Proliferation Of Follicular Cells Research Articles

The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential.

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal stem cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.

A Phosphotyrosine Switch in Estrogen Receptor β Is Required for Mouse Ovarian Function.

The two homologous estrogen receptors ERα and ERβ exert distinct effects on their cognate tissues. Previous work from our laboratory identified an ERβ-specific phosphotyrosine residue that regulates ERβ transcriptional activity and antitumor function in breast cancer cells. To determine the physiological role of the ERβ phosphotyrosine residue in normal tissue development and function, we investigated a mutant mouse model (Y55F) whereby this particular tyrosine residue in endogenous mouse ERβ is mutated to phenylalanine. While grossly indistinguishable from their wild-type littermates, mutant female mice displayed reduced fertility, decreased ovarian follicular cell proliferation, and lower progesterone levels. Moreover, mutant ERβ from female mice during superovulation is defective in activating promoters of its target genes in ovarian tissues. Thus, our findings provide compelling genetic and molecular evidence for a role of isotype-specific ERβ phosphorylation in mouse ovarian development and function.

Patterns of Angiogenic Factors (VEGF, Angiopoietin-1) in Patients with Benign Thyroid Lesions Before and After Surgery

Background: Angiogenesis plays an important role in goiter development with endothelial cell proliferation occurring before increased proliferation of the thyroid follicular cells and increase in both vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) in the serum and intrathyroid tissue. Objective: The aim of the current work was to measure the levels of VEGF and Ang-1 in patients with benign thyroid disorders before and after thyroidectomy and compare it to the normal control subjects. Patients and Methods: This prospective study included a total of 80 patients provisionally diagnosed as benign thyroid disorders and 50 apparently healthy subjects served as a control group, attending at Outpatient Clinics of Endocrine Surgery Unit, Mansoura University Hospital. This study was conducted between February 2017 to February 2020. Of the 80 patients, 12 (15%) were male and 68 (85%) were female and their age ranged from 19 to 60 years (median = 40.41 years). On admission, careful history taking, clinical examinations and different investigations were done. Results: Thirty patients had benign multinodular goiter, 20 had solitary follicular adenoma, 10 had diffuse toxic, 10 had nodular toxic goiter, and 10 had Hashimoto thyroiditis. In all patients, pre-operative circulating VEGF and Ang-1 levels were increased compared to controls (P<0.001), and a decrease after thyroidectomy was observed in the levels of VEGF (P<0.001) in all of them. This decrease was significant after total thyroidectomy compared to near total and hemi-thyroidectomy. Circulating Ang-1 were significantly increased (P<0.001) after thyroidectomy in all patients. Conclusion: It could be concluded that this study raise the potential for VEGF and Ang-1 factor to be used as biomarkers of the effectiveness of thyroidectomy in benign thyroid lesions. These results needs further investigations and may have potential prognostic implications.

MAPK, AKT/FoxO3a and mTOR pathways are involved in cadmium regulating the cell cycle, proliferation and apoptosis of chicken follicular granulosa cells

The occurrence of cadmium (Cd) in feed is a major problem in animal health and production. Studies have confirmed that Cd depresses egg production of laying hens, which is closely related to follicular atresia. This study aimed to assess the toxic impacts of Cd on the ovarian tissue, and to examine the mechanism of Cd-induced granulosa cell proliferation and apoptosis. Results from the nitric oxide (NO) and malondialdehyde (MDA) content, total superoxide dismutase (T-SOD), glutathione peroxide (GSH-Px), total nitric oxide synthase (T-NOS) and adenosine triphosphatase (ATPase) activities, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and hematoxylin-eosin (H & E) staining indicated that excess Cd induced oxidative stress, granulosa cell apoptosis and follicular atresia in the layer ovary. Low-dose Cd exposure (1 μM) induced the granulosa cell proliferation, upregulated the mRNA levels of RSK1 and RHEB, activated FoxO3a, AKT, ERK1/2, mTOR and p70S6K1 phosphorylation, and promoted cell cycle progression from phase G1 to S. However, high-dose Cd exposure (15 μM) induced reactive oxygen species (ROS) generation and cell apoptosis, upregulated the mRNA levels of the inflammatory factors, ASK1, JNK, p38 and TAK1, downregulated the expressions of RSK1 and RHEB genes, and inhibited the phosphorylation of ERK1/2, mTOR and p70S6K1 proteins, and the cell cycle progression. Rapamycin pre-treatment completely blocked the phosphorylation of mTOR and p70S6K1 proteins, and the cell cycle progression induced by 1 μM Cd, and accelerated 15 μM Cd-induced cell apoptosis and cell cycle arrest. The microRNA sequencing result showed that 15 μM Cd induced differential expression of microRNA genes, which may regulate AKT, ERK1/2 and mTOR signaling and cell cycle progression by regulating the activity of G proteins and cell cycle-related proteins. Conclusively, these results indicated that Cd can cause the ovarian damage and follicular atresia, and regulate cell cycle, cell proliferation or apoptosis of granulosa cells through MAPK, AKT/FoxO3a and mTOR pathways in laying hens.

Rabbit thyroid extracellular matrix as a 3D bioscaffold for thyroid bioengineering: a\xa0preliminary\xa0in\xa0vitro\xa0study

BackgroundAdvances in regenerative medicine technologies have been strongly proposed in the management of thyroid diseases. Mechanistically, the adoption of thyroid bioengineering requires a scaffold that shares a similar three-dimensional (3D) space structure, biomechanical properties, protein component, and cytokines to the native extracellular matrix (ECM).Methods24 male New Zealand white rabbits were used in this experimental study. The rabbit thyroid glands were decellularized by immersion/agitation decellularization protocol. The 3D thyroid decellularization scaffolds were tested with histological and immunostaining analyses, scanning electron microscopy, DNA quantification, mechanical properties test, cytokine assay and cytotoxicity assays. Meanwhile, the decellularization scaffold were seeded with human thyroid follicular cells, cell proliferation and thyroid peroxidase were determined to explore the biocompatibility in vitro.ResultsNotably, through the imaging studies, it was distinctly evident that our protocol intervention minimized cellular materials and maintained the 3D spatial structure, biomechanical properties, ECM composition, and biologic cytokine. Consequently, the decellularization scaffold was seeded with human thyroid follicular cells, thus strongly revealing its potential in reinforcing cell adhesion, proliferation, and preserve important protein expression.ConclusionsThe adoption of our protocol to generate a decellularized thyroid scaffold can potentially be utilized in transplantation to manage thyroid diseases through thyroid bioengineering.

Gonadotropin-inhibiting hormone promotes apoptosis of bovine ovary granulosa cells

Gonadotropin-inhibiting hormone (GnIH) inhibits the synthesis and release of gonadotropin by binding to its receptor. GnIH is involved in animal reproductive regulation, especially ovary function. It can regulate the proliferation, apoptosis and hormone secretion of follicular cells. However, the role and molecular mechanism of GnIH in bovine granulosa cell (bGC) apoptosis is unclear. Here, the effects of GnIH on proliferation, apoptosis, and mitochondrial function of bGCs were detected. A 10‐6 mol/mL concentration of GnIH inhibited bGC proliferation, promoted GC apoptosis, and damaged mitochondrial function. Additionally, GnIH significantly decreased the phosphorylation level of p38 (P < 0.01). To explore the role of the p38 signaling pathway in the process of GnIH-induced apoptosis in bGCs, an activator of p38 (U46619) was used to pretreat bGCs. U46619 pretreatment significantly alleviated GnIH damage to bGCs, including proliferation, apoptosis, and mitochondrial function. In conclusion, these results demonstrated that GnIH inhibited proliferation and promoted apoptosis of bGCs via the p38 signaling pathway.

Antiproliferative and Cytotoxic Effects of Schinus terebinthifolia Leaf Extract on Thyroid Follicular Cells

Schinus terebinthifolia Raddi, Anacardiaceae, is a Brazilian plant species, with anti-inflammatory and healing properties. This plant is popularly used for the treatment of several disorders, including thyroid dysfunctions. However, its influence on thyroid physiology is not fully understood. This study investigated the effects of a S. terebinthifolia leaf methanolic extract on the proliferation, viability, and reactive oxygen species (ROS) level of rat thyroid follicular cells. For this, PCCL3 cells were treated with different concentrations of the extract (1–100 μg/ml) and times of exposure (24, 48, and 72 h). The 30 μg/ml concentration significantly reduced cell viability. Thyrocytes treated with the extract presented altered cell morphologies and evidence of oxidative stress. The 50 μg/ml concentration of the extract elicited a pronounced increase in ROS level. The results demonstrated that S. terebinthifolia leaf is harmful to thyroid cells after exposure to high concentrations for prolonged periods. These potentially harmful effects should be considered when this medicinal plant is used in humans. This observation is particularly relevant to individuals with an increased risk of thyroid dysfunctions.

The effects of FAR1 and TGFBRAP1 on the proliferation and apoptosis of follicular granulosa cells in goose (Anser cygnoides).

The low laying performance of geese seriously damages the growth of the poultry industry, and is related to the development of pre- hierarchical follicles. Our previous studies have revealed that FAR1 and TGFBRAP1 were involved in follicular development, but the exact regulation mechanism still kept unclear. In recent studies, the expression of FAR1 and TGFBRAP1 mRNA were detected, and we found that their expression levels were relatively higher in hierarchical follicles than in pre-hierarchical follicles (P<0.05). Moreover, generally the level of FAR1 and TGFBRAP1 mRNA gradually increased in hierarchical follicles. In addition, the proliferation and apoptosis of granulosa cells were assayed with overexpression or knockdown technology. The results showed that by the knockdown of FAR1 mRNA level, the proliferation rate of follicular granulosa cells increased significantly, the apoptosis rate decreased (P<0.05), and the apoptosis rate also reduced obviously by transfecting TGFBRAP1-siRNA (P<0.05). Finally, the overexpression of FAR1 or TGFBRAP1 resulted in the inhabitation to the secretion of E2 and P4 in granulosa cells, while the knockdown of FAR1 or TGFBRAP1 enhanced the secretion of E2 and P4. In conclusion, the results indicated that FAR1 and TGFBRAP1 regulated the apoptosis of follicular granulosa cells and cut the secretion of E2 and P4 in geese, which provided basic data for the understanding of the regulating process of goose reproduction.

Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature.

Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. To investigate the clinical characteristics and accurate management of aromatase-deficient children. We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. Two girls and one boy (3.4-9.2years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.

The effect of total flavonoids of Epimedium on granulosa cell development in laying hens

To investigate the impact of total flavonoids of Epimedium (TFE) on the development of follicles of laying hens, 3 types of follicles including primary, prehierarchical, and preovulatory follicles were selected to obtain the follicular granulosa cells cultured in vitro. First, extraction of TFE was conducted by alcohol-soluble and ultrasonic methods. The effects of TFE on activity and proliferation of follicular granulosa cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and measuring the expression of proliferating cell nuclear antigen mRNA through real-time quantitative polymerase chain reaction, and the expression of the follicle-stimulating hormone receptor, luteinizing hormone receptor, steroidogenic acute regulatory protein, and cytochrome P450 family 11 subfamily A member 1 mRNA was detected to study the functions of TFE affecting the differentiation and hormone secretion by granulosa cells. The results showed that TFE significantly improved the proliferation of 3 types of granulosa cells and promoted the differentiation of granulosa cells and accelerated the conversion of primary follicles to prehierarchical follicles. Total flavonoids of Epimedium played an important role in promoting progesterone secretion by prehierarchical and preovulatory granulosa cells. The results indicated that TFE could promote proliferation and differentiation of follicular granulosa cells and improve hormone secretion and follicle development, which provided reference data for TFE used as a feed additive or safe Chinese veterinary medicine to promote the laying rate.

SUN-LB129 Thyroglobulin Stimulates the Secretion of Thyroxine From Thyroid Epithelial Cells in Suspension Culture via Nuclear Factor-κB Signaling Pathway

The nuclear factor (NF)-κB signaling pathway controls a variety of biological functions such as cell growth and differentiation as well as immune and inflammatory responses. Two distinct pathways of NF-κB activation are known. NF-κB signaling via non-canonical pathway plays an important role in maintaining normal thyroid function, namely, thyroid cells survival and expression of thyroid-specific proteins, such as NIS, TPO and thyroglobulin (Tg). The primary function of thyroid cells is the production of thyroid hormones, which are cleaved out by various processing enzymes from the modified tyrosine residues of the Tg molecule. Although Tg is currently recognized as no more than a scaffold protein for thyroid hormone synthesis, our group has shown that Tg stimulates the proliferation of rat thyroid follicular FRTL-5 cells via PI3K pathway. The signaling pathways underlying various functions of thyroid cells have been extensively investigated but some discrepancies still exist, depending on the experimental model systems and the types of cells used. Recently, our group discovered that Tg may directly regulate the synthesis of thyroid hormones in thyroid cells. In this study, we performed suspension culture of porcine thyroid cells and aimed to elucidate the mechanism of the effect of Tg on thyroid cells. Porcine thyroid epithelial cells were prepared from thyroid gland by enzymatic digestion and cultured in monolayer or in suspension culture. Various concentrations of Tg were added to the medium and cultured for several days. Then, the conditioned medium was collected and the amount of thyroid hormone was measured by reversed phase chromatography; the cells were harvested and mRNA levels of hormone-processing enzymes, cathepsin B, K, L and dipeptidyl peptidase I, II (DPP I, II), were measured by quantitative PCR. The amount and activation of cell signaling molecules were also evaluated by western blotting. Tg stimulated the secretion of thyroid hormone, thyroxine, from porcine thyroid cells in suspension culture, however, no stimulation by Tg was observed in monolayer culture. The expression of mRNAs of cathepsin B, K and L were reduced and that of DPP II was increased by the treatment of Tg in suspension culture. Tg increased the amount of NF-κB p52 and Rel B dose dependently. On the other hand, TSH had little effects on the amount of these proteins. Tg and TSH both activated PDK1 and MAPK p44/42 but not Akt. These results suggest that Tg regulates thyroid hormone synthesis in totally different way from TSH by altering the expression levels of hormone-processing enzymes in thyroid cells. This stimulatory effect might be mediated by NF-κB signaling pathway, whereas the proliferative effect of Tg under these conditions might be exerted via MAPK signaling pathway. The detailed mechanisms of these effects of Tg on thyroid cells are under investigation.

Interleukin-1β and TNF-α systems in ovarian follicles and their roles during follicular development, oocyte maturation and ovulation

Tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are cytokines that are involved in the development, proliferation and apoptosis of ovarian follicular cells in domestic mammals. The expression of these cytokines in various follicular compartments, depending on the stage of follicle development, demonstrates their involvement in the control of primordial follicle growth up to the preovulatory stage. The mechanism of action of these factors depends on the presence of their receptors that transduce their biological actions. This review shows the expression sites of TNF-α, IL-1β and their receptors in ovarian follicles, and discusses the mechanism of action of these cytokines during follicle development, oocyte maturation and ovulation in domestic animals.

Adiponectin is secreted by theca layer cells isolated from chicken ovarian follicles.

Adiponectin, an adipokine hormone, influences glucose utilization, insulin sensitivity and energy homeostasis by signaling through two distinct receptors, ADIPOR1 and ADIPOR2. We previously reported that adiponectin and its receptors are expressed in several organs, including testes in chicken. We report herein that adiponectin gene is expressed exclusively in theca layer while ADIPOR1 and ADIPOR2 genes are expressed in granulosa and theca layers of all preovulatory and prehierarchical follicles of the chicken ovary. Estradiol and/or progesterone treatment of sexually immature chickens significantly altered expression of adiponectin and ADIPOR1 in the ovary. Using anti-chicken adiponectin-, ADIPOR1-, or ADIPOR2- antibodies, adiponectin-immunoreactive (ir) cells were found exclusively in the theca layer, and ADIPOR1-ir and ADIPOR2-ir cells were found both in theca and granulosa layers. Theca layer cells dispersed from preovulatory and prehierarchical follicles were found to synthesize and secrete a 720 kDa heavy molecular weight (HMW) isoform of adiponectin in vitro. Recombinant chicken adiponectin (rcADN) expressed in eukaryotic cells under serum-free conditions comprised primarily of the HMW isoform. Treatment of granulosa cells dispersed from 9 to 12 mm preovulatory follicle and 6 to 8 mm prehierarchical follicle with rcADN or an adiponectin receptor agonist, adipoRon, increased pERK and pACC abundance. In addition, both rcADN and adipoRon were found to significantly decrease the expression of steroidogenic acute regulatory protein gene expression in granulosa cells of preovulatory and prehierarchical follicles. In conclusion, adiponectin secreted by theca cell layer is identical in mass to circulating adiponectin. Systemic and/or theca-derived adiponectin is likely to affect proliferation, metabolism, and steroidogenesis of ovarian follicular cells.

Effects of α-enolase gene interference expression on proliferation and apoptosis of follicular granulosa cells from Zi geese

Objective: To study the effects of α-enolase (ENO1) gene interference expression on proliferation, and cell cycle of follicular granulosa cells from Zi geese. Methods: F1 follicular granulosa cells were primary cultured (mixed culture), which were divided into four groups: ENO1 interference expression group (RNAi), unrelated sequence group (NC), culture group (Control), transfection reagent group (Lip). The apoptosis rate and cell cycle phase of the interference group and the control group were detected by the flow cytometry. Results: ENO1 gene interference expression slowed the proliferation of granulosa cells, increased the apoptosis, and increased the proportion of granulosa cells in G2/M phase. Conclusion: ENO1 gene interference expression could cause G2/M phase arrest in primary cultured goose follicular granulosa cells, induce cell apoptosis and inhibit cell proliferation.

MiR-3940-5p promotes granulosa cell proliferation through targeting KCNA5 in polycystic ovarian syndrome

Increased granulosa cell (GC) proliferation may contribute to abnormal folliculogenesis in patients with polycystic ovary syndrome (PCOS), which affects approximately 10% reproductive aged women. However, the mechanisms underlying increased GC proliferation in PCOS remain incompletely understood. In this study, we identified miR-3940-5p as a hub miRNA in GC from PCOS using weighted gene co-expression network analysis (WGCNA), and real-time polymerase chain reaction (RT-PCR) analysis confirmed that miR-3940-5p was significantly increased in GC from PCOS. Enrichment analysis of predicted target genes of miR-3940-5p indicated potential roles of miR-3940-5p in follicular development and cell proliferation regulation. Consistently, functional study confirmed that miR-3940-5p overexpression promoted granulosa cell proliferation. Integrated analysis of mRNA expression profiling data and predicted target genes of miR-3940-5p identified potassium voltage-gated channel subfamily A member 5 (KCNA5) as a potential target of miR-3940-5p, and was validated by luciferase reporter assay. Finally, functional analysis suggested that miR-3940-5p promoted GC proliferation in a KCNA5 dependent manner. In conclusion, miR-3940-5p was a hub miRNA upregulated in GC from PCOS, and promoted GC proliferation by targeting KCNA5.

Jagged1 and Epidermal Growth Factor Promoted Androgen-Suppressed Mouse Hair Growth In Vitro and In Vivo.

Recent studies have reported that T-reg cells are intimately linked with hair follicles in a stage-dependent manner and play an important role in hair follicle cycling and regeneration in murine skin. Further study revealed that T-reg cell’s regulation of hair follicle growth is through its preferential expression of the Notch ligand Jagged‐1 (Jag1), which facilitates hair follicle regeneration. However, the role of Jag1 in androgen-suppressed hair growth is yet to be investigated. In addition, although epidermal growth factor (EGF) is a mitogen for cells including skin cells, whether it works synergistically with Jag1 to enhance hair follicle development is unknown. The current study intended to investigate effects of topical application of Jag1 on androgen-suppressed hair growth, and to determine the potential synergistic effect of EGF and Jag1 in this process in vivo. Fifty mice were depilated at the dorsal back area to achieve synchronized anagen development, and randomly divided into five groups with the following topical treatments control for 14 days; testosterone to induce androgenetic alopecia; Jagged1 (testosterone + Jagged1); EGF (testosterone + EGF); and Jagged1 + EGF (testosterone + Jagged1 + EGF). It was found that EGF and Jag1 by itself respectively, did not promote androgen-suppressed hair growth significantly. This stimulating effect was enhanced in the presence of both EGF and Jagged1 (p < 0.05). The hair growth promoting effect was accompanied by better follicle growth, which is associated with increased cell proliferation in the hair follicle and altered the expression of genes that are important in hair follicular cell proliferation and differentiation. Our results provide insights into the therapeutic potential of these peptides for androgenetic alopecia.

PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells.

We aimed to investigate the role of programmed cell death protein 1 (PD-1) and T lymphocytes in the proliferation, apoptosis and secretion of cells from patients and mice with Graves' disease (GD). The levels of serum hormones, related antibodies and inflammatory cytokines in GD patients were determined by electrochemiluminescence immunoassay and ELISA. The percentages of CD4 and CD8 T-lymphocytes and PD-1 expression were examined by flow cytometry. A GD mouse model, a thyroid follicular epithelial cell, and a CD4+PD-1+, CD4+PD-1- and CD8+PD-1+, CD8+PD-1- T lymphocyte co-culture system were constructed. The viability, apoptosis-related markers, serum hormones, related antibodies and inflammatory cytokines in thyroid follicular epithelial cells were determined by CCK-8, Western blot, qTR-PCR, electrochemiluminescence immunoassay and ELISA. Elevated free thyroid hormones (FT3, FT4), thyroid hormone antibodies (TRAb, TPOAb and TGAb), inflammatory cytokines, and inhibited TSH were observed in GD patients. The percentage of CD4+ T cells was increased, while that of CD8+ T cells was reduced in GD patients. PD-1 expression level was lifted in both CD4+ and CD8+ cells from GD patients. In mouse thyroid follicular epithelial cells co-cultured with CD4+PD-1+ and CD8+PD-1+ T lymphocytes, the cell viability, TH and TRAb levels and inflammatory cytokines level were the highest, while the TSH level and apoptosis were the lowest. PD-1 positive T lymphocytes were able to promote viability and inhibit apoptosis of thyroid follicular epithelial cells, which further caused a more accelerated development of GD.

Boehmite enhances hair follicle growth via stimulation of dermal papilla cells by upregulating β-catenin signalling.

Hair growth, a complex process, has long been the subject of intense research. Recent developments in material technology have revealed boehmite as a new therapeutic modality for use in wound healing and scar reduction, indicating its beneficial effects. Nonetheless, the biological bases of the beneficial effects of boehmite remain unknown. We investigated the hair growth properties of boehmite in vitro and in vivo and observed dose-dependent proliferation of human dermal papilla cells (hDPCs) in vitro and hair regrowth in a mouse model. To investigate the effects of boehmite on the promotion of cell transition to the anagen phase, we evaluated hDPC viability, alkaline phosphatase (ALP) activity, protein expression and vascular endothelial growth factor (VEGF) secretion in vitro and assessed the anagen-promoting effects of boehmite via gross observation and histological analysis in a mouse model. Boehmite increased hDPC viability, ALP activity, AKT/GSK3ß/ß-catenin pathway activity, anagen-related gene expression and VEGF secretion; moreover, it accelerated hair regrowth in a catagen-anagen transition model via upregulation of β-catenin signalling and follicular cell proliferation. Collectively, our results indicate that boehmite accelerates hair growth, partly via its effects on critical events in the active phase of the hair follicle cycle, including the promotion of the proliferation of hDPCs and their immediate progeny to the follicle base.

Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells.

The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.

Double negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4−CD8− double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.