Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. AIM: Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. CONCLUSION: There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

In vivo investigation of the anti-liver fibrosis impact of Balanites aegyptiaca/ chitosan nanoparticles.

Balanites aegyptiaca (B. aegyptiaca) is an African herb with traditional medical applications. Various pathogenic factors cause hepatic fibrosis and require novel treatment alternatives. Nanoformulation-based natural products can overcome the available drug problems by increasing the efficacy of natural products targeting disease markers. The current study investigated B. aegyptiaca methanolic extract using high-pressure liquid chromatography (HPLC), and B. aegyptiaca/chitosan nanoparticles were prepared. In vivo, evaluation tests were performed to assess the curative effect of the successfully prepared B. aegyptiaca/chitosan nanoparticles. For 30 days, the rats were divided into six groups, typical and fibrosis groups, where the liver fibrosis groups received B. aegyptiaca extract, silymarin, chitosan nanoparticles, and B. aegyptiaca/chitosan nanoparticles daily. In the current investigation, phenolic molecules are the major compounds detected in B. aegyptiaca extract. UV showed that the prepared B. aegyptiaca /chitosan nanoparticles had a single peak at 280 nm, a particle size of 35.0 ± 6.0 nm, and a negative charge at - 8.3 mV. The animal studies showed that the synthetic B. aegyptiaca/chitosan nanoparticles showed substantial anti-fibrotic protective effects against CCl4-induced hepatic fibrosis in rats when compared with other groups through optimization of biochemical and oxidative markers, improved histological changes, and modulated the expression of Col1a1, Acta2 and Cxcl9 genes, which manage liver fibrosis. In conclusion, the current research indicated that the prepared B. aegyptiaca/chitosan nanoparticles improved histological structure and significantly enhanced the biochemical and genetic markers of liver fibrosis in an animal model.

Microenvironmental Changes in Mediastinal Fat-associated Lymphoid Clusters and Lungs in Early and Late Stages of Metastatic Lung Cancer Induction.

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.

Impact of intravenous/intranasal polyinosinic-polycytidylic acid administration on the mediastinal fat-associated lymphoid clusters and lung tissue in healthy mice.

BACKGROUND: Polyinosinic-polycytidylic acid (pIC) is a synthetic analog of double-stranded RNA. It is used as a synthetic adjuvant to induce an adaptive immune response. However, the effect of pIC on the development of mediastinal fat-associated lymphoid clusters (MFALCs) that regulate intrathoracic hemostasis has remained unidentified. METHODS: We investigated the impact of intranasal (i.n.) administration (pIC i.n. group) and intravenous (i.v.) administration (pIC i.v. group) of pIC on both MFALCs and lung tissue. RESULTS: Compared with the control phosphate-buffered saline (PBS) groups, both pIC-administered groups displayed a significant increase in the MFALC size (particularly in the pIC i.n. group), area of MFALC high endothelial venules (HEVs), area of lymphatic vessels (LVs), number of proliferating cells (particularly in the pIC i.v. group), and number of immune cells (B220+ B-lymphocytes, CD3+ T-lymphocytes, Iba1+ macrophages, and Gr-1+ granulocytes) in both MFALCs and lung tissues. In addition, a positive correlation was detected between MFALC size and proliferating cells, immune cell population, LVs, and HEVs within MFALCs in both groups. Except for the proliferating cell and B-lymphocyte populations in the i.n. administered group and granulocyte populations in both i.n. and i.v. administered routes, such correlations were significant. CONCLUSION: In all, our data indicate that local or systemic administration of pIC induces the development of MFALCs and can be used as an immunostimulant therapeutic strategy.

Parkinson's Disease Risk and Hyperhomocysteinemia: The Possible Link.

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.

Barhi date (Phoenix dactylifera) extract ameliorates hepatocellular carcinoma in male rats.

Hepatocellular carcinoma (HCC) is a malignant tumor with limited treatment options. Given this fact, it may be important to develop new molecular targeted therapies from natural products, especially those which are primary sources of effective anticancer drugs with distinct mechanisms. Moreover, the complementary use of traditional herbs or fruit may increase the possibility of finding curative options for cancer. Here we explore the anticancer effects and possible molecular mechanism of Barhi date extract using an HCC rat model. Thirty two male albino rats were arbitrarily allocated into four groups: a negative control group (NCG); a positive control group (PCG), which received CCl4 (1 ml/kg b.wt./ i.p.) twice a week for three months; a Barhi date extract (400 mg/kg b.wt./day/orally) treatment group (DTG) during the third month of CCl4 administration; and a cisplatin (1.5 mg/kg b.wt./ i.p.) treatment group ( CTG) during the third month of CCl4 administration. After treatment we performed biochemical analyses of all groups to assess relative eukaryotic initiation factor 2 alpha (eIF2α), extracellular signal-regulated kinases (ERKs), protein kinase RNA-like endoplasmic reticulum kinase (PERK), poly (ADP-ribose) polymerase (PARP), and CASPASE 3 protein content, and examined expression of the genes phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). We also performed an immunohistochemistry assay for alpha-fetoprotein (AFP). Our data showed higher PARP and CASPASE3 levels and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) in the PCG compared to the DTG and the cisplatin treatment group CTG. However, we also found a significant decrease in PTEN in the PCG relative to both the DTG and the CTG. We conclude that the anti-tumor activity of Barhi date extract may be mediated by the inhibition of cell proliferation and apoptosis via the ERK /PARP/caspase3 pathway and the AKT/ PTEN signaling pathways.

Cellular infiltration, cytokines, and histopathology of skin lesions associated with different clinical forms and stages of naturally occurring lumpy skin disease in cattle.

Lumpy skin disease (LSD) caused by the Capripoxvirus LSD virus which infects cattle, leading to a serious disease characterized by fever and the eruption of skin nodules all over the surface of the body. Our understanding of the pathogenesis of this disease is still incomplete, particularly the immunopathological alterations occurring in the skin nodules of infected animals. Therefore, we collected skin nodules from naturally infected cattle with different forms of the disease, both in the early stage of clinical infection and after disease progression. The skin samples were examined both histopathologically and immunohistochemically using a variety of antibodies targeting immune cellular markers and cytokines. As a result, the dermatohistopathology revealed orthokeratotic hyperkeratosis, vasculitis, epidermal microvesicles, and cellules claveleuses of Borrel in the early stage of infection, with the severity of the lesions correlating with the severity of the clinical disease. Meanwhile, late-stage samples had epidermal hyperkeratosis as well as dermal lymphocytic and histiocytic infiltrations. The predominant cellular infiltrates in the cutaneous lesions of early-stage LSD samples were interferon (IFN)-γ+ cells and CD4+ T lymphocytes with few macrophage lineage cells. However, in the late-stage samples, numerous Iba-1+ macrophages, with few IFN-γ+ cells and CD4+ T lymphocytes, were detected. Our findings indicate that IFN-γ+ cells, CD4+ T lymphocytes, and macrophages play a key role in the immunity against natural LSD virus infection and imply that cutaneous vasculopathy associated with LSD virus infection is an immune-mediated lesion. The current study contributes to our understanding of the pathogenesis of LSD.

Ureteral morphology and pathology during urolithiasis in cats.

Cats exhibit high susceptibility to urinary organ-related diseases. We investigated the healthy ureter morphologies and compared these with ureters that were surgically resected distal to a urolithiasis obstruction in cats. Healthy ureters (total length 9.88 ± 0.38 cm) developed adventitia composed of collagen fibers (ADCF), containing a longitudinal muscular layer, toward the distal segment. The healthy ureter was the smallest in the middle segment (4.71-6.90 cm from the urinary bladder) with significantly decreased luminal and submucosal areas compared to those in the proximal segment. Diseased cats exhibited a high incidence of calcium oxalate urolithiasis with renal dysfunction, regardless of age, sex, and body size. Diseased ureters showed increased perimeters, inflammation, and decreased nerves in ADCF. Collagen fibers were increased in the submucosal area, intermuscular spaces, and ADCF, particularly near the obstructed lesion. The mean resected ureter length was 5.66 ± 0.49 cm, suggesting a high obstruction risk in the middle segment. The middle segment also increased the cross-sectional area of the ureter and ADCF, regardless of the distance from the obstructed lesion. The ureters in several cases either lacked the transitional epithelium, or exhibited transitional epithelial hyperplasia, and some of these formed the mucosal folds. In conclusion, we demonstrated the following characteristics and histopathological features of cat ureters: decreases in the ureter size, lumen area, and submucosa area from proximal to middle segment in healthy; ADCF changes in urolithiasis, including increased connective tissues with inflammation and decreased nerves. These data are important to understand the pathogenesis of feline ureteral obstruction.

Modified foreign body reaction to silicone imbedded in subcutaneous tissues by different mouse systemic immune conditions.

Foreign body reaction (FBR) causes unexpected adverse effects due to implanted materials in humans and animals. Inflammation and subsequent fibrosis during FBR seems to be affected by recipient immunity, such as the balance of T helper (Th) response that has the potential to regulate FBR-related macrophage function. Here, the immunological effects of FBR on subcutaneously imbedded silicone tubes (ST) at 8 weeks were investigated histologically by comparing Th1-biased C57BL/6N, Th2-biased MRL/MpJ, and autoimmune disease-prone MRL/MpJ-Faslpr/lpr . Tissue surrounding ST (TSS) was analyzed at day (D) 7 and 14 (reaction phase) or D35 (stability phase) after surgery. In all strains, the TSS was composed of a thin layer (TL) containing fibrous tissues and loose connective tissues formed outside the TL. Few lymphocytes and mast cells, several neutrophils, and numerous macrophages infiltrated the TSS. Active vascularization was observed at D14 in all strains. For the examined indices, M1-type macrophage density in the TSS of C57BL/6N mice was significantly higher at D14 compared to other strains. No significant strain difference relating to M2-type macrophages was detected, suggesting the effects of Th1-biased immunity on FBR-related inflammation. Collagen fibers in the TSS increased in density and became stable with age in all strains. In particular, MRL/MpJ-Faslpr/lpr showed progressive fibrotic features. Serum autoantibody levels in MRL/MpJ-Faslpr/lpr mice were inversely correlated with M1-type macrophage density. These data from MRL/MpJ-Faslpr/lpr mice suggested modifications of FBR-related inflammation and fibrosis by autoimmune abnormalities. The results provide crucial insights into the pathological modification of FBR by recipient immunity and emphasize its clinicopathological importance in humans and animals.

Oral supplementation of policosanol alleviates carbon tetrachloride-induced liver fibrosis in rats.

Liver fibrosis is a prevalent liver disease that requires rapid and effective treatment prior to its progression to cirrhosis and liver damage. Recently, several reports have investigated the efficacy of phytotherapy using natural herbal extracts rather than synthetic drugs to treat several liver diseases. Policosanol is a herbal extract used to treat patients with cardiovascular. However, its therapeutic effect on liver fibrosis is still unknown. Therefore, the present study aimed to assess the potential antifibrotic effect of policosanol compared to silymarin and the possible underlying molecular mechanisms. Rats were categorized into four groups; negative control group "NCG", the fibrotic group "FG", silymarin treated group "STG", and policosanol treated group "PTG". Serum liver enzymes, oxidative stress markers, angiogenic growth factors, and pro-inflammatory cytokines were measured biochemically. The relative mRNA expressions of liver caspase-3 and alpha-smooth muscle actin (α-SMA) were assessed. Immunohistochemical staining was carried out using anti- α-SMA, and anti-caspase-3 antibodies. Compared to NCG, the FG group demonstrated a significant decrease in the level of serum liver enzymes "GSH, TAC, and SDF. Nevertheless, it demonstrateda significant increase in the level of pro-inflammatory cytokines "Il-6, TNF"; oxidative stress markers "NO, MDA", and angiogenic growth factors "VEGF and PDGF" and the expression of α-SMA, and Caspase-3. Interestingly, the values of these measurements were restored to normal levels in the treated groups, particularly the PTG. In conclusion, our data revealed the beneficial effects of co-administration of policosanol or silymarin on the fibrotic liver rat model and thus could be a promising natural therapeutic drug.

Histopathological Impact of Bleomycin on Lung Injury and Development of Mediastinal Fat-Associated Lymphoid Clusters in the Lymphoproliferative Mouse Model.

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.

The Ameliorative Effect of Dexamethasone on the Development of Autoimmune Lung Injury and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model.

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.

Genital organ-associated lymphoid tissues arranged in a ring in the mucosa of cow vaginal vestibules.

Female reproductive tracts are equipped with local and mucosal immune systems; however, structural information remains unclear for farm animals. In this study, the mucosa-associated lymphoid tissue-like structures in cow reproductive tracts were described. Vaginal vestibule (VV) and external parts of the genital organ, including the clitoris and vulva, were morphologically analyzed. Whole-mount specimens revealed several hematoxylin-positive spots arranged in a ring in the mucosa. Histologically, these spots were aggregated immune cells and defined as genital organ-associated lymphoid tissues (GOALTs). GOALTs were composed of lymphatic follicles (LFs) or diffuse lymphoid tissues (DLTs) at different depths of lamina propria. LFs frequently contained germinal centers. Scattered lymphocytes occupied the border area between follicles and epithelium, whereas DLTs had indefinite shapes. GOALTs contained immune cells and high endothelial venules. B cells were dominant both in LFs and DLTs. Abundant collagenous fibers were stretched across VV lamina propria, whereas reticular fibers were primarily observed in the DLT rather than LF. The epithelium covering of GOALTs was partially or fully disrupted by the invasion of immune cells toward the VV lumen. These findings suggest GOALTs function as a "genital lymphoid ring" as in Waldeyer's pharyngeal ring and act as immunological gate systems in cow reproductive tracts.

Close Association between Altered Urine-Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis.

BACKGROUND: Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear. METHODS: RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures. RESULTS: Regardless of infection, TLSs in the RP, termed urinary tract-associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development. CONCLUSIONS: TLS formation in the RP is possible and altered urine-urothelium barrier-based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

Morphological Features of the Testis among Autoimmune Mouse Model and Healthy Strains.

Autoimmune diseases play a critical role in the progression of infertility in both sexes and their severity has been reported to increase with age. However, few reports have discussed their effect on the morphological features of the testis. Therefore, we compared the morphological alterations in the testes of autoimmune model mice (MRL/MpJ-Faslpr) and the control strain (MRL/MpJ) with those of their background strain (C57BL/6N) at 3 and 6 months. Furthermore, we analyzed the changes in spermatocytes, Sertoli cells, immune cells, and Zonula occludens-1 junctional protein by immunohistochemical staining. The MRL/MpJ-Faslpr mice showed a significant increase in the serum Anti-double stranded DNA antibody level, relative spleen weight, and seminiferous luminal area when compared with other studied two strains. In contrast, a significant decrease in the relative testis weight, and numbers of both Sertoli, meiotic spermatocyte was observed in MRL/MpJ-Faslpr and MRL/MpJ mice compared with C57BL/6N mice especially at 6 months. Similarly, Zonula occludens-1 junctional protein positive cells showed a significant decrease in the same strains at 6 months. However, no immune cell infiltration could be observed among the studied three strains. Our findings suggest that the increase in autoimmune severity especially with age could lead to infertility through loss of spermatogenic and Sertoli cells, rather than the disturbance of the blood-testis barrier.

Dual Effect of Bleomycin on Histopathological Features of Lungs and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model.

Mediastinal fat-associated lymphoid clusters (MFALCs) are novel immune clusters that function in the pathogenesis of bleomycin (BLM)-induced pneumonitis in a C57BL/6 mouse model. However, we lack literature on the effects of BLM in an autoimmune disease mouse model (AIDM). In the present study, BLM sulfate (BLM group) or phosphate-buffered saline (PBS group) were intranasally administered in BXSB/MpJ-Yaa (Yaa) AIDM and its wild-type strains (BXSB/MpJ "BXSB") and the histopathology of MFALCs and lungs were examined on days 7 and 21 days. Immunohistochemical analysis was performed to detect lymphatic vessels (LVs), high endothelial venules (HEVs), proliferating, and immune cells. Furthermore, the mRNA expression of Yaa locus genes (TLR7, TLR8, Arhgap6, Msl3, and Tceanc) was detected in the lung tissues. Here, we show a dual effect of BLM on intra-thoracic immune hemostasis among Yaa AIDM and its corresponding wild-type strain (BXSB mice). The BLM group of BXSB mice displayed significantly higher values of lung injury scores (LIS) and size of MFALCs as compared with the corresponding PBS group. However, an opposite effect was detected in Yaa mice. Furthermore, Yaa mice displayed decreased serum autoantibody titers and downregulated expression of TLR7, TLR8, Msl3, and Tceanc in the lungs following BLM administration, especially on day 21. Interestingly, significant positive correlations were detected in both strains between the LIS and the size of MFALCs, LVs, HEVs, and proliferating cells. Conclusively, our findings revealed a crucial function of HEVs on the extent of lung injury and the development of MFALCs in BLM-administered Yaa AIDM and control BXSB mice with dual effects. Moreover, our data suggest that down regulation of Yaa locus genes could contribute as an important attributing factor leading to decrease in the degree of autoimmunity and lung injury in AIDM. Therefore, we suggest that genetic background contributes to BLM diversity among AIDM and the wild-type strain. Targeting some genes or venules could provide novel therapeutic approaches for some autoimmune-associated respiratory diseases via controlling the MFALCs development.

Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model.

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.

Comparison of Ovarian Morphology and Follicular Disturbances between Two Inbred Strains of Cotton Rats (Sigmodon hispidus).

Most mammalian ovarian follicles contain only a single oocyte having a single nucleus. However, two or more oocytes and nuclei are observed within one follicle and one oocyte, respectively, in several species, including cotton rat (CR, Sigmodon hispidus). The present study compared ovarian histology, focusing on folliculogenesis, between two inbred CR strains, HIS/Hiph and HIS/Mz. At 4 weeks of age, ovarian sections from both the strains were analyzed histologically. Multi-oocyte follicles (MOFs) and double-nucleated oocytes (DNOs) were observed in all stages of developing follicles in HIS/Hiph, whereas HIS/Mz had MOFs up to secondary stages and lacked DNOs. The estimated total follicles in HIS/Mz were almost half that of HIS/Hiph, but interstitial cells were well developed in HIS/Mz. Furthermore, immunostaining revealed no clear strain differences in the appearance of oocytes positive for Ki67, PCNA, and p63 in MOF or DNOs; no cell death was observed in these oocytes. Ultrastructural analysis revealed more abundant mitochondrial clouds in oocytes of HIS/Hiph than HIS/Mz. Thus, we clarified the strain differences in the CR ovary. These findings indicate that early events during folliculogenesis affect the unique ovarian phenotypes found in CRs, including MOFs or DNOs, and their strain differences.

Possible Crosstalk of the Immune Cells within the Lung and Mediastinal Fat-Associated Lymphoid Clusters in the Acute Inflammatory Lung Asthma-Like Mouse Model.

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.

Altered Renal Pathology in an Autoimmune Disease Mouse Model After Induction of Diabetes Mellitus.

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.