognitive and behavioral symptoms. These AD-related manifestations result from the alteration of neural circuitry by aggregated forms of amyloid-β (Aβ) and hyperphosphorylated tau, which are neurotoxic. From a neuroscience perspective, identifying neural circuits that integrate various inputs and outputs to determine behaviors can provide insight into the principles of behavior. Therefore, it is crucial to understand the alterations in the neural circuits associated with AD-related behavioral and psychological symptoms. Interestingly, it is well known that the alteration of neural circuitry is prominent in the brains of patients with AD. Here, we selected specific regions in the AD brain that are associated with AD-related behavioral and psychological symptoms, and reviewed studies of healthy and altered efferent pathways to the target regions. Moreover, we propose that specific neural circuits that are altered in the AD brain can be potential targets for AD treatment. Furthermore, we provide therapeutic implications for targeting neuronal circuits through various therapeutic approaches and the appropriate timing of treatment for AD.

The introduction of nitrogen to carbonyl groups is considered both challenging and highly desirable by those who work in the field of organic synthesis. In this study, a diphenylethylenediamine-derived catalyst demonstrating N-selectivity was designed using a quantum calculation for the nitroso aldol reaction. The reductive monoalkylation of (R,R)-(+)-1,2-diphenylethylenediamine afforded an organic chiral diamine catalyst in high yield. The expected reaction mechanism for the nitroso aldol reaction was determined, and the product and solvent conditions were optimized through quantum calculations. The calculation results revealed that the enantioselectivity is determined by the hydrogen bond between the alkyl substituent of the chiral diamine and the oxygen of the aromatic aldehyde on the ammonium moiety. The reaction was found to proceed optimally in the presence of 5 mol % catalyst at −10 °C in brine. Using these conditions, an eco-friendly nitroso aldol reaction was performed in which the organic catalyst and cyclohexanone formed enamine. Nitrosobenzene, activated by hydrogen bonding with an ammonium catalyst, was used to minimize the steric hindrance between the catalyst and the reactant, resulting in high enantioselectivity. A nitroso aldol product with high N-selectivity and enantioselectivity (98% ee) was obtained in 95% yield. The catalyst developed in this study provides a less expensive and more environmentally friendly alternative for the nitroso aldol reaction.

Thiourea was introduced into (R,R)-1,2-diphenylethylenediamine as an organocatalyst to promote the reaction between isobutyraldehydes and maleimides. Enantioselective Michael addition reaction was carried out as an eco-friendly method using water as the solvent. As a result of the reaction between isobutyraldehyde and maleimide, ≥97% yield and 99% enantioselectivity were obtained at a low catalyst loading of 0.01 mol%. The solvent effect can be explained by theoretical calculations that indicate the participation of a transition state, in which the CF3 substituent of the catalyst is a hydrogen bond activated by the surrounding water molecules. This discovery enabled the use of low catalyst loading in the organic reactions of chiral substances for pharmaceutical applications. Furthermore, a solvent effect for Michael reaction of the organocatalysts was proposed, and the organic reaction mechanisms were determined through quantum calculations.

Michael addition is an important reaction because it can be used to synthesize a wide range of natural products or complex compounds that exhibit biological activities. In this study, a mirror image of an aldehyde and α,β-unsaturated nitroalkene were reacted in the presence of (R,R)-1,2-diphenylethylenediamine (DPEN). Herein, thiourea was introduced as an organic catalyst, and a selective Michael addition reaction was carried out. The primary amine moiety of DPEN reacts with aldehydes to form enamines, which is activated by the hydrogen bond formation between the nitro groups of α,β-unsaturated nitroalkenes and thiourea. Our aim was to obtain an asymmetric Michael product by adding 1,4-enamine to an alkene to form a new carbon–carbon bond. As a result, the primary amine of the chiral diamine was converted to an enamine. The reaction proceeded with a relatively high degree of enantioselectivity, which was achieved using double activation via hydrogen bonding of the nitro group and thiourea. Michael products with a high degree of enantioselectivity (97–99% synee) and diastereoselectivity (syn/anti = 9/1) were obtained in yields ranging from 94–99% depending on the aldehydes.

As the number of older adults increases, the prevalence of dementias, such as Alzheimer’s dementia (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementias, also increases. Despite research into pharmacological approaches for treating diverse diseases, there is still no cure. Recently, novel non-pharmacological interventions are attracting attention. Non-pharmacological approaches include cognitive stimulation, alterations in diet, physical activity, and social engagement. Cognitive stimulating activities protect against the negative effects of cognitive decline caused by age-related neurogenerative diseases. Bilingualism is one form of cognitive stimulation that requires multiple aspects of brain activity and has been shown to delay the onset of dementia symptoms in patients by approximately 4–5 years as compared with monolingual patients through cognitive reserve. The purpose of this review was to bilingualism protects against cognitive decline associated with AD and other dementias. We discuss potential underlying neurological mechanisms, including: (1) stimulating adult neurogenesis, (2) enhancing synaptogenesis, (3) strengthening functional connectivity that bilingualism may delay clinical AD symptoms, (4) protecting white matter integrity, and (5) preserving gray matter density.

Catalysts based on (R, R)-1,2-diphenylethylenediamine are, as chiral organic catalysts, applied to the asymmetric Michael addition to α, β-unsaturated nitroalkenes under neutral conditions. The role of an aqueous medium for organic catalytic activity can be reversed concerning hydrophilic-hydrophobic function depending on the reaction conditions. In this study, to provide an environmentally friendly system, the thiourea-based catalyst substituted with 3,5-(CF3)2-Ph was used in water solvents. The hydrophobic effect of the substituent provided fast reaction, high chemical yield, and mirror-image selectivity. This reaction allowed the preparation of GABAB agonists in an optically pure manner. Additionally, GABA (γ-aminobutyric acid) analogs such as baclofen and phenibut were synthesized as R-type S-type with high optical purity.

Michael addition is one of the most important carbon–carbon bond formation reactions. In this study, an (R, R)-1,2-diphenylethylenediamine (DPEN)-based thiourea organocatalyst was applied to the asymmetric Michael addition of nitroalkenes and cycloketones to produce a chiral product. The primary amine moiety in DPEN reacts with the ketone to form an enamine and is activated through the hydrogen bond formation between the nitro group in the α, β-unsaturated nitroalkene and thiourea. Here, the aim was to obtain an asymmetric Michael product through the 1,4-addition of the enamine to an alkene to form a new carbon–carbon bond. As a result, the primary amine of the chiral diamine was converted into an enamine. The reaction proceeded with a relatively high level of enantioselectivity achieved using double activation through the hydrogen bonding of the nitro group and thiourea. Michael products with high levels of enantioselectivity (76–99% syn ee) and diastereoselectivity (syn/anti = 9/1) were obtained with yields in the range of 88–99% depending on the ketone.

Infection is one of several factors that can delay normal wound healing. Antibacterial wound dressings can therefore promote normal wound healing. In this study, we prepared an antibacterial wound dressing, consisting of visible light-cured methacrylated collagen (ColMA) hydrogel and a 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD)/triclosan (TCS) complex (CD-ic-TCS), and evaluated its wound healing effects in vivo. The 1H NMR spectra of ColMA and CD-ic-TCS revealed characteristic peaks at 1.73, 5.55, 5.94, 6.43, 6.64, 6.84, 6.95, 7.31, and 7.55 ppm, indicating successful preparation of the two material types. In addition, ultraviolet–visible (UV–vis) spectroscopy proved an inclusion complex formation between HP-β-CD and TCS, judging by a unique peak observed at 280 cm−1. Furthermore, ColMA/CD-ic-TCS exhibited an interconnected porous structure, controlled release of TCS, good biocompatibility, and antibacterial activity. By in vivo animal testing, we found that ColMA/CD-ic-TCS had a superior wound healing capacity, compared to the other hydrocolloids evaluated, due to synergistic interaction between ColMA and CD-ic-TCS. Together, our findings indicate that ColMA/CD-ic-TCS has a clinical potential as an antibacterial wound dressing.

Accelerating wound healing with minimized bacterial infection has become a topic of interest in the development of the new generation of tissue bio-adhesives. In this study, we fabricated a hydrogel system (MGC-g-CD-ic-TCS) consisting of triclosan (TCS)-complexed beta-cyclodextrin (β-CD)-conjugated methacrylated glycol chitosan (MGC) as an antibacterial tissue adhesive. Proton nuclear magnetic resonance (1H NMR) and differential scanning calorimetry (DSC) results showed the inclusion complex formation between MGC-g-CD and TCS. The increase of storage modulus (G’) of MGC-g-CD-ic-TCS after visible light irradiation for 200 s indicated its hydrogelation. The swollen hydrogel in aqueous solution resulted in two release behaviors of an initial burst and sustained release. Importantly, in vitro and in vivo results indicated that MGC-g-CD-ic-TCS inhibited bacterial infection and improved wound healing, suggesting its high potential application as an antibacterial tissue bio-adhesive.

We prepared a drug carrier which consisted of injectable methacrylated glycol chitosan (MGC) hydrogel, and a conjugate of 6-monodeoxy-6-monoamino-β-cyclodextrin⋅hydrochloride (6-NH2-β-CD⋅HCl), polyethylene glycol (PEG), and folic acid (FA) for the local delivery and improved cellular uptake of paclitaxel (PTX) (MGC/CDPF-ic-PTX). CDPF refers to a conjugate of 6-NH2-β-CD⋅HCl, PEG, and FA. The anti-cancer effect was investigated using a xenograft mouse model. As controls, the animal study on MGC/PTX and MGC/CD-ic-PTX was performed. The swelling ratio of all samples was analyzed for 7 days, and it showed a gradual increase for 3 days and a maintained state afterward. From the release result, the MGC-based samples have an initial burst for 1 day and a sustained release for 7 days. Results of cytotoxicity and animal study showed the biocompatibility and superior anti-cancer effect of MGC/CDPF-ic-PTX against breast cancer. Furthermore, histological results showed the anti-cancer capacity of MGC/CDPF-ic-PTX against breast cancer. These findings suggest that MGC/CDPF-ic-PTX has clinical potential for breast cancer therapy.

Patients with dementia suffer from psychological symptoms such as depression, agitation, and aggression. One purpose of dementia intervention is to manage patients’ inappropriate behaviors and psychological symptoms while taking into consideration their quality of life (QOL). Animal-assisted intervention (AAI) and pet-robot intervention (PRI) are effective intervention strategies for older people with cognitive impairment and dementia. In addition, AAI and PRI have been shown to have positive effects on behavioral and psychological symptoms of dementia (BPSD). However, studies into the association between AAI/PRI and BPSD have elicited inconsistent results. Thus, we performed a meta-analysis to investigate this association. We analyzed nine randomized controlled trials on AAI and PRI for dementia patients published between January 2000 and August 2019 and evaluated the impact of AAI/PRI on agitation, depression, and QOL. We found that AAI and PRI significantly reduce depression in patients with dementia. Subsequent studies should investigate the impact of AAI and PRI on the physical ability and cognitive function of dementia patients and conduct a follow-up to investigate their effects on the rate of progression and reduction of symptoms of dementia. Our research will help with neuropsychological and environmental intervention to delay or improve the development and progression of BPSD.

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aβ) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aβ in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aβ-overexpressing model. We found that omega-3 PUFAs significantly improved Aβ-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aβ accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.

BackgroundThe role of small GTPase molecules is poorly understood under high glucose conditions.MethodsWe analyzed the expression pattern of Vav3 in skeletal muscle C2C12 cells under high glucose culture condition with reverse transcription-polymerase chain reaction and Western blot analysis. We also measured glucose uptake using isotope-labelled glucose.ResultsWe showed that expression of Vav3 (a guanine nucleotide exchange factor for RhoA) increased. mRNA and protein levels in skeletal muscle C2C12 cells under high glucose conditions. The AMP-activated protein kinase (AMPK) activator AMPK agonist 5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside (AICAR) suppressed high glucose-induced Vav3 induction. In addition, exposure of cells to high glucose concentration increased the phosphorylation of PAK-1, a molecule downstream of RhoA. The phosphorylation of paxillin, a downstream molecule of PAK-1, was also increased by exposure to high glucose. Phosphorylation of these molecules was not observed in the presence of AICAR, indicating that AMPK is involved in the RhoA signal pathway under high glucose conditions. Knock down of Vav3 enhances metformin-mediated glucose uptake. Inhibition of AMPK blocked the increases of Vav3 knock down-induced glucose uptake. Metformin-mediated Glut4 translocation was also increased by Vav3 knock-down, suggesting that Vav3 is involved in metformin-mediated glucose uptake.ConclusionThese results demonstrate that Vav3 is involved in the process of metformin-mediated glucose regulation.

BackgroundThe tubby protein has a motif that might be relevant for its action in the insulin signaling pathway. Previous studies have indicated that tubby undergoes phosphorylation on tyrosine residues in response to several stimuli and is known to localize in the nucleus as well as in the plasma membrane. However, the relationship between phosphorylation and nuclear translocation is not well understood. Here, we report that insulin directly phosphorylates tubby, which translocates into the nucleus.MethodsThe effects of insulin on Tubby were performed with Western blot. The immunoprecipitation and confocal microscopy were performed to prove phosphorylation and nuclear translocation.ResultsMutation study reveals that tyrosine residue 464 of tubby gene (Tub) is a phosphorylation site activated by insulin. In addition, major portions of tubby protein in the plasma membrane are translocated into the nucleus after insulin treatment. Tyrosine kinase inhibitor pretreatment blocked insulin-induced tubby translocation, suggesting that phosphorylation is important for nuclear translocation. Moreover, mutant tyrosine residue 464 did not translocate into the nucleus in respond to insulin. These findings demonstrate that insulin phosphorylates tyrosine residue 464 of Tub, and this event is important for insulin-induced tubby nuclear translocation.ConclusionInsulin phosphorylates tyrosine residue 464 of Tub and translocates tubby into the nuclei of HIRcB cells.

Perilla (Perilla frutescens L.) leaves have shown therapeutic efficacy in the treatment of inflammatory disorders, allergies, bronchial asthma, and systemic damage due to free radicals. In the present study we analyzed the active constituents in perilla leaves using high-performance liquid chromatography (HPLC) and isolated luteolin, a polyphenolic flavonoid. We investigated the anti-inflammatory and antipruritic properties of luteolin. Luteolin inhibited the secretion of inflammatory cytokines such as interleukin-1β (IL-1 β) and tumor necrosis factor-α (TNF-α) from human mast cells (HMC-1) stimulated with phorbol myristate acetate plus calcium ionophore A23187 in a dose-dependent manner. Luteolin also significantly reduced the histamine release from rat peritoneal mast cells stimulated by compound 48/80, a potent histamine liberator. Furthermore, the administration of luteolin markedly inhibited the scratching behavior and vascular permeability induced by pruritogens, such as compound 48/80 or serotonin, in ICR mice. These results suggested that luteolin has potential as a therapeutic agent against inflammation and itch-related skin diseases.

EPA, an omega-3 polyunsaturated fatty acid, exerts beneficial effects on human health. However, the molecular mechanisms underlying EPA function are poorly understood. The object was to illuminate molecular mechanism underlying EPA’s role. Here, 1H-NMR-based metabolic analysis showed enhanced branched-chain amino acids (BCAAs) and lactate following EPA treatment in skeletal muscle cells. EPA regulated mitochondrial oxygen consumption rate. Furthermore, EPA induced calcium/calmodulin-dependent protein kinase kinase (CaMKK) through the generation of intracellular calcium. This induced the phosphorylation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK) that led to glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) in muscles. In conclusion, EPA exerts benign effects on glucose through the activation of AMPK-p38 MAPK signaling pathways in skeletal muscles.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Dibenzoylmethane (DBM) has been shown to exert a variety of beneficial effects on human health. However, the mechanism of action is poorly understood. In this study, DBM increased phosphorylation of AMP-activated protein kinase (AMPK) and stimulated glucose uptake in a skeletal muscle cell line. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor blocked DBM-induced glucose uptake. DBM increased the concentration of intracellular calcium and glucose uptake due to DBM was abolished by STO-609 (a calcium/calmodulin-dependent protein kinase inhibitor). DBM stimulated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which was blocked by pretreatment with compound C, an AMPK inhibitor. The expression of glucose transporter type 4 (GLUT4) was increased by DBM. The translocation of GLUT4 to the plasma membrane was also increased by DBM in AMPK dependently. In addition, DBM suppressed weight gain and prevented fat accumulation in the liver and abdomen in mice fed a high-fat diet. In pre-adipocyte cells, DBM decreased the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis. Expression of the adipogenic gene, fatty acid synthase (FAS), was suppressed by DBM in an AMPK-dependent manner. These results showed that the beneficial metabolic effects of DBM might be due to regulation of glucose uptake via AMPK in skeletal muscle and inhibition of adipogenesis in pre-adipocytes.

Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-alpha-mediated activation of the IKK/NF-kappaB survival pathway via direct interaction with IKKalpha/beta in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kappaB activation and the expression of NF-kappaB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-alpha. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-kappaB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-kappaB pathway.