scholarly journals Kola nut from Cola nitida vent. Schott administered to pregnant rats induces histological alterations in pups’ cerebellum

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247573
Author(s):  
Foluso A. Atiba ◽  
Amos A. Fatokun ◽  
Innocent O. Imosemi ◽  
Adefolarin O. Malomo
Keyword(s):  
Human Brain ◽  
Granular Layer ◽  
Molecular Layer ◽  
B Cell Lymphoma ◽  
First Trimester ◽  
Cresyl Violet ◽  
Pregnant Rats ◽  
Over Expression ◽  
Initial Reduction ◽  
Cola Nitida

Kola nut (from Cola nitida) is popular in Nigeria and West Africa and is commonly consumed by pregnant women during the first trimester to alleviate morning sickness and dizziness. There is, however, a dearth of information on its effects on the developing brain. This study, therefore, investigated the potential effects of kola nut on the structure of the developing neonatal and juvenile cerebellum in the rat. Pregnant Wistar rats were administered water (as control) or crude (aqueous) kola nut extract at 400, 600, and 800 mg/kg body weight orally, from pregnancy to day 21 after birth. On postnatal days 1, 7, 14, 21 and 28, the pups were weighed, anaesthetised, sacrificed and perfused with neutral buffered formalin. Their brains were dissected out, weighed and the cerebellum preserved in 10% buffered formalin. Paraffin sections of the cerebellum were stained with haematoxylin and eosin for cerebellar cytoarchitecture, cresyl violet stain for Purkinje cell count, Glial Fibrillary Acidic Protein (GFAP) immunohistochemistry (IHC) for estimation of gliosis, and B-cell lymphoma 2 (Bcl-2) IHC for apoptosis induction. The kola nut-treated rats exhibited initial reduction in body and brain weights, persistent external granular layer, increased molecular layer thickness, and loss of Bergmann glia. Their Purkinje cells showed reduction in density, loss of dendrites and multiple layering, and their white matter showed neurodegeneration (spongiosis) and GFAP and Bcl-2 over-expression, with evidence of reactive astrogliosis. This study, therefore, demonstrates that kola nut, administered repeatedly at certain doses to pregnant dams, could disrupt normal postnatal cerebellar development in their pups. The findings suggest potential deleterious effects of excessive kola nut consumption on human brain and thus warrant further studies to understand the wider implications for human brain development.

scholarly journals Prenatal treatment with metronidazole induces cerebellar folia alteration in guinea pig fetuses

2020 ◽  
Vol 72 (4) ◽  
pp. 473-482
Author(s):  
Ivan Capo ◽  
Ivan Milenkovic ◽  
Natasa Capo ◽  
Nebojsa Stilinovic ◽  
Sasa Vukmirovic ◽  
...  
Keyword(s):  
Animal Studies ◽  
Granular Layer ◽  
Molecular Layer ◽  
Sensitive Period ◽  
Insufficient Data ◽  
Prenatal Treatment ◽  
External Granular Layer ◽  
Areal Fraction ◽  
Experimental Group ◽  
Partial Atrophy

The most sensitive period in brain development is during prenatal life. The use of antibiotics in pregnancy is still controversial. Recent studies revealed the high neurotoxic potential of the antibiotic and antiprotozoal medication, metronidazole. However, there are insufficient data from animal studies about prenatal treatment effects. We investigated the effect of prenatal treatment with metronidazole on cerebellar development in guinea pigs. Treatment with metronidazole was performed from the 42nd to the 49th day of gestation. On the 50th day of pregnancy, all dams were killed, and the cerebella of the fetuses were analyzed. Gross cerebellar changes characterized by malposition of the folia with partial atrophy were found in 12 of 19 fetuses in the experimental group, but in none of 20 control fetuses that received saline. The most affected were folia VII with depletion of the areal fraction of the external granular layer, molecular layer and the internal granular layer. Purkinje cells displayed cell distortion with loss of normal dendritic polarity. The investigation revealed cell depletion, with a disturbance of the cytoarchitectonic of the cerebellar cortex and folia alteration.

Anisotropic and heterogeneous diffusion in the turtle cerebellum: implications for volume transmission

1993 ◽  
Vol 70 (5) ◽  
pp. 2035-2044 ◽  
Author(s):  
M. E. Rice ◽  
Y. C. Okada ◽  
C. Nicholson
Keyword(s):  
Time Course ◽  
Granular Layer ◽  
Volume Fraction ◽  
Molecular Layer ◽  
Extracellular Volume ◽  
Striking Difference ◽  
Volume Transmission ◽  
Anisotropic Porous Media ◽  
Parallel Fibers ◽  
Ion Shifts

1. Measurements of extracellular diffusion properties were made in three orthogonal axes of the molecular and granular layers of the isolated turtle cerebellum with the use of iontophoresis of tetramethylammonium (TMA+) combined with ion-selective microelectrodes. 2. Diffusion in the extracellular space of the molecular layer was anisotropic, that is, there was a different value for the tortuosity factor, lambda i, associated with each axis of that layer. The x- and y-axes lay in the plane parallel to the pial surface of this lissencephalic cerebellum with the x-axis in the direction of the parallel fibers. The z-axis was perpendicular this plane. The tortuosity values were lambda x = 1.44 +/- 0.01, lambda y = 1.95 +/- 0.02, and lambda z = 1.58 +/- 0.01 (mean +/- SE). By contrast, the granular layer was isotropic with a single tortuosity value, lambda Gr = 1.77 +/- 0.01. 3. These data confirm the applicability of appropriately extended Fickian equations to describe diffusion in anisotropic porous media, including brain tissue. 4. Heterogeneity between the molecular and granular layer was revealed by a striking difference in extracellular volume fraction, alpha, for each layer. In the molecular layer alpha = 0.31 +/- 0.01, whereas in the granular layer alpha = 0.22 +/- 0.01. 5. Volume fraction and tortuosity affected the time course and amplitude of extracellular TMA+ concentration after iontophoresis. This was modeled by the use of the average parameters determined experimentally, and the nonspherical pattern of diffusion in the molecular layer was compared with the spherical distribution in the granular layer and agarose gel by computing isoconcentration ellipsoids. 6. One functional consequence of these results was demonstrated by measuring local changes in [K+]o and [Ca2+]o after microiontophoresis of a cerebellar transmitter, glutamate. The ratios of ion shifts in the x- and y-axes in the granular layer were close to unity, with a ratio of 1.04 +/- 0.08 for the rise in [K+]o and 1.03 +/- 0.17 for the decrease in [Ca2+]o. In contrast, ion shifts in the molecular layer had an x:y ratio of 1.44 +/- 0.14 for the rise in [K+]o and 2.10 +/- 0.42 for the decrease in [Ca2+]o. 7. These data demonstrate that the structure of cellular aggregates can channel the migration of substances in the extracellular microenvironment, and this could be a mechanism for volume transmission of chemical signals. For example, the preferred diffusion direction of glutamate along the parallel fibers would help constrain an incoming excitatory stimulus to stay "on-beam."

Temporal-spacial relationships between facial stimulation-evoked filed potential responses in mouse cerebellar granular layer and molecular layer

2019 ◽  
Vol 705 ◽  
pp. 106-111 ◽  
Author(s):  
Chang Ma ◽  
Di Lu ◽  
Li-Xin Cao ◽  
Yan-Hua Bing ◽  
Chun-Ping Chu ◽  
...  
Keyword(s):  
Granular Layer ◽  
Molecular Layer

scholarly journals PD-L1 over-expression is driven by B-cell receptor signaling in diffuse large B-cell lymphoma

2019 ◽  
Vol 99 (10) ◽  
pp. 1418-1427 ◽  
Author(s):  
Wei-Ge Wang ◽  
Xiang-Nan Jiang ◽  
Dong Sheng ◽  
Chen-Bo Sun ◽  
Jimmy Lee ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Over Expression ◽  
Large B Cell Lymphoma ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling ◽  
Large B Cell

Peripheral Blood Lymphocytic Profile in Patients with Diffuse Large B Cell Lymphoma and Follicular Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4656-4656
Author(s):  
Fernando Cavallin ◽  
Giovanni Vicario ◽  
Paolo Manente ◽  
Rosa Di Gaetano ◽  
Giuseppe Tagariello
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Peripheral Blood Lymphocytes ◽  
Over Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common adult low-grade non Hodgkin’s lymphomas. The influence of these diseases in peripheral blood lymphocytes is not well defined. Indeed the lymphocytic arrangement can be altered on account of the leukaemic form (although it slightly ever occurs); on the other hand the cause of occasional anomalies can be the involvement of the immune system against neoplasm. In order to contribute to the knowledge of these conditions we have analysed, at diagnosis, the lymphocytic immunophenotype in peripheral blood of 61 subjects: 27 were affected by DLBCL, average age 68, and 34 by FL, average age 61 years. Therefore we quantified the number of lymphocytes and evaluated essential markers, using flow cytometry, to define T, B, NK subsets by: CD3, CD4, CD8, CD19, SIgk, Sigl, CD56, and expression of CD11a molecule on T CD8. The absolute peripheral blood lymphocytes count presented a reduction in 51% and in 32% of the cases with an increase in 4% and in 3% of the subjects respectively considering DLBCL and FL. On the contrary T cells (CD3) had similar decrease, 33% and 32%, and different augmentation 15% and 3%. T cells ratio CD4/CD8 was under normal in 23% and in 12% of the patients but over normal in 12% and 29% always in DLBCL and FL. B cells (CD19) were reduced in 35% and in 12% of the subjects but increased in 8% and in 14%, whereas clonal restriction was present in 8% and in 20% of the components of the two groups. Natural Killer lymphocytes (CD56) were under normal in 12% and in 6% of bthe cases but over in 40% and 20%. Finally CD11a was over-expressed in 87% and in 68% of the patients of the respective pathologies. After selecting patients aged over 60 years, following four parameters that showed a significant variability was obtained: 1) lymphopenia in 50% of the cases in both groups; 2) similar results 11% and 15% about clonal restriction; 3) increase of the NK population 42% and 30% in DLBCL and FL; 4) very high over-expression of CD11a on T CD8 of 90% and 80%. Therefore DLBCL and FL are lymphoproliferative diseases where there is an important subtraction of lymphocytes, particularly in elderly people, from peripheral blood (perhaps because of accumulation in lymphnodes). These lesions present clonal restriction of B cells only in few cases (confirming the low known leukaemic form) while Natural Killer population are well represented especially in DLBCL. The over-expression of CD11a is the most altered parameter and seems almost a typical marker of these diseases above all in over 60 years subjects. Consequently if rarely happens that a leukaemic form of DLBCL and FL are found by flow cytometry however immunological defined alterations are very frequent in most of the cases of old patients.

CD40L Modulates TRAIL-Induced Apoptosis in Germinal Center Derived B Cell Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4630-4630
Author(s):  
Marion Travert ◽  
Patricia Ame-Thomas ◽  
Thierry Fest ◽  
Céline Pangault ◽  
Gilbert Semana ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lines ◽  
Germinal Center ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Lymphoma Cells ◽  
Over Expression ◽  
Induced Apoptosis ◽  
Transformed Cell Lines

Abstract Follicular lymphoma are characterized by the rearrangement of the bcl-2 gene, present in more than 90% of patients. Over-expression of the bcl-2 protein resulting from this translocation is associated with the inability to eradicate the lymphoma, by inhibiting apoptosis. Despite the median survival ranges from 8 to 15 years, leading to the designation of indolent lymphoma, patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. Numerous reports have shown that Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide variety of transformed cell lines of diverse lineage, but does not appear to kill normal cells, even though TRAIL mRNA is expressed at significant levels in most normal tissues. As cell death induced by TRAIL occurs almost exclusively in tumor cells, it suggests that this drug is safe to use as an antitumor therapy. We therefore investigated the efficiency of this cytokine to induce apoptosis in germinal center derived B cell lymphoma, despite bcl-2 over-expression. Our study was also designed to evaluate the role of CD40L, one of the main differentiation signal involved in B cell maturation during the germinal center reaction, on the regulation of TRAIL-induced apoptosis. This study was performed on three germinal center derived tumor cell lines (BL2, VAL and RL), and on normal and tumor primary cells obtained from human tonsils and lymph nodes. Our data show that normal B lymphocytes obtained from tonsil biopsies are resistant to TRAIL-mediated apoptosis, when B lymphoma cells issued from lymph node of numerous patients are significantly sensitive to the cytokine. When we treat these lymphoma cells with trimeric huCD40L, we partly rescue these cells from spontaneous apoptosis which naturally occurs after few days of culture, and reverse by 50% TRAIL-mediated apoptosis when cells were co-treated with huCD40L for 16 hours. Similar results were reproduced on some germinal center derived cell lines. BL2 was indeed found highly sensitive to TRAIL-induced apoptosis following a 24 hour exposure. On the opposite, VAL and RL were almost insensitive. We have demonstrate that apoptosis is exclusively mediated by TRAIL-R1 in BL2. Analysis of signalling pathways revealed that the protection to TRAIL-induced apoptosis by CD40L is due to some specific anti-apoptotic molecules that will be described. Genes encoding these molecules are targets of the NFκB signalling pathway activated by CD40L. Our results suggest that activation of NFκB and induction of anti-apoptotic molecules by CD40L play an important role in the protection of germinal center derived B cell lymphomas against apoptosis. Then, NFκB inhibitors may be wise to use in clinical trials in conjunction with TRAIL against follicular lymphomas.

HDAC Class I Inhibition Acetylates a Non-Histone Protein STAT3 by Modulating p300-STAT3-HDAC1 Interaction In Activated B- Cell Like (ABC) Diffuse Large B Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 115-115
Author(s):  
Mamta Gupta ◽  
Jing Jing Han ◽  
Mary Stenson ◽  
Linda Wellik ◽  
Thomas E. Witzig
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Over Expression ◽  
Stat3 Signaling ◽  
Large B Cell Lymphoma ◽  
Dose Dependent

Abstract Abstract 115 Patients with diffuse large B- cell lymphoma (DLBCL) tumors that have an activated B-cell like (ABC) gene expression profile have a poorer prognosis. Understanding the mechanism(s) used by ABC tumor cells to resist the effects of common chemotherapy agents may lead to alternative approaches for the treatment of these tumors. ABC cell lines have been shown to have high levels of phosphorylated STAT3 (pSTAT3); however, the mechanisms that regulate STAT3 signaling in ABC DLBCL remain unclear. Histone deacetylases (HDACs) are enzymes that can deacetylate both non-histone and histone substrates. In this study we tested the hypothesis that HDACs in the tumor cells target a non-histone protein STAT3 in ABC DLBCL. In studies of HDAC expression in DLBCL tumors, we found over-expression of the type 1 HDACs, specifically HDAC1and HDAC3, in the pSTAT3- positive ABC tumors as compared to germinal centre B like (GCB) tumors. We then performed a co-immunoprecipitation (Co-IP) assay to learn the functional interaction between STAT3 and HDAC1. We found that STAT3 formed complexes with HDAC1 or HDAC3. Further Co-IP studies demonstrated that p300, a histone acetyltransferase (HAT), STAT3, and HDAC1 are all in the same complex. To determine whether p300 acetylates STAT3 in ABC cells, we immuno-precipitated endogenous p300 and blotted with acetylated STAT3 and showed that p300 acetylates STAT3 at lysine 685. We next tested whether HDAC inhibition could affect p300 mediated STAT3 acetylation in ABC cells. Inhibition of HDAC activity through the HDAC inhibitor LBH589 (LBH, Novartis Pharmaceuticals) increased STAT3 acetylation in a dose- dependent manner. Similar results were obtained when we used antiacetyl- lysine antibody. Furthermore HDAC1 over-expression inhibits STAT3 acetylation at lysine 685. This data implies a tight regulation of STAT3 acetylation and deacetylases in vivo in ABC lymphoma. In addition to acetylation, STAT3 can be modified by phosphorylation, thus the effect of HDAC inhibition on pSTAT3 both at serine and tyrosine residues was studied. We observed a dose-dependent decrease in pSTAT3 with some inhibitory effect on total STAT3. LBH was found to mediate STAT3 dephosphorylation by inhibiting the tyrosine phosphorylation of JAK2 and TYK2, the STAT3 upstream activators, in a dose- dependent manner. Since ABC lymphoma has higher levels of HDAC1 or HDAC3 and pSTAT3/STAT3 than GCB, we hypothesized that ABC cells will be more sensitive to HDAC inhibition than GCB. In fact, when ABC and GCB DLBCL cells were treated with LBH we observed that LBH was more cytotoxic to ABC than GCB as evidenced by annexin/PI staining and PARP cleavage. LD90 was 25 nM for ABC cells, however GCB cells required 5 times more LBH to kill 90% cells. STAT3 activation regulates genes involved in cell survival, including Bcl-2, Mcl-1, Bcl-XL, and c-Myc. LBH treatment resulted in down-regulation of Mcl-1 and c-Myc in ABC cells but has no effect in GCB cells; however, Bcl-2 and Bcl-XL levels were not decreased in both the subtype. Having established that HDAC1 physically associated with STAT3 and that LBH treatment elevated STAT3 acetylation in ABC cells, we proceeded to deplete endogenous HDAC1 with siRNA in Ly3 cells and found that HDAC1 knockdown up-regulated STAT3 acetylation indicating that HDAC1 negatively regulates the acetylation in vivo. HDAC1 inhibition also prevented phopshorylation of STAT3 and induces aopotosis in ABC cells. In summary, we have demonstrated that a key consequence of HATs and HDACs expression and activity is modulation of the STAT3 pathway in ABC lymphoma. Inhibition of this pathway with the HDAC inhibitor LBH inhibits constitutive STAT3 signaling and induces Mcl-1 mediated apoptosis. These studies provide the rationale for targeting the poorly responsive ABC-type DLBCL by inhibiting HDAC activity with epigenetic inhibitors such as LBH. We are currently testing LBH589 in relapsed DLBCL in a phase I clinical trial. Disclosures: No relevant conflicts of interest to declare.

CD44 over Expression Caused Drug Resistance in Activated B Cell-like Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5316-5316
Author(s):  
Qinjun Zhou ◽  
Yongqiang Wei ◽  
Xiaolei Wei ◽  
Qi Wei ◽  
Ru Feng
Keyword(s):  
Drug Resistance ◽  
B Cell ◽  
Growth Regulation ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Annexin V ◽  
B Cell Lymphoma ◽  
Over Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract CD44, a transmembrane glycocoptotein, involved in tumor cell survival, migration , invasion, metastasis and prognosis of many cancers. This study was performed to investigate the effects of CD44 over expression on the biological function and the chemotherapeutic sensitivity of ABC-DLBCL. The full length CD44 cDNA was cloned into pEASY-T vector and then transfected into activated B cell-like diffuse large B-cell lymphoma cell line OCI-ly3. QPCR and western blot confirmed that the CD44 expression was up-regulated in both mRNA and protein levels in CD44-transfected OCI-ly3 cells. The cell proliferation of OCI-ly3-CD44 cells was significantly faster than that in OCI-ly3-GFP cells and the OCI-ly3 cells (p<0.001). Annexin V-APC/PI staining results showed that the apoptosis ratio wasn't difference among three groups (p=0.676). OCI-ly3-CD44 cells showed significantly higher migration ratio than OCI-ly3-GFP cells and the OCI-ly3 cells(p=0.031). The IC50 of doxorubicin in OCI-ly3-CD44 cells (0.348±0.072uM) was higher than that in OCI-ly3-GFP (0.348±0.072uM ) and OCI-ly3cells(0.138±0.029uM ) ( P<0.001). After treatment with doxorubicin for 24h, the OCI-ly3-CD44 cells showed lower apoptotic ratio than OCI-ly3-GFP and OCI-ly3 cells ( (17.5±1.33)% VS. (41.7±9.91) %, (41.8±7.23)%), P<0.001). In conclusion, CD44 plays a key role in cell growth regulation and chemo-resistance and is a potential target to overcome drug resistance and improve prognosis in DLBCL. Disclosures No relevant conflicts of interest to declare.

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