RESUMO
Grainyhead-like 2 (Grhl2) is a transcription factor that regulates cell adhesion genes in mammary ductal development and serves as a repressor of the epithelial-mesenchymal transition. Conversely, Ovo-like2 (Ovol2) is a target gene of Grhl2 but functions as a substitute in Grhl2-deficient mice, facilitating successful epithelial barrier formation and lumen expansion in kidney-collecting ductal epithelial cells. Our objective was to examine the expression patterns of Grhl2, Ovol2, and their associated genes during the intricate phases of mouse mammary gland development. The mRNA expression of Grhl2 and Ovol2 increased after pregnancy. We observed Grhl2 protein presence in the epithelial cell's region, coinciding with acini formation, and its signal significantly correlated with E-cadherin (Cdh1) expression. However, Ovol2 was present in the epithelial region without a correlation with Cdh1. Similarly, Zeb1, a mesenchymal transcription factor, showed Cdh1-independent expression. Subsequently, we explored the interaction between Rab25, a small G protein, and Grhl2/Ovol2. The expressions of Grhl2 and Ovol2 exhibited a strong correlation with Rab25 and claudin-4, a tight junction protein. These findings suggest that Grhl2 and Ovol2 may collaborate to regulate genes associated with cell adhesion and are crucial for maintaining epithelial integrity during the different phases of mammary gland development.
Assuntos
Lactação , Glândulas Mamárias Animais , Fatores de Transcrição , Desmame , Animais , Feminino , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Gravidez , Lactação/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/metabolismo , Claudina-4/genética , Claudina-4/metabolismo , CaderinasRESUMO
The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Resistência à Insulina , Cinurenina , Metformina , Metformina/farmacologia , Metformina/uso terapêutico , Humanos , Cinurenina/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Animais , Transdução de Sinais/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.
Assuntos
Hiper-Homocisteinemia , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Hiper-Homocisteinemia/patologia , Levodopa/metabolismo , Levodopa/farmacologia , Substância Negra/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios Dopaminérgicos/metabolismoRESUMO
The prognosis of metastatic lung melanoma (MLM) has been reported to be poor. An increasing number of studies have reported the function of several immune cells in cancer regression. Although the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of inflammatory lung lesions has been previously reported, the association between MLM progression and MFALCs development has remained unexplored. Herein, we compared the microenvironmental changes in the lungs and MFALCs among phosphate-buffered saline (PBS) and cancer groups at early (1 week) and late (2 weeks) stages following the intravenous injection of B16-F10 melanoma cells into C57BL/6 mice. Except for lung CD4+ helper T-cells and Iba1+ macrophage populations of early stage, we observed a significant increase in the proliferating and immune cell (CD20+ B-lymphocytes, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, CD16+ natural killer (NK) cells populations, area of high endothelial venules, and lung lymphatic vessels in cancer groups at both the stages as compared with the PBS groups. Furthermore, a significant positive correlation was observed between immune cell populations in MFALCs and the lungs (B- and T-lymphocytes, and NK cells in both stages). Collectively, our findings suggest a promising cancer therapeutic strategy via targeting immune cells in MFALCs.
Assuntos
Neoplasias Pulmonares , Melanoma , Camundongos , Animais , Camundongos Endogâmicos C57BL , Mediastino , PulmãoRESUMO
The purpose of this study is to elucidate the impact of bleomycin on the degree of lung injury and development of mediastinal fat-associated lymphoid clusters (MFALCs) in the lymphoproliferative mouse model (MRL/MpJ-Faslpr/lpr "Lpr") and its control strain (MRL/MpJ "MpJ"). We analyzed immune cells, the degree of proliferation, lymphatic vessels (LVs), and high endothelial venules (HEVs) in lungs and MFALCs in Lpr and MpJ mice on the 7th and 21st days following intranasal instillation of either bleomycin (BLM group) or PBS (PBS group). The BLM group showed a significant increase in the size of MFALCs, lung injury score, and positive area ratios of LVs, HEVs, and immune cells (especially macrophages, B- and T-lymphocytes) on both days 7 and 21. Interestingly, the lungs in the BLM group on day 21 showed higher collagen deposition and cellular infiltration in MpJ and Lpr, respectively. Moreover, significant positive correlations were observed between the size of MFALCs and lung injury. In conclusion, BLM could exert lung fibrosis or lymphoproliferative infiltration in chronic stages in MpJ and Lpr, respectively, and this varied effect could be due to the variations in the degree of immune cell proliferation and the development of LVs and HEVs among the studied strains.
RESUMO
In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL/MpJ-Fas lpr/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions compared to the male mice. However, the effect of Dex, an immunosuppressive drug, on both lung lesions and the development of MFALCs in Lpr mice has not been identified yet. Therefore, in this study, we compared the development of lung lesions and MFALCs in female Lpr mice that received either saline (saline group "SG") or dexamethasone (dexamethasone group "DG") in drinking water as a daily dose along with weekly intraperitoneal injections for 10 weeks. Compared to the SG group, the DG group showed a significant reduction in the levels of serum anti-dsDNA antibodies, the size of MFALCs, the degree of lung injury, the area of high endothelial venules (HEVs), and the number of proliferating and immune cells in both MFALCs and the lungs. A significant positive correlation was observed between the size of MFALCs and the cellular aggregation in the lungs of Lpr mice. Therefore, this study confirmed the ameliorative effect of Dex on the development of lung injury and MFALCs via their regressive effect on both immune cells' proliferative activity and the development of HEVs. Furthermore, the reprogramming of MFALCs by targeting immune cells and HEVs may provide a therapeutic strategy for autoimmune-disease-associated lung injury.
Assuntos
Doenças Autoimunes , Lesão Pulmonar , Nefrite Lúpica , Animais , Anticorpos Antinucleares , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Lesão Pulmonar/patologia , Nefrite Lúpica/patologia , Masculino , Mediastino/patologia , CamundongosRESUMO
The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36α, IL-36ß, IL-36γ) and antagonists (IL-36Ra, IL-38). We previously reported IL-36α overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ-Faslpr/lpr mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Faslpr/lpr mice exhibited disease onset from 3 months and severe nephritis at 6-7 months (early and late stages, respectively). Briefly, IL-36γ and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36α, IL-36ß, IL-36Ra, and IL-38 was induced in MRL/MpJ-Faslpr/lpr mice. IL-36α expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44+-activated parietal epithelial cells (PECs) also exhibited higher IL-36α-positive rates, particularly in males. IL-36ß and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36α and IL-38 positively correlated with nephritis severity. Similar to IL-36α, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ-Faslpr/lpr and healthy MRL/MpJ mice possessed IL-36Ra+ smooth muscle cells in kidney arterial tunica media at both stages. IL-36γ was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ-Faslpr/lpr mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-κB- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36α-dominant imbalance could strongly impact nephritis deterioration.
Assuntos
Interleucinas/imunologia , Rim/patologia , Nefrite/imunologia , Insuficiência Renal Crônica/imunologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , CamundongosRESUMO
The ovarian bursa is a small peritoneal cavity enclosed by the mesovarium and mesosalpinx, which surrounds the ovaries and oviductal infundibulum in mammals. The ovarian bursa is considered as the structure facilitating the transport of ovulated oocytes into the oviduct. Our previous study revealed reduced oocyte pick-up function in the oviduct of lupus-prone MRL/MpJ-Faslpr/lpr mouse, suggesting the possibility of an escape of ovulated oocytes into the peritoneal cavity, despite the presence of an almost complete ovarian bursa in the mouse. In this study, we revealed anatomical and histological characteristics of the ovarian bursa in C57BL/6 N, MRL/MpJ, and MRL/MpJ-Faslpr/lpr mice. All strains had the foramen of ovarian bursa (FOB), with a size of approximately 0.04 to 0.12 cm2 , surrounded by the ligament of ovarian bursa (LOB), which is part of the mesosalpinx. The LOB was partially lined with the cuboidal mesothelial cells and consisted of a thick smooth muscle layer in all strains. In 6-month-old MRL/MpJ-Faslpr/lpr mice, in which the systemic autoimmune abnormality deteriorated and oocyte pick-up function was impaired, the size of the FOB tended to be larger than that of other strains. Additionally, in MRL/MpJ-Faslpr/lpr mice at 6 months of age, there was infiltration by numerous immune cells in the mesosalpinx suspending the isthmus; however, the LOB prevented severe inflammation and showed deposition of collagen fibers. These results not only indicate that the FOB is a common structure within mice, but also imply the physiological function of the LOB and its role in maintaining the microenvironment around the ovary, as well as regulating healthy reproduction.
Assuntos
Doenças Autoimunes/patologia , Ovário/patologia , Oviductos/patologia , Cavidade Peritoneal/patologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Reprodução/fisiologiaRESUMO
Diabetes mellitus (DM) is a predisposing factor for renal disorder progression and is referred to as diabetic kidney disease (DKD). However, there are no reports of DKD with an underlying autoimmune disorder. In this study, we compared the pathophysiological changes caused by DM induction after streptozotocin (STZ) injection in comparison with that in a control group receiving citrate buffer (CB) in the autoimmune disease model mice "BXSB/MpJ-Yaa" (Yaa) and the wild-type strain BXSB/MpJ. Both strains showed hyperglycemia after 12 weeks of STZ injection. Interestingly, the Yaa group developed membranous and proliferative glomerulonephritis, which tended to be milder glomerular lesions in the STZ group than in the CB group, as indicated by a decreased mesangial area and ameliorated albuminuria. Statistically, the indices for hyperglycemia and autoimmune abnormalities were negatively and positively correlated with the histopathological parameters for mesangial matrix production and glomerular proliferative lesions, respectively. STZ treatment induced renal tubular anisonucleosis and dilations in both strains, and they were more severe in Yaa. Significantly decreased cellular infiltration was observed in the Yaa group compared to the CB group. Thus, in DKD related to autoimmune nephritis, hyperglycemia modifies its pathology by decreasing the mesangial area and interstitial inflammation and aggravating renal tubular injury.
Assuntos
Doenças Autoimunes , Complicações do Diabetes , Diabetes Mellitus , Glomerulonefrite , Glomérulos Renais , Animais , Modelos Animais de Doenças , Glomérulos Renais/patologia , CamundongosRESUMO
Recently, we clarified the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of several respiratory diseases. However, their role has not yet been identified in the lung asthmatic condition. Hence, we compared the immune cells in lung and MFALCs of C57BL/6N mice on days 3 and 7 following intranasal instillation of either papain (papain group "PG") or phosphate buffer saline (PBS) (vehicle group "VG"). The PG showed significantly prominent MFALCs, numerous goblet cells (GCs), and higher index ratios of different immune cells (macrophages, natural helper cells (NHC), B- and T-lymphocytes) within the MFALCs and lung than in the VG on both days 3 and 7. Interestingly, a tendency of decreased size of MFALCs and a significant reduction in the number of GCs and immune cells were observed within the MFALCs and lung in the PG on day 7 than on day 3. Furthermore, the quantitative parameters of these immune cells in MFALCs were significantly and positively correlated with the size of MFALCs and immune cells in the lung. This suggested that the possible crosstalk between immune cells within MFALCs and the lung could play a critical role in the progression and recovery of the acute inflammatory lung asthma.
Assuntos
Asma/imunologia , Pulmão/imunologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tecido Adiposo/imunologia , Animais , Células Cultivadas , Células Caliciformes/imunologia , Imunidade Inata , Masculino , Mediastino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The increased prevalence of aging-related chronic kidney disease (CKD) among humans is a problem worldwide. Aged cotton rats (Sigmodon hispidus) are considered novel model animals for studying CKD, especially as the females develop severe tubulointerstitial lesions with anemia. To investigate the renal pathologic features in aged male cotton rats and their characteristic glomerular injuries, the animals were divided into young, adult, old-aged, and advanced-aged groups (1-4, 5-8, 9-12, and 13-17 months, respectively) and pathologically analyzed. Anemia and renal dysfunction, as indicated by hematologic and serologic parameters, were significantly milder in the advanced-aged males than in the old-aged females. The males had increased urinary albumin-to-creatinine ratios from the old-age period, with the advanced-aged males having significantly higher levels than those in the old-aged females and young males. The old-aged females did not show clear glomerular injuries, whereas the advanced-aged males showed membranous lesions characterized by irregular and thickened glomerular basement membranes (GBMs). Characteristically, several large-sized projections from the GBM toward the podocytes were observed by microscopy, and podocytes covering these projections effaced their foot processes. The advanced-aged males showed aging-related IgG immune-complex depositions in the paramesangial regions and along the GBM. Furthermore, the positive reaction for podocin (a podocyte molecule) was granulated along the GBM. Thus, we clarified the albuminuria associated with altered glomerular structures in advanced-aged cotton rats, and that these phenotypes were closely associated with aging. These data help to clarify the aging-related pathogenesis of glomerular injury.
Assuntos
Albuminúria/patologia , Glomérulos Renais/patologia , Insuficiência Renal Crônica/patologia , Fatores Etários , Animais , Feminino , Masculino , Fenótipo , Ratos , SigmodontinaeRESUMO
Caspase (CASP) 3 is known as a representative effector CASP of apoptosis and recently as a mediator in inflammatory cell death called pyroptosis. Interestingly, homozygotes of Casp3 knockout (KO) mice with 129-background show complete embryonic lethality; however, some of those with C57BL/6 (B6)-background (B6.129S1-Casp3tm1Flv/J) survived at a lower rate (KO, 11%; WT, 22%), developing immune abnormality-associated renal phenotypes. Homozygotes of Casp3 KO mice with B6-background that survived for 8-12 months showed abnormality in the kidney and spleen but not in other organs. Briefly, these Casp3 KO kidneys showed proliferative glomerular lesions characterized by increased cells, matrices, immune complex depositions containing IgA and complement 3 in the mesangial area, podocyte injuries and inflammatory cell infiltrations in the tubulointerstitium. However, severe membranous lesion or renal dysfunction was not observed. Increased expression of inflammation-associated gene sets and inflammatory Casps, including Casp12, was observed in these Casp3 KO kidneys. Moreover, these Casp3 KO mice showed mild splenomegaly compared with WT mice. Thus, the long-surviving Casp3 KO mice with B6-background developed renal lesions with altered immune conditions. CASP3 deficiency and aging factors could affect this phenotype by altering the function and/or development of each cell in the kidney and immune organs.
Assuntos
Caspase 3/deficiência , Nefropatias/enzimologia , Nefropatias/imunologia , Animais , Caspase 3/genética , Caspase 3/metabolismo , Feminino , Ontologia Genética , Imunidade , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de ÓrgãosRESUMO
In mammals, the reproductive system and autoimmunity regulate mutual functions. Importantly, systemic autoimmune diseases are thought to cause male infertility but the underlying pathological mechanism remains unclear. In this study, the morpho-function of the testes in BXSB/MpJ-Yaa mice was analyzed as a representative mouse model for systemic autoimmune diseases to investigate the effect of excessive autoimmunity on spermatogenesis. At 12 and 24 weeks of age, BXSB/MpJ-Yaa mice showed splenomegaly and increased levels of serum autoantibodies, whereas no controls showed a similar autoimmune condition. In histological analysis, the enlarged lumen of the seminiferous tubules accompanied with scarce spermatozoa in the epididymal ducts were observed in some of the BXSB/MpJ-Yaa and BXSB/MpJ mice but not in C57BL/6N mice. Histoplanimetrical analysis revealed significantly increased residual bodies and apoptotic germ cells in the seminiferous tubules in BXSB/MpJ-Yaa testes without apparent inflammation. Notably, in stage XII of the seminiferous epithelial cycles, the apoptotic germ cell number was remarkably increased, showing a significant correlation with the indices of systemic autoimmune disease in BXSB/MpJ-Yaa mice. Furthermore, the Sertoli cell number was reduced at the early disease stage, which likely caused subsequent morphological changes in BXSB/MpJ-Yaa testes. Thus, our histological study revealed the altered morphologies of BXSB/MpJ-Yaa testes, which were not observed in controls and statistical analysis suggested the effects of an autoimmune condition on this phenotype, particularly the apoptosis of meiotic germ cells. BXSB/MpJ-Yaa mice were shown to be an efficient model to study the relationship between systemic autoimmune disease and the local reproductive system.
Assuntos
Apoptose , Doenças Autoimunes/patologia , Infertilidade Masculina/patologia , Espermatogênese , Testículo/citologia , Animais , Doenças Autoimunes/complicações , Modelos Animais de Doenças , Células Germinativas/citologia , Células Germinativas/patologia , Infertilidade Masculina/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testículo/patologiaRESUMO
According to our previous reports, impaired oocyte pickup was observed in the oviductal infundibulum of an autoimmune disease (AD) mouse model, suggesting a relationship between female infertility and AD. This study examines the relationship between AD and infundibulum morphofunction by focusing on the epithelial cilia. Healthy MRL/MpJ and AD-prone MRL/MpJ-Faslpr/lpr mice were examined at 3 and 6 months of age, representing early and late disease stages, respectively. Oocyte pickup indices decreased with AD progression indicated by splenomegaly, autoantibody production and increased T cell counts of infundibulum mucosa in MRL/MpJ-Faslpr/lpr mice. Ciliary beating frequency (CBF) and height in the infundibulum were faster and higher in MRL/MpJ-Faslpr/lpr mice than in MRL/MpJ mice at the early AD stages, although the absolute CBF values were lower at the late AD stage. At the late stage, ciliary height did not differ between mouse lines but the morphological index of cilia beating direction indicated randomized patterns in MRL/MpJ-Faslpr/lpr mice. The tracheal mucosa was also examined as a representative example of cilia morphology; its CBF decreased at the late AD stage in MRL/MpJ-Faslpr/lpr; however, there were no AD-related morphological changes. Our results demonstrate altered cilia motility in systemic and reproductive organs, with such morphological changes of the infundibulum likely impairing function, including oocyte pickup.
Assuntos
Doenças Autoimunes/patologia , Cílios/ultraestrutura , Células Epiteliais/ultraestrutura , Tubas Uterinas/patologia , Infertilidade Feminina/patologia , Traqueia/patologia , Animais , Cílios/patologia , Modelos Animais de Doenças , Células Epiteliais/patologia , Feminino , CamundongosRESUMO
Cotton rats (Sigmodon hispidus, CRs) are commonly used as animal models in biomedical research. However, the reproductive characteristics and ovarian development in the CRs has not been widely investigated. We have previously shown that female CRs, in particular, show several unique phenotypes associated with the urogenital system, such as chronic kidney disease and pyometra. Our investigation revealed unique morphologies in CR ovaries, particularly in oocytes. Cotton rat ovaries at 6-8 weeks of age were obtained from the Hokkaido Institute of Public Health, and their sections analyzed by light microscopy and transmission electron microscopy. Although the general histology and folliculogenesis of CR ovaries were similar to those of other experimental rodents, multi-oocyte follicles (MOFs) and double nucleated oocytes (DNOs) were also observed. Although MOFs were found at all stages of follicular development, a greater frequency of MOFs was observed in the primary and secondary stages. However, DNOs tended to be frequently observed in primordial follicles. Almost all MOF oocytes and a few DNOs possessed a clear zona pellucida, expressed DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 and Forkhead box protein 2, a representative marker of oocytes and follicular epithelial cells. Thus, our investigations revealed the unique phenotypes of the CR ovary. As MOFs and DNOs are occasionally observed in human patients with infertility, the CR would be a useful animal model to study for gaining a better understanding of folliculogenesis and oocytogenesis, as well as their abnormalities in humans and other animals.
Assuntos
Células Epiteliais/fisiologia , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/fisiologia , Ovário/crescimento & desenvolvimento , Ovário/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Oócitos/citologia , Fenótipo , Ratos , Reprodução , Sigmodontinae , Zona PelúcidaRESUMO
Obesity induces metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular diseases and has become a global health concern. Recent studies imply that fat accumulation in nonadipose tissue correlates with metabolic disorders. However, there are no suitable animal models to evaluate this phenomenon. This study investigated the characteristics of metabolic disorders found in cotton rat (Sigmodon hispidus). Blood biochemical examinations revealed that cotton rats, predominantly males, developed hyperinsulinemia, hyperglycemia, and dyslipidemia when fed a normal diet. The islets increased in size through ß-cell hyperplasia, which was associated with serum insulin level in both sexes, strongly indicating insulin resistance. In male cotton rats, oxidative stress was observed in ß cells, and macrophage infiltration into the visceral white adipose tissue was reported, both of which were associated with serum insulin level without visceral obesity. In contrast, female cotton rats developed hyperinsulinemia without histopathological changes that were reported in males. Adipocytes were found to be accumulated in the pancreas but not in the liver of both sexes during aging. Pancreatic fat accumulation was associated with the serum insulin level only in females. Taken together, cotton rats developed metabolic disorders associated with visceral fat inflammation in the absence of obesity. In addition, pancreatic ectopic fat may also be related to the early stages of these conditions. Thus, the cotton rat may serve as a novel and useful model for metabolic disorders characterized by visceral adipose inflammation and ectopic fat accumulation in the pancreas without obesity.
Assuntos
Inflamação/patologia , Gordura Intra-Abdominal/patologia , Doenças Metabólicas/patologia , Obesidade/patologia , Pâncreas/patologia , Animais , Feminino , Fígado/patologia , Masculino , Doenças Metabólicas/sangue , SigmodontinaeRESUMO
BACKGROUND: Aryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions. Transgenic mice systemically expressing constitutively-active AhR (CA-AhR) have been created to mimic activated AhR signaling in vivo. However, their detailed histopathological features are unclear. In the present study, we generated CA-AhR-expressing FVB/N mice (FVB-CA-AhR mice) and clarified their phenotypes in detail. METHODS: Male and female FVB-CA-AhR and wild-type mice were histopathologically examined from 6 to 33 weeks of age. RESULTS: Among the systemic organs, only the stomachs in FVB-CA-AhR mice showed pathological changes including cystic structures beneath the serosa; in addition, stomach weights increased with age. Histopathologically, cystic structures and alcian blue-positive metaplasia were observed in the mucosa of the proper gastric glands, and these two histometric parameters were positively correlated. Furthermore, proliferating cells shifted from the isthmus to the base of the glands, and parietal cells decreased. Age-related histopathological changes were clearer in females than in males. Importantly, in FVB-CA-AhR mice, intramucosal cysts developed as extramucosal cysts beneath the serosa, penetrating the lamina muscularis mucosae and the muscularis propria. Their incidence reached 100% in 28-week-old male mice and 33-week-old female mice. Extramucosal cysts contained alcian blue-, Griffonia simplicifolia lectin II-, or trefoil factor 2-positive cells, suggesting a stomach origin for the cysts and spasmolytic polypeptide-expressing metaplasia-like lesions. CONCLUSIONS: Disease onset occurred earlier in FVB-CA-AhR mice than previously reported in C57BL/6-derived CA-AhR mice. Importantly, the histopathological features were partly similar with gastritis cystica profunda in humans and animals. Excessive activation of AhR signaling aggravated abnormalities in the gastric mucosa and were affected by both genetic- and sex-related factors.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cistos/patologia , Mucosa Gástrica/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Azul Alciano , Animais , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Lectinas de Plantas/metabolismo , Transdução de Sinais , Fator Trefoil-2/metabolismoRESUMO
BACKGROUND: The renal vasculature plays important roles in both homeostasis and pathology. In this study, we examined pathological changes in the renal microvascular in mouse models of kidney diseases. METHODS: Glomerular lesions (GLs) in autoimmune disease-prone male BXSB/MpJ-Yaa (Yaa) mice and tubulointerstitial lesions (TILs) in male C57BL/6 mice subjected to unilateral ureteral obstruction (UUO) for 7 days were studied. Collected kidneys were examined using histopathological techniques. A nonparametric Mann-Whitney U test (P < 0.05) was performed to compare healthy controls and the experimental mice. The Kruskal-Wallis test was used to compare three or more groups, and multiple comparisons were performed using Scheffe's method when significant differences were observed (P < 0.05). RESULTS: Yaa mice developed severe autoimmune glomerulonephritis, and the number of CD34+ glomerular capillaries decreased significantly in GLs compared to that in control mice. However, UUO-treated mice showed severe TILs only, and CD34+ tubulointerstitial capillaries were decreased significantly in TILs with the progression of tubulointerstitial fibrosis compared to those in untreated control kidneys. Infiltrations of B-cells, T-cells, and macrophages increased significantly in the respective lesions of both disease models (P < 0.05). In observations of vascular corrosion casts by scanning electron microscopy and of microfil rubber-perfused thick kidney sections by fluorescence microscopy, segmental absences of capillaries were observed in the GLs and TILs of Yaa and UUO-treated mice, respectively. Further, transmission electron microscopy revealed capillary endothelial injury in the respective lesions of both models. The numbers of CD34+ glomerular and tubulointerstitial capillaries were negatively correlated with all examined parameters in GLs (P < 0.05) and TILs (P < 0.01), respectively. CONCLUSIONS: From the analysis of mouse models, we identified inverse pathological correlations between the number of local capillaries in GLs and TILs and the severity of kidney diseases.
Assuntos
Antígenos CD34/metabolismo , Capilares/metabolismo , Modelos Animais de Doenças , Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais/metabolismo , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Capilares/patologia , Glomerulonefrite/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Índice de Gravidade de DoençaRESUMO
We previously discovered mediastinal fat-associated lymphoid clusters (MFALCs) as novel lymphoid clusters associated with mediastinal fat tissue in healthy mice. However, no data about their morphology in immune-associated disease conditions, and their relationship with lung infiltration, is available to date. In the present study, we compared the morphological features of MFALCs in 4-month-old male murine autoimmune disease models (MRL/MpJ-lpr mice and BXSB/MpJ-Yaa mice) with those of the corresponding control strains (MRL/MpJ and BXSB/MpJ, respectively). In addition, we analysed their correlation with lung infiltration. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1 and BrdU was performed to detect T cells and B cells, macrophages, granulocytes and proliferating cells, respectively. The spleen weight to body weight ratios and anti-double-stranded DNA autoantibody titres were found to be significantly higher in the autoimmune models than in the control strains. Furthermore, the autoimmune model presented prominent MFALCs, with a significantly greater ratio of lymphoid cluster area to total mediastinal fat tissue area, and more apparent diffused cellular infiltration into the lung lobes than the other studied strains. Higher numbers of T and B cells, macrophages and proliferating cells, but fewer granulocytes, were observed in the autoimmune models than in the control strains. Interestingly, a significant positive Pearson's correlation between the size of the MFALCs and the density of CD3-, B220- and Iba1-positive cells in the lung was observed. Therefore, our data suggest a potentially important role for MFALCs in the progression of lung disease. However, further investigation is required to clarify the pathological role of MFALCs in lung disease, especially in inflammatory disorders.
Assuntos
Tecido Adiposo/imunologia , Doenças Autoimunes/imunologia , Movimento Celular , Pulmão/imunologia , Linfócitos/imunologia , Tecido Adiposo/metabolismo , Animais , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Biomarcadores/metabolismo , Complexo CD3/imunologia , Complexo CD3/metabolismo , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Imuno-Histoquímica , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Linfócitos/metabolismo , Masculino , Mediastino , Camundongos Endogâmicos MRL lpr , Proteínas dos Microfilamentos/imunologia , Proteínas dos Microfilamentos/metabolismo , Baço/imunologia , Baço/metabolismoRESUMO
The cotton rat (Sigmodon hispidus) is a laboratory rodent that has been used for studies on human infectious diseases. In the present study, we observed that female cotton rats, not the male cotton rats, developed chronic anemia characterized by reduced red blood cell, hemoglobin, and hematocrit levels from 5 to 9 months of age without any changes in the mean corpuscular hemoglobin and volume levels. In peripheral blood, the reticulocyte count did not increase in response to anemia in female cotton rats, and no extramedullary hematopoiesis was observed in the liver or spleen. Further, the serum levels of urea nitrogen and creatinine increased from 5 to 9 months of age in female cotton rats compared to male cotton rats, and these increases became more prominent from 10 months of age onward, indicating chronic kidney disease. Histopathologically, female cotton rats manifested tubulointerstitial lesions characterized by the infiltration of mononuclear cells, including plasma cells and CD3(+) T-cells, as well as the dilation of calbindin-D28k(+) distal tubules from 5 to 9 months of age. The severity of these lesions progressed from 10 months of age onward, and renal fibrotic features and numerous tubular cysts appeared without any obvious glomerular lesions. A significant decrease in the erythropoietin protein levels was observed in the kidney of aged female cotton rats, and significant correlations were detected between anemia and tubulointerstitial damage. These results suggest that aged female cotton rats chronically develop renal anemia, and this rodent may serve as a novel model to elucidate its pathogenesis.