Protective and therapeutic effect of (S)-ginsenoside F1 on peripheral nerve degeneration targeting Schwann cells: a pharmaco-neuroanatomical approach.

Damaged peripheral nerves undergo peripheral neurodegenerative processes that are essential for the nerve regeneration. Peripheral neurodegenerative diseases, including diabetic peripheral neuropathy, are induced by irreversible nerve damage caused by abnormal peripheral nerve degeneration. However, until now, there have been no effective therapeutic treatments for these diseases. Ginsenosides are the most pharmacologically active compounds in Panax ginseng, and are being actively studied. Ginsenosides have a variety of effects, including neuroprotective, antioxidative, anti-cytotoxic, and anti-inflammatory effects. Here, we investigated the efficacy of 18 ginsenosides. We then tested the ability of the most effective ginsenoside, (S)-ginsenosides F1 (sF1), to inhibit peripheral neurodegenerative processes using mouse sciatic ex vivo culture, and several morphological and biochemical indicators. Our results suggest that sF1 could effectively protect Schwann cells against peripheral nerve degeneration.

Rapid Progression to Complete Paraplegia After Electroacupuncture in a Patient With Spinal Dural Arteriovenous Fistula: A Case Report.

Spinal dural arteriovenous fistula (SDAVF) usually has an insidious clinical course, but 5-15% of the cases have acute exacerbations. In some cases, there is an abrupt progression to paraplegia following an epidural injection or anesthesia. Electroacupuncture is a form of acupuncture that applies a small electrical current to needles inserted at specific points in the body. It is widely used for its analgesic effect on back pain. In this study, we report a rare case of SDAVF in which the symptoms of a patient worsened rapidly to complete paraplegia within a few hours after applying electroacupuncture to his back. A 49-year-old man had rapid progression to complete paraplegia within a few hours of electroacupuncture on his back. MRI showed SDAVF and worsening of cord signal change. An emergency operation was performed to ligate the SDAVF. The patient was able to walk 1 month post-operatively. Most of the neurological deficits had disappeared by 1 year post-operatively, with normalization of MRI. Our case emphasizes that SDAVF patients should be careful when exposed to any circumstances that might affect the circulation around the dural arteriovenous fistula, such as electroacupuncture. Patients should also be warned in advance about the possibility of rapid exacerbation of neurological symptoms. Regardless of the severity of the neurological symptoms, immediate treatment is essential for recovery and a better outcome.

Flavin Adenine Dinucleotide Depletion Caused by electron transfer flavoprotein subunit alpha Haploinsufficiency Leads to Hepatic Steatosis and Injury in Zebrafish.

The electron transfer flavoprotein (ETF) complex, made up of the ETF alpha subunit (ETFA), ETF beta subunit (ETFB), and ETF dehydrogenase (ETFDH), regulates fatty acid ß-oxidation activity while scavenging leaked electrons through flavin adenine dinucleotide (FAD)/reduced form FAD (FADH2) redox reactions in mitochondria. Here, we hypothesized that ETF dysfunction-mediated FAD deficiency may result in increased mitochondrial oxidative stress and steatosis and subsequent liver injury. We report that etfa haploinsufficiency caused hyperlipidemia, hypercholesterolemia, and hepatic steatosis and injury in adult zebrafish. Further, etfa+/ - mutant livers had reduced levels of FAD and glutathione and an increase in reactive oxygen species. Because FAD depletion might be critical in the pathogenesis of the liver lesion identified in etfa+/ - mutants, we used riboflavin to elevate FAD levels in the liver and found that riboflavin supplementation significantly suppressed hepatic steatosis and injury in etfa+/ - mutants through suppression of oxidative stress and de novo lipogenesis in the liver. Additionally, we found that adenosine triphosphate-linked mitochondrial oxygen consumption and mitochondrial membrane potential were reduced in etfa+/ - primary hepatocytes and that riboflavin supplementation corrected these defects. Conclusion: FAD depletion caused by etfa haploinsufficiency plays a key role in hepatic steatosis and oxidative stress-mediated hepatic injury in adult zebrafish. This raises the possibility that people with ETFA haploinsufficiency have a high risk for developing liver disease.

Adult zebrafish as an in vivo drug testing model for ethanol induced acute hepatic injury.

Chronic alcohol abuse is common and a leading cause of alcoholic liver disease (ALD). However, a safe and effective therapy for ALD is still elusive. In this study, we evaluated the utility of adult zebrafish as an in vivo model for rapid assessment of drug efficacy in ethanol-induced acute hepatic injury. We exposed adult zebrafish to 0.5 % ethanol for 24, 48, and 72 hours and measured serum alanine aminotransferase (ALT) activities. This treatment resulted in a significant increase in ALT levels at 48 and 72 h of ethanol treatment, compared to untreated control groups. Accompanying this, significant increases in mRNA expression of genes associated with inflammation was observed in the liver during ethanol exposure. To evaluate the effectiveness of drug testing using our zebrafish model for ethanol-induced acute hepatic injury, we investigated the protective function of nicotinamide riboside, a substrate for NAD+, previously shown to be protective in a rodent model of alcoholic liver disease and TES-1025, an inhibitor of α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), that increases NAD+. We found that both nicotinamide riboside and TES-1025 treatment suppressed ethanol-induced serum ALT levels, post 48 h of ethanol exposure. In a similar manner, riboflavin supplementation also suppressed ethanol-induced serum ALT increase during ethanol exposure. Additionally, both nicotinamide riboside and riboflavin supplementation inhibited the upregulation of mRNA expression of genes associated with inflammation and de novo lipogenesis. In conclusion, we established an adult zebrafish model of ethanol-induced acute hepatic injury that will be valuable for cost-effective in vivo drug screening, which may in the future offer identification of novel therapeutics to mitigate hepatic injury, associated with excessive alcohol consumption.

Identifying Active Compounds and Targets of Fritillariae thunbergii against Influenza-Associated Inflammation by Network Pharmacology Analysis and Molecular Docking.

Complications due to influenza are often associated with inflammation with excessive release of cytokines. The bulbs of Fritillariae thunbergii (FT) have been traditionally used to control airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate active compounds, the targets, and underlying mechanisms of FT for the treatment of influenza-induced inflammation, systems biology was employed. Active compounds of FT were identified through the TCMSP database according to oral bioavailability (OB) and drug-likeness (DL) criteria. Other pharmacokinetic parameters, Caco-2 permeability (Caco-2), and drug half-life (HL) were also identified. Biological targets of FT were retrieved from DrugBank and STITCH databases, and target genes associated with influenza, lung, and spleen inflammation were collected from DisGeNET and NCBI databases. Compound-disease-target (C-D-T) networks were constructed and merged using Cytoscape. Target genes retrieved from the C-D-T network were further analyzed with GO enrichment and KEGG pathway analysis. In our network, GO and KEGG results yielded two compounds (beta-sitosterol (BS) and pelargonidin (PG)), targets (PTGS1 (COX-1) and PTGS2 (COX-2)), and pathways (nitric oxide, TNF) were involved in the inhibitory effects of FT on influenza-associated inflammation. We retrieved the binding affinity of each ligand-target, and found that PG and COX-1 showed the strongest binding affinity among four binding results using a molecular docking method. We identified the potential compounds and targets of FT against influenza and suggest that FT is an immunomodulatory therapy for influenza-associated inflammation.

Antiviral Activity of Fritillaria thunbergii Extract against Human Influenza Virus H1N1 (PR8) In Vitro, In Ovo and In Vivo.

Influenza viruses cause respiratory diseases in humans and animals with high morbidity and mortality rates. Conventional anti-influenza drugs are reported to exert side effects and newly emerging viral strains tend to develop resistance to these commonly used agents. Fritillaria thunbergii (FT) is traditionally used as an expectorant for controlling airway inflammatory disorders. Here, we evaluated the therapeutic effects of FT extracts against influenza virus type A (H1N1) infection in vitro, in ovo, and in vivo. In the post-treatment assay, FT extracts showed high CC50 (7,500 µg/ml), indicating low toxicity, and exerted moderate antiviral effects compared to oseltamivir (SI 50.6 vs. 222) in vitro. Antiviral activity tests in ovo revealed strong inhibitory effects of both FT extract and oseltamivir against H1N1 replication in embryonated eggs. Notably, at a treatment concentration of 150 mg/kg, only half the group administered oseltamivir survived whereas the FT group showed 100% survival, clearly demonstrating the low toxicity of FT extracts. Consistent with these findings, FT-administered mice showed a higher survival rate with lower body weight reduction relative to the oseltamivir group upon treatment 24 h after viral infection. Our collective results suggest that FT extracts exert antiviral effects against influenza H1N1 virus without inducing toxicity in vitro, in ovo or in vivo, thereby supporting the potential utility of FT extract as a novel candidate therapeutic drug or supplement against influenza.

Antiviral activity of Poncirus trifoliata seed extract against oseltamivir-resistant influenza virus.

The emergence of oseltamivir-resistant variants of influenza virus has highlighted the necessity for the development of more effective novel antiviral drugs. To date, numerous researchers have focused on developing antiviral drugs using natural resources, such as traditional herbal medicines. Poncirus trifoliata is widely used in oriental medicine as a remedy for gastritis, dysentery, inflammation and digestive ulcers. In this study, we investigated the potential antiviral effect of the Poncirus trifoliata orange seed extract against influenza virus. An ethanol extract of Poncirus trifoliata seeds (PTex) inhibited the activity of influenza viruses, in particular, oseltamivir- resistant strains, in Madin-Darby canine kidney cells. In contrast to oseltamivir, PTex exerted a significant inhibitory effect on the cellular penetration pathway of the virus rather than HA receptor binding. The potent antiviral effect and novel working mechanism of PTex support its further development as an effective natural antiviral drug with a wide spectrum of activity against influenza and oseltamivir-resistant viruses.

Modified high-density lipoproteins by artificial sweetener, aspartame, and saccharin, showed loss of anti-atherosclerotic activity and toxicity in zebrafish.

Safety concerns have been raised regarding the association of chronic consumption of artificial sweeteners (ASs) with metabolic disorders, especially in the heart and brain. There has been no information on the in vivo physiological effects of AS consumption in lipoprotein metabolism. High-dosage treatment (final 25, 50, and 100 mM) with AS (aspartame, acesulfame K, and saccharin) to human high-density lipoprotein (HDL) induced loss of antioxidant ability along with elevated atherogenic effects. Aspartame-treated HDL3 (final 100 mM) almost all disappeared due to putative proteolytic degradation. Aspartame- and saccharin-treated HDL3 showed more enhanced cholesteryl ester transfer activity, while their antioxidant ability was disappeared. Microinjection of the modified HDL3 exacerbated the inflammatory death in zebrafish embryos in the presence of oxLDL. These results show that AS treatment impaired the beneficial functions of HDL, resulting in loss of antioxidant and anti-atherogenic activities. These results suggest that aspartame and saccharin could be toxic to the human circulation system as well as embryonic development via impairment of lipoprotein function.

Ethanol and water extract of purple sweet potato exhibits anti-atherosclerotic activity and inhibits protein glycation.

It is well known that extracts of purple sweet potato (PSP) have potent antioxidant activity. However, it has not been established whether extracts of PSP inhibit oxidation of low-density lipoprotein (LDL) or protein glycation. LDL oxidation and protein glycation are well-known risk factors for chronic metabolic diseases, such as atherosclerosis and diabetes mellitus. Chopped and sliced PSP and yellow sweet potato (YSP) were extracted individually at a concentration of 1 g of PSP tuber/mL using either ethanol or water for 6 hours. The PSP ethanol extract (100-fold diluted) showed stronger radical (2,2-diphenyl-1-picrylhydrazyl radical) scavenging activity than the water extract of PSP and the ethanol extract of YSP (up to a sixfold higher activity). The ethanol extract of PSP also exhibited the highest increase in ferric reducing ability among all extracts. Cupric ion-mediated LDL oxidation was strongly inhibited by the ethanol extract of PSP, with similar potency to vitamin C treatment (final concentration, 10 mM). The PSP extract strongly inhibited fructose-mediated protein glycation as determined by fluorescence spectroscopy. The PSP extract-treated apolipoprotein (apo) A-I showed a decreased multimerization pattern on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas glycated apoA-I showed the strongest multimeric band. PSP extract treatment also inhibited the uptake of oxidized LDL into human macrophage cells with suppression of malondialdehyde production in the cell culture medium. In conclusion, these results suggest that the extract of PSP can be used as a putative anti-atherosclerotic and antidiabetic agent with strong antioxidant functions. This is the first report to show the biological functions of PSP extract to treat hyperlipidemic and hyperglycemic disorders.