Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

Long-term comparison of the performance of biostimulation and phytoextraction in soil contaminated with diesel and heavy metals.

The long-term remediation performance under the natural conditions is required to establish the appropriate remediation strategy for contaminated soil. The objective of this study was to compare the long-term remediation efficiency of biostimulation and phytoextraction in contaminated soil containing petroleum hydrocarbons (PHs) and heavy metals. Two types of contaminated soil (soil contaminated with diesel only and co-contaminated with diesel and heavy metals) were prepared. For the biostimulation treatments, the soil was amended with compost, whereas maize, a representative phytoremediation plant, was cultivated for the phytoextraction treatments. There was no significant difference in remediation performance of biostimulation and phytoextraction in the diesel-contaminated soil, in which the maximum total petroleum hydrocarbon (TPH) removability was 94-96% (p < 0.05). However, phytoextraction exhibited the higher removability for TPH and heavy metals than biostimulation in the co-contaminated soil. There was no considerable change in the TPH removal in biostimulation (16-25%), while phytoextraction showed a 75% of TPH removal rate in the co-contaminated soil. Additionally, no significant changes were observed in heavy metals concentration of biostimulation, whereas the removability of heavy metals was 33-63% in phytoextraction. Meanwhile, maize, which is a suitable plant for phytoextraction, showed a translocation factor (translocating efficiency from roots to shoots) value of >1. Correlation analysis revealed that soil properties (pH, water content, and organic content) negatively correlated with pollutants removal. Additionally, the soil bacterial communities were changed over the investigated period, and the types of pollutants exerted a significant influence on the bacterial community dynamics. This study performed a pilot-scale comparison of two types of biological remediation technologies under natural environmental conditions and provided information on changes in the bacterial community structures. This study can be useful for establishing appropriate biological remediation methods to restore soil contaminated with PHs and heavy metals.

Seasonal Dynamics of Bacterial Community Structure in Diesel Oil-Contaminated Soil Cultivated with Tall Fescue (Festuca arundinacea).

The objective of this study was to explore the seasonal characteristics of rhizoremediation and the bacterial community structure over the course of a year in soil contaminated with diesel oil. The soil was contaminated with diesel oil at a total petroleum hydrocarbon (TPH) concentration of 30,000 mg-TPH·kg-soil-1. Tall fescue seedlings were planted in the contaminated soil and rhizoremediation performance was monitored for 317 days. The TPH concentration gradually declined, reaching 75.6% after day 61. However, the TPH removability decreased by up to 30% after re-contamination in the fall and winter. The bacterial community structure exhibited distinct seasonal dynamics. Genus Pseudomonas significantly increased up to 55.7% in the winter, while the genera Immundisolibacter and Lysobacter, well-known petroleum hydrocarbon (PH)-degrading bacteria, were found to be positively linked to the TPH removal rate. Consequently, knowledge of this seasonal variation in rhizoremediation performance and the bacterial community structure is useful for the improvement of rhizoremediation in PH-contaminated environments.

Aucuparin Suppresses Bleomycin-Induced Pulmonary Fibrosis Via Anti-Inflammatory Activity.

Idiopathic pulmonary fibrosis (IPF) is a lung disease that results in scarring of the lungs for an unknown reason. Although many studies have been conducted on IPF, precise mechanisms and treatments have not yet been identified. In this study, we found that aucuparin, a natural product isolated from Sorbus aucuparia, inhibited pulmonary fibrosis in a bleomycin (BLM)-induced lung fibrosis mouse model. In the lung samples of mice treated with aucuparin, the gene expression of inflammation and macrophage activation markers was reduced compared to those treated with BLM alone. Moreover, aucuparin decreased the expression of profibrotic marker genes and increased the expression of antifibrotic marker genes. Finally, we observed that aucuparin significantly suppressed transforming growth factor-ß-induced activation of inflammatory cytokine production and collagen synthesis from macrophages and fibroblasts, respectively. Taken together, these data demonstrate that aucuparin inhibits lung fibrosis via its anti-inflammatory action and support its potential to be a therapeutic drug for IPF treatment.

Plumbagin Suppresses Pulmonary Fibrosis via Inhibition of p300 Histone Acetyltransferase Activity.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis similar to that of malignancy. The causes of IPF are not clearly known, and there is no effective therapy to date. In this study, the natural compound plumbagin, which was isolated from Plumbago rosea root extract, was screened for p300 inhibitory activity. Plumbagin specifically inhibited the activity of p300 toward histone acetyltransferases. Plumbagin treatment significantly suppressed transforming growth factor-ß-induced profibrotic target-gene expression and proliferation of fibroblast cell lines. Moreover, plumbagin significantly inhibited bleomycin-induced pulmonary fibrosis in mice. Taken together, these data demonstrate the inhibitory effects of plumbagin on lung fibrosis and its promise as a therapeutic agent for IPF.

Quality characteristics of reduced-fat frankfurters with pork fat replaced by sunflower seed oils and dietary fiber extracted from makgeolli lees.

The effects of reducing pork fat levels from 30% to 20% by partially substituting pork fat with a mix of sunflower seed oil (0, 5, 10, 15, and 20%) and makgeolli lees fiber (2%) were investigated based on physicochemical properties, textural properties, and sensory characteristics of reduced-fat frankfurters. The moisture and ash content, and lightness were higher in reduced-fat frankfurter samples containing sunflower seed oil and makgeolli lees fiber than in the control. The results showed that reduced-fat frankfurter samples with higher sunflower seed oil levels had lower redness and yellowness values, as well as less cooking loss, emulsion stability, hardness, springiness, and apparent viscosity. The results of this study show that incorporating sunflower seed oil and makgeolli lees fiber into the formulation successfully reduced animal fat in frankfurters, while improving quality characteristics.

In vitro apoptotic effects of methanol extracts of Dianthus chinensis and Acalypha australis L. targeting specificity protein 1 in human oral cancer cells.

BACKGROUND: The aims of this study were to evaluate the apoptotic activities and molecular mechanisms of methanol extracts of Dianthus chinensis (MEDC) and Acalypha australis L. (MEAL) in human oral cancer cells. METHODS: The apoptotic effects and related molecular mechanisms of MEDC and MEAL on oral cancer cells were evaluated using MTS assay, DAPI staining, immunostaining, Western blotting, and reverse transcriptase-polymerase chain reaction. RESULTS: Sp1 was overexpressed in oral tumor tissues compared with normal oral mucosa. Downregulation of Sp1 inhibited the growth of SCC-15 and YD-15 oral cancer cells. MEDC and MEAL inhibited cell growth and induced apoptosis in both cell lines by decreasing the expression of Sp1. In addition, treatment of cells with MEDC and MEAL decreased Mcl-1 expression, which is a downstream target of Sp1. CONCLUSION: Our results indicate that MEDC and MEAL are bioactive natural products that can potentially induce apoptosis of tumor cells that overexpress the Sp1 protein.