Bioinformatics and network pharmacology analysis of DWYG capsule for improving liver regeneration: identification of active compounds and mechanisms.

Aimed to explore the mechanisms and targets of Diwu Yanggan Capsule (DWYG), a traditional Chinese medicine in liver regeneration, we used the TCMSP to obtain the active ingredients and targets of DWYG and the GEO database to obtain the DEGs related to liver regeneration. We also searched for liver regeneration-related genes in disease databases and integrated them with the herbal and GEO data to screen for potential targets of DWYG in liver regeneration. Enrichment analysis using R language and molecular docking of the key targets and active ingredients were constructed. We found 73 potential targets of DWYG in liver regeneration and revealed that DWYG may act through pathways such as MAPK, TNF, and IL-17. We also found that quercetin was a major component of DWYG with low binding energy to three key targets. Our results suggest that DWYG can facilitate liver regeneration and quercetin may be its core ingredient.

The pharmacology and mechanisms of traditional Chinese medicine in promoting liver regeneration: A new therapeutic option.

BACKGROUND: The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases. PURPOSE: This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients. METHODS: We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed. RESULTS: Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review. CONCLUSION: This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.

Alcohol intake masked the protective effects of tea consumption against all-cause mortality and blood pressure progression: Findings from CHNS cohort, 1993-2011.

OBJECTIVES: Whether the protective effects of tea consumption interact with the status of alcohol consumption remains unknown. The present study aimed to investigate the relationship between tea consumption and mortality and blood pressure changes between alcohol consumers and non-consumers in a Chinese population. METHODS: This study was conducted with a cohort of 6387 participants from the China Health and Nutrition Survey data between 1993 and 2011. Group-based trajectory modeling was conducted to identify distinct tea consumption trajectories. Kaplan-Meier and Cox regression methods were used to estimate the cumulative rate of all-cause mortality. Restricted cubic spline was performed to determine the nonlinear relationships between mean tea consumption and mortality. Generalized linear mixed-effects models (GLMM) were conducted to assess the blood pressure changes among tea consumption trajectories. RESULTS: We identified three tea consumption trajectories. After a median follow-up of 17.9 y, 580 (9.1%) participants died. The association between tea consumption and death interacted with alcohol drinking status. A lower morality risk for the high tea consumption trajectory was observed only in non-alcohol drinkers (hazard ratio, 0.56; 95% confidence interval, 0.40-0.77). The tea-mortality association was linear in current alcohol drinkers (Plinear = 0.002), demonstrating that mortality increased with increasing tea consumption. The results of GLMM showed that alcohol intake masked the protective effect against blood pressure progression. CONCLUSIONS: The results of this study demonstrated that individuals with a long-term high tea consumption trajectory had a lower risk for all-cause mortality and a slower blood pressure growth rate. The beneficial effects of tea consumption were attenuated by alcohol intake or even harmful to health.

Cerebral blood flow regulates iron overload in the cerebral nuclei of hemodialysis patients with anemia.

Hemodialysis patients exhibit anemia-related cerebral hyperperfusion and iron deposition (ID). However, the mechanisms underlying the pathology of cerebral ID are not clear. We investigated the role of cerebral blood flow (CBF) in the pathophysiology of cerebral ID in hemodialysis patients with anemia. This study recruited 33 hemodialysis patients with anemia and thirty-three healthy controls (HCs). All the subjects underwent quantitative susceptibility mapping (QSM) and arterial spin labeling (ASL) to measure ID and CBF in the cerebral nuclei. Furthermore, we evaluated lacunar infarction (LI), cerebral microbleeds, and total white matter hyperintensity volume (TWMHV). Hemodialysis patients with anemia showed significantly higher ID and CBF in some nuclei compared to the HCs after adjusting for age, sex, and total intracranial volume (TIV) [P < 0.05, false discovery rate (FDR) corrected]. CBF showed a positive correlation with ID in both patients and HCs after adjustments for age, gender, and TIV (P < 0.05, FDR corrected). Serum phosphorus, calcium, TWMHV, hypertension, and dialysis duration were independently associated with ID (P < 0.05). Hemoglobin, serum phosphorus, and LI were independently associated with CBF (P < 0.05). Mediation analysis demonstrated that CBF mediated the effects between hemoglobin and ID. Our study demonstrated that CBF mediated aberrant cerebral ID in hemodialysis patients with anemia.

A five-year review of prevalence and treatment outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis in the Henan Provincial Tuberculosis Clinical Medicine Research Centre.

OBJECTIVES: This study investigated the prevalence and significant clinical outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis (pre-XDR-plus) in Henan Provincial Chest Hospital between 2017 and 2021. METHODS: We analysed and summarized the drug sensitivity test (DST) results of clinical Mycobacterium tuberculosis (MTB) strains in TB patients seeking care in the Tuberculosis Clinical Medical Research Centre of Henan Province between 2017 and 2021. Medical records of pre-extensively drug-resistant plus additional drug-resistant TB patients were statistically analysed, including demographic characteristics, regimens, and outcomes. RESULTS: Of the 3689 Mycobacterium tuberculosis strains, 639 (17.32%), 353 (9.56%), and 109 (2.95%), multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (pre-XDR), and pre-XDR-plus, respectively. The proportion of MDR decreased from 19.1% in 2017 to 17.5% in 2021 (χ2 = 0.686, P = 0.407), the proportion of pre-XDR from 11.4% in 2017 to 9.0% in 2021 (χ2 = 2.39, P = 0.122), and pre-XDR-plus from 4.7% in 2017 to 1.8% in 2020, with the declining trend was significant (χ2 = 9.348, P = 0.002). The most commonly used anti-TB drugs were pyrazinamide (PZA, 37/46, 80.43%) and cycloserine (CS, 32/46, 69.57%), followed by linezolid (LZD, 25/46, 54.35%), protionamide (TH, 25/46, 54.35%), and para-aminosalicylic acid (PAS, 23/46, 50.00%). Patients receiving the LZD regimen were 5 times more likely to have a favourable outcome than those not receiving LZD (OR = 6.421, 95% CI 2.101-19.625, P = 0.001). Patients receiving a regimen containing CS were 4 times more likely to have a favourable outcome compared to those not taking CS (OR = 5.444, 95% CI 1.650-17.926, P = 0.005). CONCLUSIONS: Our data suggest that the population of pre-XDR-plus had significantly decreased over the past five years in the Henan Provincial Chest Hospital. The COVID-19 and flood disaster affect TB patients' selection of medical services. In addition, the pre-XDR-plus patients whose regimens contain LZD or CS were more likely to have favourable outcomes.

Reactive organic radical-doped Ag(I)-based coordination compounds for highly efficient antibacterial wound therapy.

Antibiotics, being critical antimicrobial agents, have been widely used for treating bacterial infections. However, prolonged use of antibiotics can induce drug resistance resulting in "superbug" that threatens human health. Therefore, developing antibiotic-free materials with intrinsic antibacterial properties is the key to the "superbug" challenge. In this study, two highly efficient metal-organic frameworks (MOFs) were successfully assembled through synergistic use of the antibacterial properties of reactive organic radicals and silver (Ag) cations. These hybrid Ag-based materials possessed radical-doped characteristics, continuously releasing Ag+, which significantly inhibited the growth of four common Gram-negative and Gram-positive human pathogens (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus), and particularly two multi-drug-resistance bacteria (MRSA and MDR-PA). Furthermore, in vivo assays indicated that the synergistic antibacterial effect of these compounds could significantly accelerate the healing rate of infected wounds in mice. Blood biochemistry and histological analyses of main organs in treated mice also exhibited negligible cytotoxicity. This study unveiled the promising potential of Ag-MOFs for anti-infective therapies and future clinical applications.

Geraniol relieves mycoplasma pneumonia infection-induced lung injury in mice through the regulation of ERK/JNK and NF-κB signaling pathways.

BACKGROUND: Pneumonia is a serious pediatric lung injury disease caused by Mycoplasma pneumoniae (M. pneumoniae) with increasing global prevalence every year. The WHO has reported that nearly 19% of children die due to pneumonia worldwide. OBJECTIVE: The present research was conducted to discover the ameliorative properties of geraniol against M. pneumoniae-provoked pneumonia in mice through the modulation of inflammatory responses. METHODOLOGY: The pneumonia was provoked in the male Swiss albino mice via infecting animals with 100 µl of M. pneumoniae for 2 days and supplemented concurrently with 20 mg/kg of geraniol for 3 days. 100 mg/kg of azithromycin was used as a standard drug. The nitric oxide (NO) level and MPO activity were measured using kits. The SOD activity, GSH, and MDA levels were studied using standard methods. The polymerase chain reaction (PCR) study was performed to examine the M. pneumoniae DNA load. The inflammatory cytokines status was assessed by assay kits. The ERK1/2, JNK1/2, and NF-κB expressions were studied by reverse-transcription (RT-PCR). The lung tissues were analyzed microscopically to investigate the histological alterations. RESULTS: Geraniol treatment effectively reduced lung weight, NO level, and MPO activity in the pneumonia mice. The total cells and M. pneumoniae DNA load were also decreased by the geraniol. The SOD activity and GSH level were improved and MDA was decreased by the geraniol treatment. The IL-1, IL-6, IL-8, TNF-α, and TGF status were appreciably depleted by the geraniol in the pneumonia mice. Geraniol also suppressed the ERK1/2 and NF-κB expressions in the lung tissues. Histological findings also suggest the therapeutic roles of geraniol against pneumonia in mice. CONCLUSION: In summary, our results proved the beneficial roles of geraniol against the M. pneumoniae-provoked pneumonia. Geraniol could be a hopeful therapeutic agent to treat pneumonia in the future.

Highly Bright AIE Nanoparticles by Regulating the Substituent of Rhodanine for Precise Early Detection of Atherosclerosis and Drug Screening.

Fluorescent probes capable of precise detection of atherosclerosis (AS) at an early stage and fast assessment of anti-AS drugs in animal level are particularly valuable. Herein, a highly bright aggregation-induced emission (AIE) nanoprobe is introduced by regulating the substituent of rhodanine for early detection of atherosclerotic plaque and screening of anti-AS drugs in a precise, sensitive, and rapid manner. With dicyanomethylene-substituted rhodanine as the electron-withdrawing unit, the AIE luminogen named TPE-T-RCN shows the highest molar extinction coefficient, the largest photoluminescence quantum yield, and the most redshifted absorption/emission spectra simultaneously as compared to the control compounds. The nanoprobes are obtained with an amphiphilic copolymer as the matrix encapsulating TPE-T-RCN molecules, which are further surface functionalized with anti-CD47 antibody for specifically binding to CD47 overexpressed in AS plaques. Such nanoprobes allow efficient recognition of AS plaques at different stages in apolipoprotein E-deficient (apoE-/- ) mice, especially for the recognition of early-stage AS plaques prior to micro-computed tomography (CT) and magnetic resonance imaging (MRI). These features impel to apply the nanoprobes in monitoring the therapeutic effects of anti-AS drugs, providing a powerful tool for anti-AS drug screening. Their potential use in targeted imaging of human carotid plaque is further demonstrated.

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities.

Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

Increased iron deposition of deep cerebral gray matter structures in hemodialysis patients: A longitudinal study using quantitative susceptibility mapping.

BACKGROUND: The cerebral iron overload in hemodialysis patients has been reported in a previous study, in which the evaluation of the changes in iron content could be affected by the cross-sectional analysis. PURPOSE: To investigate the longitudinal changes of iron deposition in hemodialysis patients using quantitative susceptibility mapping (QSM) and correlate these findings with the longitudinal changes of neurocognitive function and clinical factors. STUDY TYPE: Prospective; longitudinal. POPULATION: In all, 34 patients and 30 healthy controls (HCs); the mean follow-up interval was 22 ± 7 months. FIELD STRENGTH/SEQUENCE: 3.0T, susceptibility-weighted imaging (SWI). ASSESSMENT: QSM reconstructed from original phase data of SWI was used to measure the susceptibility of gray matter structures including bilateral caudate nucleus (CN), globus pallidus (GP), putmen (PUT), red nucleus (RN), substantia nigra (SN), dentate nucleus (DN), thalamus (THA), pulvinar of thalamus (PT). The Mini-Mental State Examination (MMSE) test and clinical factors were recorded. STATISTICAL TESTING: Analysis of covariance adjusting for age and gender as covariates or a paired t-test for the differences in susceptibility, MMSE scores, and clinical factors among baseline, follow-up patients, and HCs. Correlation and stepwise regression analysis for the relationship between susceptibility, MMSE scores, and clinical factors. RESULTS: The susceptibility of bilateral CN, GP, PUT, RN, SN, DN, THA, PT in follow-up patients was significantly higher than that in baseline between patients and HCs except for left THA (all P < 0.05; Bonferroni corrected). MMSE scores significantly negatively correlated with the susceptibility of bilateral CN, PUT, and RRN in the baseline examination and bilateral CN, PUT, RN, and DN in the follow-up examination (all P < 0.05; false discovery rate [FDR] corrected). The follow-up interval, creatinine, phosphorus, and calcium were independent factors for the increased susceptibility of some nuclei (all P < 0.05). DATA CONCLUSION: The iron deposition of gray matter nuclei in hemodialysis patients increased over roughly a 2-year period and may be a risk factor for neurocognitive impairment. Creatinine and abnormal calcium-phosphorus metabolism were independent risk factors for abnormal iron deposition. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:786-799.

(4Z,15Z)-Octadecadienoic Acid Inhibits Glycogen Synthase Kinase-3ß and Glucose Production in H4IIE Cells.

Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological effects of naturally occurring NMI FA in eukaryotic cells, the biological activities of structurally analogous (4Z,15Z)-octadecadienoic acid (1), (9Z,20Z)-tricosadienoic acid (2), and (12Z,23Z)-hexacosadienoic acid (3) were examined by using a yeast-based drug-screening system using the Ca2+-sensitive mutant strain, Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ). Among 1-3, 1 showed restored growth activity at a dose of 80 µg/disc in the mutant yeast strain. This phenotype suggests that 1 suppresses Ca2+-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3ß (GSK-3ß) or calcineurin pathways or both. From this result, the inhibitory activity of 1-3 against GSK-3ß was further determined. 1-3 showed potent inhibitory activity against GSK-3ß with IC50 values ranging from 8.7 to 21.9 µM. Inhibition of GSK-3ß reduces gene expression of the gluconeogenic key enzymes in liver, so we analyzed glucose production in rat hepatoma H4IIE cells to assess GSK-3ß inhibitory activity of 1-3. Acid 1 inhibited glucose production at 25 µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of 1 and might provide important insights into understanding the biological properties of naturally occurring NMI FA.

Coptisine attenuates obesity-related inflammation through LPS/TLR-4-mediated signaling pathway in Syrian golden hamsters.

It is known that obesity resulted from consumption of diets high in fat and calories and associated with a chronic low-grade inflammation. Because the fat, sterol and bile acid metabolism of male Syrian golden hamster are more similar to that of human, in the present study, high fat and high cholesterol (HFHC) induced obese hamsters were used to evaluate the anti-inflammation and hypolipidemic role of coptisine. The results showed that body weight, plasma lipid levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-c), very low density lipoprotein-cholesterol (VLDL-c), ApoB and pro-inflammatory cytokines including TNF-α, IL-6 and lipopolysaccharide (LPS) were significantly altered in hamsters fed with HFHC diet. A strong correlation was observed between the LPS level in serum and the level of LBP and pro-inflammatory cytokines. Coptisine from the concentrations of 60 to 700 mg/L dose-dependently inhibited Enterobacter cloacae growth, which can easily induce obesity and insulin resistance. The results of endotoxin neutralization assay suggest that coptisine is capable of reducing the LPS content under inflammation status. Real time RT-PCR analyses revealed that coptisine suppressed TLR-4 in visceral fat of hamsters and decreased CD14 expression in livers of hamsters. These encouraging findings make the development of coptisine a good candidate for preventing obesity-related diseases through the LPS/TLR-4-mediated signaling pathway.

Novel function of N,N-bis(2-chloroethyl)docos-13-enamide for reversal of multidrug resistance in tongue cancer.

Multidrug resistance (MDR) is a key element in the failure of chemotherapies, and development of agents to overcome MDR is crucial to improving cancer treatments. The overexpression of glutathione-S-transferases (GSTs) is one of the major mechanisms of MDR. Because some agents used in traditional Chinese medicine have strong antitumor effects coupled with low toxicity; we investigated the ability of N,N-bis(2-chloroethyl)docos-13-enamide (compound J), the synthesized analog of a highly unsaturated fatty acid from Isatis tinctoria L., to reverse the MDR induced by adriamycin (ADM) in TCA8113/ADM cells. We found that compound J significantly increased the cytotoxicity of ADM in TCA8113/ADM cells, with a reversal fold of 2.461. Analysis of the mechanisms through which compound J reversed MDR indicated that compound J significantly decreased the activity of GSTs and enhanced the depletion of GSH in TCA8113/ADM cells, but did not affect the P-glycoprotein (P-gp) efflux. Taken together, our data suggested that compound J was an excellent candidate for reversing MDR in cancer therapy.

Impact of intensive statin use on the level of inflammation and platelet activation in stable angina after percutaneous coronary intervention: a clinical study.

BACKGROUND AND OBJECTIVE: This study was designed to investigate whether high-dose atorvastatin before percutaneous coronary intervention (PCI) can reduce inflammation, platelet activation, and major adverse cardiac events (MACE) in patients with stable angina who are undergoing long-term statin therapy. METHODS: In total, 215 patients with chronic stable angina were randomized to pretreatment with 80 mg of atorvastatin (12 h before PCI; n = 106) or with 20 mg of atorvastatin (12 h before PCI; n = 109). All patients underwent PCI. Serum levels of interleukin-6, high-sensitivity C-reactive protein, tumor necrosis factor-α, GMP-140, and p-selectin were measured 24 h before and after PCI. The 30-day incidence of MACE was determined. RESULTS: No differences in baseline characteristics were observed between the groups. The levels of inflammation and platelet activation were significantly lower after 24 h in the group that received intensive statin therapy (P < 0.05). The levels of inflammation and platelet activation increased sharply 24 h after PCI in the group that received the lower dose of atorvastatin (P > 0.05). In other words, pretreatment with a high dose of atorvastatin decreased the incidence of MACE sharply within 30 days (P < 0.05). CONCLUSIONS: Pretreatment with a high dose of atorvastatin significantly reduced inflammation, platelet activation, and the incidence of MACE in patients with stable angina.

Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors.

A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)-hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine fumaric acid (17h, IC(50)=78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.