Phytochemicals targeting lncRNAs: A novel direction for neuroprotection in neurological disorders.

Neurological disorders with various etiologies impacting the nervous system are prevalent in clinical practice. Long non-coding RNA (lncRNA) molecules are functional RNA molecules exceeding 200 nucleotides in length that do not encode proteins, but participate in essential activities. Research indicates that lncRNAs may contribute to the pathogenesis of neurological disorders, and may be potential targets for their treatment. Phytochemicals in traditional Chinese herbal medicine (CHM) have been found to exert neuroprotective effects by targeting lncRNAs and regulating gene expression and various signaling pathways. We aim to establish the development status and neuroprotective mechanism of phytochemicals that target lncRNAs through a thorough literature review. A total of 369 articles were retrieved through manual and electronic searches of PubMed, Web of Science, Scopus and CNKI databases from inception to September 2022. The search utilized combinations of natural products, lncRNAs, neurological disorders, and neuroprotective effects as keywords. The included studies, a total of 31 preclinical trials, were critically reviewed to present the current situation and the progress in phytochemical-targeted lncRNAs in neuroprotection. Phytochemicals have demonstrated neuroprotective effects in preclinical studies of various neurological disorders by regulating lncRNAs. These disorders include arteriosclerotic ischemia-reperfusion injury, ischemic/hemorrhagic stroke, Alzheimer's disease, Parkinson's disease, glioma, peripheral nerve injury, post-stroke depression, and depression. Several phytochemicals exert neuroprotective roles through mechanisms such as anti-inflammatory, antioxidant, anti-apoptosis, autophagy regulation, and antagonism of Aß-induced neurotoxicity. Some phytochemicals targeted lncRNAs and served a neuroprotective role by regulating microRNA and mRNA expression. The emergence of lncRNAs as pathological regulators provides a novel direction for the study of phytochemicals in CHM. Elucidating the mechanism of phytochemicals regulating lncRNAs will help to identify new therapeutic targets and promote their application in precision medicine.

TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons.

The TET family of dioxygenases promote DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Hypothalamic agouti-related peptide-expressing (AGRP-expressing) neurons play an essential role in driving feeding, while also modulating nonfeeding behaviors. Besides AGRP, these neurons produce neuropeptide Y (NPY) and the neurotransmitter GABA, which act in concert to stimulate food intake and decrease energy expenditure. Notably, AGRP, NPY, and GABA can also elicit anxiolytic effects. Here, we report that in adult mouse AGRP neurons, CRISPR-mediated genetic ablation of Tet3, not previously known to be involved in central control of appetite and metabolism, induced hyperphagia, obesity, and diabetes, in addition to a reduction of stress-like behaviors. TET3 deficiency activated AGRP neurons, simultaneously upregulated the expression of Agrp, Npy, and the vesicular GABA transporter Slc32a1, and impeded leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induced 5hmC modification that was associated with a chromatin-modifying complex leading to transcription inhibition, and this regulation occurred in both the mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism and revealed its unexpected dual role in the control of feeding and other complex behaviors through AGRP neurons.

Network Pharmacology and Molecular Docking Analysis Explores the Mechanisms of Cordyceps sinensis in the Treatment of Oral Lichen Planus.

Objective: Oral lichen planus (OLP) is the most common potentially malignant disorder of the oral cavity. This study aimed to investigate the mechanism of action of Cordyceps sinensis in the treatment of OLP and provides a theoretical support for improving current treatment regimens for OLP. Methods: The active components and therapeutic targets of Cordyceps sinensis were predicted and screened using the TCMSP, SymMap, PubMed, HIT 2.0, and PharmMapper databases, while the relevant OLP targets were predicted and screened using the DisGeNET and GeneCards databases. Protein-protein interactions (PPI) were examined using the String database, and Cytoscape was used to combine and illustrate the findings. GO and KEGG pathway enrichment analyses were carried out using RStudio, and AutoDock Vina and Pymol were used for molecular docking and visualization, respectively. Results: A total of 404 potential target genes were discovered after evaluating 21 active compounds from Cordyceps sinensis. Potential therapeutic targets included 67 targets that matched and overlapped with OLP, including TNF, IL-6, CD4, EGFR, and IL1B. Key targets were predominantly engaged in the PI3K-Akt signaling pathway and the MAPK signaling pathway, according to the GO and KEGG analyses. These targets have a connection to biological processes including apoptosis signaling pathway regulation, T cell activation, and oxidative stress response. The molecular docking results showed that TNF, IL-6, CD4, EGFR, and IL1B could bind to their corresponding active components. Conclusions: Cordyceps sinensis contains multiple components and acts on multiple targets and multiple pathways. Particularly, Cordyceps sinensis targets TNF, IL-6, CD4, EGFR, and IL1B, regulates PI3K-Akt and MAPK signaling pathways, as well as takes part in biological processes including apoptosis, T cell activation, and oxidative stress. Cordyceps sinensis could be a crucial choice in the therapy of OLP.

Modified Banxia Xiexin Decoction Ameliorates Polycystic Ovarian Syndrome With Insulin Resistance by Regulating Intestinal Microbiota.

Objective: To analyze the characteristics of the intestinal microbiota of polycystic ovarian syndrome with insulin resistance (PCOS-IR) and explore the possible mechanism of modified Banxia Xiexin Decoction in the treatment of PCOS-IR. Methods: A total of 17 specific pathogen-free (SPF) female Sprague-Dawley (SD) rats, aged 21 days, were selected and randomly divided into the control group (group Z, n = 6), model group (group M, n = 6), and treatment group (group A, n = 5). Letrozole combined with a high-fat diet was used to induce the PCOS-IR model. Rats in group A were treated with modified Banxia Xiexin Decoction for 2 weeks after the end of modeling; then the characteristics of reproductive, metabolic, inflammatory, and intestinal microbiota were compared among three groups. Results: The PCOS-IR model had an imbalance of intestinal microbiota, and the enriched microbiota was mainly class Coriobacteria, order Clostridiales, and genus Clostridium_sensu_stricto_1. Modified Banxia Xiexin Decoction can regulate the disorder of intestinal microbiota diversity, significantly increase the abundance of phyla Verrucomicrobiota Proteobacteria and genera Akkermansia and Blautia, and decrease the abundance of genus Clostridium_sensu_stricto_1. Conclusion: Genus Clostridium_sensu_stricto_1 might be the pivotal pathogenic bacteria of PCOS-IR. Modified Banxia Xiexin Decoction may ameliorate PCOS-IR by regulating intestinal microbiota imbalance and improving metabolic disorders.

Investigation of Tannins Transformation in Sanguisorbae Radix Over Carbonizing by Stir-Frying.

Carbonizing by stir-frying (CSF) is the most common technology in botanical folk medicines to enhance the convergence, hemostasis, and antidiarrheal effects. Sanguisorbae Radix (SR), a well-known herbal medicine in China, has extensive therapeutic functions, while charred SR is known as an additional product obtained from SR after CSF. In this study, mass spectrometry was used to investigate the effect of charring on tannins transformation of SR. The findings showed that the content level of tannins in SR decreased significantly after carbonizing process, while their three categories, gallotannins, ellagitannins, and procyanidins, had downward trends in general. Moreover, CSF also induced the polyphenol in SR to release relevant monomers from its origins. Significant amount of hydrolyzable tannins were detected by mass spectrometry, including gallotannins and ellagitannins, suggesting that hydrolysis during CSF yielded gallic and ellagic acid and their derivatives, in addition to sugar moieties. Subsequently, gallic and ellagic acid can further polymerize to form sanguisorbic acid dilactone. The amount of proanthocyanidins, the oligomers of catechin, including procyanidin, procyanidin C2, procyanidin B3, and 3-O-galloylprocyanidin B3, decreased to form catechin and its derivatives, which may further degrade to protocatechualdehyde. Quantitative analysis illustrated that the amount of gallic, pyrogallic, and ellagic acid and methyl gallate, the essential effectors in SR, significantly increased after CSF, with increased ratios of 1.36, 4.28, 10.33, and 4.79, respectively. In contrast, the contents of cathechin and epigallocatechin dropped remarkably with increased ratios of 0.04 and 0.02. Tannins exhibit moderate absorption, while their relevant monomers have a higher bioavailability. Therefore, CSF is proved here to be an effective technique to the release of active monomers from the original polyphenol precursor. This study explored the mechanism by which tannins are transformed upon CSF of SR.

A Tensor-Based Frequency Features Combination Method for Brain-Computer Interfaces.

With the development of the brain-computer interface (BCI) community, motor imagery-based BCI system using electroencephalogram (EEG) has attracted increasing attention because of its portability and low cost. Concerning the multi-channel EEG, the frequency component is one of the most critical features. However, insufficient extraction hinders the development and application of MI-BCIs. To deeply mine the frequency information, we proposed a method called tensor-based frequency feature combination (TFFC). It combined tensor-to-vector projection (TVP), fast fourier transform (FFT), common spatial pattern (CSP) and feature fusion to construct a new feature set. With two datasets, we used different classifiers to compare TFFC with the state-of-the-art feature extraction methods. The experimental results showed that our proposed TFFC could robustly improve the classification accuracy of about 5% ( ). Moreover, visualization analysis implied that the TFFC was a generalization of CSP and Filter Bank CSP (FBCSP). Also, a complementarity between weighted narrowband features (wNBFs) and broadband features (BBFs) was observed from the averaged fusion ratio. This article certificates the importance of frequency information in the MI-BCI system and provides a new direction for designing a feature set of MI-EEG.

Grape Seed Proanthocyanidin Ameliorates FB1-Induced Meiotic Defects in Porcine Oocytes.

Fumonisin B1 (FB1), as the most prevalent and toxic fumonisin, poses a health threat to humans and animals. The cytotoxicity of FB1 is closely related to oxidative stress and apoptosis. The purpose of this study is to explore whether Grape seed proanthocyanidin (GSP), a natural antioxidant, could alleviate the meiotic maturation defects of oocytes caused by FB1 exposure. Porcine cumulus oocyte complexes (COCs) were treated with 30 µM FB1 alone or cotreated with 100, 200 and 300 µM GSP during in vitro maturation for 44 h. The results show that 200 µM GSP cotreatment observably ameliorated the toxic effects of FB1 exposure, showing to be promoting first polar body extrusion and improving the subsequent cleavage rate and blastocyst development rate. Moreover, 200 µM GSP cotreatment restored cell cycle progression, reduced the proportion of aberrant spindles, improved actin distribution and protected mitochondrial function in FB1-exposed oocytes. Furthermore, reactive oxygen species (ROS) generation was significantly decreased and the mRNA levels of CAT, SOD2 and GSH-PX were obviously increased in the 200 µM GSP cotreatment group. Notably, the incidence of early apoptosis and autophagy level were also significantly decreased after GSP cotreatment and the mRNA expression levels of BAX, CASPASE3, LC3 and ATG5 were markedly decreased, whereas BCL2 and mTOR were observably increased in the oocytes after GSP cotreatment. Together, these results indicate that GSP could exert significant preventive effects on FB1-induced oocyte defects by ameliorating oxidative stress through repairing mitochondrial dysfunction.

Efficacy of gecko polysaccharide on suppressed immune response induced by cyclophosphamide in mice.

OBJECTIVE: To evaluate the efficacy of gecko polysaccharide on the cyclophosphamide-induced suppressed immune response in mice. METHODS: Polysaccharides were extracted from fresh gecko for the first time using an orthogonal method and protein was removed using Sevag reagent (chloroform:N-butanol, 5:1, v/v). The gecko polysaccharide (GPCE) content was determined by the phenol-concentrated sulfuric acid method. An immunocompromised mouse model was established by intraperitoneally injecting cyclophosphamide at 100 mg/kg into 48 mice. The effects of GPCE on immune regulation in mice were assessed by a thymus-spleen index, serum hemolysin levels, and the proliferation of splenic lymphocytes. Spleen cell CD4+, CD8+, and the CD4+/CD8+ ratio were evaluated by flow cytometry and the tumor necrosis factor-α (TNF-α) levels were measured by ELISA. RESULTS: The optimal extraction process for gecko polysaccharide included a 1:20 ratio of material to liquid (v/v), an extraction temperature of 60 ℃ and a time of 2 h. The polysaccharide content of the extract was 65.74%. GPCE was analyzed by HPLC and primarily contained glucose and small amounts of mannose, rha, and gal. Compared with the model, the thymus index, the spleen index were indices for GPCE increased with dose, whereas the high and medium groups exhibited significant differences (P < 0.05, P < 0.01). Higher doses of GPCE increased serum TNF-α levels and there was a significant difference between the medium and high GPCE doses and the model (P < 0.05, P < 0.01); The number of CD4+ cells and the CD4+/CD8+ ratio in the gecko polysaccharide group were increased (P < 0.05) and there was no statistical difference in the number of CD8+ cells in the gecko polysaccharide group (P > 0.05); The high GPCE dose significantly increased the level of serum hemolysin (P < 0.01). CONCLUSIONS: Gecko polysaccharide significantly improved the suppressed immune response induced by cyclophosphamide in mice and promoted the secretion of tumor necrosis factor. The mechanism of gecko polysaccharide as an antitumor agent warrants further study.

Fine tuning of medium chain fatty acids levels increases fruity ester production during alcoholic fermentation.

Pichia fermentans Z9Y-3 and its intracellular enzymes were inoculated along with S. cerevisiae in synthetic grape must to modulate fruity ester production. The levels of ester-related enzymes, ester precursors, and fruity esters were monitored every 24 h during fermentation. Results showed that the levels of ethyl acetate, acetate higher alcohol esters (AHEs), short chain fatty acid ethyl esters (SFEs), and medium chain fatty acid ethyl esters (MFEs) were significantly enhanced in mixed fermentation. Pearson correlation analysis further revealed that higher alcohols and fatty acids played a more important role in fruity ester production than enzymes; Particularly, the correlation coefficient between fatty acids and MFEs was 0.940. In addition, supplementation of medium chain fatty acids (7.2 mg/L) at the metaphase of single S. cerevisiae fermentation improved ethyl acetate, AHE, SFE, and MFE production by 42.56%, 21.00%, 61.33%, and 90.04%, respectively, although the high level of ethyl acetate might result in off-flavors.

Zenglv Fumai Granule protects cardiomyocytes against hypoxia/reoxygenation-induced apoptosis via inhibiting TRIM28 expression.

Myocardial ischemia/reperfusion (MIR) injury, which occurs following acute myocardial infarction, can cause secondary damage to the heart. Tripartite interaction motif (TRIM) proteins, a class of E3 ubiquitin ligases, have been recognized as critical regulators in MIR injury. Zenglv Fumai Granule (ZFG) is a clinical prescription for the treatment of sick sinus syndrome, a disease that is associated with MIR injury. The present study aimed to investigate the effect of ZFG on MIR injury and to determine whether ZFG exerts its effects via regulation of TRIM proteins. In order to establish an in vitro MIR model, human cardiomyocyte cell line AC16 was cultured under hypoxia for 5 h and then under normal conditions for 1 h. Following hypoxia/reoxygenation (H/R) treatment, these cells were cultured with different ZFG concentrations. ZFG notably inhibited H/R-induced cardiomyocyte apoptosis. The expression levels of four TRIM proteins, TRIM7, TRIM14, TRIM22 and TRIM28, were also detected. These four proteins were significantly upregulated in H/R-injured cardiomyocytes, whereas their expression was inhibited following ZFG treatment. Moreover, TRIM28 knockdown inhibited H/R-induced cardiomyocyte apoptosis, whereas TRIM28 overexpression promoted apoptosis and generation of reactive oxygen species (ROS) in cardiomyocytes. However, the effects of TRIM28 overexpression were limited by the action of ROS inhibitor N-acetyl-L-cysteine. In addition, the mRNA and protein levels of antioxidant enzyme glutathione peroxidase (GPX)1 were significantly downregulated in H/R-injured cardiomyocytes. TRIM28 knockdown restored GPX1 protein levels but had no effect on mRNA expression levels. Co-immunoprecipitation and ubiquitination assays demonstrated that TRIM28 negatively regulated GPX1 via ubiquitination. In sum, the present study revealed that ZFG attenuated H/R-induced cardiomyocyte apoptosis by regulating the TRIM28/GPX1/ROS pathway. ZFG and TRIM28 offer potential therapeutic options for the treatment of MIR injury.

Loss of two families of SPX domain-containing proteins required for vacuolar polyphosphate accumulation coincides with the transition to phosphate storage in green plants.

Phosphorus is an essential nutrient for plants. It is stored as inorganic phosphate (Pi) in the vacuoles of land plants but as inorganic polyphosphate (polyP) in chlorophyte algae. Although it is recognized that the SPX-Major Facilitator Superfamily (MFS) and VPE proteins are responsible for Pi influx and efflux, respectively, across the tonoplast in land plants, the mechanisms that underlie polyP homeostasis and the transition of phosphorus storage forms during the evolution of green plants remain unclear. In this study, we showed that CrPTC1, encoding a protein with both SPX and SLC (permease solute carrier 13) domains for Pi transport, and CrVTC4, encoding a protein with both SPX and vacuolar transporter chaperone (VTC) domains for polyP synthesis, are required for vacuolar polyP accumulation in the chlorophyte Chlamydomonas reinhardtii. Phylogenetic analysis showed that the SPX-SLC, SPX-VTC, and SPX-MFS proteins were present in the common ancestor of green plants (Viridiplantae). The SPX-SLC and SPX-VTC proteins are conserved among species that store phosphorus as vacuolar polyP and absent from genomes of plants that store phosphorus as vacuolar Pi. By contrast, SPX-MFS genes are present in the genomes of streptophytes that store phosphorus as Pi in the vacuoles. These results suggest that loss of SPX-SLC and SPX-VTC genes and functional conservation of SPX-MFS proteins during the evolution of streptophytes accompanied the change from ancestral polyP storage to Pi storage.

Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men.

SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.

Integrating metabolomics and network pharmacology to explore the protective effect of gross saponins of Tribulus terrestris L. fruit against ischemic stroke in rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Tribulus terrestris L. belongs to the family Zygophyllaceae and has been widely used as a folk medicine for a long history in Asian countries. Gross saponins of Tribulus terrestris L. fruit (GSTTF) has an obvious neuroprotective effect on the treatment of ischemic stroke, but its potential therapeutic mechanisms have not been thoroughly studied. AIM OF THE STUDY: To investigate the protective effect of GSTTF against ischemic stroke in rat. MATERIALS AND METHODS: The combination of metabolomics and network pharmacology analysis was applied to investigate the protective effects of GSTTF on ischemic stroke and its putative mechanism. The related pathway of the biomarkers highlighted from metabolomics analysis was explored, then the possible targets of GSTTF were further revealed by network pharmacology analysis. Molecular docking was conducted to investigate the interaction between the active compound and target protein. RESULTS: Metabolomics analysis showed that metabolic disturbances were observed in serum for the rats in middle cerebral artery occlusion (MCAO). These MCAO-induced deviations in serum metabolism can be reversely changed by GSTTF via metabolic pathways regulation. Twenty-four proteins with the connectivity degree larger than 15 were selected by the network pharmacology analysis, which are considered as the possible therapeutic targets of the GSTTF against ischemic stroke. The results of molecular docking showed that the active compounds were capable of binding to the representative potential targets HSD11B1 and AR, respectively. And the docking mode of two compounds with the lowest binding energy to their target protein was illustrated by the ribbon binding map. CONCLUSION: The present study combines metabolomics and network pharmacology analysis to investigate the mechanism of MCAO-induced ischemic stroke and reveal the efficiency and possible mechanisms of GSTTF for ischemic stroke. Further studies on the bioactive saponin as well as their synergistic action on ischemic stroke will be conducted to better reveal the underlying mechanisms.

A comparison of graph- and kernel-based -omics data integration algorithms for classifying complex traits.

BACKGROUND: High-throughput sequencing data are widely collected and analyzed in the study of complex diseases in quest of improving human health. Well-studied algorithms mostly deal with single data source, and cannot fully utilize the potential of these multi-omics data sources. In order to provide a holistic understanding of human health and diseases, it is necessary to integrate multiple data sources. Several algorithms have been proposed so far, however, a comprehensive comparison of data integration algorithms for classification of binary traits is currently lacking. RESULTS: In this paper, we focus on two common classes of integration algorithms, graph-based that depict relationships with subjects denoted by nodes and relationships denoted by edges, and kernel-based that can generate a classifier in feature space. Our paper provides a comprehensive comparison of their performance in terms of various measurements of classification accuracy and computation time. Seven different integration algorithms, including graph-based semi-supervised learning, graph sharpening integration, composite association network, Bayesian network, semi-definite programming-support vector machine (SDP-SVM), relevance vector machine (RVM) and Ada-boost relevance vector machine are compared and evaluated with hypertension and two cancer data sets in our study. In general, kernel-based algorithms create more complex models and require longer computation time, but they tend to perform better than graph-based algorithms. The performance of graph-based algorithms has the advantage of being faster computationally. CONCLUSIONS: The empirical results demonstrate that composite association network, relevance vector machine, and Ada-boost RVM are the better performers. We provide recommendations on how to choose an appropriate algorithm for integrating data from multiple sources.

Chloroquine attenuates paraquat-induced lung injury in mice by altering inflammation, oxidative stress and fibrosis.

Paraquat is one of the most extensively used herbicides and has high toxicity for humans and animals. However, there is no effective treatment for paraquat poisoning. The aim of the present study was to evaluate the effects of chloroquine on paraquat-induced lung injury in mice. Mice received a single intraperitoneal injection of paraquat and a daily intraperitoneal injection of the indicated dosages of chloroquine or dexamethasone. The histological changes, inflammation and oxidative stress in the lungs were examined at day 3, and the degree of pulmonary fibrosis was examined at day 28. H&E staining showed that chloroquine markedly attenuated lung injury induced by paraquat. In addition, the inflammatory responses induced by paraquat were inhibited after treatment with chloroquine, as indicated by the decreased number of leukocytes, the reduced levels of TNF-α, IL-1ß and IL-6 in the bronchoalveolar lavage fluid, the reduced NO content, and downregulation of iNOS expression in lung tissues. No different effect was found between high-dose chloroquine and dexamethasone. Additionally, the treatment with chloroquine increased the activity of SOD and decreased the level of MDA in the lung tissues. The expressions of the anti-oxidative proteins, Nrf2, HO-1 and NQO1, were also upregulated by chloroquine treatment. The high-dose chloroquine was more effective than dexamethasone in its anti-oxidation ability. Finally, the results of Masson's staining illustrated that chloroquine markedly attenuated fibrosis in the paraquat-exposed lungs. Immunohistochemistry staining showed that the expressions of the pro-fibrotic proteins TGF-ß and α-SMA were downregulated after treatment with chloroquine. In conclusion, chloroquine effectively attenuated paraquat-induced lung injury in mice.

Safety evaluation of soybean protein isolate oxidized by a hydroxyl radical-generating system.

The oxidative modification of soybean protein isolate (SPI) induced by a hydroxyl radical-generating system (HRGS) has a broad range of applications. However, few toxicology studies exist on this material. The safety of HRGS-oxidized SPI was assessed using subchronic and genotoxicity studies. A 30-day subchronic study (250, 500 and 1000 mg/kg∙BW) in rats showed no significant adverse effects on food consumption, body weight (BW), mortality, hematology, biochemistry, necropsy, organ weight or histopathology. The result of an Ames test showed that HRGS-oxidized SPI was not mutagenic to the test strains. The results of a bone marrow micronucleus test and mouse sperm abnormality test showed HRGS-oxidized SPI (417.5, 835.0 and 1670.0 mg/kg⋅BW) did not produce any aberrant effects on bone marrow cells or mouse sperm. Therefore, HRGS-oxidized SPI showed no genotoxicity in vivo or in vitro. In conclusion, these results support the safe use of HRGS-oxidized SPI as a food and dietary supplement.

Epigallocatechin-3-gallate alleviates paraquat-induced acute lung injury and inhibits upregulation of toll-like receptors.

AIMS: To evaluate the detoxifying effect of epigallocatechin-3-gallate (EGCG) on paraquat (PQ)-induced acute lung injury in mice, and to explore the action mechanisms. MAIN METHODS: Following administration of PQ, the mice received a low, a medium or a high dose of EGCG daily for three days. Histopathology of the lungs were examined by H&E staining. The levels of inflammatory cytokines, such as TNF-α, IL-1ß and IL-6, in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. Activation of NF-κB was assessed by Western blot and electrophoretic mobility gel shift assay. The expression of toll-like receptor (TLR)-2, 4, 9 and TLR adaptors (MyD88 and TRAF6) was detected by Western blot and immunohistochemical staining. The protective effect of EGCG against PQ toxicity was validated in vitro using A549 lung cancer cell line. KEY FINDINGS: Treatment with EGCG dose-dependently attenuated PQ-induced acute lung injury in mice by reducing alveolar edema, hemorrhage, inflammatory cell infiltration and production of inflammatory cytokines. EGCG inhibited the activation of NF-κB and the upregulation of TLR 2, 4 and 9 as well as their adaptors MyD88 and TRAF6 in the lungs following PQ challenge. In addition, EGCG significantly reduced PQ-induced cell death, cytokine production, activation of NF-κB, and upregulation of TLRs and adaptors in A549 cells. SIGNIFICANCE: Our data suggest that TLR-mediated activation of NF-κB in the non-immune pulmonary cells could be involved in PQ-induced acute lung injury, and it may serve as a target of EGCG against PQ pulmonary toxicity.

Glycyrrhizic Acid Attenuates Sepsis-Induced Acute Kidney Injury by Inhibiting NF-κB Signaling Pathway.

Glycyrrhizic acid (GA) is a major active ingredient in licorice. In our study, the effects of GA on acute kidney injury (AKI) in rats and its underlying molecular mechanisms were investigated. The sepsis model was produced by caecal ligation and puncture (CLP) in rats. The molecular and histological experiments were performed in the kidney tissues and serum samples of rats. According to the results obtained, GA alleviated sepsis-induced AKI by improving the pathological changes, decreasing the levels of blood urea nitrogen (BUN), creatinine (Cre), and increasing the survival rate of rats with AKI significantly. The production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, was markedly inhibited by GA. Moreover, treatment with GA inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and expression levels of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in kidney tissues. Furtherly, the apoptosis in kidney tissue induced by AKI was suppressed by GA. Finally, GA could inhibit the activation of NF-κB signaling pathway. Our study suggests that GA alleviates sepsis-induced AKI by inhibiting the NF-κB signaling pathway, which provides a strong evidence for a new approach for treating sepsis-induced AKI.

PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment.

PHY906 (KD018) is a four-herb Chinese Medicine Formula. It has been shown to potentially enhance the therapeutic indices of different class anticancer agents in vivo. Here, PHY906 is reported to enhance the anti-tumor activity of Sorafenib in nude mice bearing HepG2 xenografts. Among the four herbal ingredients of PHY906, Scutellaria baicalensis Georgi (S) and Paeonia lactiflora Pall (P) are required; however, S plays a more important role than P in increasing tumor apoptosis induced by Sorafenib with an increase of mouse(m)FasL and human(h)FasR expression. PHY906 may potentiate Sorafenib action by increasing hMCP1 expression and enhancing infiltration of macrophages into tumors with a higher M1/M2 (tumor rejection) signature expression pattern, as well as affect autophagy by increasing AMPKα-P and ULK1-S555-P of tumors. Depletion of macrophage could counteract PHY906 to potentiate the anti-tumor activity of Sorafenib. It was reported that tumor cells with higher levels of ERK1/2-P are more susceptible to Sorafenib, and the S component of PHY906 may increase ERK1/2-P via inhibition of ERK1/2 phosphatase in HepG2 tumors. PHY906 may potentiate the anti-hepatoma activity of Sorafenib by multiple mechanisms targeting on the inflammatory state of microenvironment of tumor tissue through two major ingredients (P and S) of PHY906.

Stress-related alcohol consumption in heavy drinkers correlates with expression of miR-10a, miR-21, and components of the TAR-RNA-binding protein-associated complex.

BACKGROUND: Alterations in stress-related gene expression may play a role in stress-related drinking and the risk of alcohol dependence. METHODS: Microarrays were used to measure changes in gene expression in peripheral blood in nonsmoking, social drinking subjects exposed to 3 types of personalized imagery: neutral, stressful (but not alcohol related), and alcohol-related cues. Gene expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750 cc of beer in a "taste test" following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene-expression levels were compared in 2 groups of nonsmoking subjects (n = 11/group): heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 standard drinks per week for women and at least 15 standard drinks per week for men), and moderate drinkers (MD; defined as up to 7 standard drinks per week for women and 14 standard drinks per week for men). Expression of microRNA-10a (miR-10a) and microRNA-21 (miR-21) was assessed by quantitative real-time polymerase chain reaction. RESULTS: After correction for multiple testing (false discovery rate < 0.05), 79 genes were identified that changed by >1.3-fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol-related imagery. Pathway analysis suggested that many of these genes, form part of the transactivation responsive (TAR)-RNA-binding protein (TRBP)-associated complex and are positively regulated by miR-10a and miR-21. Expression of both miR-10a and miR-21 was up-regulated following psychological stress in HD, but not MD subjects; however, the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR-10a, R(2)  = 0.59, miR-21 R(2)  = 0.57) with amount drunk in HD, but not MD subjects. CONCLUSIONS: Expression of miR-10a, miR-21, and several of their target genes is regulated by acute psychological stress and is correlated with stress-induced drinking in a laboratory setting. Alterations in miRNA expression may be one mechanism linking psychological stress with changes in gene expression and increased alcohol intake in binge/HD.