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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 β-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.

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.

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.

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 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.

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.

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