Advances in Flavonoid Research: Sources, Biological Activities, and Developmental Prospectives.

At present, the occurrence of a large number of infectious and non-communicable diseases poses a serious threat to human health as well as to drug development for the treatment of these diseases. One of the most significant challenges is finding new drug candidates that are therapeutically effective and have few or no side effects. In this respect, the active compounds in medicinal plants, especially flavonoids, are potentially useful compounds with a wide range of pharmacological activities. They are naturally present in nature and valuable in the treatment of many infectious and non-communicable diseases. Flavonoids are divided into fourteen categories and are mainly derived from plant extraction, chemical synthesis and structural modification, and biosynthesis. The structural modification of flavonoids is an important way to discover new drugs, but biosynthesis is currently considered the most promising research direction with the potential to revolutionize the new production pipeline in the synthesis of flavonoids. However, relevant problems such as metabolic pathway analyses and cell synthesis protocols for flavonoids need to be addressed on an urgent basis. In the present review, new research techniques for assessing the biological activities of flavonoids and the mechanisms of their biological activities are elucidated and their modes of interaction with other drugs are described. Moreover, novel drug delivery systems, such as nanoparticles, bioparticles, colloidals, etc., are gradually becoming new means of addressing the issues of poor hydrophilicity, lipophilicity, poor chemical stability, and low bioavailability of flavonoids. The present review summarizes the latest research progress on flavonoids, existing problems with their therapeutic efficacy, and how these issues can be solved with the research on flavonoids.

Effects of music therapy on degree of cooperation with anesthesia induction and preoperative anxiety in children with simple congenital heart disease: A protocol of systematic review and meta-analysis.

BACKGROUND: Anxiety is a common preoperative symptom in children with simple congenital heart disease (SCHD). Music therapy shows potential as a non-drug intervention. However, it is unclear how it impacts the level of cooperation during the induction of anesthesia and preoperative anxiety, as well as the factors that influence its effectiveness. Therefore, we will conduct a comprehensive review and meta-analysis to assess the impact of music therapy on the level of cooperation during anesthesia induction and preoperative anxiety in children with SCHD. METHODS: Electronic searches will be conducted through various databases including PubMed, Embase, Web of Science, Medline, and CNKI to gather randomized controlled trials (RCTs) examining the impact of music therapy on the level of cooperation during anesthesia induction and preoperative anxiety among children with SCHD. Two evaluators will independently review the literature, extract information, and assess the risk of bias in the included studies. Afterwards, data analysis will be conducted using Stata 14.0 software and Revman 5.4 software. The results will be based on random-effects models. The reliability and quality of evidence will be evaluated by using the Grading of Recommendations, Development, and Evaluation (GRADE) system. Heterogeneity will be examined by subgroup analysis stratified by age, gender ratio, type of surgery, drop-out rate, measurement tools, and country of origin. We will assess potential publication bias using funnel plot symmetrical and Begg's ang Egger's regression tests. DISCUSSION: Given the multiple advantages that may be associated with music therapy, this therapy may be a desirable alternative to existing therapies for preoperative cooperation and anxiety issues in children with SCHD. We hope that this systematic review will guide clinical decision-making for future efforts related to coping with preoperative fit and anxiety in children with SCHD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42023445313. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023445313.

Effects of traditional Chinese exercise on sleep quality: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of traditional Chinese exercise (TCE)-based interventions in the improvement of sleep quality is controversial. In this systematic review, we aimed to summarize randomized controlled trials (RCTs) that outline the effects of TCE on sleep quality. METHODS: Five databases (Web of Science, Embase, PubMed, Medline, and China National Knowledge Infrastructure) were searched for literature published before July 2022. RCTs examining TCE interventions were included. The treatment effects were estimated using a random-effect meta-analysis model with mean differences (MDs). There were 2 outcome scales for sleep quality; however, because they were extremely contrastive to be analyzed by standard MD, the scales were analyzed separately to ensure the accuracy of the results. This review was registered in the International Prospective Register of Systematic Reviews (identifier CRD42023421314). RESULTS: Twenty studies were included for analysis at last. The outcome was calculated using the Verran and Snyder-Halpern Sleep Scale (MD: 344.17, 95% confidence interval: 316.95 to 371.39, P < .00001) and Pittsburgh Sleep Quality Index to measure sleep quality (MD: -2.24, 95% confidence interval: -3.05 to -1.43, P < .00001), both showed improvement effect. In subgroup analysis, for patients with fibromyalgia, normal older adults, and non-Hodgkin lymphoma, chronic fatigue syndrome-like illness, knee osteoarthritis, nasopharyngeal carcinoma, pausimenia, insomnia, TCE could improve sleep quality. However, there was no significant improvement in stroke patients, breast cancer patients, normal college students, and episodic migraine patients. Tai Chi had greater effects in improving sleep quality than Qigong. In addition, the participants practice site, duration, and age did not influence the effects of TCE. CONCLUSION: TCE can improve sleep quality in specific populations in specific populations clinical applications. Tai chi should be considered first to improve sleep quality. However, further extensive trials and rigorous study designs should be conducted to strengthen the findings of this study. In addition, considering the large heterogeneity, the findings of our study should be interpreted cautiously.

[Multi-scale feature extraction and classification of motor imagery electroencephalography based on time series data enhancement].

The brain-computer interface (BCI) based on motor imagery electroencephalography (MI-EEG) enables direct information interaction between the human brain and external devices. In this paper, a multi-scale EEG feature extraction convolutional neural network model based on time series data enhancement is proposed for decoding MI-EEG signals. First, an EEG signals augmentation method was proposed that could increase the information content of training samples without changing the length of the time series, while retaining its original features completely. Then, multiple holistic and detailed features of the EEG data were adaptively extracted by multi-scale convolution module, and the features were fused and filtered by parallel residual module and channel attention. Finally, classification results were output by a fully connected network. The application experimental results on the BCI Competition IV 2a and 2b datasets showed that the proposed model achieved an average classification accuracy of 91.87% and 87.85% for the motor imagery task, respectively, which had high accuracy and strong robustness compared with existing baseline models. The proposed model does not require complex signals pre-processing operations and has the advantage of multi-scale feature extraction, which has high practical application value.

ß-asarone prolongs sleep via regulating the level of glutamate in the PVN.

People of all ages could suffer from sleep disorders, which are increasingly recognized as common manifestations of neurologic disease. Acorus tatarinowii is a herb that has been used in traditional medicine to promote sleep. ß-asarone, as the main component of volatile oil obtained from Acorus tatarinowii, may be the main contributor to the sleeping-promoting efficacy of Acorus tatarinowii. In the study, adult male C57BL/6 mice were administered ß-asarone at 12.5 mg/kg, 25 mg/kg, and 50 mg/kg. Behavioral experiments showed that ß-asarone at 25 mg/kg could significantly improve sleep duration. It was also observed that the proportion of NREM (Non-Rapid Eye Movement) sleep increased considerably after administration of ß-asarone. In the PVN (paraventricular nucleus of hypothalamus) region of the hypothalamus, it was observed that the glutamate content decreased after ß-asarone treatment. At the same time, the expression of VGLUT2 (vesicular glutamate transporters 2) decreased while the expression of GAD65 (glutamic acid decarboxylase 65) and GABARAP (GABA Type A Receptor-Associated Protein) increased in the hypothalamus, suggesting that ß-asarone may suppress arousal by reducing glutamate and promoting transformation of glutamate to the inhibitory neurotransmitter GABA (γ-aminobutyric acid). This study is the first to focus on the association between ß-asarone and sleep, shedding perspectives for pharmacological applications of ß-asarone and providing a new direction for future research.

Effect of pistachio shell as a carbon source to regulate C/N on simultaneous removal of nitrogen and phosphorus from wastewater.

Acid-pretreated pistachio shells were used as carbon sources to investigate the effects of carbon source dosage on simultaneous nitrogen and phosphorus removal under different carbon/nitrogen (C/N) ratios (7, 9, and 11). Results showed that C/N was positively correlated with mixed liquor suspended solids (MLSS) (R2 = 0.998, p < 0.01) and f value (R2 = 0.975, p < 0.05). Moreover, it was negatively correlated with the sludge volume index (SVI) (R2 =  - 0.959, p < 0.05). C/N was also significantly negatively related to chemical oxygen demand removal rate (R2 =  - 0.986, p < 0.05) and positively related to ammonia nitrogen (NH4+-N), total nitrogen (TN), and total phosphorus (TP) removal rate (p < 0.05), the correlation coefficients were 0.992, 0.990 and 0.994, respectively. In the reactor with C/N of 11, the MLSS concentration and f value were the highest, the SVI was the lowest, and the removal efficiencies of NH4+-N (85.49 % ± 1.96 %), TN (84.19 % ± 1.42 %) and TP (94.10 % ± 1.67 %) were the highest. Furthermore, the relative abundance of denitrifying bacteria was the highest in the reactor. The abundance of nitrifying bacteria and phosphorus-removal bacteria was also relatively high.

Zinc intake ameliorates intestinal morphology and oxidative stress of broiler chickens under heat stress.

Zinc (Zn), an essential trace element for poultry, plays a crucial role in promoting growth, improving feed conversion efficiency, enhancing antioxidant activity, and preventing disease. This study investigated the impact of different levels and sources of dietary Zn supplementation on the growth performance, intestinal morphology and antioxidant activity of broiler chickens under heat stress conditions. In this experiment, 1024 Xueshan chickens were divided into eight groups and subjected to heat stress conditions with different levels of Zn supplementation (30 mg/kg, 60 mg/kg, and 90 mg/kg) using organic or inorganic sources. Our findings indicated that dietary Zn supplementation significantly increased the feed-to-weight ratio of broilers during the experimental period under heat stress. Moreover, Zn supplementation positively increased the villus height and villus width in the jejunum and ileum at 74 and 88 days old, with the 60 and 90 mg/kg groups outperforming other groups, and organic Zn was more effective than inorganic Zn. Furthermore, Zn supplementation significantly increased serum antioxidant levels, with higher superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-px) activities, and organic Zn was more effective than inorganic Zn. This study concludes that Zn supplementation is beneficial in mitigating the detrimental impacts of heat stress on broilers. The findings suggest that employing Zn as a strategy can enhance productivity in the poultry industry by positively influencing intestinal morphology and bolstering antioxidant activity to counteract potential stress.

Berberine a traditional Chinese drug repurposing: Its actions in inflammation-associated ulcerative colitis and cancer therapy.

Berberine (BBR), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has a long history of treating dysentery in the clinic. Over the past two decades, the polytrophic, pharmacological, and biochemical properties of BBR have been intensively studied. The key functions of BBR, including anti-inflammation, antibacterial, antioxidant, anti-obesity, and even antitumor, have been discovered. However, the underlying mechanisms of BBR-mediated regulation still need to be explored. Given that BBR is also a natural nutrition supplement, the modulatory effects of BBR on nutritional immune responses have attracted more attention from investigators. In this mini-review, we summarized the latest achievements of BBR on inflammation, gut microbes, macrophage polarization, and immune responses associated with their possible tools in the pathogenesis and therapy of ulcerative colitis and cancer in recent 5 years. We also discuss the therapeutic efficacy and anti-inflammatory actions of BBR to benefit future clinical applications.

Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming.

BACKGROUND & AIMS: Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it. METHODS: A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPARα, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro. RESULTS: We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPARα-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPARα inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPARα and SREBP2 to the genomic DNA response element. We showed that NR RORγ functions as an essential mediator that facilitates the interaction of PPARα and SREBP2 to modulate the cholesterol biosynthesis genes expression. CONCLUSIONS: Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPARα-RORγ-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.

Secondary acidogenic fermentation of waste activated sludge via voltage supplementation: Insights from sludge structure and enzymes activity.

Microbial electrolysis cells were integrated with the anaerobic digestion at different fermentation stage (0th day and 30th day) to explore the bio-electrochemical enhancement of acidogenic fermentation from waste activated sludge. Results showed that significant increases in volatile fatty acid production can be achieved by electrically-assisted acidogenic fermentation (0th day to 12th day). In comparison, volatile fatty acid production during secondary acidogenic fermentation (30th day to 42nd day) via voltage supplementation was also investigated. The concentrations of soluble total organic carbon, soluble protein, soluble polysaccharide via voltage supplementation during the secondary acidogenic fermentation process were improved from 69.9, 50.3, and 18.8 mg/L to 260.6, 135.6, and 43.8 mg/L, respectively. Meanwhile, fractal dimension (Df) value was decreased via voltage supplementation along with the significantly improving of protease and α-glucosidase activities. These results suggest that the presence of voltage brought a secondary solubilization and hydrolysis of sludge via loosening sludge structure and promoting corresponding enzymes activities, thus improved the secondary acidogenic fermentation performance of sludge.

Co-option of PPARα in the regulation of lipogenesis and fatty acid oxidation in CLA-induced hepatic steatosis.

Nonalcoholic-fatty-liver-disease (NAFLD) is the result of imbalances in hepatic lipid partitioning and is linked to dietary factors. We demonstrate that conjugated linoleic acid (CLA) when given to mice as a dietary supplement, induced an enlarged liver, hepatic steatosis, and increased plasma levels of fatty acid (FA), alanine transaminase, and triglycerides. The progression of NAFLD and insulin resistance was reversed by GW6471 a small-molecule antagonist of peroxisome proliferator-activated receptor α (PPARα). Transcriptional profiling of livers revealed that the genes involved in FA oxidation and lipogenesis as two core gene programs controlled by PPARα in response to CLA and GW6471 including Acaca and Acads. Bioinformatic analysis of PPARα ChIP-seq data set and ChIP-qPCR showed that GW6471 blocks PPARα binding to Acaca and Acads and abolishes the PPARα-mediated local histone modifications of H3K27ac and H3K4me1 in CLA-treated hepatocytes. Thus, our findings reveal a dual role of PPARα in the regulation of lipid homeostasis and highlight its druggable nature in NAFLD.

Epigenetic and SP1-mediated regulation is involved in the repression of galactokinase 1 gene in the liver of neonatal piglets born to betaine-supplemented sows.

PURPOSE: In this study, we sought to investigate the effects of maternal betaine supplementation on the expression and regulation of GALK1 gene in the liver of neonatal piglets. METHODS: Sixteen sows of two groups were fed control or betaine-supplemented diets (3 g/kg), respectively, throughout the pregnancy. Newborn piglets were individually weighed immediately after birth, and one male piglet close to mean body weight from the same litter was selected and killed before suckling. Serum samples of newborn piglets were analyzed for biochemical indexes, hormone and amino acid levels. Liver samples were analyzed for GALK1 expression by real-time PCR and western blotting, while GALK1 regulational mechanism was analyzed by methylated DNA immunoprecipitation, chromatin immunoprecipitation and microRNAs expression. RESULTS: Betaine-exposed neonatal piglets had lower serum concentration of galactose, which was associated with significantly down-regulated hepatic GALK1 expression. The repression of GALK1 mRNA expression was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3 on its promoter. Binding sites of SP1, GR and STAT3 were predicted on GALK1 promoter, and decreased SP1 protein content and lower SP1 binding to GALK1 promoter were detected in the liver of betaine-exposed piglets. Furthermore, the expression of miRNA-149 targeting GALK1 was up-regulated in the liver of betaine-exposed piglets, along with elevated miRNAs-processing enzymes Dicer and Ago2. CONCLUSIONS: Our results suggest that maternal dietary betaine supplementation during gestation suppresses GALK1 expression in the liver of neonatal piglets, which involves complex gene regulation mechanisms including DNA methylation, histone modification, miRNAs expression and SP1-mediated transcriptional modulation.

Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification.

Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring.

Selenium modification of ß-lactoglobulin (ß-Lg) and its biological activity.

ß-Lg is a major whey protein in cow's milk. This study was aimed to find a new kind of organic selenium compound synthesized with ß-Lg and selenium dioxide as raw materials under the conditions of vacuum and low temperature. Fourier transformed infrared spectroscopy revealed that seleno-ß-lactoglobulin (Se-ß-Lg) displayed a strong band at 878cm(-1), belonging to SeO. Circular dichroism spectra results indicated that the conformation of Se-ß-Lg was transformed and α-helical, and unordered structures were increased by 9% and 11.2%, respectively, while ß-sheet and ß-turn were reduced by 14.2% and 6%, respectively. Electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry results showed that there were two protein bands (1-Seß-Lg and 2-Seß-Lg) in Se-ß-Lg, only one ß-Lg connected with selenate in 1-Seß-Lg, but two ß-Lgs, connected to each other, and with selenate, in 2-Seß-Lg. Morphological observation and hematoxylin and eosin staining indicated that Se-ß-lg could induce K562 cell apoptosis. These results indicated that Se-ß-Lg could be synthesized by selenium conjugating ß-Lg and it had antitumor activity.

Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms.

Methyl donors play critical roles in nutritional programming through epigenetic regulation of gene expression. Here we fed gestational sows with control or betaine-supplemented diets (3g/kg) throughout the pregnancy to explore the effects of maternal methyl-donor nutrient on neonatal expression of hepatic lipogenic genes. Betaine-exposed piglets demonstrated significantly lower liver triglyceride content associated with down-regulated hepatic expression of lipogenic genes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD) and sterol regulatory element-binding protein-1c. Moreover, s-adenosyl methionine to s-adenosyl homocysteine ratio was elevated in the liver of betaine-exposed piglets, which was accompanied by DNA hypermethylation on FAS and SCD gene promoters and more enriched repression histone mark H3K27me3 on SCD gene promoter. Furthermore, glucocorticoid receptor (GR) binding to SCD gene promoter was diminished along with reduced serum cortisol and liver GR protein content in betaine-exposed piglets. GR-mediated SCD gene regulation was confirmed in HepG2 cells in vitro. Dexamethasone (Dex) drastically increased the luciferase activity of porcine SCD promoter, while the deletion of GR response element on SCD promoter significantly attenuated Dex-mediated SCD transactivation. In addition, miR-let-7e, miR-1285 and miR-124a, which respectively target porcine SCD, ACC and GR, were significantly up-regulated in the liver of betaine-exposed piglets, being in accordance with decreased protein content of these three genes. Taken together, our results suggest that maternal dietary betaine supplementation during gestation attenuates hepatic lipogenesis in neonatal piglets via epigenetic and GR-mediated mechanisms.

Maternal gestational betaine supplementation-mediated suppression of hepatic cyclin D2 and presenilin1 gene in newborn piglets is associated with epigenetic regulation of the STAT3-dependent pathway.

Betaine, which donates methyl groups through methionine metabolism for DNA and protein methylation, is critical for epigenetic gene regulation, especially during fetal development. Here we fed gestational sows with control or betaine supplemented diets (3 g/kg) throughout the pregnancy to explore the effects of maternal betaine on hepatic cell proliferation in neonatal piglets. Neonatal piglets born to betaine-supplemented sows demonstrated a reduction of cell number and DNA content in the liver, which was associated with significantly down-regulated hepatic expression of cell cycle regulatory genes, cyclin D2 (CCND2) and presenilin1 (PSEN1). Moreover, STAT3 binding to the promoter of CCND2 and PSEN1 was also lower in betaine-exposed piglets, accompanied by strong reduction of STAT3 mRNA and protein expression, along with its phosphorylation at Tyr705 and Ser727 residues. Also, prenatal betaine exposure significantly attenuated upstream kinases of STAT3 signaling pathway (phospho-ERK1/2, phospho-SRC and phospho-JAK2) in the livers of neonates. Furthermore, the repressed STAT3 expression in the liver of betaine-exposed piglets was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3 on its promoter, together with significantly up-regulated expression of H3K27me3 and enhancer of zeste homolog 2 (EZH2) proteins, as well as miR-124a, which targets STAT3. Taken together, our results suggest that maternal dietary betaine supplementation during gestation inhibits hepatic cell proliferation in neonatal piglets, at least partly, through epigenetic regulation of hepatic CCND2 and PSEN1 genes via a STAT3-dependent pathway. These neonatal changes in cell cycle and proliferation regulation may lead to lower liver weight and hepatic DNA content at weaning.