C5L2 CRISPR KO enhances dental pulp stem cell-mediated dentinogenesis via TrkB under TNFα-induced inflammation

Background and Objectives: Dental caries is one of the most common human pathological conditions resulting from the invasion of bacteria into the dentin. Current treatment options are limited. In many cases, endodontic therapy leads to permanent pulp tissue loss. Dentin–pulp complex regeneration involves dental pulp stem cells (DPSCs) that differentiate into odontoblast-like cells under an inflammatory context. However, limited information is available on how DPSC differentiation processes are affected under inflammatory environments. We identified the crucial role of complement C5a and its receptor C5aR in the inflammation-induced odontoblastic DPSC differentiation.Methodology: Here, we further investigated the role of a second and controversial C5a receptor, C5L2, in this process and explored the underlying mechanism. Human DPSCs were examined during 7-, 10-, and 14-day odontogenic differentiation treated with TNFα, C5L2 CRISPR, and tyrosine receptor kinase B (TrkB) antagonist [cyclotraxin-B (CTX-B)].Results: Our data demonstrate that C5L2 CRISPR knockout (KO) enhances mineralization in TNFα-stimulated differentiating DPSCs. We further confirmed that C5L2 CRISPR KO significantly enhances dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) expression after 14-day odontoblastic DPSC differentiation, and treatment with CTX-B abolished the TNFα/C5L2 CRISPR KO-induced DSPP and DMP-1 increase, suggesting TrkB’s critical role in this process.Conclusion and Key applications: Our data suggest a regulatory role of C5L2 and TrkB in the TNFα-induced odontogenic DPSC differentiation. This study may provide a useful tool to understand the mechanisms of the role of inflammation in dentinogenesis that is required for successful DPSC engineering strategies

Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum

<p>Abstract</p> <p>Background</p> <p>The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify <it>Zac1</it>, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex.</p> <p>Results</p> <p>We found that Zac1 has a complex expression profile in the developing cerebellum, including in two proliferating progenitor populations; the cerebellar ventricular zone and the external granular layer overlying posterior cerebellar lobules IX and X. Zac1 is also expressed in some postmitotic cerebellar neurons, including a subset of GABAergic interneurons in the medial cerebellar nuclei. Notably, GABAergic interneurons in the cerebellar nuclei are derived from the cerebellar ventricular zone, where Zac1 is also expressed, consistent with a lineage relationship between these two Zac1⁺populations. Zac1 is also expressed in a small subset of cells in the posterior vermis, including some neurogranin-immunoreactive (NG⁺) Golgi cells, which, based on short-term birthdating, are derived from the EGL, where Zac1 is also expressed. However, Zac1⁺cells and NG⁺Golgi cells in the cerebellar cortex also display unique properties, as they are generated within different, albeit overlapping, time windows. Finally, consistent with the expression profile of Zac1, two conspicuous abnormalities were found in the cerebellum of <it>Zac1 </it>null mice: the medial cerebellar nuclei, and not the others, were significantly reduced in size; and the number of Golgi cells in cerebellar lobule IX was reduced by approximately 60% compared to wild-type littermates.</p> <p>Conclusions</p> <p>The data presented here indicate that the tumor suppressor gene <it>Zac1 </it>is expressed in a complex fashion in the developing cerebellum, including in two dividing progenitor populations and in specific subsets of postmitotic neurons, including Golgi cells and GABAergic neurons in the medial nuclei, which require Zac1 for their differentiation. We thus conclude that Zac1 is a critical regulator of normal cerebellar development, adding a new transcriptional regulator to the growing list of factors involved in generating neuronal diversity in the developing cerebellum.</p

Loss of prostatic acid phosphatase and α-synuclein cause motor circuit degeneration without altering cerebellar patterning

Prostatic acid phosphatase (PAP), which is secreted by prostate, increases in some diseases such as prostate cancer. PAP is also present in the central nervous system. In this study we reveal that α-synuclein (Snca) gene is co-deleted/mutated in PAP null mouse. It is indicated that mice deficient in transmembrane PAP display neurological alterations. By using immunohistochemistry, cerebellar cortical neurons and zone and stripes pattern were studied in Pap-/- ;Snca-/- mouse cerebellum. We show that the Pap-/- ;Snca-/- cerebellar cortex development appears to be normal. Compartmentation genes expression such as zebrin II, HSP25, and P75NTR show the zone and stripe phenotype characteristic of the normal cerebellum. These data indicate that although aggregation of PAP and SNCA causes severe neurodegenerative diseases, PAP -/- with absence of the Snca does not appear to interrupt the cerebellar architecture development and zone and stripe pattern formation. These findings question the physiological and pathological role of SNCA and PAP during cerebellar development or suggest existence of the possible compensatory mechanisms in the absence of these genes.Peer reviewe

Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5 mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20 mg/kg) augmented the protective effects of tropisetron (1 mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100 mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral corte

Islamic legal methodologies and Shariah screening standards: application in the Indonesian stock market

This article provides a framework for applying the principles of Islamic legal methodology to determine the optimal Shariah screening standards for Islamic equity markets. It is argued that using maslahah mursalah (unrestricted benefit) is an appropriate method for identifying appropriate financial standards and its principles stipulate that the benchmark that yields the best economic returns to investors should be chosen. The methodological framework is applied to the Indonesia equity market where the economic implications of the Islamic stock screening standards of the Indonesian Islamic Shariah Stock Index and four global indices are assessed. Portfolios are constructed by applying Islamic stock screening standards for each of the indices by using data on 377 stocks listed in the Indonesian stock market for 5 years. The performances measured by the Sharpe ratio, Treynor index, and Jensen alpha reveal that the Dow Jones Islamic Index screening criteria performs the best. Based on the method of maslahah mursalah, the article recommends using the screening standard of this index in the Indonesian stock market to maximize benefits to investors. While the approach used in this article is applied to Islamic equity markets, the methodological framework can also be used for other similar cases in Islamic finance

Cerebellum: from Development to Disease—the 8th International Symposium of the Society for Research on the Cerebellum and Ataxias

In recent years, there has been tremendous growth in research on cerebellar motor and non-motor functions. Cerebellum is particularly involved in the spectrum of neurodevelopmental diseases. The 8th International Symposium of the Society for Research on the Cerebellum and Ataxia (SRCA) was held in Winnipeg, Manitoba, (Canada) on May 24–26, 2017. The main theme of the 8th International Symposium was “Development of the Cerebellum and Neurodevelopmental Disorders.” Advances in genetics, epigenetic, cerebellar neurogenesis, axonogenesis and gliogenesis, cerebellar developmental disorders including autism spectrum disorders (ASD), neuroimaging, cerebellar ataxias, medulloblastoma, and clinical investigation of cerebellar diseases were presented. The goal of this symposium was to provide a platform to discuss cutting-edge knowledge while allowing researchers and trainees the opportunity to share and discuss their front-line research and ideas with others in the field, make connections, and strengthen international collaborations. The Ferdinando Rossi lecture was delivered by Dr. Richard Hawkes on the topic of patterning of the cerebellar cortex. This symposium emphasized the major importance of the involvement of the cerebellum in neurodevelopmental diseases from the clinical, radiological, biological, and genetic standpoint.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

In Vivo Study of Diethylstilbestrol Teratogenicity on Mouse Embryo: Teratogenicity of diethylstilbestrol

Diethylstilbestrol (DES) was widely used in the past, as the morning after contraception, but its application became extremely limited due to several complications including delayed clear cell adenocarcinoma in female infants. However, the use of DES increased during the past decade for hormone replacement therapy. The aim of this study was to investigate possible teratogenicity of this synthetic oestrogen. The experiment was conducted on N-MRI mice. Various concentrations of DES were administered i.p. to pregnant animals throughout the period of organogenesis (days 9 and 10 of pregnancy). The control group received ethanol as vehicle. Pregnancy was terminated on the 18th day by cervical dislocation. The embryos were then removed and fixed in Bouin’s solution, and parameters currently used in teratogenic studies were assessed. Severe embryo toxicity score was observed following the application of DES at doses of 200 and 400 mg/kg (71.4% and 83.6%, respectively). The weight and the average size of some of the examined parameters were markedly decreased by embryological observation. Furthermore, the size of derm and mosaic cells of urinary bladder, shortening in the length of femur, and abnormal disposition of&nbsp; calcium compound in embryos were markedly different in the treated mice