Individualized medication based on pharmacogenomics and treatment progress in children with IgAV nephritis.

Immunoglobulin A vasculitis (IgAV) nephritis, also known as Henoch-Schönlein purpura nephritis (HSPN), is a condition in which small blood vessel inflammation and perivascular IgA deposition in the kidney caused by neutrophil activation, which more often leads to chronic kidney disease and accounts for 1%-2% of children with end-stage renal disease (ESRD). The treatment principles recommended by the current management guidelines include general drug treatment, support measures and prevention of sequelae, among which the therapeutic drugs include corticosteroids, immunosuppressive agents and angiotensin system inhibitors. However, the concentration range of immunosuppressive therapy is narrow and the individualized difference is large, and the use of corticosteroids does not seem to improve the persistent nephropathy and prognosis of children with IgAV. Therefore, individualized maintenance treatment of the disease and stable renal prognosis are still difficult problems. Genetic information helps to predict drug response in advance. It has been proved that most gene polymorphisms of cytochrome oxidase P450 and drug transporter can affect drug efficacy and adverse reactions (ADR). Drug therapy based on genetics and pharmacogenomics is beneficial to providing safer and more effective treatment for children. Based on the pathogenesis of IgAV, this paper summarizes the current therapeutic drugs, explores potential therapeutic drugs, and focuses on the therapeutic significance of corticosteroids and immunosuppressants in children with IgAV nephritis at the level of pharmacogenomics. In addition, the individualized application of corticosteroids and immunosuppressants in children with different genotypes was analyzed, in order to provide a more comprehensive reference for the individualized treatment of IgAV nephritis in children.

The Role of GM130 in Nervous System Diseases.

Golgi matrix protein 130 (GM130) is a Golgi-shaping protein located on the cis surface of the Golgi apparatus (GA). It is one of the most studied Golgin proteins so far. Its biological functions are involved in many aspects of life processes, including mitosis, autophagy, apoptosis, cell polarity, and directed migration at the cellular level, as well as intracellular lipid and protein transport, microtubule formation and assembly, lysosome function maintenance, and glycosylation modification. Mutation inactivation or loss of expression of GM130 has been detected in patients with different diseases. GM130 plays an important role in the development of the nervous system, but the studies on it are limited. This article reviewed the current research progress of GM130 in nervous system diseases. It summarized the physiological functions of GM130 in the occurrence and development of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), microcephaly (MCPH), sepsis associated encephalopathy (SAE), and Ataxia, aiming to provide ideas for the further study of GM130 in nervous system disease detection and treatment.

Effects of FER1L4-miR-106a-5p/miR-372-5p-E2F1 regulatory axis on drug resistance in liver cancer chemotherapy.

Liver cancer presents a challenge in today's healthcare system. This study aimed at investigating the effects of Fer-1 like family member 4 (FER1L4) on chemotherapy resistance and liver cancer development by using clinically collected liver cancer tissues and commercially purchased human liver cancer cisplatin-resistant cell line HUH-7/DDP. Bioinformatics analysis, dual luciferase reporter gene assay, and RNA pull-down were applied to predict and verify the possible binding relationships. The expressions of FER1L4, E2F transcription factor 1 (E2F1), microRNA-106a-5p (miR-106a-5p), or miR-372-5p were altered in the cells, followed by flow cytometry, Cell Counting Kit-8 (CCK-8), and Transwell assays to evaluate apoptotic, proliferative, and invasive abilities in vitro and nude mice xenografts to observe tumor growth in vivo. FER1L4 was highly expressed and miR-106-5p and miR-372-5p were poorly expressed in tumor cells and tissues. FER1L4 knockdown or the overexpression of miR-106-5p and miR-372-5p inhibited the cancerous cell proliferation and invasion while promoting apoptosis. FERIL4 silencing increased the miR-106-5p/miR-372-5p expression to inhibit the E2F1-activated nuclear factor κB (NF-κB) pathway. Besides, overexpressing FER1L4 led to an increased tumor growth in nude mice, which was reversed by the NF-κB inhibitor pyrollidine dithiocarbamate (PDTC). In conclusion, the results indicated that FER1L4 could inhibit the expression of miR-106a-5p/miR-372-5p, to activate E2F1-mediated NF-κB pathway, leading to drug resistance in liver cancer.

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

BACKGROUND: Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive. METHODS: Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation. FINDINGS: TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7. INTERPRETATION: Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. FUNDING: This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).

[Regulatory effect of IkappaBalpha on NF-kappaB activity during viral gene transactivation in patients with steroid responsive simple nephrotic syndrome].

OBJECTIVE: To investigate the expression of inhibitory kappa B alpha (IkappaBalpha) and it's regulatory effect on nuclear factor kappa B (NF-kappaB) during viral gene transactivation triggered by respiratory tract viruses in steroid responsive simple nephrotic syndrome (SRSNS). METHODS: Children with SRSNS (including at active and remissive stage) were examined for this research project, and healthy children were chosen as controls. TaqMan reverse transcription-PCR (RT-PCR), Western blot, electro-mobility shift assays were performed to study the protein expression of IkappaBalpha gene and the activity of NF-kappaB in peripheral blood mononuclear cells (PBMCs). Simultaneously, RT-PCR was used to detect the gene expression of respiratory tract viruses (including respiratory syncytial virus and influenza virus), and viral antibody was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Comparing with that from SRSNS at remissive stage and healthy children, the activity of NF-kappaB from SRSNS at active stage was much higher statistically (P < 0.05). The positive correlation between NF-kappaB activation and the gene expression of respiratory tract viruses was observed (OR = 27, Kappa coefficient = 0.59, P <0. 05). In addition, levels of IkappaBalpha protein from children with SRSNS at active stage were much lower than those from healthy children and those from children with SRSNS at remissive stage (P < 0.05). There was a linear negative correlation between the activity of NF-kappaB and the protein level of IkappaBalpha (r = -0.884, P < 0.05). On the other hand, levels of IkappaBalpha mRNA from SRSNS at active stage were much higher than those from healthy children, but much lower than those from children with SRSNS at remissive stage (P < 0.05). CONCLUSION: Abnormal expression of IkappaBalpha, which is attributed to regulate activity of NF-kappaB, occurs during viral gene transactivation triggered by respiratory tract viruses in SRSNS.