How does multiple substrate binding lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan? A theoretical study.

CYP2D6 is one of the most important metalloenzymes involved in the biodegradation of many drug molecules in the human body. It has been found that multiple substrate binding can lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan (DM), but the corresponding theoretical mechanism is rarely reported. Therefore, we chose DM as the probe and performed molecular dynamics simulations and quantum mechanical calculations on CYP2D6-DM systems to investigate the mechanism of how the multiple substrate binding leads to the substrate inhibition of CYP2D6 metabolizing substrates. According to our results, three gate residues (Arg221, Val374, and Phe483) for the catalytic pocket are determined. We also found that the multiple substrate binding can lead to substrate inhibition by reducing the stability of CYP2D6 binding DM and increasing the reactive activation energy of the rate-determining step. Our findings would help to understand the substrate inhibition of CYP2D6 metabolizing the DM and enrich the knowledge of the drug-drug interactions for the cytochrome P450 superfamily.

Clinical and dermoscopic characteristics of onychophagia and onychotillomania: a retrospective study of 63 cases.

Onychophagia and onychotillomania are common forms of nail-biting and nail-picking disorders, but there is insufficient literature documenting their comparison and coexistence. In fact, overlapping features can be involved in different nail self-injuries, and significant variations also exist. We conducted a retrospective study aimed at identifying differences between onychophagia and onychotillomania, and providing more detailed findings of both conditions.

JAK-inhibitors for dermatomyositis: A concise literature review.

Refractory dermatomyositis (DM) is defined as cases that do not show improvement after initial treatment with two different immunosuppressives combined with corticosteroids with or without intravenous immunoglobulins. In recent years, few studies have reported a positive response to the use of Janus kinase inhibitors (JAK-inhibitors) for the treatment of refractory DM. A systematic literature review was performed for articles studying the use of JAK-inhibitors for the treatment of refractory DM. We identified 38 females and 15 males treated with JAK-inhibitors without serious side effects. Tofacitinib was the most frequently used JAK-inhibitor followed by ruxolitinib. Significant improvement in CDASI score, muscle strength, body weight, and skin lesions were reported in most of the studies. The duration of follow-up ranged from 1 to 15 months without relapse. Therefore, the use of JAK-inhibitors looks promising in the treatment of refractory DM and further high volume research may be required to validate the current concept. As only case reports and series were identified without direct comparison for review, there is a potential risk of bias. Despite these limitations, we believe that the result of this analysis allows a better understanding of treatment options for refractory DM and will help generate a hypothesis that can be further tested.

[Correlation between genotypes with metabolic markers and microstructure of bones in children with Gitelman syndrome].

OBJECTIVE: To explore the correlation between the genotypes and metabolic markers and microstructure of bones in children with Gitelman syndrome (GS). METHODS: For 15 children with GS and 10 healthy individuals, baseline data and bone metabolic markers including parathyroid hormone, alkaline phosphatase, osteocalcin, N-terminal propeptide of type I procollagen, beta isomer of the C-terminal telopeptide of type I collagen and 25-hydroxyvitamin D, high-resolution peripheral quantitative computed tomography indicators (volumetric bone mineral density, bone microstructure indicators) were collected. Genetic testing was carried out to determine their genotypes. RESULTS: The volumetric bone mineral density, bone geometry and bone microstructure parameters of the GS group were better than those of the healthy controls (P<0.05). Variants of the SLC12A3 gene were identified in 9 of the 15 patients but none of the 10 healthy controls. CONCLUSION: The phenotype of GS children is influenced by the interaction of genetic variants, though the phenotype associated with high frequency mutations showed no specificity. There is also a correlation between their genotype and the bone microstructure.

[Genetic analysis of 46,XY disorders of sex development in children caused by a new NR5A1 gene variant].

OBJECTIVE: To explore the genetic basis for a child with 46,XY disorders of sex development (DSD) and explore its genotype-phenotype correlation. METHODS: The child was subjected to whole exome sequencing (WES), and exons 1 to 7 of NR5A1 were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: The patient presented with rudimentary vulva of a female with Tanner stage 1. B-mode ultrasonography has detected ovary and uterus. The child was found to have a chromosome karyotype of 46,XY. WES revealed that the patient has harbored heterozygous deletion of exon 5 of the NR5A1 gene, which was a novel pathogenic variant inherited from the mother. No abnormality was found in the father. CONCLUSION: The main symptoms of 46,XY DSD children are insufficient external genitalia masculinization, for which variants of the NR5A1 gene are an important cause. WES has improved the detection rate of genetic variants and provided a solid basis for genetic counseling of the affected families.

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia.

Background and Aims: The role of platelet autophagy in cirrhotic thrombocytopenia (CTP) remains unclear. This study aimed to investigate the impact of platelet autophagy in CTP and elucidate the regulatory mechanism of hydrogen sulfide (H2S) on platelet autophagy. Methods: Platelets from 56 cirrhotic patients and 56 healthy individuals were isolated for in vitro analyses. Autophagy markers (ATG7, BECN1, LC3, and SQSTM1) were quantified using enzyme-linked immunosorbent assay, while autophagosomes were visualized through electron microscopy. Western blotting was used to assess the autophagy-related proteins and the PDGFR/PI3K/Akt/mTOR pathway following treatment with NaHS (an H2S donor), hydroxocobalamin (an H2S scavenger), or AG 1295 (a selective PDGFR-α inhibitor). A carbon tetrachloride-induced cirrhotic BALB/c mouse model was established. Cirrhotic mice with thrombocytopenia were randomly treated with normal saline, NaHS, or hydroxocobalamin for 15 days. Changes in platelet count and aggregation rate were observed every three days. Results: Cirrhotic patients with thrombocytopenia exhibited significantly decreased platelet autophagy markers and endogenous H2S levels, alongside increased platelet aggregation, compared to healthy controls. In vitro, NaHS treatment of platelets from severe CTP patients elevated LC3-II levels, reduced SQSTM1 levels, and decreased platelet aggregation in a dose-dependent manner. H2S treatment inhibited PDGFR, PI3K, Akt, and mTOR phosphorylation. In vivo, NaHS significantly increased LC3-II and decreased SQSTM1 expressions in platelets of cirrhotic mice, reducing platelet aggregation without affecting the platelet count. Conclusions: Diminished platelet autophagy potentially contributes to thrombocytopenia in cirrhotic patients. H2S modulates platelet autophagy and functions possibly via the PDGFR-α/PI3K/Akt/mTOR signaling pathway.

The role of Nrf2 in protection against Pb-induced oxidative stress and apoptosis in SH-SY5Y cells.

Lead exerts severe adverse effects on the nervous system in which oxidative stress might mediate impairments. In this study, we focused on Nrf2, which has been identified to significantly influence the protection of a cellular system against many xenobiotic compounds. We found that PbAc exhibited neurotoxicity mainly through oxidant-based processes and could be inhibited by NAC and DPI in SH-SY5Y cells. As a defense response, Nrf2 was activated when exposed to PbAc, thereby inducing a rapid increase in Nrf2 nuclear accumulation, as well as Nrf2-ARE binding activities in a ROS-dependent manner. Analysis of Nrf2-regulated gene expression and protein showed that PbAc could induce the mRNA transcription of HO-1, GSTα1, GCLM, GCLC, and NQO1, as well as the protein expression of HO-1 and γ-GCS. The responses of these genes to PbAc were regulated by Nrf2. Silencing Nrf2 expression in SH-SY5Y cells inhibited PbAc-induced gene transcription and protein expression. Overexpression of Nrf2 led to decreased ROS production and cell apoptosis, as well as increased cell viability under PbAc exposure. These results indicated that the Nrf2-ARE system exhibited a protective role in Pb-induced neurotoxicity, providing potential therapeutic strategies for the prevention and treatment of Pb-related diseases.