Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice

Experimental autoimmune encephalomyelitis (EAE) was induced in a mouse model (C57/BL6) to investigate the antioxidant status of animals at various clinical stages of the disease. For this purpose, blood, brain and spinal cord samples from EAE mice were collected and examined at different scores following post-immunization with myelin oligodendrocyte glycoprotein (MOG). The clinical sign of mobility of animals on different days was associated with gradual increase in lipid peroxidation products (malondialdehyde, i.e. MDA) in brain and spinal cord. Changes in lipid peroxidation during EAE progression was inversely related to superoxide dismutase (SOD) activity in erythrocyte preparation. However, suppression of catalase in erythrocytes, tissue glutathione (GSH) and plasma total antioxidant capacity (FRAP assay) were the early events in EAE, occurred during scores 1 and 2. Biochemical alterations were corroborated with histopathological observations showing demyelination and inflammatory foci in central nervous system (CNS) of animals suffering from partial hind limb paralysis (score 3). These data suggest that generation of MDA in CNS is a continuous process during EAE induction and suppression of antioxidant factors are early events of the disease, but crucial in increasing the vulnerability of CNS to demyelinating lesions.     

Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)

The aptly named inflammasomes are powerful signaling complexes that sense inflammatory signals under a myriad of conditions, including those from infections and endogenous sources. The inflammasomes promote inflammation by maturation and release of the pro‐inflammatory cytokines, IL‐1β and IL‐18. Several inflammasomes have been identified so far, but this review focuses mainly on the NLRP3 inflammasome. By still ill‐defined activation mechanisms, a sensor molecule, NLRP3 (NACHT, LRR and PYD domains‐containing protein 3), responds to danger signals and rapidly recruits ASC (apoptosis‐associated speck‐like protein containing a CARD) and pro‐caspase‐1 to form a large oligomeric signaling platform—the inflammasome. Involvement of the NLRP3 inflammasome in infections, metabolic disorders, autoinflammation, and autoimmunity, underscores its position as a central player in sensing microbial and damage signals and coordinating pro‐inflammatory immune responses. Indeed, evidence in patients with multiple sclerosis (MS) suggests inflammasome activation occurs during disease. Experiments with the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), specifically describe the NLRP3 inflammasome as critical and necessary to disease development. This review discusses recent studies in EAE and MS which describe associations of inflammasome activation with promotion of T cell pathogenicity, infiltration of cells into the central nervous system (CNS) and direct neurodegeneration during EAE and MS.     

Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse

Chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti‐myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1‐related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti‐complement agents might be of benefit in MS.     

Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation,demyelination and axonal injury in experimental autoimmune encephalomyelitis mice

Clinicopathological paradox has hampered significantly the effective assessment of the efficacy of therapeutic intervention for multiple sclerosis. Neuroimaging biomarkers of tissue injury could guide more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging‐derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by the complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel technique of diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T‐cell expansion in a non‐cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing–remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. The therapeutic efficacy of Lenaldekar treatment was evaluated via daily clinical score, cross‐sectional ex vivo diffusion basis spectrum imaging examination and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging‐derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axonal injury, myelin integrity and inflammation‐associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation. Copyright © 2014 John Wiley & Sons, Ltd.     

The effect of Nigella sativa extract on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs

OBJECTIVE:

To examine the preventive effect of a hydro-ethanolic extract of Nigella sativa on the tracheal responsiveness and white blood cell count in the lung lavage fluid of sensitized guinea pigs.

METHODS:

Three groups of guinea pigs sensitized to intraperitoneally injected and inhaled ovalbumin were given drinking water alone (group S), drinking water containing a low concentration of N. sativa extract (group S+LNS) or drinking water containing a high concentration of N. sativa extract (group S+HNS). The tracheal responses of control animals (group C) and the three groups of sensitized guinea pigs (n = 7 for all groups) to methacholine were measured by the assessment of the tracheal smooth muscle response to increasing concentrations of methacholine, and the effective concentration causing 50% of the maximum response (EC₅₀) was determined. Tracheal responses to 0.1% ovalbumin and white blood cell counts in the lung lavage fluid were also examined.

RESULTS:

The tracheal response of the group S guinea pigs to both methacholine and ovalbumin was significantly higher than the response of the controls (p<0.01 for both cases). The tracheal responses of the S+LNS and S+HNS groups to both methacholine and ovalbumin were significantly decreased compared to those of the S group (p<0.05 to p<0.01). The total white blood cell and eosinophil counts in the lung lavage fluid of group S were significantly higher than those of group C (p<0.01). The white blood cell counts in both treated groups showed significant improvements (p<0.01 for both cases).

CONCLUSIONS:

These results demonstrate the preventive effect of the N. sativa extract on the tracheal response and lung inflammation in sensitized guinea pigs.     

Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

OBJECTIVESThis study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers.METHODS:Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration.RESULTSNigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO.CONCLUSION:The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension.     

Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate

The respective roles of inflammatory and neurodegenerative processes in the pathology of multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. Novel treatment strategies aim to operate within the CNS to induce neuroprotection and repair processes in addition to their anti-inflammatory properties. In this study we analyzed and compared the in situ pathological manifestations of EAE utilizing two different models, namely the relapsing-remitting PLP-induced and the chronic MOG-induced diseases. To characterize pathological changes, both transmission electron microscopy (TEM) and immunohistochemistry were employed. The effect of the approved MS drug glatiramer acetate (GA, Copaxone) on myelin damage/repair and on motor neuron loss/preservation was studied in both EAE models. Ultrastructural spinal cord analysis revealed multiple white matter damage foci, with different patterns in the two EAE models. Thus, the relapsing-remitting model was characterized mainly by widespread myelin damage and by remyelinating fibers, whereas in the chronic model axonal degeneration was more prevalent. Loss of lower motor neurons was manifested only in mice with chronic MOG-induced disease. In the GA-treated mice, smaller lesions, increased axonal density and higher prevalence of normal appearing axons were observed, as well as decreased demyelination and degeneration. Furthermore, quantitative analysis of the relative remyelination versus demyelination, provides for the first time evidence of significant augmentation of remyelination after GA treatment. The loss of motor neurons in GA-treated mice was also reduced in comparison to that of EAE untreated mice. These effects were obtained even when GA treatment was applied in a therapeutic schedule, namely after the appearance of clinical symptoms. Hence, the remyelination and neuronal preservation induced by GA are in support of the neuroprotective consequences of this treatment.     

Evaluation of the protective effect of Nigella sativa extract and its primary active component thymoquinone against DMBA-induced breast cancer in female rats

Introduction

The historical use of black cumin seed (Nigella sativa) dates back centuries, being embedded in Arabian culture and having a long history of unsurpassed medicinal value with versatility to treat a wide range of ailments. Thymoquinone (TQ) is now known to be the primary active constituent of black cumin seed oil (BCS oil) responsible for its medicinal effects and also showing promise for treatment of cancer.

Material and methods

In the current study, we have studied the effects of TQ and BCS oil on tumor markers (MDA, LDH, ALP and AST), histopathological alterations and the regulation of several genes (Brca1, Brca2, Id-1 and P53 mutation) related to breast cancer in female rats induced by 7,12-dimethylbenz[a]anthracene (DMBA) treatment. Rats received a single dose (65 mg/kg b.w.) of DMBA via an intragastric tube to induce breast cancer. Animals that received DMBA were treated orally with 1, 5, 10 mg/kg of TQ or BCS oil via an intragastric tube three times per week for 4 months.

Results

We found that TQ and then BCS reduced the rate of tumor markers (levels of MDA and LDH as well as ALP and AST activities), inhibited the histopathological alterations and decreased the expression of the Brca1, Brca2, Id-1 and P53 mutations in mammary tissues of female rats induced by DMBA treatment.

Conclusions

The results suggest that TQ and BCS oil exert a protective effect against breast carcinogens. The antioxidant property of TQ and BCS oil is mediated by their actions and investigating other underlying mechanisms merits further studies.     

Oral administration of probiotic bacteria,Lactobacillus casei and Bifidobacterium breve,does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis

To evaluate the safety of two probiotic bacterial strains, Lactobacillus casei strain Shirota (LcS) and Bifidobacterium breve strain Yakult (BbY), these probiotics were orally administered to Lewis rats with experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We examined three experimental designs by combining different antigen types and probiotic administration periods: (1) EAE was induced with a homogenate of guinea pig spinal cord as the sensitizing antigen, and LcS was orally administered from one week before this sensitization until the end of the experiment; (2) EAE was induced using guinea pig originated myelin basic protein (MBP) as the sensitizing antigen, and LcS was orally administered from one week before this sensitization to the end of the experiment; (3) EAE was induced using guinea pig MBP as the sensitizing antigen, and the probiotic strains (LcS and BbY) were administered starting in infancy (two weeks old) and continued until the end of the experiment. In experiment 1, oral administration of LcS tended to suppress the development of neurological symptoms. Differences in neurological symptoms between the control group and the administration groups did not reach statistical significance in experiments 2 and 3. These results support the notion that neither LcS nor BbY exacerbates autoimmune disease.     

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

IL‐22 is an alpha‐helical cytokine which belongs to the IL‐10 family of cytokines. IL‐22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL‐22 receptor is expressed primarily by non‐haematopoietic cells. IL‐22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL‐22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL‐22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL‐22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL‐22 modulation on the EAE course. IL‐22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN‐γ+IL‐17A+Th17 cells into the central nervous system (CNS). The neutralization of IL‐22 did not alter the EAE pathology significantly. We show that IL‐22‐mediated protection is independent of Reg3γ, an epithelial cell‐derived antimicrobial peptide induced by IL‐22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN‐γ+IL‐17A+ and IL‐17A+GM‐CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL‐2‐mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL‐22 and IL‐22‐induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.     

FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage

FTY720 (fingolimod) is an oral sphingosine-1 phosphate (S1P) receptor modulator in phase III development for the treatment of multiple sclerosis. To further investigate its mode of action, we analyzed gene expression in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). FTY720 downregulated inflammatory genes in addition to vascular adhesion molecules. It decreased the matrix metalloproteinase gene MMP-9 and increased its counterregulator—tissue inhibitor of metalloproteinase, TIMP-1—resulting in a proteolytic balance that favors preservation of blood-brain-barrier (BBB) integrity. Furthermore, FTY720 reduced S1P lyase that increases the S1P concentration in the brain, in line with a marked reversal of neurological deficits and raising the possibility for enhanced triggering of S1P receptors on resident brain cells. This is accompanied by an increase in S1P₁ and S1P₅ in contrast with the attenuation of S1P₃ and S1P₄. Late-stage rescue therapy with FTY720, even up to 1 month after EAE onset, reversed BBB leakiness and reduced demyelination, along with normalization of neurologic function. Our results indicate rapid blockade of ongoing disease processes by FTY720, and structural restoration of the CNS parenchyma, which is likely caused by the inhibition of autoimmune T cell infiltration and direct modulation of microvascular and/or glial cells.     

Phospholipase D1 mediates lymphocyte adhesion and migration in experimental autoimmune encephalomyelitis

Lymphocyte adhesion and subsequent trafficking across endothelial barriers are essential steps in various immune‐mediated disorders of the CNS, including MS. The molecular mechanisms underlying these processes, however, are still unknown. Phospholipase D1 (PLD1), an enzyme that generates phosphatidic acid through hydrolysis of phosphatidylcholine and additionally yields choline as a product, has been described as regulator of the cell mobility. By using PLD1‐deficient mice, we investigated the functional significance of PLD1 for lymphocyte adhesion and migration in vitro and after myelin oligodendrocyte glycoprotein (MOG)_35–55‐induced EAE, a model of human MS. The lack of PLD1 reduced chemokine‐mediated static adhesion of lymphocytes to the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM‐1) and intercellular adhesion molecule 1 (ICAM‐1) in vitro, and was accompanied by a decreased migratory capacity in both blood brain barrier and cell migration models. Importantly, PLD1 is also relevant for the recruitment of immune cells into the CNS in vivo since disease severity after EAE was significantly attenuated in PLD1‐deficient mice. Furthermore, PLD1 expression could be detected on lymphocytes in MS patients. Our findings suggest a critical function of PLD1‐dependent intracellular signaling cascades in regulating lymphocyte trafficking during autoimmune CNS inflammation.     

Progesterone modulates cadmium-induced oxidative stress and inflammation in hepatic tissues of Wistar rats

In recent times, there has been an increased risk of human exposure to cadmium especially in developing countries. We studied the role of progesterone as an anti-inflammatory and antioxidant agent in cadmium induced toxicity. Cadmium toxicity was induced with cadmium chloride (30 mg/kg) per oral while the control group was given distilled water. The Cd group was given CdCl₂ only, P₄ group; progesterone only (10 mg/kg intraperitoneally) and Cd+P₄ group; CdCl₂ and progesterone. All treatments lasted for 21 days. Following sacrifice, liver function tests and antioxidant status were assessed using standard kits; TNFα was immunolocalized across the study groups and the staining intensity measured using Image J software. Cadmium administration induced oxidative stress by a significant elevation in MDA and GC6P levels and a significant reduction in SOD, CAT, and GSH. These were attenuated by progesterone administration. While cadmium exposure caused an increase in serum ALT, AST, and ALP activities, progesterone significantly alleviated these effects. Inflammation shown by significant immunoreactivity in the TNFα positive cells in the liver in the cadmium group was reversed by progesterone. We conclude that cadmium toxicity induces oxidative stress that was attenuated by progesterone.     

Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex plays a role in both canonical and noncanonical autophagy, key processes that control immune-cell responsiveness to a variety of stimuli. Our previous studies found that PIK3C3 is a critical regulator that controls the development, homeostasis, and function of dendritic and T cells. In this study, we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice. We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex (MHC) class I and class II molecules. In addition, myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4. Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery (initiation/nucleation) of the classical autophagy pathway. Consequently, myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis (EAE), a primarily CD4⁺ T-cell-mediated mouse model of multiple sclerosis (MS). This disease protection was associated with reduced accumulation of myelin-specific CD4⁺ T cells in the central nervous system and decreased myeloid cell IL-1β production. Further, administration of SAR405, a selective PIK3C3 inhibitor, delayed disease progression. Collectively, our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE. Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.     

Combination therapy of Nigella sativa and human parathyroid hormone on bone mass, biomechanical behavior and structure in streptozotocin-induced diabetic rats

Extracts of the seeds of Nigella sativa (NS), an annual herbaceous plant of the Ranunculaceae family, have been used for many years for therapeutic purposes, including their potential anti-diabetic properties. The aim of the present study was to test the hypothesis that combined treatment with NS and human parathyroid hormone (hPTH) is more effective than treatment with NS or hPTH alone in improving bone mass, connectivity, biomechanical behaviour and strength in insulin-dependent diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) at a single dose of 50mg/kg. The diabetic rats received NS (2ml/kg/day, i.p.), hPTH (6microg/kg/day, i.p.) or NS and hPTH combined for 4 weeks, starting 8 weeks after STZ injection. The beta-cells of the pancreatic islets of Langerhans were examined by immunohistochemical methods. In addition, bone sections of femora were processed for histomorphometry and biomechanical analysis. In diabetic rats, the beta-cells were essentially negative for insulin-immunoreactivity. NS treatment (alone or in combination with hPTH) significantly increased the area of insulin immunoreactive beta-cells in diabetic rats; however, hPTH treatment alone only led to a slightly increase in the insulin-immunoreactivity. These results suggest that NS might be used in a similar manner to insulin as a safe and effective therapy for diabetes and might be useful in the treatment of diabetic osteopenia.     

TGF‐β regulation of encephalitogenic and regulatory T cells in multiple sclerosis

Transforming growth factor beta (TGF‐β) is a pleiotropic cytokine that has been shown to influence the differentiation and function of T cells. The role that TGF‐β plays in immune‐mediated disease, such as multiple sclerosis (MS), has become a major area of investigation since CD4⁺ T cells appear to be a major mediator of autoimmunity. This review provides an analysis of the literature on the role that TGF‐β plays in the generation and regulation of encephalitogenic and regulatory T cells (Treg) in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as well as in T cells of MS patients. Since TGF‐β plays a major role in the development and function of both CD4⁺ effector and Treg, which are defective in MS patients, recent studies have found potential mechanisms to explain the basis for these T‐cell defects to establish a foundation for potentially modulating TGF‐β signaling to restore normal T‐cell function in MS patients.     

2-BFI对EAE大鼠的神经保护作用及其免疫调节机制

目的探讨2-（2-苯并呋喃基）-2-咪唑啉[2-（-2-benzofuranyl）-2-imidazoline,2-BFI]干预大鼠实验性自身免疫性脑脊髓炎（ EAE）免疫调节机制。方法50只雌性SD大鼠随机分为5组：对照组、EAE组、2-BFI 低剂量组（1．5 mg/kg ）、2-BFI 中剂量组（3 mg/kg ）和2-BFI 高剂量组（6 mg/kg）。采用豚鼠脊髓匀浆（ GPSCH）免疫诱导建立EAE模型。通过观察大鼠行为学变化进行临床症状评分;采用HE染色观察中枢神经系统（ CNS）的炎性浸润;采用免疫组化观察腰髓中激活的星形胶质细胞和小胶质细胞细胞数量;用酶联免疫吸附法（ ELISA ）检测颈髓中IL-1β、IFN-γ、IL-4和IL-10的含量。结果与EAE组比较,大、中、小剂量2-BFI组大鼠EAE发病率下降,临床症状减轻,潜伏期延长,CNS内炎性细胞浸润减少,但仅中剂量3 mg/kg 2-BFI组在EAE临床症状和病理学改变方面差异有统计学意义（P＜0．05）;免疫组化结果显示,与EAE组比较,中剂量2-BFI组的活化的小胶质细胞数量显著减少,活化的星形胶质细胞数量显著增多（P＜0．05）;组织ELISA结果显示,与EAE组比较,2-BFI干预后,脊髓中的IL-1β、IFN-γ下降, IL-4和IL-10水平上升,中剂量2-BFI 组最为显著（ P＜0．05）。结论中剂量2-BFI对EAE大鼠具有神经保护作用,其作用机制可能与免疫调节作用有关。     

Antidiabetic effects of Corni Fructus extract in streptozotocin-induced diabetic rats

Purpose

Diabetes is the leading cause of end-stage renal failure. The present study was undertaken to characterize the effects of Corni Fructus on diabetic nephropathy in streptozotocin-induced diabetic rats and their mechanisms.

Materials and Methods

Streptozotocin-diabetic rats were orally administrated with Corni Fructus at a dose of 100, 200 or 400 mg/kg body mass for 40 days.

Results

Corni Fructus-treated diabetic rats showed significant decreases of blood glucose, urinary protein levels and water consumption. Corni Fructus also reduced serum total cholesterol, total triglyceride and low-density lipoprotein cholesterol levels, and showed a tendency of enhancing high-density lipoprotein cholesterol level. Levels of serum albumin and creatinine in diabetic rats were also significantly reduced by Corni Fructus administration at a dose of 200 and 400 mg/kg body mass compared with non-treated diabetic rats. Corni Fructus increased catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidose (GSH-px) activities in the kidneys of diabetic rats. Furthermore, Corni Fructus treatment enhanced renal peroxisome proliferator-activated receptor-γ (PPARγ) expression in diabetic rats.

Conclusion

These results demonstrated that Corni Fructus may have the potential to protect the animals from diabetic nephropathy by amelioration of oxidative stress and stimulation of PPARγ expression.     

Peripheral T cell lymphoma,not otherwise specified with myelofibrosis: report of a case with review of the literature

A 68-year-old man presented to us with pancytopenia, erythroderma, and multiple lymphadenopathies. Lymph node biopsy led to the diagnosis of peripheral T-Cell lymphoma-not otherwise specified (PTCL-NOS). Immunostaining of the lymph node biopsy specimens for cytokines revealed that the tumor cells were positive for plated-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-2 (IL-2), and transforming growth factor-β (TGF-β). Bone marrow biopsy revealed infiltration by the PTCL-NOS and myelofibrosis (MF). Bone marrow blood was negative for JAK-2V617F. Bone marrow immunostaining for cytokines showed that the tumor cells were positive for PDGF, b-FGF, VEGF, TNF-α, IFN-γ, IL-1β, IL-2, and TGF-β. The patient was initiated on treatment, and after the first course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF improved. Repeat immunostaining of bone marrow biopsy specimens for cytokines showed that the tumor cells had become negative for PDGF, VEGF, TNF-α and TGF-β. However, after the second course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF worsened. Immunostaining of bone marrow specimens for cytokines again revealed positive staining results of the tumor cells for PDGF, TNF-α, and TGF-β. At the completion of the first course of treatment, the infiltration by the PTCL-NOS improved, but not the pancytopenia.     

Pentraxin‐3 is upregulated in the central nervous system during MS and EAE,but does not modulate experimental neurological disease

Pentraxin‐3 (PTX3), an acute‐phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2‐mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti‐inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3‐deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.