Comprehensive consideration of multiple determinants from evidence to recommendations in guidelines for most traditional Chinese medicine was suboptimal: a systematic review.

BACKGROUND: The overall comprehensive consideration of the factors influencing the recommendations in the traditional Chinese medicine (TCM) guidelines remains poorly studied. This study systematically evaluate the factors influencing recommendations formation in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) clinical practice guidelines (CPGs) and TCM CPGs. METHODS: This was a methodological review in which we searched six databases and multiple related websites. The GRADE CPGs were identified as the guidelines developed by the GRADE Working Group or the two Co-Chairs. For the TCM CPGs, we randomly selected guidelines that were published by the TCM or integrative medicine academic societies from China mainland (published by the TCM or integrative medicine academic societies of China mainland). Two reviewers independently screened and extracted data. We included CPGs published in 2018-2022. We extracted information on the influencing factors of evidence to recommendation and conducted the analyses using descriptive statistics and calculated the proportion of relevant items by IBM SPSS Statistics and Microsoft Excel to compare the differences between the GRADE CPGs and the TCM CPGs. RESULTS: Forty-five GRADE CPGs (including 912 recommendations) and 88 TCM CPGs (including 2452 recommendations) were included. TCM recommendations mainly considered the four key determinants of desirable anticipated effects, undesirable anticipated effects, balance between desirable and undesirable effects, certainty of evidence, with less than 20% of other dimensions. And TCM CPGs presented more strong recommendations (for or against) and inappropriate discordant recommendations than GRADE CPGs. GRADE CPGs were more comprehensive considered about the factors affecting the recommendations, and considered more than 70% of all factors in the evidence to recommendation. CONCLUSIONS: The TCM CPGs lack a comprehensive consideration of multiple influencing determinants from evidence to recommendations. In the future, the correct application of the GRADE approaches should be emphasized.

An UHPLC-QTOF-MS-based strategy for systematic profiling of chemical constituents and associated in vivo metabolites of a famous traditional Chinese medicine formula, Yinchenhao decoction.

Yinchenhao decoction (YCHD), a famous traditional Chinese medicine formula, has been applied for relieving jaundice in China for more than 1800 years. However, the material basis for YCHD is still unclear, and the chemical composition and metabolism characteristic in vivo are undefined, making the potential effective constituents and mechanism of action unclear. Herein, an ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS)-based strategy was applied for the chemical profiling of YCHD, as well as their in vivo prototypes and global metabolites that defined the metabolome. Our results showed that a total of 139 chemicals were identified in YCHD, including 28 organic acids, 12 monoterpenoids, five diterpenes, three triterpenoids, 17 iridoids, 23 anthraquinones, 26 flavonoids, four coumarins and 21 other types. Moreover, 58 prototypes and 175 metabolites were found in rat biological samples after oral administration of YCHD; those distributed in plasma, liver, intestine and feces were suggested to be potentially effective substances. Oxidation, hydrogenation, decarboxylation and conjugations with methyl, sulfate and glucuronate were considered as the predominant metabolic pathways in vivo. In conclusion, this is a systemic study of chemical constituents and in vivo metabolome profiles of YCHD, contributing to the material basis understanding and further mechanism research.

Kaempferol attenuates carbon tetrachloride (CCl4)-induced hepatic fibrosis by promoting ASIC1a degradation and suppression of the ASIC1a-mediated ERS.

BACKGROUND: Kaempferol is a flavonoid derived from the herb, Kaempferia galanga L., in addition to exhibiting a wide range of pharmacological properties, kaempferol is also an anti-inflammatory, anti-lipid metabolizing, and anti-oxidative stress agent. The underlying molecular mechanisms of its effects on vascular endothelial growth factor (VEGF) secretion and activation of hepatic stellate cells (HSCs) are yet unknown. Activated HSCs induces VEGF release and extracellular matrix (ECM) accumulation which are important factors in hepatic fibrosis. PURPOSE: Our aim is to explore how kaempferol may affect hepatic fibrosis and the mechanisms behind its effects. METHODS: The in vivo model was Sprague-Dawley rats induced with carbon tetrachloride (CCl4). Histological staining was used to observe histological features of the liver. The levels of (alanine aminotransferase) ALT and (aspartate aminotransferase) AST were detected by the corresponding kits. Platelet-derived growth factor (PDGF) was used to stimulate the HSC-T6 rat hepatic stellate cells. The mechanisms underlying this process were investigated using a variety of molecular approaches, including immunofluorescence, RT-qPCR, and western blotting. Moreover, intracellular Ca2+ were observed by laser confocal microscope. RESULTS: It was found that kaempferol significantly reduced the expression of ASIC1a, VEGF, α-SMA and Collagen-I proteins in a model of CCl4-induced hepatic fibrosis in rats. In HSC-T6, kaempferol inhibits activation of HSCs by decreasing expression of ASIC1a, eIF2α, p-eIF2α and ATF-4. Laser confocal fluorescence showed that kaempferol inhibited Ca2+ influx and reduced Ca2+ concentration around the endoplasmic reticulum. Molecular docking and cellular thermal shift assay (CETSA) results further indicated that kaempferol interacted with ASIC1a. We found that kaempferol may promote the degradation of ASIC1a and inhibited ASIC1a- mediated upregulation of ERS. CONCLUSION: The data from our in vivo experiments demonstrate that kaempferol effectively attenuates hepatic fibrosis. In vitro studies we further propose a novel mechanism of kaempferol against hepatic fibrosis which can interact with ASIC1a and promote ASIC1a degradation while inhibiting the activation and VEGF release of HSCs by suppressing the ASIC1a-eIF2α-ATF-4 signaling pathway.

Identifications of metabolic differences between Hedysari Radix Praeparata Cum Melle and Astragali Radix Praeparata Cum Melle for spleen-qi deficiency rats: A comparative study.

Hedysari Radix Praeparata Cum Melle (HRPCM) and Astragali Radix Praeparata Cum Melle (ARPCM) are capable of improving spleen-qi deficiency (SQD) syndrome especially in the gastrointestinal dysfunction and decreased immunity in traditional Chinese medicine clinically. This study aims to compare and reveal the metabolic differences between HRPCM and ARPCM for SQD rats. Firstly, HRPCM (12.6 g/kg) and ARPCM (12.6 g/kg) were used to intervene SQD rats to further evaluate the effect. The results showed that HRPCM and ARPCM were able to improve the spleen pathology, increase the body weight, the rectal temperature, the spleen index, the thymus index, the levels of GAS and D-xylose in serum, and decrease the levels of IL-2, IL-6 and TNF-α in serum for SQD rats. Then, the studies of metabolic differences in serum and spleen were carried out using UPLC-Q-TOF-MS. The findings emphasized that HRPCM and ARPCM not only regulated metabolic profiling of serum and spleen in SQD rats, but also existed differences. HRPCM and ARPCM regulated metabolic pathways mainly including lipid metabolism, energy metabolism, amino acid metabolism, nucleotide metabolism, sugar metabolism and other types of metabolism for SQD rats. However, the metabolite profiles in SQD rats changed significantly, mainly involving abnormal glycine synthesis occurred in SQD rats. The expression trends of metabolites in HRPCM and ARPCM intervention for SQD rats were partly the same. Interestingly, there are similarities and differences in metabolic profiling between HRPCM and ARPCM for SQD rats. The differences were mainly in the synthesis of L-glutamine in amino acid metabolism.

Effect of Different Phosphates on Pyrolysis Temperature-Dependent Carbon Sequestration and Phosphorus Release Performance in Biochar.

Carbon sequestration is the primary function of biochar. Hence, it is necessary to design biochar with high carbon (C) retention and low C loss. In this study, three P compounds, including KH2PO4, Ca(H2PO4)2, and NH4H2PO4, were premixed with corn stalk (1:4, w/w), aiming to produce biochars (CSB+K, CSB+Ca, and CSB+N) with high C sequestration and slow release of P at three temperatures (300, 500, and 700 °C). The addition of all P sources obviously increased C retention, with the order of NH4H2PO4 (65.6-83.5%) > Ca(H2PO4)2 (60.4-78.2%) > KH2PO4 (50.1-76.1%), compared with the pristine biochar (47.8-73.6%). The addition of Ca(H2PO4)2 and KH2PO4 led to an increase in aromaticity and graphitization, as evidenced by H/C, FTIR, Raman and XPS analysis, whereas an opposite result occurred on CSB+N. Furthermore, all three phosphates reduced C loss of biochars with H2O2 oxidation, and CSB+Ca showed the best effect. Ca(H2PO4)2 and KH2PO4 pretreated biochars had higher resistance to K2Cr2O7 oxidation and thermal treatment. In contrast, the C loss of NH4H2PO4-added biochar at 500 and 700 °C with K2Cr2O7 oxidation was increased by 54% and 36%, respectively. During the pyrolysis process, Ca(H2PO4)2 was transformed into insoluble Ca2P2O7, leading to the lowest P release rate of CSB+Ca. This study indicates that co-pyrolysis of corn stalk and Ca(H2PO4)2 is optimal for increasing C retention, enhancing C stability and improving slow-release performance of P regardless of pyrolysis temperature.

Correlation of Serum FGF23 and Chronic Kidney Disease-Mineral and Bone Abnormality Markers With Cardiac Structure Changes in Maintenance Hemodialysis Patients.

Background: CKD-MBD is a mineral and bone metabolism syndrome caused by chronic kidney disease. FGF23 is an important factor regulating phosphorus and is the main influencer in the CKD-MBD process. In this study, we observed the correlation among serum FGF23 and calcium, phosphorus and parathyroid hormone, and the correlation between FGF23 levels and cardiac structural changes in MHD patients. Methods: We examined serum FGF23 concentrations in 107 cases of MHD patients using the ELISA method, recorded demographic information and biochemical data, and analyzed the correlation between serum FGF23 levels and blood calcium and blood phosphorus and PTH levels. All patients were evaluated by cardiac color ultrasound, and we finally analyzed the association between the FGF23 level and cardiac structural changes. Results: In 107 cases of MHD patients, serum FGF23 levels were linearly associated with serum calcium (r = 0.27 P < 0.01) and parathyroid hormone levels (r = 0.25, P < 0.05). FGF 23 was negatively correlated with age (r = -0.44, P < 0.01).Serum FGF23 levels were correlated with right atrial hypertrophy in HD patients (P < 0.05). No correlation was found among FGF23, left ventricular hypertrophy/enlargement, and valve calcification stenosis (P > 0.05). Conclusion: Serum FGF23 showed a positive correlation among blood calcium levels and PTH levels in hemodialysis patients, and FGF23 levels can affect the incidence of right atrial hypertrophy in MHD patients.

Naringin Prevents Cognitive Dysfunction in Aging Rats by Inhibiting Toll-Like Receptor 4 (TLR4)/NF-κB Pathway and Endoplasmic Reticulum Stress.

Objective: Naringin is a flavonoid derived from Chinese herbs. According to earlier studies, naringin may have the potential to alleviate aging-induced cognitive dysfunction. Therefore, this study attempted to explore the protective effect and underlying mechanism of naringin on aging rats with cognitive dysfunction. Methods: After the construction of a model of aging rats with cognitive dysfunction through subcutaneous injection of D-galactose (D-gal; 150 mg/kg), intragastric administration of naringin (100 mg/kg) was performed for treatment. Behavioral tests, including Morris water maze test (MWM), novel object recognition test (NORT), and fear conditioning test, were used to measure the cognitive function; ELISA and biochemical tests were used to determine the levels of interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the hippocampus of rats in each group, respectively; H&E staining was used to observe the pathological changes in the hippocampus; Western blot was used to examine the expression of toll-like receptor 4 (TLR4)/NF-κB pathway-related proteins and endoplasmic reticulum (ER) stress-related proteins in the hippocampus. Results: The model was successfully constructed by subcutaneous injection of D-gal (150 mg/kg). The behavioral test results showed that naringin could ameliorate the cognitive dysfunction and alleviate the histopathological damage of hippocampus. Moreover, naringin significantly improve the inflammatory response (the levels of IL-1ß, IL-6, and MCP-1 were decreased), oxidative stress response (MDA level was increased while GSH-Px activity was decreased), and ER stress (the expression of glucose-regulated protein 78 (GRP78), C/-EBP homologous protein (CHOP), and transcription factor 6 (ATF6) expression was downregulated), and increased the levels of neurotrophic factors BDNF and NGF in D-gal rats. Besides, further mechanistic studies revealed the downregulation of naringin on TLR4/NF-κB pathway activity. Conclusion: Naringin may inhibit inflammatory response, oxidative stress, and ER stress by downregulating TLR4/NF-κB pathway activity, thereby improving cognitive dysfunction and alleviating histopathological damage of hippocampus in aging rats. Briefly, naringin is an effective drug for the treatment of cognitive dysfunction.

The integrated exposure assessment and potential risks of five organophosphorus pesticides in vegetables in Zhejiang, China (2018-2020).

This research surveyed the concentrations of five organophosphorus pesticides (OPs) in vegetables with the purpose of assessing the potential integrated health risks of residents. From 2018 to 2020, 870 samples of eight kinds of vegetables from Zhejiang Province were collected. Gas chromatography coupled with a flame photometric detector (GC-FPD) analyzed the five OPs. OPs were most frequently detected in celery (18.9% of samples), cowpeas (18.3% of samples), and leeks (16.9% of samples) compared to other vegetables. Among the 11 cities in Zhejiang, the cities with high detection rates of OPs were Ningbo and Hangzhou. The integrated concentrations of OPs in different cities ranged from 71.9 to 376 µg/kg. The cumulative risk assessment revealed that the estimated daily intake (EDI) of leek in Wenzhou was the highest, which was 0.0077 (mg/kg bw) and 0.0059 (mg/kg bw) in adults and children respectively. The health risks of residents who consume these vegetables were within a safe range. The data provided demonstrate the distribution and potential health hazards of OPs in commonly consumed vegetables.

Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups.

Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The antiliver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its "pharmacodynamic group". By searching the research on the antihepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, ß-elemene, can act on multi-target and multi-channel to play an antihepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an antihepatoma role. Network pharmacological analysis showed that the core targets of the "pharmacodynamic group" for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and "pharmacodynamic group", it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and "pharmacodynamic group" in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and "pharmacodynamic group".

[Medication law and mechanism of traditional Chinese medicine in prevention and treatment of epidemic diseases: based on traditional Chinese medicine theory of cold pestilence].

Epidemic diseases have caused huge harm to the society. Traditional Chinese medicine(TCM) has made great contributions to the prevention and treatment of them. It is of great reference value for fighting diseases and developing drugs to explore the medication law and mechanism of TCM under TCM theory. In this study, the relationship between the TCM theory of cold pestilence and modern epidemic diseases was investigated. Particularly, the the relationship of coronavirus disease 2019(COVID-19), severe acute respiratory syndrome(SARS), and influenza A(H1 N1) with the cold pestilence was identified and analyzed. The roles of TCM theory of cold pestilence in preventing and treating modern epidemic diseases were discussed. Then, through data mining and textual research, prescriptions for the treatment of cold pestilence were collected from major databases and relevant ancient books, and their medication laws were examined through analysis of high-frequency medicinals and medicinal pairs, association rules analysis, and cluster analysis. For example, the prescriptions with high confidence levels were identified: "Glycyrrhizae Radix et Rhizoma-Bupleuri Radix-Paeoniae Radix Alba" "Glycyrrhizae Radix et Rhizoma-Pinelliae Rhizoma-Bupleuri Radix", and TCM treatment methods with them were analyzed by clustering analysis to yield the medicinal combinations: "Zingiberis Rhizoma-Aconiti Lateralis Radix Praeparata-Ginseng Radix et Rhizoma" "Poria-Atractylodis Macrocephalae Rhizoma" "Cinnamomi Ramulus-Asari Radix et Rhizoma" "Citri Reticulatae Pericarpium-Perillae Folium" "Pinelliae Rhizoma-Magnoliae Officinalis Cortex-Atractylodis Rhizoma" "Paeoniae Radix Alba-Angelicae Sinensis Radix-Glycyrrhizae Radix et Rhizoma-Bupleuri Radix-Scutellariae Radix-Rhizoma Zingiberis Recens" "Ephedrae Herba-Armeniacae Semen Amarum-Gypsum Fibrosum" "Chuanxiong Rhizoma-Notopterygii Rhizoma et Radix-Angelicae Dahuricae Radix-Platycodonis Radix-Saposhnikoviae Radix". Then, according to the medication law for cold pestilence, the antiviral active components of medium-frequency and high-frequency medicinals were retrieved. It was found that these components exerted the antiviral effect by inhibiting virus replication, regulating virus proteins and antiviral signals, and suppressing protease activity. Based on network pharmacology, the mechanisms of the medicinals against severe acute respiratory syndrome coronavirus(SARS-CoV), 2019 novel coronavirus(2019-nCoV), and H1 N1 virus were explored. It was determined that the key targets were tumor necrosis factor(TNF), endothelial growth factor A(VEGFA), serum creatinine(SRC), epidermal growth factor receptor(EGFR), matrix metalloproteinase 9(MMP9), mitogen-activated protein kinase 14(MAPK14), and prostaglandin-endoperoxide synthase 2(PTGS2), which were involved the mitogen-activated protein kinase(MAPK) pathway, advanced glycation end-products(AGE)-receptor for AGE(RAGE) pathway, COVID-19 pathway, and mTOR pathway. This paper elucidated the medication law and mechanism of TCM for the prevention and treatment of epidemic diseases under the guidance of TCM theory of cold pestilence, in order to build a bridge between the theory and modern epidemic diseases and provide reference TCM methods for the prevention and treatment of modern epidemic diseases and ideas for the application of data mining to TCM treatment of modern diseases.

Partial Nitrification and Enhanced Biological Phosphorus Removal in a Sequencing Batch Reactor Treating High-Strength Wastewater.

Complex and high levels of various pollutants in high-strength wastewaters hinder efficient and stable biological nutrient removal. In this study, the changes in pollutant removal performance and microbial community structure in a laboratory-scale anaerobic/aerobic sequencing batch reactor (SBR) treating simulated pre-fermented high-strength wastewater were investigated under different influent loading conditions. The results showed that when the influent chemical oxygen demand (COD), total nitrogen (TN), and orthophosphate (PO43--P) concentrations in the SBR increased to 983, 56, and 20 mg/L, respectively, the COD removal efficiency was maintained above 85%, the TN removal efficiency was 64.5%, and the PO43--P removal efficiency increased from 78.3% to 97.5%. Partial nitrification with simultaneous accumulation of ammonia (NH4+-N) and nitrite (NO2--N) was observed, which may be related to the effect of high influent load on ammonia- and nitrite-oxidising bacteria. The biological phosphorus removal activity was higher when propionate was used as the carbon source instead of acetate. The relative abundance of glycogen accumulating organisms (GAOs) increased significantly with the increase in organic load, while Tetrasphaera was the consistently dominant polyphosphate accumulating organism (PAO) in the reactor. Under high organic loading conditions, there was no significant PAO-GAO competition in the reactor, thus the phosphorus removal performance was not affected.

[Research progress of Curcuma kwangsiensis root tubers and analysis of liver protection and anti-tumor mechanisms based on Q-markers].

Curcuma kwangsiensis root tuber is a widely used genuine medicinal material in Guangxi, with the main active components of terpenoids and curcumins. It has the effects of promoting blood circulation to relieve pain, moving Qi to relieve depression, clearing heart and cooling blood, promoting gallbladder function and anti-icterus. Modern research has proved its functions in liver protection, anti-tumor, anti-oxidation, blood lipid reduction and immunosuppression. Considering the research progress of C. kwangsiensis root tubers and the core concept of quality marker(Q-marker), we predicted the Q-markers of C. kwangsiensis root tubers from plant phylogeny, chemical component specificity, traditional pharmacodynamic properties, new pharmacodynamic uses, chemical component measurability, processing methods, compatibility, and components migrating to blood. Curcumin, curcumol, curcumadiol, curcumenol, curdione, germacrone, and ß-elemene may be the possible Q-markers. Based on the predicted Q-markers, the mechanisms of the liver-protecting and anti-tumor activities of C. kwangsiensis root tubers were analyzed. AKT1, IL6, EGFR, and STAT3 were identified as the key targets, and neuroactive ligand-receptor interaction signaling pathway, nitrogen metabolism pathway, cancer pathway, and hepatitis B pathway were the major involved pathways. This review provides a basis for the quality evaluation and product development of C. kwangsiensis root tubers and gives insights into the research on Chinese medicinal materials.

Efficacy and Safety of Chinese Herbal Medicine Compared With Losartan for Mild Essential Hypertension: A Randomized, Multicenter, Double-Blind, Noninferiority Trial.

BACKGROUND: Hypertension is one of the most challenging public health problems worldwide. Previous studies suggested that the Songling Xuemaikang capsule (SXC)-a Chinese herbal formula-was effective for essential hypertension. However, the efficacy of SXC monotherapy for hypertension remains unclear. We aimed to compare the blood pressure (BP)-lowering efficacy and safety of SXC versus losartan in patients with essential hypertension. METHODS: In this multicenter, randomized, double-blind, noninferiority trial in China, patients 18 to 65 years of age with mild essential hypertension were randomly allocated to receive either SXC or losartan for 8 weeks. The primary outcome was the change in sitting diastolic BP from baseline to 8 weeks, with a predefined noninferiority margin of -2.5 mm Hg. RESULTS: Of the 755 patients who entered a 2-week run-in period, 628 patients (327 women and 301 men; mean [SD] age, 52.6 [9.2] years) were randomly assigned to the SXC (n=314) or losartan (n=314) group. The primary analysis based on the intention-to-treat principle showed that the change in diastolic BP from baseline to 8 weeks was similar between the SXC and losartan groups (-7.9 [8.0] versus -8.1 [7.9]). The lower boundary of 95% CI (mean difference, -0.24 [95% CI, -1.51 to 1.03]) was above the margin of -2.5 mm Hg, showing noninferiority. Results were consistent with per-protocol analysis. SXC produced greater improvements in total hypertension symptom score (-5.7 [4.2] versus -5.0 [4.0]; P=0.020) and total cholesterol (-0.1 [1.0] versus 0.1 [1.2]; P=0.025). There were no differences between groups in the other BP and patient-reported outcomes. Incidence and severity of adverse events were similar between groups. CONCLUSIONS: SXC was well tolerated and demonstrated noninferior to losartan in BP lowering in patients with mild hypertension. SXC might be an alternative for mild hypertension, particularly for patients with a preference for natural medicine. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR-IPR-16008108.

Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

BACKGROUND: The nuclear receptor Rev-erbα/ß, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. METHODS: We generated mouse lines with cardiac-specific Rev-erbα/ß knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. RESULTS: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/ß in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. CONCLUSIONS: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.

Abnormal methylation caused by folic acid deficiency in neural tube defects.

Neural tube closure disorders, including anencephaly, spina bifida, and encephalocele, cause neural tube defects (NTDs). This congenital disability remained not only a major contributor to the prevalence of stillbirths and neonatal deaths but also a significant cause of lifelong physical disability in surviving infants. NTDs are complex diseases caused by multiple etiologies, levels, and mechanisms. Currently, the pathogenesis of NTDs is considered to be associated with both genetic and environmental factors. Here, we aimed to review the research progress on the etiology and mechanism of NTDs induced by methylation modification caused by folic acid deficiency. Folic acid supplementation in the diet is reported to be beneficial in preventing NTDs. Methylation modification is one of the most important epigenetic modifications crucial for brain neurodevelopment. Disturbances in folic acid metabolism and decreased S-adenosylmethionine levels lead to reduced methyl donors and methylation modification disorders. In this review, we summarized the relationship between NTDs, folic acid metabolism, and related methylation of DNA, imprinted genes, cytoskeletal protein, histone, RNA, and non-coding RNA, so as to clarify the role of folic acid and methylation in NTDs and to better understand the various pathogenesis mechanisms of NTDs and the effective prevention.

Evaluation of the acute toxic effects of crude oil on intertidal mudskipper (Boleophthalmus pectinirostris) based on antioxidant enzyme activity and the integrated biomarker response.

With the development of marine oil industry, oil spill accidents will inevitably occur, further polluting the intertidal zone and causing biological poisoning. The muddy intertidal zone and Boleophthalmus pectinirostris were selected as the research objects to conduct indoor acute exposure experiments within 48 h of crude oil pollution. Statistical analysis was used to reveal the activity changes of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) in the gills and liver of mudskipper. Then, integrated biomarker response (IBR) indicators were established to comprehensively evaluate the biological toxicity. The results showed that the activities of SOD, CAT and GST in livers were higher than those in gills, and the maximum induction multipliers of SOD, CAT and GPx in livers appeared earlier than those in gills. Both SOD and GPx activities were induced at low pollutant concentrations and inhibited at high pollutant concentrations. For the dose-effect, the change trends of CAT and SOD were roughly inversed. There was substrate competition between GPx and CAT, with opposite trends over time. The activating mechanism of GST was similar to that of GPx, and the activation time was earlier than that of GPx. In terms of dose-effect trends, the IBR showed that the antioxidant enzymes activities in biological tissues were induced by low and inhibited by high pollutant concentrations. Overall, SOD and GPx in gills and CAT and GST in livers of the mudskippers were suitable as representative markers to comprehensively analyze and evaluate the biotoxicity effects of oil pollution in the intertidal zone. The star plots and IBR values obtained after data standardization were consistent with the enzyme activity differences, which can be used as valid supplementary indexes for biotoxicity evaluation. These research findings provide theoretical support for early indicators of biological toxicity after crude oil pollution in intertidal zones.

2D Materials Enabled Next-Generation Integrated Optoelectronics: from Fabrication to Applications.

2D materials, such as graphene, black phosphorous and transition metal dichalcogenides, have gained persistent attention in the past few years thanks to their unique properties for optoelectronics. More importantly, introducing 2D materials into silicon photonic devices will greatly promote the performance of optoelectronic devices, including improvement of response speed, reduction of energy consumption, and simplification of fabrication process. Moreover, 2D materials meet the requirements of complementary metal-oxide-semiconductor compatible silicon photonic manufacturing. A comprehensive overview and evaluation of state-of-the-art 2D photonic integrated devices for telecommunication applications is provided, including light sources, optical modulators, and photodetectors. Optimized by unique structures such as photonic crystal waveguide, slot waveguide, and microring resonator, these 2D material-based photonic devices can be further improved in light-matter interactions, providing a powerful design for silicon photonic integrated circuits.

Vitamin K2 Alleviates Insulin Resistance in Skeletal Muscle by Improving Mitochondrial Function Via SIRT1 Signaling.

Aims: High-fat diet (HFD)-induced insulin resistance (IR) impairs skeletal muscle mitochondrial biogenesis and functions, adversely affecting human health and lifespan. Vitamin K2 (VK2) has a beneficial role in improving insulin sensitivity and glucose metabolism. However, the underlying molecular mechanisms of VK2 on insulin sensitivity have not been well established. We investigated VK2's modulation of mitochondrial function to protect against IR in mice and cell models. Results: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and palmitate acid-exposed cells. We revealed for the first time that HFD-caused mitochondrial dysfunction could be reversed by VK2 treatment. VK2 enhanced the mitochondrial function by improving mitochondrial respiratory capacity, increasing mitochondrial biogenesis and the enzymatic activities of mitochondrial complexes through SIRT1 signaling. The benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA but not in C2C12 transfected with AMPK siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving mitochondrial function via SIRT1 signaling. Thus, SIRT1 is required for VK2 improvement in skeletal muscle. Further, the beneficial effects of both VK2 and geranylgeraniol contribute to inhibited IR in skeletal muscle via SIRT1. Innovation and Conclusion: These studies demonstrated a previously undiscovered mechanism by which VK2 alleviates IR in skeletal muscle by improving mitochondrial function via SIRT1. Naturally occurring VK2 prevents IR by improving mitochondrial function through SIRT1 signaling. These results could provide a foundation to identify new VK2-based preventive and therapeutic strategies for IR.

Material Basis of the Difference between Hedysari Radix and Honey-Processed Hedysari Radix in Buzhong Yiqi.

OBJECTIVE: To compare the changes of chemical components of Hedysari Radix (HR) before and after honey-processing, and to explore the material basis of the difference between HR and honey-processed Hedysari Radix (HPHR) in Buzhong Yiqi. METHODS: Different compounds in aqueous extracts of HR and HPHR were analysed by UPLC-MS. A rat model of spleen qi deficiency was established. The rats were treated with different doses of water extracts of HR or HPHR, and pathological differences in spleen tissue, serum levels of D-xylose, gastrin (GAS) and amylase (AMS) interleukin-2 (IL)-2 and tumour necrosis factor-α (TNF-α), as well as spleen and thymus indices, were used as indicators. Differences in the efficacy of HR and HPHR in Buzhong Yiqi were studied. RESULTS: The research showed that compared with the blank group, the spleen tissue of rats in the model group showed spleen tissue damage, which mainly manifested as unclear boundaries between red pulp and white pulp, irregular spleen morphology and irregular arrangement, and the structure of white pulp destruction, less lymphocytes, the number of germinal centers decreased or atrophied. Compared with the model group, the middle and high dose groups of HR and HPHR had protective effects on spleen tissue of spleen-qi deficiency rats, and HPHR had a stronger effect; compared with those in the model group, rats in each treatment group showed remarkably higher serum D-xylose, GAS and AMS levels and thymus and spleen indices, and remarkably lower serum IL-2 and TNF-α levels, among which HPHR group showed better regulation effect than HR group. A total of 16 differential compounds were found in the aqueous extracts of HR and HPHR, of which 10 compounds in HPHR were up regulated, while 6 compounds were down regulated compare to HR. CONCLUSION: The results indicated that both HR and HPHR can improve spleen qi deficiency syndrome of rats, the pharmacodynamic effect of the latter was better than the former. Differences in components of HR and HPHR potentially leading to variations in efficacy.

Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder.

The prevalence of autism spectrum disorders (ASD) is increasing, but its etiology remains elusive and hence an effective treatment is not available. Previous research conducted on animal models suggests that microbiota-gut-brain axis may contribute to ASD pathology and more human research is needed. This study was divided into two stages,.At the discovery stage, we compared the differences in gut microbiota profiles (using 16S rRNA sequencing), fecal SCFAs (using GC-MS) and plasma neurotransmitters (using UHPLC-MS/MS) of 26 children with ASD and 24 normal children. All 26 children with ASD participated in the intervention stage, and we measured the gut microbiota profiles, SCFAs and neurotransmitters before and after probiotics + FOS (n = 16) or placebo supplementation (n = 10). We found that gut microbiota was in a state of dysbiosis and significantly lower levels of Bifidobacteriales and Bifidobacterium longum were observed at the discovery stage in children with ASD. An increase in beneficial bacteria (Bifidobacteriales and B. longum) and suppression of suspected pathogenic bacteria (Clostridium) emerged after probiotics + FOS intervention, with significant reduction in the severity of autism and gastrointestinal symptoms. Compared to children in the control group, significantly lower levels of acetic acid, propionic acid and butyric acid were found, and a hyperserotonergic state (increased serotonin) and dopamine metabolism disorder (decreased homovanillic acid) were observed in children with ASD. Interestingly, the above SCFAs in children with autism significantly elevated after probiotics + FOS intervention and approached those in the control group. In addition, our data demonstrated that decreased serotonin and increased homovanillic acid emerged after probiotics + FOS intervention. However, the above-mentioned changes did not appear in the placebo group for ASD children. Probiotics + FOS intervention can modulate gut microbiota, SCFAs and serotonin in association with improved ASD symptoms, including a hyper-serotonergic state and dopamine metabolism disorder.