[Synergistic effect and compatibility structure of active anti-inflammatory ingredients from Lamiophlomis rotata based on network pharmacology and component structure theory].

The synergistic effect and compatibility structure of active anti-inflammatory ingredients(iridoid glycosides: shanzhiside methylester and 8-O-acetylshanzhiside methyl ester, flavonoid glycoside: luteoloside, and phenylethanoid glycoside: forsythoside B) from Lamiophlomis rotata were explored based on network pharmacology and component structure theory. In network pharmacology, CTD, SwisseTargetPrediction, and PharmMapper databases were used to collect and screen the targets of all active ingredients. The inflammation-related targets were obtained from CTD and GeneCards databases. The core targets were obtained by Venny 2.1.0, STRING, and Cytoscape 3.9.1. Core targets were annotated by the GO function and enriched by the KEGG pathway based on the DAVID database. In terms of component structure, based on a uniform design method and xylene-induced ear swelling model in mice, tumor necrosis factor-α and interleukin-6 were taken as the dependent variables, and the compatibility relationship among anti-inflammatory ingredients from L. rotata was explored through the quadratic polynomial stepwise regression. In addition, in vivo pharmacological experiments were conducted to verify the results. A network pharmacology study showed that compared with a single ingredient, the combined action of the three ingredients can synergistically exert anti-inflammatory effects through more biological processes, pathways, and targets. Component structure study showed that the optimal structural ratio of shanzhiside methylester and 8-O-acetylshanzhiside methyl ester in the iridoid glycoside ingredient was 1.21∶1. The optimal structural ratio among the three types of ingredients(iridoid glycosides∶phenylethanol glycoside∶flavonoid glycoside) was 4.8∶1.6∶1. In conclusion, each anti-inflammatory ingredient from L. rotata can work synergistically, and there is an optimal compatibility ratio relationship among these ingredients. This work provides a new experimental basis for the intrinsic quality control of L. rotata.

Residue quality drives SOC sequestration by altering microbial taxonomic composition and ecophysiological function in desert ecosystem.

Plant residues are important sources of soil organic carbon in terrestrial ecosystems. The degradation of plant residue by microbes can influence the soil carbon cycle and sequestration. However, little is known about the microbial composition and function, as well as the accumulation of soil organic carbon (SOC) in response to the inputs of different quality plant residues in the desert environment. The present study evaluated the effects of plant residue addition from Pinus sylvestris var. mongolica (Pi), Artemisia desertorum (Ar) and Amorpha fruticosa (Am) on desert soil microbial community composition and function in a field experiment in the Mu Us Desert. The results showed that the addition of the three plant residues with different C/N ratios induced significant variation in soil microbial communities. The Am treatment (low C/N ratio) improved microbial diversity compared with the Ar and Pi treatments (medium and high C/N ratios). The variations in the taxonomic and functional compositions of the dominant phyla Actinobacteria and Proteobacteria were higher than those of the other phyla among the different treatments. Moreover, the network links between Proteobacteria and other phyla and the CAZyme genes abundances from Proteobacteria increased with increasing residue C/N, whereas those decreased for Actinobacteria. The SOC content of the Am, Ar and Pi treatments increased by 45.73%, 66.54% and 107.99%, respectively, as compared to the original soil. The net SOC accumulation was positively correlated with Proteobacteria abundance and negatively correlated with Actinobacteria abundance. These findings showed that changing the initial quality of plant residue from low C/N to high C/N can result in shifts in taxonomic and functional composition from Actinobacteria to Proteobacteria, which favors SOC accumulation. This study elucidates the ecophysiological roles of Actinobacteria and Proteobacteria in the desert carbon cycle, expands our understanding of the potential microbial-mediated mechanisms by which plant residue inputs affect SOC sequestration in desert soils, and provides valuable guidance for species selection in desert vegetation reconstruction.

Effect of deoxynivalenol on inflammatory injury on the glandular stomach in chick embryos.

Deoxynivalenol (DON) has a strong toxic effect on the gastrointestinal mucosa of poultry. In this study, we evaluated chicken embryo development and glandular stomach damage to clarify the immunotoxic effects of DON injected through the allantoic cavity of chicken embryos. The glandular stomach index, routine blood indices, plasma inflammatory factors, pathological changes in the glandular stomach, and transcriptome results were analyzed in the hatching chicks. The results showed that DON was supertoxic to chicken embryos, causing edema, shedding, and bleeding of the mucosa of the glandular stomach, which triggered inflammatory reactions. As the toxin concentration increased, the immune system was successively activated and inhibited, and regulation was carried out by the differential regulation of the mitogen-activated protein kinase (MAPK) signal pathway. These results suggested that the immunotoxic effect of DON on the glandular stomach of chicken embryos was closely related to the regulation of the MAPK signaling pathway.

Coupling Root Diameter With Rooting Depth to Reveal the Heterogeneous Assembly of Root-Associated Bacterial Communities in Soybean.

Root diameter and rooting depth lead to morphological and architectural heterogeneity of plant roots; however, little is known about their effects on root-associated microbial communities. Bacterial community assembly was explored across 156 samples from three rhizocompartments (the rhizosphere, rhizoplane, and endosphere) for different diameters (0.0-0.5 mm, 0.5-1.0 mm, 1.0-2.0 mm, and>2.0 mm) and depths (0-5 cm, 5-10 cm, 10-15 cm, and 15-20 cm) of soybean [Glycine max (L.) Merrill] root systems. The microbial communities of all samples were analyzed using amplicon sequencing of bacterial 16S rRNA genes. The results showed that root diameter significantly affected the rhizosphere and endosphere bacterial communities, while rooting depth significantly influenced the rhizosphere and rhizoplane bacterial communities. The bacterial alpha diversity decreased with increasing root diameter in all three rhizocompartments, and the diversity increased with increasing rooting depth only in the rhizoplane. Clearly, the hierarchical enrichment process of the bacterial community showed a change from the rhizosphere to the rhizoplane to the endosphere, and the bacterial enrichment was higher in thinner or deeper roots (except for the roots at a depth of 15-20 cm). Network analysis indicated that thinner or deeper roots led to higher bacterial network complexity. The core and keystone taxa associated with the specific root diameter class and rooting depth class harbored specific adaptation or selection strategies. Root diameter and rooting depth together affected the root-associated bacterial assembly and network complexity in the root system. Linking root traits to microbiota may enhance our understanding of plant root-microbe interactions and their role in developing environmentally resilient root ecosystems.

Long non-coding RNA HEIH: a novel tumor activator in multiple cancers.

The last decade has witnessed the altered expression levels of long non-coding RNA HEIH in different types of cancer. More than half of the HEIH studies in cancer have been published within the last two years. To our knowledge, this is the first review to discuss very recent developments and insights into HEIH contribution to carcinogenesis. The functional role, molecular mechanism, and clinical significance of HEIH in human cancers are described in detail. The expression of HEIH is elevated in a broad spectrum of cancers, and its disorder contributes to cell proliferation, migration, invasion, and drug resistance of cancer cells through different underlying mechanisms. In addition, the high expression of HEIH is significantly associated with advanced tumor stage, tumor size and decreased overall survival, suggesting HEIH may function as a prognostic biomarker and potential therapeutic target for human cancers.

Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels.

Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C0/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C0 values were 2-7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C0/Dose ratio. The C0/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C0/Dose ratio in patients aged 1-≤6 and 6-≤12 years was significantly lower than that in patients aged 12-≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C0/Dose ratio in younger children (1-≤6 years), rather than older children (6-≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C0) of 2-7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.

Valproate decreases vitamin D levels in pediatric patients with epilepsy.

PURPOSE: To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS: A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS: Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION: This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.

Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update.

BACKGROUND: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. METHODS: We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized. RESULTS: The formation of VPA reactive metabolites, inhibition of fatty acid ß-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. CONCLUSION: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug.

Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation.

Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.

Complete mitochondrial genome of the Partridge Shank chicken (Galliformes: Phasianidae).

Partridge Shank chicken is a valuable broiler breed in China. The first complete mitochondrial DNA (mtDNA) sequence of Partridge Shank chicken had been obtained using PCR amplification, sequencing and assembling. The complete mitochondrial genome was 16,788 bp in length, with the base composition of 30.2% for A, 23.7% for T, 32.5% for C and 13.5% for G. It exhibited the typical mitochondrial structure, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and a non-coding control region (D-loop region). The phylogenetic tree construced with maximum-likelihood (ML) method based on the complete chicken mitochondrial genomes showed that the 26 chicken breeds could be divided into two groups.

Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?

There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis.

Individualized Tacrolimus Therapy for Pediatric Nephrotic Syndrome: Considerations for Ontogeny and Pharmacogenetics of CYP3A.

Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It's important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.