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The bursa of Fabricius, the acknowledged humoral immune organ unique to birds, plays a vital role in B cell development. Bursopentin (BP5) derived from the bursa is reported to induce the development and formation of B cells. However, the mechanism of BP5 on B cell differentiation is still unclear. In this paper, total B lymphocytes from mice immunized with H9N2 subtype AIV vaccine were stimulated with BP5. The results show that BP5 at the experimental dosages promoted B cell differentiation, including the total B cells, activated B cells, differentiated B cells, mature B cells and plasma cells. Then, the in vivo immune experiment proved that the percentages of activated and differentiated B cells from mice immunized with AIV vaccine and 0.25 mg/mL BP5 were increased. To investigate the molecular mechanism of BP5 on B cell differentiation, the gene expression profiles of B cells purified from the spleen cells of mice immunized with AIV vaccine and BP5 were detected following RNA sequencing technology. The results show that BP5 at 0.05 and 0.25 mg/mL induced the enrichment of various biological functions, and stimulated five common significant enrichment pathways in B cells from the immunized mice. Additionally, 120 and 59 differentially expressed genes (DEG) represented transcriptional factors in B cells following 0.05 and 0.25 mg/mL BP5 immunization, respectively. In summary, these results suggest that BP5 regulates various gene expression involved in regulation of B cell development, which provides the knowledge required for additional studies on B cell differentiation in response to bursal-derived peptides and also provides an important experimental basis for improving vaccine immunity., (© 2022. The Author(s).)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese., Methods: Whole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed., Results: WES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p < 0.0001) and 65 age-matched and neurologically normal individuals (0/65) (p < 0.0001). The A382T and G298S mutations were prevalent in Europeans and Eastern Asians, respectively. Additionally, carriers for the M337V mutation are dominated by bulbar onset with a long survival, whereas those for G298S are dominated by limb onset with a short survival., Conclusions: Some prevalent TARDBP mutations are distributed in a geographic pattern and related to clinical profiles. TARDBP G298S mutation is a founder mutation in the Southern Chinese ALS population., (© 2022. The Author(s).)

Iron regulatory protein 2 (IRP2) is a key regulator of iron homeostasis and is found to be altered in several types of human cancer. However, how IRP2 contributes to tumorigenesis remains to be elucidated. In this study, we sought to investigate the role of IRP2 in tumorigenesis and found that IRP2 promotes cell growth by repressing TAp63, a member of p53 tumor suppressor family. Specifically, we found that IRP2 overexpression decreased, whereas IRP2 deficiency increased, TAp63 expression. We also showed that the repression of TAp63 by IRP2 was independent of tumor suppressor p53. To uncover the molecular basis, we found that IRP2 stabilized TAp63 mRNA by binding to an iron response element in the 3'UTR of p63 mRNA. To determine the biological significance of this regulation, we showed that IRP2 facilitates cell proliferation, at least in part, via repressing TAp63 expression. Moreover, we found that IRP2 deficiency markedly alleviated cellular senescence in TAp63 -deficient mouse embryo fibroblasts. Together, we have uncovered a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities at least in part by repressing TAp63 expression. IMPLICATIONS: We have revealed a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities, at least in part, by repressing TAp63 expression., (©2020 American Association for Cancer Research.)

p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53 R270H/- MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR +/- ; p53 R270H/- mice as compared with p53 R270H/- mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.

The p63 transcription factor, a p53 family protein, regulates genes involved in various cellular processes, including cell growth and differentiation. We previously showed that RNA-binding motif protein (Rbm38) is a p63 target and, in turn, regulates p63α mRNA stability by binding to the AU/U-rich element in its 3'UTR. Interestingly, Rbm38 can be phosphorylated at serine 195, altering its ability to regulate mRNA translation. However, whether the Ser-195 phosphorylation affects Rbm38's ability to destabilize p63 mRNA remains unclear. Here, using MCF7 and HaCaT cells, we showed that ectopic expression of phosphomimetic Rbm38-S195D increases, whereas WT Rbm38 and nonphosphorylatable Rbm38-S195A decrease p63α protein and transcript levels. We also found that upon activation of glycogen synthase kinase 3β (GSK3β), phosphorylation of Rbm38 at Ser-195 is increased, enhancing p63α expression in an Rbm38-dependent manner. To confirm this, we generated mouse embryo fibroblasts (MEFs) in which Ser-193 in mouse Rbm38 (equivalent to Ser-195 in human Rbm38) was substituted with aspartic acid ( Rbm38 S193D/S193D ) or alanine ( Rbm38 S193A/S193A ). We observed that the p63 transcript level was increased in Rbm38 S193D/S193D MEFs, but decreased in Rbm38 S193A/S193A MEFs. Mechanistically, we found that WT Rbm38, but not Rbm38-S195D, is required for p63 mRNA degradation mediated by microRNA 203 (miR203). Furthermore, we noted that Argonaute 2 (Ago2), a key regulator in microRNA-mediated mRNA decay, associates with WT Rbm38, and this association was reduced by Ser-195 phosphorylation. Together, our results reveal a critical mechanism by which Ser-195 phosphorylation in Rbm38 increases p63 expression by attenuating the association of Rbm38 with the Ago2-miR203 complex., (© 2019 Zhang et al.)

Background: Ophiocordyceps sinensis ( C. sinensis ) extracts have been found to have a therapeutic effect on patients with chronic obstructive pulmonary disease (COPD). Silent information regulator 1 (SIRT1) plays an important role in the regulation of inflammatory mediators and correlates with lung function and COPD exacerbations. The objective of this work was to explore the anti-inflammatory effect and preliminary pathways of nucleosides from cultured C. sinensis on RAW264.7 macrophages and COPD mice., Materials and Methods: The nucleosides were extracted from cultured C. sinensis powder and further purified by macroporous resin D101 and glucan G10 columns. Inflammation and oxidative stress models in RAW264.7 macrophages and in mice were established by injection of cigarette smoke extract (CSE). We then examined how the isolated nucleosides regulated the production of the associated inflammatory mediators in vitro and in vivo by enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and Western blot., Results: The nucleosides inhibited inflammatory mediator expression of tumor necrosis factor-α, interleukin-6, interleukin-1β, and nitric oxide in both the CSE-stimulated RAW264.7 macrophages and mice. Moreover, the nucleosides elevated SIRT1 activation and suppressed nuclear factor-κB (NF-κB)/p65 activation in vitro and in vivo. Nucleoside treatment significantly decreased the levels of the inflammatory mediators in the bronchoalveolar lavage fluid (BALF) and serum of the CSE-induced mice. The nucleosides also altered the recruitment of inflammatory cells in BALF and improved characteristic features of the lungs in the CSE-induced mice., Conclusion: These results show that the nucleosides suppressed COPD inflammation through the SIRT1-NF-κB/p65 pathway, suggesting that the nucleosides may be partly responsible for the therapeutic effects of cultured C . sinensis on COPD patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To study polymorphisms of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) genes among Chinese patients with Parkinson's disease., Methods: Genotypes of the COMT and MAO-B genes of 1408 patients with Parkinson's disease was sequenced using Sanger method. And these patients were recruited by Chinese Parkinson Study Group from 29 research centers throughout the country., Results: The genotypic frequencies of COMT rs4680 AA, AG, GG were 8.9%, 42.0% and 49.1%. Those of rs4818 CC, CG, GG were 42.5%, 45.6% and 11.9%, respectively. The genotype frequencies of MAO-B rs1799836 A/AA, AG, G/GG were 74.4%, 14.1% and 11.5%, respectively. The haplotype formed by COMT rs4680 (GG) and MAO-B rs1799836 (A/AA) genotype has a frequency of 36.86%., Conclusion: Polymorphisms of COMT and MAO-B genes has a unique characteristics among Chinese patients with Parkinson's disease. They may be related with differences in drug response in such patients.

Epitope-based vaccination might play an important role in the protective immunity against Japanese encephalitis virus (JEV) infection. The purpose of the study is to evaluate the immune characteristics of recombinant MVA carrying multi-epitope gene of JEV (rMVA-mep). The synthetic gene containing critical epitopes (B-cell, CTL and Th) of JEV was cloned into the eukaryotic expression vector pGEM-K1L, and the rMVA-mep was prepared. BALB/c mice were immunized with different dosages of purified rMVA-mep and the immune responses were determined in the form of protective response against JEV, antibodies titers (IgG1 and IgG2a), spleen cell lymphocyte proliferation, and the levels of interferon-γ and interleukin-4 cytokines. The results showed that live rMVA-mep elicited strongly immune responses in dose-dependent manner, and the highest level of immune responses was observed from the groups immunized with 107 TCID50 rMVA-mep among the experimental three concentrations. There were almost no difference of cytokines and neutralizing antibody titers among 107 TCID50 rMVA-mep, recombinant ED3 and inactivated JEV vaccine. It was noteworthy that rMVA-mep vaccination potentiates the Th1 and Th2-type immune responses in dose-dependent manner, and was sufficient to protect the mice survival against lethal JEV challenge. These findings demonstrated that rMVA-mep can produce adequate humoral and cellular immune responses, and protection in mice, which suggested that rMVA-mep might be an attractive candidate vaccine for preventing JEV infection.