L-arginine metabolism inhibits arthritis and inflammatory bone loss.

OBJECTIVES: To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss. METHODS: L-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by µCT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. RESULTS: L-arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. CONCLUSION: Our study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.

Chemical index components and quality control of Traditional Chinese Medicine: "Never change a winning team"? -A case study of volatile oil from Bupleuri radix.

Chemical index components, especially those defined as quality control (QC) markers through spectrum-effect relationship approach, are commonly suggested and adopted as indicator for quality control of Traditional Chinese Medicines (TCMs). However, are chemical index components and quality control of TCMs "never change a winning team"? In this study, under the ponderation of the applicability of QC markers strategy, spectrum-effect relationship and OPLS-DA between GC×GC-MS fingerprint and inhibitory effect on the expression of extracellular secretory TNF-α of volatile oil from Bupleuri radix (BVO) was studied with the purpose of discovery of QC markers and establish a bioactive compounds-based QC method. 290 compounds of BVO were identified by GC×GC-MS. Besides, BVO had significant inhibitory effects on the expression of extracellular secretory TNF-α in a dose-dependent manner. The potency of different batches of BVOs could be distinguished with this bioassay-based method, which has been validated in terms of intermediate precision, repeatability, linearity, range and credibility tests. The QC markers of BVO were investigated by Spearman's correlation test and OPLS-DA. It is regrettable that there were no ideal QC markers of BVO could be found. In conclusion, quality control method relayed on chemical QC markers is not feasible for TCMs with complex composition but lack of ingredients that dominate in content, just like BVO. Alternatively, a bioassay-based method established in our study is suitable for quality control of BVO.

Rapid recognition and targeted isolation of potential anti-breast cancer xanthones in Hypericum bellum Li by "seed" mass spectra-based molecular networking and in silico MS/MS fragmentation.

INSTRUCTION: Hypericum bellum Li is rich in xanthones with various bioactivities, especially in anti-breast cancer. While the scarcity of mass spectral data of xanthones in Global Natural Products Social Molecular Networking (GNPS) libraries have challenged the rapid recognition of xanthones with similar structures. OBJECTIVE: This study is aimed to enhance the molecular networking (MN)-based dereplication and visualisation ability of potential anti-breast cancer xanthones from H. bellum to overcome the scarcity of xanthones mass spectral data in GNPS libraries. Separating and purifying the MN-screening bioactive xanthones to verify the practicality and accuracy of this rapid recognition strategy. METHODOLOGY: A combined strategy of "seed" mass spectra-based MN, in silico annotation tools, substructure identification tools, reverse molecular docking, ADMET screening, molecular dynamics (MDs) simulation experiments, and an MN-oriented separation procedure was first introduced to facilitate the rapid recognition and targeted isolation of potential anti-breast cancer xanthones in H. bellum. RESULTS: A total of 41 xanthones could only be tentatively identified. Among them, eight xanthones were screened to have potential anti-breast cancer activities, and six xanthones that were initially reported in H. bellum were obtained and verified to have good binding abilities with their paired targets. CONCLUSION: This is a successful case study that validated the application of "seed" mass spectral data could overcome the drawbacks of GNPS libraries with limited mass spectra and enhance the accuracy and visualisation of natural products (NPs) dereplication, and this rapid recognition and targeted isolation strategy can be also applicable for other types of NPs.

Effects of plant growth regulators on the contents of rutin, hyperoside and quercetin in Hypericum attenuatum Choisy.

To explore the accumulation of rutin, hyperoside and quercetin in Hypericum attenuatum Choisy under treatment with different plant growth regulators, 100 mg/L, 200 mg/L and 300 mg/L cycocel, 100 mg/L, 200 mg/L and 300 mg/L mepiquat chloride and 1 mg/L, 2 mg/L and 3 mg/L naphthalene acetic acid were foliage sprayed on Hypericum attenuatum Choisy plants at the early growth stage. We sampled and determined the important flavonoid contents at the flowering stage. The results showed that the three plant growth regulators had different effects on the accumulation of rutin, hyperoside and quercetin in the leaves, stems and flowers of Hypericum attenuatum Choisy at the flowering stage. After spraying 1 mg/L naphthalene acetic acid at the early growth stage, the rutin contents in the leaves, stems and flowers increased by approximately 60.33%, 223.85% and 192.02%, respectively (P < 0.05). Spraying 100 mg/L mepiquat chloride increased the hyperoside contents in the leaves and flowers by approximately 7.77% and 12.87%, respectively (P < 0.05). Spraying 2 mg/L naphthalene acetic acid significantly increased the quercetin contents in the flowers and leaves by approximately 95.62% and 47.85%, respectively (P < 0.05). Therefore, at the early growth stage, spraying 1 mg/L naphthalene acetic acid significantly increased rutin content, spraying 100 mg/L mepiquat chloride significantly increased hyperoside content, and spraying 2 mg/L naphthalene acetic acid significantly increased quercetin content in Hypericum attenuatum Choisy. In conclusion, the accumulation of flavonoids in Hypericum attenuatum Choisy was regulated by plant growth regulators.

Fermented Bamboo Fiber Improves Productive Performance by Regulating Gut Microbiota and Inhibiting Chronic Inflammation of Sows and Piglets during Late Gestation and Lactation.

Sows exhibit metabolic syndrome and significant changes in intestinal microbiota during late gestation and lactation, affecting sow performance and piglet health. Dietary fiber (DF) is widely applied to improve sow performance by modulating gut microbiota and their by-products. Here, 60 sows were randomly allocated to groups, including CON (8% wheat bran), FBF-1 (1% fermented bamboo fiber), FBF-2 (2.5% fermented bamboo fiber), and FBF-3 (4% fermented bamboo fiber) from day 80 of gestation (G80d) to the end of lactation (L21d). Compared with CON, the FBF-3 diet decreased lactation backfat loss, increased average daily feed intake (ADFI) during lactation, and the weight gain of piglets, while supplementation of FBF increased fecal water content and reduced the rate of constipation in sows. Further, the yield and quality of milk of sows in FBF groups were improved. The FBF-3 diet significantly reduced markers of intestinal permeability (diamine oxidase and endotoxin) and systemic inflammation (interleukin-6 [IL-6] and tumor necrosis factor alpha) in sow serum during lactation, while it increased the anti-inflammatory marker (IL-10). Similarly, the piglets in the FBF-2 and FBF-3 groups had lower levels of IL-6 and higher levels of IgG, IgM, and insulin-like growth factor in serum. In addition, sows fed the 4% FBF diet had higher levels of acetate, propionate, butyrate, and total short-chain fatty acids (SCFAs) in feces than CON, and total SCFAs were promoted in piglets from the FBF-3 group. Spearman correlation analysis showed that immunity, inflammation, and intestinal microbiota are closely related to sow performance, which can affect piglet growth. The potential mechanism could be that FBF promoted the enrichment of beneficial genera such as Lachnospira, Lachnospiracea_XPB1014_Group, and Roseburia and the production of SCFAs in the sow's intestine, and reduced the relative abundance of harmful bacteria such as Fusobacterium, Sutterellaceae, and Sutterella. Meanwhile, the intake of FBF by sows affected the gut microbial composition of their offspring piglets, significantly increasing the relative abundance of beneficial bacteria Alistipes and Lachnoclostridium and decreasing the relative abundance of pathogenic bacteria Trueperella among colonic microorganisms. IMPORTANCE Dietary fiber is widely applied in the nutrition of sows due to its potential value in improving performance and intestinal health. Fermented bamboo fiber, rich in dietary fiber, has not been fully evaluated to be used in sow diets. Sows mobilize body reserves during gestation and lactation due to nutrients being prioritized for lactation purposes while feeding piglets, which generally leads to metabolism and immunity undergoing drastic changes. The main manifestations are increased inflammation and intestinal permeability and disturbed intestinal flora, which ultimately reduces the ADFI and milk quality, thus affecting the growth of piglets. The study described here is the first attempt to provide FBF for sows in late gestation and lactation can reverse this process. The 4% FBF was initially explored to have the most significantly beneficial effect. It provides a potentially effective method for dietary modification to control the gut microbiota and its metabolites to improve sow and piglet health. Moreover, the sow-piglet model offers a reference for investigating the impact of dietary fiber on the intestinal health of human mothers and infants.

Effects of hepatitis B virus infection and strategies for preventing mother-to-child transmission on maternal and fetal T-cell immunity.

One of the most common routes of chronic hepatitis B virus (HBV) infection is mother-to-child transmission (MTCT). Approximately 6.4 million children under the age of five have chronic HBV infections worldwide. HBV DNA high level, HBeAg positivity, placental barrier failure, and immaturity of the fetal immune are the possible causes of chronic HBV infection. The passive-active immune program for children, which consists of the hepatitis B vaccine and hepatitis B immunoglobulin, and antiviral therapy for pregnant women who have a high HBV DNA load (greater than 2 × 105 IU/ml), are currently two of the most important ways to prevent the transmission of HBV from mother to child. Unfortunately, some infants still have chronic HBV infections. Some studies have also found that some supplementation during pregnancy can increase cytokine levels and then affect the level of HBsAb in infants. For example, IL-4 can mediate the beneficial effect on infants' HBsAb levels when maternal folic acid supplementation. In addition, new research has indicated that HBV infection in the mother may also be linked to unfavorable outcomes such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, and premature rupture of membranes. The changes in the immune environment during pregnancy and the hepatotropic nature of HBV may be the main reasons for the adverse maternal outcomes. It is interesting to note that after delivery, the women who had a chronic HBV infection may spontaneously achieve HBeAg seroconversion and HBsAg seroclearance. The maternal and fetal T-cell immunity in HBV infection is important because adaptive immune responses, especially virus-specific CD8 T-cell responses, are largely responsible for viral clearance and disease pathogenesis during HBV infection. Meanwhile, HBV humoral and T-cell responses are important for the durability of protection after fetal vaccination. This article reviews the literature on immunological characteristics of chronic HBV-infected patients during pregnancy and postpartum, blocking mother-to-child transmissions and related immune mechanisms, hoping to provide new insights for the prevention of HBV MTCT and antiviral intervention during pregnancy and postpartum.

The Effects of Theta/Beta-based Neurofeedback Training on Attention in Children with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis.

Neurofeedback training is a common treatment option for attention deficit hyperactivity disorder (ADHD). Given theta/beta-based neurofeedback (T/B NF) training targets at the electrophysiological characteristics of children with ADHD, benefits for attention may be expected. PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science were searched through December 31, 2020. Studies were evaluated with Risk of Bias tools. Within-group effects based on Pre- and Post-treatment comparisons of the Intervention Group, and Between-group effects based on the between-group differences from Pre-treatment to Post-treatment were calculated. Nineteen studies met selection criteria for systematic review, 12 of them were included in meta-analysis. Within-group effects were medium at Post-treatment and large at Follow-up. Between-group analyses revealed that T/B NF was superior to waitlist control and physical activities, but not stimulant medication. Results showed that T/B NF has benefits for attention in children with ADHD, however, cautions should be taken when interpreting the findings.

Glutamine exerts a protective effect on osteoarthritis development by inhibiting the Jun N-terminal kinase and nuclear factor kappa-B signaling pathways.

Strategies for treating osteoarthritis (OA) have become a research focus because an effective treatment for OA is unavailable. The objective of this study was to explore the effects and underlying mechanisms of glutamine (Gln) in OA. First, the chondrocytes were identified and a standard IL-1ß-induced OA model was established. After treatment with Gln or saline, the viability and apoptosis of chondrocytes were evaluated using a CCK-8 assay and flow cytometry analysis, which revealed that Gln can improve the IL-1ß-induced OA cells. Meanwhile, Gln can enhance the expression of aggrecan and collagen II, which are protective proteins for articular cartilage. Instead, Gln inhibited the expression of matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13), which can degrade cartilage. To better understand the underlying mechanisms of Gln in IL-1ß-induced chondrocytes, the classical OA pathways of JNK and NF-κB were examined at the protein and mRNA levels using western blot and qRT-PCR analyses. We found that JNK and NF-κB were downregulated gradually depending on the Gln dose and protective and destructive factors changed based on changes of JNK and NF-κB. The effects of high-dose Gln were more effective than low-dose. Moreover, Gln was applied to the animal OA model to check the effects in vivo. The results showed that Gln attenuated cartilage degeneration and decreased OARSI scores, which demonstrated that Gln can improve OA. The experiments showed that Gln can benefit mice with OA by inhibiting the JNK and NF-κB signaling pathways.

In vivo and in vitro protective effects of shengmai injection against doxorubicin-induced cardiotoxicity.

CONTEXT: Shengmai injection (SMI) has been used to treat heart failure. OBJECTIVE: This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX). MATERIALS AND METHODS: In vivo, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. In vitro, H9c2 cells were divided into control group, model group (2 mL 1 µM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed. RESULTS: SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group in vivo. Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway. CONCLUSIONS: This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.

The Fitting Optimization Path Analysis on Scale Missing Data: Based on the 507 Patients of Poststroke Depression Measured by SDS.

OBJECTIVE: To explore the optimal fitting path of missing data of the Scale to make the fitting data close to the real situation of patients' data. METHODS: Based on the complete data set of the SDS of 507 patients with stroke, the data simulation sets of Missing Completely at Random (MCAR), Missing at Random (MAR), and Missing Not at Random (MNAR) were constructed by R software, respectively, with missing rates of 5%, 10%, 15%, 20%, 25%, 30%, 35%, and 40% under three missing mechanisms. Mean substitution (MS), random forest regression (RFR), and predictive mean matching (PMM) were used to fit the data. Root mean square error (RMSE), the width of 95% confidence intervals (95% CI), and Spearman correlation coefficient (SCC) were used to evaluate the fitting effect and determine the optimal fitting path. RESULTS: when dealing with the problem of missing data in scales, the optimal fitting path is ① under the MCAR deletion mechanism, when the deletion proportion is less than 20%, the MS method is the most convenient; when the missing ratio is greater than 20%, RFR algorithm is the best fitting method. ② Under the Mar mechanism, when the deletion ratio is less than 35%, the MS method is the most convenient. When the deletion ratio is greater than 35%, RFR has a better correlation. ③ Under the mechanism of MNAR, RFR is the best data fitting method, especially when the missing proportion is greater than 30%. In reality, when the deletion ratio is small, the complete case deletion method is the most commonly used, but the RFR algorithm can greatly expand the application scope of samples and save the cost of clinical research when the deletion ratio is less than 30%. The best way to deal with data missing should be based on the missing mechanism and proportion of actual data, and choose the best method between the statistical analysis ability of the research team, the effectiveness of the method, and the understanding of readers.

Oat fiber supplementation alleviates intestinal inflammation and ameliorates intestinal mucosal barrier via acting on gut microbiota-derived metabolites in LDLR-/- mice.

OBJECTIVE: Gut microbiota-derived metabolites are involved in intestinal inflammation, which can affect the development of atherosclerotic plaques. Previous studies have shown that oat fiber can delay the progression of atherosclerosis via improving lipid metabolism. The aim of this study was to evaluate how oat fiber acted on gut microbiota-derived metabolites, inhibited intestinal inflammation, and protected the intestinal mucosal barrier. METHODS: Male low-density lipoprotein receptor knock-out (LDLR-/-) mice were fed a high-fat/cholesterol diet with or without oat fiber for 14 wk. Histopathology of the aorta was detected by Oil Red O staining, and the small intestine mucosal pathology was measured through hematoxylin and eosin staining. Non-targeted metabolomics of feces was performed using liquid chromatography-mass spectrometry. Western blot method was used to assess the relative levels of the proteins involved in the toll-like receptor (TLR)4 signal pathway and intestinal mucosal barrier in interest tissues. RESULTS: Pathologically, oat fiber reversed the increment of the atherosclerotic lesion and ameliorated intestinal mucosal barrier in LDLR-/- mice. Oat fiber regulated the levels of gut microbiota-derived metabolites along with a decrease in isobutyrylcarnitine, valerylcarnitine, 1-methylguanosine, and 2-methylguanosine, and an increase in l-tyrosine and niacinamide. Notably, oat fiber blocked the TLR4 signal pathway and decreased the expression of nuclear factor-κB p65 in both the aorta and gut tissues. Also, oat fiber raised the expression of tight junction proteins including ZO-1 and occludin. CONCLUSION: Taken together, the present study revealed that oat fiber feeding effectively attenuated the development of atherosclerosis, at least partly via affecting gut microbiota-derived metabolites, inhibiting the intestinal inflammatory response, and maintaining the integrity of the intestinal mucosal barrier.

Rhubarb granule promotes diethylnitrosamine-induced liver tumorigenesis by activating the oxidative branch of pentose phosphate pathway via G6PD in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhubarb is a natural herbal medicine widely used clinically with numerous pharmacological activities including anti-cancer. Specifically, several studies reported that free anthraquinones from Rhubarb suppressed the proliferation of hepatoma cells. Nonetheless, recent studies revealed that Rhubarb caused hepatotoxicity in vivo, confirming its "two-way" effect on the liver. Therefore, the efficacy and safety of Rhubarb in the in vivo treatment of liver cancer should be further elucidated. AIM OF THE STUDY: This study investigated the presence of hepatoprotection or hepatotoxicity of Rhubarb in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. MATERIAL AND METHODS: A total of 112 male Sprague-Dawley rats weighing 190-250 g were enrolled. The rats were induced hepatocarcinogenesis using diethylnitrosamine (0.002 g/rat) until 17 weeks. Starting at week 11, Rhubarb granules (4 g/kg and 8 g/kg) were intragastrically administered daily for 7 weeks. All rats were euthanized at week 20 and the livers were analyzed via non-targeted metabolomics analysis. We established hepatic glucose 6 phosphate (6PG) levels and glucose 6 phosphate dehydrogenase (G6PD) activities to assess the pentose phosphate pathway (PPP). And the liver injuries of rats were analyzed via histological changes, hepatic function, as well as hepatic protein levels of alpha-fetoprotein (AFP), pyruvate kinase isozyme type M2 (PKM2), and proliferating cell nuclear antigen (PCNA). Furthermore, polydatin (0.1 g/kg/d) as a specific inhibitor of G6PD was used to treat rats. Notably, their histological changes, hepatic function, hepatic 6PG levels, hepatic G6PD activities, PCNA levels, and PKM2 levels were recorded. RESULTS: Non-targeted metabolomics revealed that Rhubarb regulated the PPP in the liver of Rhubarb-DEN-treated rats. Besides, Rhubarb activated the oxidative branch of the PPP by activating G6PD (a rate-limiting enzyme in the oxidative PPP) in the liver of Rhubarb-DEN-treated rats. Meanwhile, Rhubarb promoted DEN-induced hepatocarcinogenesis. Moreover, polydatin attenuated the promoting effect of Rhubarb on DEN-induced hepatocarcinogenesis. CONCLUSIONS: Rhubarb promoted DEN-induced hepatocarcinogenesis by activating the PPP, indicating that the efficacy and safety of Rhubarb in the treatment of liver cancer deserve to be deliberated.

Saikosaponins and the deglycosylated metabolites exert liver meridian guiding effect through PXR/CYP3A4 inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Bupleuri (RB), traditionally used to treat inflammatory disorders and infectious diseases, represents one of the most successful and widely used herbal drugs in Asia over the past 2000 years. Being realized the role in regulating metabolism and controlling Yin/Yang, RB is not only chosen specifically for treating liver meridian and the corresponding organs, but also believed to have liver meridian guiding property and help potentiate the therapeutic effects of liver. However, the ingredients in RB with liver meridian guiding property and the underly mechanism have not been comprehensively investigated. AIM OF STUDY: Considering the important role of CYP3A4 in first-pass metabolism and the liver exposure of drugs, the present study aimed to determine whether saikosaponins (SSs) and the corresponding saikogenins (SGs) have a role in inhibiting the catalytic activity of CYP3A4 in human liver microsomes and HepG2 hepatoma cells and whether they could suppress CYP3A4 expression by PXR-mediated pathways in HepG2 hepatoma cells. MATERIALS AND METHODS: The effect of SSs and SGs on CYP3A4-mediated midazolam1'-hydroxylation activities in pooled human liver microsomes (HLMs) was first studied. Dose-dependent experiments were performed to obtain the half inhibit concentration (IC50) values. HepG2 cells were used to assay catalytic activity of CYP3A4, reporter function, mRNA levels, and protein expression. The inhibitory effects of SSa and SSd on CYP3A4 activity are negligible, while the corresponding SGs (SGF and SGG) have obvious inhibitory effects on CYP3A4 activity, with IC50 values of 0.45 and 1.30 µM. The similar results were obtained from testing CYP3A4 catalytic activity in HepG2 cells, which correlated well with the suppression of the mRNA and protein levels of CYP3A4. Time-dependent testing of CYP3A4 mRNA and protein levels, as well as co-transfection experiments using the CYP3A4 promoter luciferase plasmid, further confirmed that SSs and SGs could inhibit the expression of CYP3A4 at the transcription level. Furthermore, PXR protein expression decreased in a concentration- and time-dependent manner after cells were exposed to SSs and SGs. PXR overexpression and RNA interference experiments further showed that SSs and SGs down-regulate the catalytic activity and expression of CYP3A4 in HepG2 may be mainly through PXR-dependent manner. CONCLUSION: SSs and SGs inhibit the catalytic activity and expression of CYP3A4 in a PXR-dependent manner, which may be highly related to the liver meridian guiding property of RB.

Integrated multiplatform-based metabonomics and network analysis to explore the mechanism of Polygonum cuspidatum on hyperlipidemia.

Hyperlipidemia is a major risk factor and pathological basis for cardiovascular diseases. Polygonum cuspidatum (HZ), a famous traditional Chinese medicine, is frequently used to treat hyperlipidemia. However, little is known about its underlying mechanism. Herein, an integrated approach combining multiplatform-based metabonomics and network analysis was adopted to elucidate the ameliorative mechanism of HZ on hyperlipidemia. The global metabolomic characters of HZ on hyperlipidemia were investigated by GC-MS and LC-MS based metabonomics. Significant metabonomic alterations were observed in hyperlipidemic group, which could be restored by HZ supplementation. Furthermore, the drug-ingredients-target-metabolic pathway network was constructed, and the result indicated that HZ exhibited hypolipidemic efficacy through resveratrol, polydatin, torachrysone-8-O-ß-D-(6'-oxayl)-glucoside, physciondiglucoside, (+)-catechin, ß-sitosterol, quercetin, luteolin and physovenine acting on phospholipase A2, unspecific monooxygenase, arachidonate 15-lipoxygenase, aromatic-L-amino-acid decarboxylase, alcohol dehydrogenase and triacylglycerol lipase. In conclusion, this study explored potential mechanism of HZ on hyperlipidemia with the aid of the integrated approach combining multiplatform-based metabonomics and network analysis, which might provide a theoretical basis for the clinical application of HZ.

Association of folate intake and colorectal cancer risk in the postfortification era in US women.

BACKGROUND: Folate may play a preventive role in the early stages of colorectal carcinogenesis, but long latencies may be needed to observe a reduction in colorectal cancer (CRC) incidence. In addition, concerns have been raised about the potential for cancer promotion with excessive folate intake, especially after the mandatory folic acid fortification in the United States in 1998. OBJECTIVE: We aimed to examine the association between folate intake in different chemical forms and CRC risk, especially in the postfortification era in the United States. DESIGN: We prospectively followed 86,320 women from the Nurses' Health Study (1980-2016). Folate intake was collected by validated food frequency questionnaires. CRC was self reported and confirmed by review of medical records. The association between the folate intake and CRC risk was assessed using Cox proportional hazards regression. RESULTS: We documented 1988 incident CRC cases during follow-up. Analyzing folate intake as a continuous variable, greater total folate intake 12-24 y before diagnosis was associated with lower risk of CRC (per increment of 400 dietary folate equivalents (DFE)/d, HR: 0.93, 95% CI: 0.85, 1.01 for 12-16 y; HR: 0.83, 95% CI: 0.75, 0.92 for 16-20 y; and HR: 0.87, 95% CI: 0.77, 0.99 for 20-24 y); and greater synthetic folic acid intake 16-24 y before diagnosis was also associated with a lower CRC risk (per increment of 400 DFE/d, HR: 0.91, 95% CI: 0.84, 0.99 for 16-20 y and HR: 0.91, 95% CI: 0.83-1.01 for 20-24 y). In the postfortification period (1998-2016), intake of total or specific forms of folate was not associated with CRC risk, even among multivitamin users. CONCLUSIONS: Folate intake, both total and from synthetic forms, was associated with a lower risk of overall CRC after long latency periods. There was no evidence that high folate intake in the postfortification period was related to increased CRC risk in this US female population.

Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries.

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3,801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals were presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g., eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxy docosapentaenoic acid) and higher levels of some omega-6 metabolites (P < 0.02) including 15-keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

Functional Outcome After Minimally Invasive Endoscopic Evacuation of Thalamic Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating form of stroke, with thalamic hemorrhages carrying the worst outcomes. Minimally invasive (MIS) endoscopic ICH evacuation is a promising new therapy for the condition. However, it remains unclear whether therapy success is location dependent. Here we present long-term functional outcomes after MIS evacuation of spontaneous thalamic hemorrhages. METHODS: Patients presenting to a single urban health system with spontaneous ICH were triaged to a central hospital for management of ICH. Operative criteria for MIS evacuation included hemorrhage volume ≥15 mL, age ≥18, National Institutes of Health Stroke Scale ≥6, and baseline modified Rankin Score (mRS) ≤3. Demographic, radiographic, and clinical data were collected prospectively, and descriptive statistics were performed retrospectively. Functional outcomes were assessed using 6-month mRS scores. RESULTS: Endoscopic ICH evacuation was performed on 21 patients. Eleven patients had hemorrhage confined to the thalamus, whereas 10 patients had hemorrhages in the thalamus and surrounding structures. Eighteen patients (85.7%) had intraventricular extension. The average preoperative volume was 39.8 mL (standard deviation [SD]: 31.5 mL) and postoperative volume was 3.8 mL (SD: 6.1 mL), resulting in an average evacuation rate of 91.4% (SD: 11.1%). One month after hemorrhage, 2 patients (9.5%) had expired and all other patients remained functionally dependent (90.5%). At 6-month follow-up, 4 patients (19.0%) had improved to a favorable outcome (mRS ≤ 3). CONCLUSION: Among patients with ICH undergoing medical management, those with thalamic hemorrhages have especially poor outcomes. This study suggests that MIS evacuation can be safely performed in a thalamic population. It also presents long-term functional outcomes that can aid in planning randomization schemes or subgroup analyses in future MIS evacuation clinical trials.

A PRISMA-compliant systematic review and meta-analysis of integrated Chinese and Western medicine in treating hepatitis C.

OBJECTIVE: To conduct a meta-analysis evaluating the effect of combining traditional Chinese medicine (TCM) with Western medicine in treating hepatitis C, and to provide an evidence-based medical strategy. METHODS: Randomized controlled trials (RCTs) comparing the effect of pegylated interferon (Peginterferon) combined with ribavirin (PR) alone and its combination with TCM were manually retrieved from the Weipu Information Resources System (VIP), Wan Fang Database, PubMed, and the Chinese Journal Full Text Database (CNKI). Studies meeting the inclusion criteria were selected and analyzed using the Review Manager 5.3 software. Suitable tests were also performed to determine the quality, heterogeneity, and sensitivity of the studies included in the meta-analysis. RESULTS: Twenty-eight RCTs met the inclusion criteria. The combination therapy or intervention group showed significantly greater HCV-RNA negative rate post-treatment compared to the monotherapy or the control group (P < .05). In addition, the serum levels of the liver function indicators alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were significantly improved after the combination therapy compared to PR alone (P < .05), while total bilirubin (TB) and r-glutamyltransferase (GGT) levels were not affected by TCM (P > .05). Finally, the parameters of liver fibrosis were also reduced by the combination therapy more effectively than the monotherapy. CONCLUSION: The combination of TCM and PR can improve the Comprehensive Clinical Efficacy of hepatitis C and have a better negative rate of HCV-RNA with a better benefit in the liver function. The effect of TCM + PR is better than that of PR alone in treating hepatitis C.

Traditional Chinese medicine combined with conventional therapy for female kidney stone: A protocol for systematic review.

INTRODUCTION: Kidney stone is caused by abnormal accumulation of crystalline substances in the kidneys. Kidney stone is one of the urinary system diseases with a high incidence. In this study, we will use the research method of randomized controlled trials to explore the effects of Traditional Chinese medicine combined with western medicine on renal function and urine metabolism in women with kidney stones. We hope that the results of this study will provide more evidence-based medical evidence for TCM to treat kidney stones, and also provide patients with more treatment options. METHODS/DESIGN: This pragmatic randomized controlled trial will recruit 100 patients who are diagnosed with kidney stone. Simple randomization to conventional drug treatment with a 1:1 allocation ratio will be used. The participants will continue to receive ESWL treatment and TCM therapy. The selection of outcomes will be evaluated by the overall effectiveness of clinical efficacy. DISCUSSION: This trial may provide evidence regarding the clinical effectiveness, safety, and cost-effectiveness of Traditional Chinese medicine for patients with Female kidney stone.

Yindan Jiedu Granules, a Traditional Chinese Medicinal Formulation, as a Potential Treatment for Coronavirus Disease 2019.

Background: Yindan Jiedu Granules (YDJDG) have been newly prescribed as a Chinese herbal formula. This study aimed to compare the efficacy of YDJDG and lopinavir-ritonavir in the treatment of coronavirus disease 2019 (COVID-19). Methods: Overall, 131 patients with COVID-19 were included in this study. In addition to standard care, 60 of these patients received YDJDG (YDJDG group) and 71 received lopinavir-ritonavir (lopinavir-ritonavir group). Propensity score matching (PSM) was used to match the characteristics of individuals in the two groups, while the Kaplan-Meier method was used to compare the proportion recovery observed. Results: Cox analysis revealed that YDJDG and CD4 ≥ 660 cells/µL were independent predictive factors of proportion recovery. At baseline, disease types differed between the YDJDG and lopinavir-ritonavir treatment groups. Furthermore, no significant adverse effects or toxicities relevant to YDJDG were observed. The median recovery time was 21 days in the YDJDG group and 27 days in the lopinavir-ritonavir group. After PSM (1:1), 50 patient pairs, YDJDG vs. lopinavir-ritonavir, were analyzed. In the YDJDG group, the proportion of recovered patients was remarkably higher than that observed in the lopinavir-ritonavir group (p = 0.0013), especially for those presenting mild/moderate disease type and CD4 < 660 cells/µL. In the YDJDG group, the mean duration of fever and pulmonary exudative lesions was significantly shorter than that observed in the lopinavir-ritonavir group (p = 0.0180 and p = 0.0028, respectively). Conclusion: YDJDG reveals the potential to hasten the recovery period in COVID-19 patients with mild/moderate disease type or CD4 < 660 cells/µL by shortening the mean duration of fever and pulmonary exudative lesions.