The landscape of very important pharmacogenes variants and potential clinical relevance in the Chinese Jingpo population: a comparative study with worldwide populations.

BACKGROUND: Pharmacogenomics is a facet of personalized medicine that explores how genetic variants affect drug metabolism and adverse drug reactions. Therefore, this study aims to detect distinct pharmacogenomic variations among the Jingpo population and explore their clinical correlation with drug metabolism and toxicity. METHODS: Agena MassARRAY Assay was used to genotype 57 VIP variants in 28 genes from 159 unrelated Jingpo participants. Subsequently, the chi-squared test and Bonferroni's statistical tests were utilized to conduct a comparative analysis of genotypes and allele frequencies between the Jingpo population and the other 26 populations from the 1000 Genome Project. RESULTS: We discovered that the KHV (Kinh in Ho ChiMinh City, Vietnam), CHS (Southern Han Chi-nese, China) and JPT (Japanese in Tokyo, Japan) exhibited the smallest differences from the Jingpo with only 4 variants, while ESN (Esan in Nigeria) exhibited the largest differences with 30 variants. Besides, a total of six considerably different loci (rs4291 in ACE, rs20417 in PTGS2, rs1801280 and rs1799929 in NAT2, rs2115819 in ALOX5, rs1065852 in CYP2D6, p < 3.37 × 10-5) were identified in this study. According to PharmGKB, rs20417 (PTGS2), rs4291 (ACE), rs2115819 (ALOX5) and rs1065852 (CYP2D6) were found to be associated with the metabolism efficiency of non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, montelukast and tamoxifen, respectively. Meanwhile, rs1801280 and rs1799929 (NAT2) were found to be related to drug poisoning with slow acetylation. CONCLUSION: Our study unveils distinct pharmacogenomic variants in the Jingpo population and discovers their association with the metabolic efficiency of NSAIDs, montelukast, and tamoxifen.

SOWAHB polymorphisms affect thyroid cancer risk in the Chinese Han population.

OBJECTIVES: This study aimed to detect the correlation between SOWAHB polymorphisms and Thyroid cancer (TC) risk in the Chinese Han population. METHODS: We genotyped SOWAHB variants in 510 TC patients and 509 controls using Agena MassARRAY. We assessed the association between SOWAHB polymorphisms and TC susceptibility, with the significant results evaluated through FPRP analysis. We predicted TC risk by the SNP-SNP interaction, analyzed by MDR. RESULTS: Carriers with rs2703129 CC had a lower probability of TC (codominant, recessive: p = 0.002), while subjects with rs1874564 AG had an increased risk of developing TC (codominant, recessive: p = 0.000, log-additive: p = 0.028). In subjects aged > 45 years, rs2703129 may reduce TC predisposition (codominant: p = 0.011, recessive: p = 0.007), but there was an increased association between rs1874564 and TC risk (codominant: p = 0.030, dominant: p = 0.047). Also, rs2703129 was associated with a lower risk of TC among males (codominant: p = 0.018, recessive: p = 0.013). Conversely, rs1874564 was associated with an increased risk of TC in females (codominant: p = 0.001, dominant: p = 0.003). CONCLUSION: SOWAHB SNPs were related to the occurrence of TC, and rs2703129 may be a protective site for TC.

Transcriptome analysis in an AEG­1­deficient neuronal HT22 cell line.

Astrocyte elevated gene-1 (AEG-1) is a key regulatory factor of progression in multiple types of tumor and neurodegenerative disease development. AEG-1 is associated with glutamate excitotoxicity due to its reported function of repressing excitatory amino acid transporter 2 expression in astrocytes. Although the function of AEG-1 has been demonstrated in neurological disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis, the underlying mechanism of neuronal AEG-1 function remains unclear. The aim of the present study was to clarify the function and related mechanism of AEG-1 in neurons. A stable AEG-1-deficient HT22 neuronal cell line was constructed using CRISPR/Cas9 gene-editing technology. Reverse transcription-quantitative PCR and western blotting were carried out to analyze the knockdown efficiency of AEG-1-deficient HT22 cell line. RNA Sanger sequencing analysis was performed in AEG-1-deficient HT22 cells and wild-type HT22 cells without knockout (KO). Results from RNA sequencing revealed that AEG-1 modulated neuronal morphology and development by regulating the expression of numerous genes, such as ubiquitin C, C-X-C motif chemokine ligand 1, MMP9, Notch1, neuropilin 1 and ephrin type-A receptor 4. In addition, AEG-1 deficiency impacted several signaling pathways by mediating cell survival differentiation, apoptosis, and migration; this included the TNF-α pathway, the NF-κB pathway, the MAPK signaling pathway, the Notch signaling pathway and Axon guidance. Downregulation in cellular ion homeostasis, including ion channel function and neurotransmitter release, were observed after knocking out AEG-1 expression. Collectively, the present study provides insights into AEG-1-dependent gene regulation and signaling pathway transduction in neurons. The results of the present study may be applied for improving the understanding of AEG-1-associated central nervous system diseases.

Ursolic Acid Protects Neurons in Temporal Lobe Epilepsy and Cognitive Impairment by Repressing Inflammation and Oxidation.

Temporal lobe epilepsy (TLE) is characterized as an impaired ability of learning and memory with periodic and unpredictable seizures. Status epilepticus (SE) is one of the main causes of TLE. Neuroinflammation and oxidative stress are directly involved in epileptogenesis and neurodegeneration, promoting chronic epilepsy and cognitive deficit. Previous studies have shown that ursolic acid (UA) represses inflammation and oxidative stress, contributing to neuroprotection. Herein, we demonstrated that UA treatment alleviated seizure behavior and cognitive impairment induced by epilepsy. Moreover, UA treatment rescued hippocampal neuronal damage, aberrant neurogenesis, and ectopic migration, which are commonly accompanied by epilepsy occurrence. Our study also demonstrated that UA treatment remarkably suppressed the SE-induced neuroinflammation, evidenced by activated microglial cells and decreased inflammation factors, including TNF-α and IL-1ß. Likewise, the expression levels of oxidative stress damage markers and oxidative phosphorylation (OXPHOS) enzyme complexes of mitochondria were also remarkably downregulated following the UA treatment, suggesting that UA suppressed the damage caused by the high oxidative stress and the defect mitochondrial function induced by SE. Furthermore, UA treatment attenuated GABAergic interneuron loss. In summary, our study clarified the notable anti-seizure and neuroprotective properties of UA in pilocarpine-induced epileptic rats, which is mainly achieved by abilities of anti-inflammation and anti-oxidation. Our study indicates the potential advantage of UA application in ameliorating epileptic sequelae.

Constitutive Description of Extra Strengthening in Gradient Nanotwinned Metals.

Gradient nanotwinned (GNT) metals exhibit extra strengthening and work hardening behaviors, which endow them impressive potentials in engineering applications. The increased strength is attributed to the dense interactions between dislocations and boundaries in the grain interiors. However, a constitutive model elucidating the extra strengthening effect is currently lacking. Here, we propose a theoretical framework to describe the mechanical response of GNT metals, especially the unusual extra strengthening behavior. The model captures the deformation mechanisms of GNT metals and coincides well with the reported experiment. The constitutive description developed in this work presents a tool to guide the structural design for developing gradient metallic materials.