The Effects of Body Fat Reduction through the Metabolic Control of Steam-Processed Ginger Extract in High-Fat-Diet-Fed Mice.

The prevalence of metabolic syndrome is increasing globally due to behavioral and environmental changes. There are many therapeutic agents available for the treatment of chronic metabolic diseases, such as obesity and diabetes, but the data on their efficacy and safety are lacking. Through a pilot study by our group, Zingiber officinale rhizomes used as a spice and functional food were selected as an anti-obesity candidate. In this study, steam-processed ginger extract (GGE) was used and we compared its efficacy at alleviating metabolic syndrome-related symptoms with that of conventional ginger extract (GE). Compared with GE, GGE (25-100 µg/mL) had an increased antioxidant capacity and α-glucosidase inhibitory activity in vitro. GGE was better at suppressing the differentiation of 3T3-L1 adipocytes and lipid accumulation in HepG2 cells and promoting glucose utilization in C2C12 cells than GE. In 16-week high-fat-diet (HFD)-fed mice, GGE (100 and 200 mg/kg) improved biochemical profiles, including lipid status and liver function, to a greater extent than GE (200 mg/kg). The supplementation of HFD-fed mice with GGE (200 mg/kg) resulted in the downregulation of SREBP-1c and FAS gene expression in the liver. Collectively, our results indicate that GGE is a promising therapeutic for the treatment of obesity and metabolic syndrome.

Suppression of P2X4 and P2X7 by Lactobacillus rhamnosus vitaP1: effects on hangover symptoms.

This study aimed to identify substances including Lactobacillus rhamnosus vitaP1 (KACC 92054P) that alleviate hangover-induced emotional anxiety and liver damage. The association between emotional anxiety caused by hangover and the genes P2X4, P2X7, SLC6A4 was investigated. In vitro and in vivo analyses were conducted to assess the influence of free-panica on alcohol-induced upregulated gene expression. Additionally, the concentration of AST, ALT, alcohol, and acetaldehyde in blood was measured. Free-panica, consisting of five natural products (Phyllanthus amarus, Phoenix dactylifera, Vitis vinifera, Zingiber officinale, and Lactobacillus rhamnosus), were evaluated for their regulatory effects on genes involved in alcohol-induced emotional anxiety and liver damage. The combination of these natural products in free-panica successfully restored emotional anxiety, and the concentration of AST, ALT, alcohol, and acetaldehyde in blood to those of the normal control group. These findings support the potential development of free-panica as a health functional food or medicinal intervention for relieving hangover symptoms and protecting liver from alcohol consumption.

Cytotoxic Effects of Ardisiacrispin A from Labisia pumila on A549 Human Lung Cancer Cells.

BACKGROUND: Lung cancer is the predominant cause of cancer-related fatalities. This prompted our exploration into the anti-lung cancer efficacy of Labisia pumila, a species meticulously selected from the preliminary screening of 600 plants. METHODS: Through the strategic implementation of activity-guided fractionation, ardisiacrispin A (1) was isolated utilizing sequential column chromatography. Structural characterization was achieved employing various spectroscopic methods, including nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared spectroscopy (IR). RESULTS: L. pumila 70% EtOH extract showed significant toxicity in A549 lung cancer cells, with an IC50 value of 57.04 ± 10.28 µg/mL, as well as decreased expression of oncogenes and induced apoptosis. Compound 1, ardisiacrispin A, induced a 50% cell death response in A549 cells at a concentration of 11.94 ± 1.14 µg/mL. CONCLUSIONS: The present study successfully investigated ardisiacrispin A extracted from L. pumila leaves, employing a comprehensive spectroscopic approach encompassing NMR, IR, and MS analyses. The anti-lung cancer efficacy of ardisiacrispin A and L. pumila extract was successfully demonstrated for the first time, to the best of our knowledge.

Biomechanical Evaluation of Aortic Valve Stenosis by Means of a Virtual Stress Test: A Fluid-Structure Interaction Study.

The impact of aortic valve stenosis (AS) extends beyond the vicinity of the narrowed leaflets into the left ventricle (LV) and into the systemic vasculature because of highly unpredictable valve behavior and complex blood flow in the ascending aorta that can be attributed to the strong interaction between the narrowed cusps and the ejected blood. These effects can become exacerbated during exercise and may have implications for disease progression, accurate diagnosis, and timing of intervention. In this 3-D patient-specific study, we employ strongly coupled fluid-structure interaction (FSI) modeling to perform a comprehensive biomechanical evaluation of systolic ejection dynamics in a stenosed aortic valve (AV) during increasing LV contraction. Our model predictions reveal that the heterogeneous ∆P vs. Q relationship that was observed in our previous clinical study can be attributed to a non-linear increase (by ~ 1.5-fold) in aortic valve area as LV heart rate increases from 70 to 115 bpm. Furthermore, our results show that even for a moderately stenotic valve, increased LV contraction during exercise can lead to high-velocity flow turbulence (Re = 11,700) in the aorta similar to that encountered with a severely stenotic valve (Re ~ 10,000), with concomitant greater viscous loss (~3-fold increase) and elevated wall stress in the ascending aorta. Our FSI predictions also reveal that individual valve cusps undergo distinct and highly non-linear increases (>100%) in stress during exercise, potentially contributing to progressive calcification. Such quantitative biomechanical evaluations from realistic FSI workflows provide insights into disease progression and can be integrated with current stress testing for AS patients to comprehensively predict hemodynamics and valve function under both baseline and exercise conditions.

Storage Stability of Atheroglitatide, an Echogenic Liposomal Formulation of Pioglitazone Targeted to Advanced Atheroma with a Fibrin-Binding Peptide.

We have conducted a stability study of a complex liposomal pharmaceutical product, Atheroglitatide (AGT), stored at three temperatures, 4, 24, and 37 °C, for up to six months. The six parameters measured were functions of liposomal integrity (size and number), drug payload (loading efficiency), targeting peptide integrity (conjugation efficiency and specific avidity), and echogenicity (ultrasound-dependent controlled drug release), which were considered most relevant to the product's intended use. At 4 °C, liposome diameter trended upward, indicative of aggregation, while liposome number per mg lipid and echogenicity trended downward. At 24 °C, peptide conjugation efficiency (CE) and targeting efficiency (TE, specific avidity) trended downward. At 37 °C, CE and drug (pioglitazone) loading efficiency trended downward. At 4 °C, the intended storage temperature, echogenicity, and liposome size reached their practical tolerance limits at 6 months, fixing the product expiration at that point. Arrhenius analysis of targeting peptide CE and drug loading efficiency decay at the higher temperatures indicated complete stability of these characteristics at 4 °C. The results of this study underscore the storage stability challenges presented by complex nanopharmaceutical formulations.

Enhanced Cerebroprotection of Xenon-Loaded Liposomes in Combination with rtPA Thrombolysis for Embolic Ischemic Stroke.

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in vivo embolic middle cerebral artery occlusion (eMCAO) rat model. The treatment groups received intravenous administration of Xe-liposomes (20 mg/kg) at 2 h post-stroke onset, followed by the administration of rtPA (10 mg/kg) at either 2 or 4 h after the onset. Three days after the stroke, behavioral tests were conducted, and brain sections were collected for triphenyltetrazolium chloride (TTC) and TUNEL staining. Infarct size was determined as normalized infarct volume (%). Both in vitro and in vivo clot lysis experiments demonstrated that Xe-liposomes in combination with rtPA resulted in effective clot lysis comparable to the treatment with free rtPA alone. Animals treated with Xe-liposomes in combination with rtPA showed reduced TUNEL-positive cells and demonstrated improved neurological recovery. Importantly, Xe-liposomes in combination with late rtPA treatment reduced rtPA-induced hemorrhage, attributing to the reduction of MMP9 immunoreactivity. This study demonstrates that the combined therapy of Xe-liposomes and rtPA provides enhanced therapeutic efficacy, leading to decreased neuronal cell death and a potential to mitigate hemorrhagic side effects associated with late rtPA treatment.

Liposome-Based Carriers for CRISPR Genome Editing.

The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field.

Automated Cephalometric Landmark Detection Using Deep Reinforcement Learning.

Accurate cephalometric landmark detection leads to accurate analysis, diagnosis, and surgical planning. Many studies on automated landmark detection have been conducted, however reinforcement learning-based networks have not yet been applied. This is the first study to apply deep Q-network (DQN) and double deep Q-network (DDQN) to automated cephalometric landmark detection to the best of our knowledge. The performance of the DQN-based network for cephalometric landmark detection was evaluated using the IEEE International Symposium of Biomedical Imaging (ISBI) 2015 Challenge data set and compared with the previously proposed methods. Furthermore, the clinical applicability of DQN-based automated cephalometric landmark detection was confirmed by testing the DQN-based and DDQN-based network using 500-patient data collected in a clinic. The DQN-based network demonstrated that the average mean radius error of 19 landmarks was smaller than 2 mm, that is, the clinically accepted level, without data augmentation and additional preprocessing. Our DQN-based and DDQN-based approaches tested with the 500-patient data set showed the average success detection rate of 67.33% and 66.04% accuracy within 2 mm, respectively, indicating the feasibility and potential of clinical application.

Co-Delivery of Therapeutics and Bioactive Gas Using a Novel Liposomal Platform for Enhanced Treatment of Acute Arterial Injury.

Atherosclerosis is a complex, multi-stage disease characterized by pathological changes across the vascular wall. Endothelial dysfunction, inflammation, hypoxia, and vascular smooth muscle cell proliferation contribute to its progression. An effective strategy capable of delivering pleiotropic treatment to the vascular wall is essential to limit neointimal formation. Echogenic liposomes (ELIP), which can encapsulate bioactive gases and therapeutic agents, have the potential to deliver enhanced penetration and treatment efficacy for atherosclerosis. In this study, liposomes loaded with nitric oxide (NO) and rosiglitazone, a peroxisome proliferator-activated receptor agonist, were prepared using hydration, sonication, freeze-thawing, and pressurization. The efficacy of this delivery system was evaluated in a rabbit model of acute arterial injury induced by balloon injury to the common carotid artery. Intra-arterial administration of rosiglitazone/NO co-encapsulated liposomes (R/NO-ELIP) immediately following injury resulted in reduced intimal thickening after 14 days. The anti-inflammatory and anti-proliferative effects of the co-delivery system were investigated. These liposomes were echogenic, enabling ultrasound imaging to assess their distribution and delivery. R/NO-ELIP delivery exhibited a greater attenuation (88 ± 15%) of intimal proliferation when compared to NO-ELIP (75 ± 13%) or R-ELIP (51 ± 6%) delivery alone. The study demonstrates the potential of echogenic liposomes as a promising platform for ultrasound imaging and therapeutic delivery.

Photobiomodulation improves the synapses and cognitive function and ameliorates epileptic seizure by inhibiting downregulation of Nlgn3.

BACKGROUND: Temporal lobe epilepsy (TLE) remains one of the most drug-resistant focal epilepsies. Glutamate excitotoxicity and neuroinflammation which leads to loss of synaptic proteins and neuronal death appear to represent a pathogen that characterizes the neurobiology of TLE. Photobiomodulation (PBM) is a rapidly growing therapy for the attenuation of neuronal degeneration harboring non-invasiveness benefits. However, the detailed effects of PBM on excitotoxicity or neuroinflammation remain unclear. We investigated whether tPBM exerts neuroprotective effects on hippocampal neurons in epilepsy mouse model by regulating synapse and synapse-related genes. METHODS: In an in vitro study, we performed imaging analysis and western blot in primary hippocampal neurons from embryonic (E17) rat pups. In an in vivo study, RNA sequencing was performed to identify the gene regulatory by PBM. Histological stain and immunohistochemistry analyses were used to assess synaptic connections, neuroinflammation and neuronal survival. Behavioral tests were used to evaluate the effects of PBM on cognitive functions. RESULTS: PBM was upregulated synaptic connections in an in vitro. In addition, it was confirmed that transcranial PBM reduced synaptic degeneration, neuronal apoptosis, and neuroinflammation in an in vivo. These effects of PBM were supported by RNA sequencing results showing the relation of PBM with gene regulatory networks of neuronal functions. Specifically, Nlgn3 showed increase after PBM and silencing the Nlgn3 reversed the positive effect of PBM in in vitro. Lastly, behavioral alterations including hypoactivity, anxiety and impaired memory were recovered along with the reduction of seizure score in PBM-treated mice. CONCLUSIONS: Our findings demonstrate that PBM attenuates epileptic excitotoxicity, neurodegeneration and cognitive decline induced by TLE through inhibition of the Nlgn3 gene decrease induced by excitotoxicity.

Network pharmacology and molecular docking approaches to elucidate the potential compounds and targets of Saeng-Ji-Hwang-Ko for treatment of type 2 diabetes mellitus.

BACKGROUND: Saeng-Ji-Hwang-Ko (SJHK) is a traditional Korean medicine formula derived from Donguibogam, a classic medical textbook, published in 1613. It is described as a general treatment for So-gal (wasting-thirst, ) known as type 2 diabetes mellitus (T2DM) in a modern clinical term. It is necessary to elucidate the potential compounds and targets of SJHK for T2DM treatment by conducting network pharmacology and molecular docking analyses. METHODS: Information about the chemical constituents of SJHK were collected, and druggable compounds were screened based on oral bioavailability and drug-likeness. Putative target genes of druggable compounds and T2DM-related genes were retrieved from public databases. A compound-target network was constructed to visualize the relationship between the druggable compounds in SJHK and common targets related to T2DM. The constructed network was further investigated through Protein-Protein Interaction, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analyses, and molecular docking. RESULTS: Compound-target network analysis demonstrated that kaempferol, salicylic acid, estrone, and ß-sitosterol were key compounds of SJHK with PTGS2, ESR1, PRKAA2, PRKAB1, and CYP19A1 being its key targets. Estrogen signaling, AGE-RAGE signaling, insulin resistance, non-alcoholic fatty liver disease, and TNF signaling pathway were potential pathways involved in the effect of SJHK on T2DM. Molecular docking simulations revealed that estrone and ß-sitosterol had the strong binding energies for all the key target proteins. CONCLUSIONS: This study demonstrates that network pharmacology and molecular docking analyses help to better understand the potential key compounds and targets of SJHK for treating T2DM as a complementary medicine. SUMMARY: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder caused by genetic and/or environmental factors. There has been a growing attention to new therapeutic approaches to treat T2DM using traditional medicine as a complementary treatment which is expected to have synergistic effects with few side effects. Saeng-Ji-Hwang-Ko (SJHK) is a traditional Korean medicine (TKM) formula derived from Donguibogam, a classic medical textbook, published in 1613. It is described as a general treatment for So-gal (wasting-thirst, ) known as type 2 diabetes mellitus (T2DM) in a modern clinical term. It is necessary to elucidate the potential compounds and targets of SJHK for T2DM treatment by conducting network pharmacology and molecular docking analyses. Compound-target network analysis demonstrated that kaempferol, salicylic acid, estrone, and ß-sitosterol were key compounds of SJHK with PTGS2, ESR1, PRKAA2, PRKAB1, and CYP19A1 being its key targets. Estrogen signaling, AGE-RAGE signaling, insulin resistance, non-alcoholic fatty liver disease, and TNF signaling pathway were potential pathways involved in the effect of SJHK on T2DM. Molecular docking evaluation revealed that estrone and ß-sitosterol had the highest binding energies for all key target proteins, suggesting potential key compounds of SJHK. Although additional future studies including further experimental and clinical validation are needed, this study demonstrates that SJHK has a great potential for treating T2DM as a complementary medicine.

Deep Learning-Based Near-Fall Detection Algorithm for Fall Risk Monitoring System Using a Single Inertial Measurement Unit.

Proactively detecting falls and preventing injuries are among the primary keys to a healthy life for the elderly. Near-fall remote monitoring in daily life could provide key information to prevent future falls and obtain quantitative rehabilitation status for patients with weak balance ability. In this study, we developed a deep learning-based novel classification algorithm to precisely categorize three classes (falls, near-falls, and activities of daily living (ADLs)) using a single inertial measurement unit (IMU) device attached to the waist. A total of 34 young participants were included in this study. An IMU containing accelerometer and gyroscope sensors was fabricated to acquire acceleration and angular velocity signals. A comprehensive experiment including thirty-six types of activities (10 types of falls, 10 types of near-falls, and 16 types of ADLs) was designed based on previous studies. A modified directed acyclic graph-convolution neural network (DAG-CNN) architecture with hyperparameter optimization was proposed to predict fall, near-fall, and ADLs. Prediction results of the modified DAG-CNN structure were found to be approximately 7% more accurate than the traditional CNN structure. For the case of near-falls, the modified DAG-CNN demonstrated excellent prediction performance with accuracy of over 98% by combining gyroscope and accelerometer features. Additionally, by combining acceleration and angular velocity the trained model showed better performance than each model of acceleration and angular velocity. It is believed that information to preemptively handle the risk of falls and quantitatively evaluate the rehabilitation status of the elderly with weak balance will be provided by monitoring near-falls.

Improving transcatheter aortic valve interventional predictability via fluid-structure interaction modelling using patient-specific anatomy.

Transcatheter aortic valve replacement (TAVR) is now a standard treatment for high-surgical-risk patients with severe aortic valve stenosis. TAVR is being explored for broader indications including degenerated bioprosthetic valves, bicuspid valves and for aortic valve (AV) insufficiency. It is, however, challenging to predict whether the chosen valve size, design or its orientation would produce the most-optimal haemodynamics in the patient. Here, we present a novel patient-specific evaluation framework to realistically predict the patient's AV performance with a high-fidelity fluid-structure interaction analysis that included the patient's left ventricle and ascending aorta (AAo). We retrospectively evaluated the pre- and post-TAVR dynamics of a patient who underwent a 23 mm TAVR and evaluated against the patient's virtually de-calcified AV serving as a hypothetical benchmark. Our model predictions were consistent with clinical data. Stenosed AV produced a turbulent flow during peak-systole, while aortic flow with TAVR and de-calcified AV were both in the laminar-to-turbulent transitional regime with an estimated fivefold reduction in viscous dissipation. For TAVR, dissipation was highest during early systole when valve deformation was the greatest, suggesting that an efficient valve opening may reduce energy loss. Our study demonstrates that such patient-specific modelling frameworks can be used to improve predictability and in the planning of AV interventions.

Traction Performance Evaluation of the Electric All-Wheel-Drive Tractor.

This study aims to design, develop, and evaluate the traction performance of an electric all-wheel-drive (AWD) tractor based on the power transmission and electric systems. The power transmission system includes the electric motor, helical gear reducer, planetary gear reducer, and tires. The electric system consists of a battery pack and charging system. An engine-generator and charger are installed to supply electric energy in emergency situations. The load measurement system consists of analog (current) and digital (battery voltage and rotational speed of the electric motor) components using a controller area network (CAN) bus. A traction test of the electric AWD tractor was performed towing a test vehicle. The output torques of the tractor motors during the traction test were calculated using the current and torque curves provided by the motor manufacturer. The agricultural work performance is verified by comparing the torque and rpm (T-N) curve of the motor with the reduction ratio applied. The traction is calculated using torque and specifications of the wheel, and traction performance is evaluated using tractive efficiency (TE) and dynamic ratio (DR). The results suggest a direction for the improvement of the electric drive system in agricultural research by comparison with the conventional tractor through the analysis of the agricultural performance and traction performance of the electric AWD tractor.

Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo.

BACKGROUND: Elaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biological activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. PURPOSE: In this study, we investigated the antiviral activity of the 50% aqueous ethanolic extract of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. METHODS: To investigate the in vitro antiviral activity of ESE and its main ingredients, 1,​2,​3,​4,​6-​penta-​O-​galloyl-ß-d-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Molecular docking analysis was performed to determine the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. RESULTS: ESE and its gallate main ingredients (PGG and GE) strongly inhibited the production of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Molecular docking analysis revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. CONCLUSION: ESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.

Preclinical evaluation of Zanthoxylum piperitum Benn., traditional muscle pain remedy, for joint inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum piperitum has been used as a traditional Asian medicine to treat hypertension, stroke, bruise and muscle pain. It has been known to induce detoxification; affect anti-bacterial, anti-oxidant, and tyrosinase activity; inhibit osteosarcoma proliferation; anti-osteoarthritis inflammation. In this study, we aim to identify the therapeutic effect of Z. piperitum 90% EtOH extract (ZPE-LR) on rheumatoid arthritis. MATERIAL AND METHODS: We investigated the anti-rheumatoid arthritis and -immunomodulatory activities of the ZPE-LR in collagen-induced arthritic (CIA) mice, a rheumatoid arthritis animal model. In order to assess the analgesic effects of ZPE-LR in vivo, acetic acid injection, formaldehyde injection, hot plate model was used. The mechanism for anti-inflammatory activity of ZPE-LR was identified with LPS-stimulated Raw 264.7 cells. RESULTS: Pharmacologically, oral administration of ZPE-LR into CIA mice resulted in a significant and dose-dependent decrease in clinical arthritis score and paw swelling compared to untreated negative control. Pathologic examination showed that ZPE-LR prevented morphological change in cartilage and destruction of phalanges in CIA mice. This protective effect was associated with reduced pain, inflammatory mediators such as NO, TNF-α, IL-1ß, and IL-6, as well as COX-2 and iNOS expression. Furthermore, reduction of phosphor-ERK and BDNF indicates a novel rheumatoid arthritis-regulating mechanism by ZPE-LR treatment. CONCLUSIONS: These data suggest that the administration of ZPE-LR remarkably inhibited CIA progression and might be helpful in suppressing inflammation and pain in rheumatoid arthritis.

Anti-varicella zoster virus and related anti-inflammation effects of ethanolic extract of Elaeocarpus sylvestris.

ETHNOPHARMACOLOGICAL RELEVANCE: Elaeocarpus sylvestris var. ellipticus (ES), a plant that grows in Taiwan, Japan, and Jeju Island in Korea. ES root bark, known as "sanduyoung," has long been used in traditional oriental medicine. ES is also traditionally used to treat anxiety, asthma, arthritis, stress, depression, palpitation, nerve pain, epilepsy, migraine, hypertension, liver diseases, diabetes, and malaria. However, lack of efficacy and mechanism studies on ES. AIM OF THE STUDY: In the present study, we aim to investigate the VZV-antiviral efficacy, pain suppression, and the anti-inflammatory and antipyretic effects of ES. METHODS: and methods: Inhibition of VZV was evaluated by hollow fiber assays. Analgesic and antipyretic experiments were conducted using ICR mice and SD Rats, and anti-inflammatory experiments were conducted using Raw264.7 cells. RESULTS: To evaluate the efficacy of ESE against VZV, we conducted antiviral tests. ESE inhibited cell death by disrupting virus and gene expression related to invasion and replication. In addition, ESE suppressed the pain response as measured by writhing and formalin tests and suppressed LPS-induced inflammatory fever. Further, ESE inhibited the phosphorylation of IκB and NF-κB in LPS-induced Raw264.7 cells and expression of COX-2, iNOS, IL-1ß, IL-6, and TNF-α. CONCLUSION: E. sylvestris shows potential as a source of medicine. ESE had a direct effect on VZV and an inhibitory effect on the pain and inflammation caused by VZV infection.

A Comparative Study of the Hepatoprotective Effect of Centella asiatica Extract (CA-HE50) on Lipopolysaccharide/d-galactosamine-Induced Acute Liver Injury in C57BL/6 Mice.

Acute liver failure (ALF) refers to the sudden loss of liver function and is accompanied by several complications. In a previous study, we revealed the protective effect of Centella asiatica 50% ethanol extract (CA-HE50) on acetaminophen-induced liver injury. In the present study, we investigate the hepatoprotective effect of CA-HE50 in a lipopolysaccharide/galactosamine (LPS-D-Gal)-induced ALF animal model and compare it to existing therapeutic silymarin, Lentinus edodes mycelia (LEM) extracts, ursodeoxycholic acid (UDCA) and dimethyl diphenyl bicarboxylate (DDB). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group. In particular, AST and ALT levels of the 200 mg/kg CA-HE50 group were significantly decreased compared to positive control groups. Lactate dehydrogenase (LDH) levels were significantly decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group and LDH levels of the 200 mg/kg CA-HE50 group were similar to those of the positive control groups. Superoxide dismutase (SOD) activity was significantly increased in the 100 mg/kg CA-HE50, LEM and UDCA groups compared to the vehicle control group and, in particular, the 100 mg/kg CA-HE50 group increased significantly compared to positive control groups. In addition, the histopathological lesion score was significantly decreased in the CA-HE50 and positive control groups compared with the vehicle control group and the histopathological lesion score of the 200 mg/kg CA-HE50 group was similar to that of the positive control groups. These results show that CA-HE50 has antioxidant and hepatoprotective effects at a level similar to that of silymarin, LEM, UDCA and DDB, which are known to have hepatoprotective effects; further, CA-HE50 has potential as a prophylactic and therapeutic agent in ALF.

Characteristics of the New Insulin-Resistant Zebrafish Model.

Insulin resistance, which occurs when insulin levels are sufficiently high over a prolonged period, causing the cells to fail to respond normally to the hormone. As a system for insulin resistance and diabetes drug development, insulin-resistant rodent models have been clearly established, but there is a limitation to high-throughput drug screening. Recently, zebrafish have been identified as an excellent system for drug discovery and identification of therapeutic targets, but studies on insulin resistance models have not been extensively performed. Therefore, we aimed to make a rapid insulin-resistant zebrafish model that complements the existing rodent models. To establish this model, zebrafish were treated with 10 µM insulin for 48 h. This model showed characteristics of insulin-resistant disease such as damaged pancreatic islets. Then we confirmed the recovery of the pancreatic islets after pioglitazone treatment. In addition, it was found that insulin-resistant drugs have as significant an effect in zebrafish as in humans, and these results proved the value of the zebrafish insulin resistance model for drug selection. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that insulin resistance altered gene expression due to the MAPK signaling and calcium signaling pathways. This model demonstrates the utility of the zebrafish model for drug testing and drug discovery in insulin resistance and diabetes.

Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica, on aceclofenac-induced acute enteritis.

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4+ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6 , IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1ß, GMCSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ+ Th1 cells, IL-4+ Th2 cells, IL-9+ Th9 cells, IL-17+ Th17 cells, and Foxp3+ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.