Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling.

BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.

Mechanisms of catapol inhibiting differentiation and glycolysis of Thl7 cells through MiR-143-3p / 中国药理学通报

Aim To investigate the mechanism of eata- pol (CAT) inhibiting differentiation and glyeolysis of Thl7 eel Is through miR-143-3p.Method The peripheral hloorl CD4 ∗ T eells of HA patients were obtained to deteet the expression of miR-143-3p and the mRNA levels of key glycolytic enzymes, ineluding glucose transporter 1 ( Glutl ) , hexokinase 2 ( HK2 ) , pyruvate kinase 2 (PKM2) , laetate dehydrogenase A ( LDHA).The differentiation of Thl7 eells was induced in vitro, and the ShRNA/lentivirus was applied to achieve the overexpression or knockdown of miR- 143-3 p.Un-transfected eells were divided into control group and CAT group (20, 40, 80 mg • L 1 ) , and transfected eells were divided into four groups: negative control group, miR-143-3p inhibitor group, miR- 143-3p mimies group, miR-143-3p inhibitor + CAT group.The percentage of Thl7 eells was deteeted by flow cytometry, and the level of IL-17A was detected by EL1SA.Quantitative real-time PCR was used to detect the mRNA expression of miR-143-3p and key glycolytic enzymes, and the levels of pyruvate and lactate were also detected.Results The mRNA expression of miR-143-3p in RA peripheral blood CD4 ∗ T cells was negatively correlated with disease severity ( DAS28 ) , transcription factor ROR-yt, and the key glycolytic enzymes Glutl/HK2/LDHA.Compared with negative control group, the down-expression of miR-143-3p markedly elevated the mRNA expression of ROR-yt, Glutl, HK2, LDHA, and the levels of IL-17A, pyruvate, lactate.Catalpol groups significantly up-regula- ted the expression of miR-143-3p, decreased the mRNA expression of HK2/LDHA and the levels of pvru- vate/lactate, and inhibited Thl7 cells differentiation.Compared with miR - 1 4 3 - 3 p inhibitor group , catapol could significantly inhibit the abnormal up-regulated of HK2/LDHA mRNA relative expression, pyruvate/lactate levels and the abnormal differentiation of Thl7 eells.Conclusion MiR-143-3p inhibits the differentiation and glycolysis of Thl7 cells.Catalpol could sup-press the glycolysis and differentiation of Thl7 eells by regulating mill-143-3p.

Research Advance on the Role of Spleen Tyrosine Kinase Inhibitors in Hematologic Malignancies / 中国实验血液学杂志

Abstract　　Spleen tyrosine kinase (SYK) is not only a key kinase in the B-cell receptor (BCR) signaling pathway, but also a critical component of other signal transduction pathways such as Fc receptor, complement receptor and integrin. Abnormal activation of SYK closely related to the occurrence and development of hematological malignancies, thus targeting SYK has become a research hotspot. Several SYK inhibitors including Fostamatinib, Entospletinib and Cerdulatinib were being evaluated in clincal trials. As a second generation SYK inhibitor, Entospletinib has achieved good efficacy in lymphoid and myeloid hematologic tumors. Furthermore, Entospletinib can significantly relieve hematopoietic stem cell transplantation(HCT) related graft versus host disease (GVHD). In this review the role of SYK inhibitors in treatment of hematological malignancies is summarized brifely.

Reaserch Advance on Bruton Tyrosine Kinase Inhibitors in the Treatment of B-Cell Tumors--Review / 中国实验血液学杂志

Abstract　　In recent years, development of the targeted drugs according to the biological characteristics of tumors have provided more treatment options for tumor patients. It was found that the overactivation or abnormality of B cell receptor (BCR) signal pathway closely related to the occurrence and development of various B cell tumors, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a key kinase in the BCR pathway, BTK inhibitors have obvious anti-tumor effect when its activity is being inhibitered. Currently, BTK inhibitors developed include the first-generation Ibrutinib and the second-generation Acalabrutinib, which can be targeted at the inhibition of BTK and its downstream signaling pathway, and have important therapeutic value for a variety of B-cell tumors, such as CLL and partial non-Hodgkin's lymphoma (NHL). However, its side effects and drug-resistance also gradually emerged, effective drug combination therapy has shown a certain clinical activity. This reviews summarizes briefly the mechanism and status of BTK inhibitors in the treatment of various B-cell tumors.

Research Progress of m6A-Methylation in Acute Leukemia-Review / 中国实验血液学杂志

Epigenetic abnormalities play an important role in the pathogenesis of hematological malignancies, especially acute leukemia (AL). Similar to DNA methylation and histone modifications, RNA methylation is another important epigenetic modification. m6A methylation is one of the most prevalent and extensively studied RNA methylation. m6A methylation is involved in many biological and pathological process. Recent studies have found that m6A methylation is involved in the occurrence, development and drug-resistance of AL. This review focuses on the research progress of m6A methylation in AL.

Association between the HOTAIR Polymorphism and Susceptibility to Lead Poisoning in a Chinese Population / 生物医学与环境科学（英文）

This study explored the association between the lncRNA HOTAIR polymorphism and susceptibility to lead poisoning in a Chinese population. We speculated that lead poisoning caused elevated levels of oxidative stress, which, in turn, activate the HOTAIR gene to cause apoptosis. Three lncRNA HOTAIR tagSNPs (rs7958904, rs4759314, and rs874945) were genotyped by TaqMan genotyping technology in 113 lead-sensitive and 113 lead-resistant Chinese workers exposed to lead. Rs7958904 was significantly associated with susceptibility to lead poisoning (P = 0.047). The rs7958904 G allele had a protective effect compared with the C allele and reduced the risk of lead poisoning (P = 0.016). Rs7958904 may act as a potential biomarker for predicting the risk of lead poisoning and distinguishing lead-sensitive individuals from lead-resistant individuals.

Risk factors of nurses' occupational adaptability / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To explore factors affecting occupational adaptability in nurses for offering basis to increase their occupational adaptability.</p><p><b>METHODS</b>Five hundred and forty-five nurses were investigated with work ability index questionnaire and occupational stress instruments.</p><p><b>RESULTS</b>There were many risk factors affecting occupational adaptability in nurses. The main variables that influenced occupational adaptability included work-overtime, mental load, social support, physical environment, and job hazards. The social support was the factor increasing the occupational adaptability of the nurses (P < 0.01, OR = 0.912). Five factors including work overtime, mental load, social support, physical environment and job hazards were introduced in the Logistic equation. The established functions were: Logit (P) = -11.357 + 1.011x(1) + 0.335x(2) - 0.076x(3) + 0.260x(4) + 0.129x(5).</p><p><b>CONCLUSION</b>There are many risk factors affecting occupational adaptability in nurses. Relevant measures should be taken to promote the occupational adaptability in nurses to reduce the risk factors.</p>

Expression of heat shock protein 70 mRNA in guinea pig cochlea with ototoxicity of gentamicin / 生理学报

To examine the significance of heat shock protein 70 mRNA in ototoxicity resulted from gentamicin (GM), twenty healthy albino guinea pigs (200-250 g) of either sex with a positive Prier reflex were divided into two groups randomly. In GM group the animals received 100 mg/kg GM daily by intraperitoneal injection for 10 d. In saline control group the animals received 2.5 ml/kg saline daily by intraperitoneal injection for 10 d. Auditory brainstem response (ABR) thresholds were recorded in each animal before and 1 d after GM or saline administration. After the second ABR measurement, the expression of HSP70 mRNA in guinea pig cochlea was observed with in situ hybridization and image quantitative analysis system. The results showed that the threshold of ABR in the GM group was significantly higher than that of the saline control (P< 0.001). The expression of HSP70 mRNA was more intensive in stria vascularis, spiral ligament and spiral ganglion cells in the GM group than that of the saline control group. These results suggest that administration of gentamicin can induce the expression of HSP 70 mRNA in guinea pig cochlea, and that this effect may protect hearing function from ototoxicity.

Heat shock response in guinea pigs cochlea with gentamicin ototoxicity / 中国应用生理学杂志

<p><b>AIM</b>To explore the effects of gentamicin ototoxicity on the expression of heat shock protein 70 in guinea pigs cochlea.</p><p><b>METHODS</b>We used immunohistochemistry staining and image quantitative analysis system, combined with auditory brainstem response (ABR) measurement to investigate the change on the expression of HSP70 in guinea pigs cochlea of gentamicin ototoxicity.</p><p><b>RESULTS</b>The levels of HSP70 immunoreactivity in guinea pigs cochlea of experimental animals were high including Corti's organ, stria vascularis, medial spiral limbus, spiral ganglion cells and the threshold of ABR was in high correlation with the expression of HSP70 ([ r] > 0.8, P < 0.01).</p><p><b>CONCLUSION</b>Gentamicin can induce expression of HSP 70 in guinea pigs cochlea and protect hearing function.</p>