Intranasal AdipoRon Mitigated Anxiety and Depression-Like Behaviors in 6-OHDA-Induced Parkinson 's Disease Rat Model: Going Beyond Motor Symptoms.

Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10 µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1ß), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC.

Bone marrow-derived c-kit positive stem cell administration protects against diabetes-induced nephropathy in a rat model by reversing PI3K/AKT/GSK-3ß pathway and inhibiting cell apoptosis.

Stem cell-based therapy has been proposed as a novel therapeutic strategy for diabetic nephropathy. This study was designed to evaluate the effect of systemic administration of rat bone marrow-derived c-kit positive (c-kit+) cells on diabetic nephropathy in male rats, focusing on PI3K/AKT/GSK-3ß pathway and apoptosis as a possible therapeutic mechanism. Twenty-eight animals were randomly classified into four groups: Control group (C), diabetic group (D), diabetic group, intravenously received 50 µl phosphate-buffered saline (PBS) containing 3 × 105 c-kit- cells (D + ckit-); and diabetic group, intravenously received 50 µl PBS containing 3 × 105 c-Kit positive cells (D + ckit+). Control and diabetic groups intravenously received 50 µl PBS. C-kit+ cell therapy could reduce renal fibrosis, which was associated with attenuation of inflammation as indicated by decreased TNF-α and IL-6 levels in the kidney tissue. In addition, c-kit+ cells restored the expression levels of PI3K, pAKT, and GSK-3ß proteins. Furthermore, renal apoptosis was decreased following c-kit+ cell therapy, evidenced by the lower apoptotic index in parallel with the increased Bcl-2 and decreased Bax and Caspase-3 levels. Our results showed that in contrast to c-kit- cells, the administration of c-kit+ cells ameliorate diabetic nephropathy and suggested that c-kit+ cells could be an alternative cell source for attenuating diabetic nephropathy.

Type 2 diabetes mellitus stimulated pulmonary vascular inflammation and exosome biogenesis in rats.

It has been shown that type 2 Diabetes Mellitus (T2DM) changes the paracrine activity of several cell types. Whether the biogenesis of exosomes is changed during diabetic conditions is the subject of debate. Here, we investigated the effect of T2M on exosome biogenesis in rat pulmonary tissue. Rats received a high-fat diet regime and a single low dose of Streptozocin to mimic the T2DM-like condition. A total of 8 weeks after induction of T2DM, rats were subjected to several analyses. Besides histological examination, vascular cell adhesion molecule 1 (VCAM-1) levels were detected using immunohistochemistry (IHC) staining. Transcription of several genes such as IL-1ß, Alix, and Rab27b was calculated by real-time polymerase chain reaction assay. Using western blot analysis, intracellular CD63 levels were measured. The morphology and exosome secretion activity were assessed using acetylcholinesterase (AChE) assay and scanning electron microscopy, respectively. Histological results exhibited a moderate-to-high rate of interstitial pneumonia with emphysematous changes. IHC staining showed an increased VCAM-1 expression in the diabetic lungs compared with the normal conditions (p < .05). Likewise, we found the induction of IL-1ß, and exosome-related genes Alix and Rab27b under diabetic conditions compared with the control group (p < .05). Along with these changes, protein levels of CD63 and AChE activity were induced upon the initiation of T2DM, indicating accelerated exosome biogenesis. Taken together, current data indicated the induction of exosome biogenesis in rat pulmonary tissue affected by T2DM. It seems that the induction of inflammatory niche is touted as a stimulatory factor to accelerate exosome secretion.

Intra-tracheal delivery of mesenchymal stem cell-conditioned medium ameliorates pathological changes by inhibiting apoptosis in asthmatic rats.

BACKGROUND: Asthma, an inflammatory illness of the lungs, remains the most common long-term disease amongst children. This study tried to elaborate the status of apoptosis in asthmatic pulmonary niche after the application of rat mesenchymal stem cells (MSC-CM)-derived secretome. METHODS AND RESULTS: Here, we randomly allocated male Wistar rats into three groups (n = 8); Control animals were intratracheally given 50 µl vehicle. In control-matched sensitized rats, 50 µl normal saline was used. In the last group, 50 µl MSC-CM was applied. Two-week post-administration, transcription of T-bet, GATA-3, Bax, Bcl-2 and Caspase-3 was measured by gene expression analysis. Pathological injuries were monitored using H&E staining. The BALF level of TNF-α was measured using ELISA assay. In asthmatic rats received MSC-CM, the expression of T-bet was increased while the level of GATA-3 decreased compared to the S group (p < 0.05). Levels of BALF TNF-α were suppressed in asthmatic niche after MSC-CM administration (p < 0.05). Compared to the asthmatic group, MSC-CM had potential to alter the expression of apoptosis-related genes in which the expression of Bax and Caspase 3 was decreased and the expression of pro-survival factor, Bcl-2 increased (p < 0.05). CONCLUSION: Our data notified the potency of direct administration of MSC-CM in the alleviation of airway inflammation, presumably by down regulating apoptotic death in pulmonary niche.

Chronic asthmatic condition modulated the onset of aging in bone marrow mesenchymal stem cells.

The emergence of an inflammatory condition such as asthma could affect the therapeutic potential of stem cells. Synopsis of previous documents yielded controversial outcomes, leading to a limitation of stem cell-based therapy in the clinical setting. This study aimed to assess the impact of asthmatic serum on the MSCs aging and dynamic growth in vitro. Rats were divided into control and asthmatic groups randomly. The asthmatic change was induced using OVA sensitization. The asthmatic structural changes are monitored by conventional Haematoxylin-Eosin staining. Thereafter, blood samples were taken and sera provided from each group. In this study, primary bone marrow mesenchymal stem cells were cultured in culture medium supplemented with normal and asthmatic serum for 7 days. The MSCs viability was examined using the MTT assay. The expression of the aging-related gene (ß-galactosidase), and stemness-related markers such as Sox2, Kfl-4 and p16INK4a were analysed by real-time PCR assay. Histological examination revealed chronic inflammatory remodelling which is identical to asthmatic changes. MTT assay showed a reduction of mesenchymal stem cell viability compared to the control group (P < .05). Real-time PCR analysis revealed a down-regulation of stemness-related markers Sox2, Kfl-4 and p16INK4a coincided with aging changes (ß-galactosidase) compared to the control group (P < .05). These data show the detrimental effect of asthmatic condition on bone marrow regenerative potential by accelerating early-stage aging in different stem cells and further progenitor cell depletion. SIGNIFICANCE OF THE STUDY: In such inflammatory conditions as asthma, the therapeutic potential of stem cells may be altered. We demonstrate that serum from asthmatic rats had the potential to reduce the viability of mesenchymal stem cells in vitro. Furthermore, we observed that the expression of the aging-related gene known ß-galactosidase was statistically increased in cells co-cultured with asthmatic serum. At the same time, expression of stemness-related markers Sox2, Kfl-4 and p16INK4a down-regulated. These results support the damaging effect of asthmatic condition on bone marrow regenerative ability by inducing early-stage aging in stem cells and additional progenitor cell reduction.

The effects of Nigella sativa on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review.

Nigella sativa (N. sativa) seed had been used traditionally due to several pharmacological effects. The updated experimental and clinical effects of N. sativa and its constituents on respiratory, allergic and immunologic disorders are provided in this comprehensive review article. Various databases including PubMed, Science Direct and Scopus were used. The preventive effects of N. sativa on pulmonary diseases were mainly due to its constituents such as thymoquinone, thymol, carvacrol and alpha-hederin. Extracts and constituents of N. sativa showed the relaxant effect, with possible mechanisms indicating its bronchodilatory effect in obstructive pulmonary diseases. In experimental animal models of different respiratory diseases, the preventive effect of various extracts and constituents of N. sativa was demonstrated by mechanisms such as antioxidant, immunomodulatory and antiinflammatory effects. Bronchodilatory and preventive effects of the plant and its components on asthma, COPD and lung disorders due to exposure to noxious agents as well as on allergic and immunologic disorders were also shown in the clinical studies. Various extracts and constituents of N. sativa showed pharmacological and therapeutic effects on respiratory, allergic and immunologic disorders indicating possible remedy effect of that the plant and its effective substances in treating respiratory, allergic and immunologic diseases.

C-Kit+ progenitors restore rat asthmatic lung function by modulation of T-bet and GATA-3 expression.

NEW FINDINGS: What is the central question of this study? The aim of the experiment was to highlight the regenerative capacity of bone marrow Kit+ cells in the restoration of asthmatic pulmonary function in the rat model. What is the main finding and its importance? Data showed that these cells were recruited successfully to the asthmatic niche after intratracheal administration and accelerated the regeneration of asthmatic lungs by the modulation of inflammation via the control of Gata3 and Tbx21 expression, leading to decreased tracheal responsiveness to methacholine and reduction of pathological remodelling. ABSTRACT: Allergic asthma is a T helper (Th) 2 immunological disorder with consequential uncontrolled inflammatory responses. There is an increasing demand to use new methods for the treatment of asthma based on modulation of the Th2-to-Th1 ratio in favour of the Th1 population. Accordingly, we decided to evaluate the effects of intratracheal administration of Kit+ bone marrow cells on tracheal responsiveness and the expression of Gata3 and Tbx21 genes. Forty male Wistar rats were allocated  randomly  into four experimental groups: healthy rats (control group), sensitized rats (OVA group), sensitized rats receiving Kit- cells (OVA+Kit- group) and sensitized rats receiving Kit+ cells (OVA+Kit+ group). Total and differential white blood cell counts, tracheal responsiveness to cumulative methacholine concentrations and histopathological analysis were evaluated. The results showed a statistically significant increase in total white blood cell, eosinophil and neutrophil counts, tracheal contractility, Gata3 expression and prototypical histopathology of asthma. Along with these conditions, we found that the number of lymphocytes was decreased and expression of Tbx21 diminished in sensitized rats compared with control animals. Monitoring of labelled tagged cells confirmed successful engraftment of transplanted cells in pulmonary tissue. Juxtaposition of Kit+ cells changed the blood leucogram closer to the control values. Kit+ cells increased the expression of Tbx21 and suppressed Gata3 (P < 0.05). In the OVA+Kit+ group, tracheal responsiveness was improved coincident with increased pulmonary regeneration. In conclusion, this study showed that intratracheal administration of bone marrow-derived Kit+ cells, but not Kit- cells, could be effective in the alleviation of asthma, presumably by the modulation of Gata3 and Tbx21.

Can troxerutin pretreatment prevent testicular complications in prepubertal diabetic male rats?

OBJECTIVE: The vast majority of type 1 diabetes leads to a higher prevalence of reproductive system's impairments. Troxerutin has attracted much attention owing to its favorable properties, including antihyperglycemic, anti-inflammatory, and antiapoptotic effects. This investigation was proposed to evaluate whether pretreatment with troxerutin could prevent apoptosis-induced testicular disorders in prepubertal diabetic rats. METHODS: Fifty prepubertal male Wistar rats were randomly allocated into five groups: control (C), troxerutin (TX), diabetic (D), diabetic+troxerutin (DTX), and diabetic+insulin (DI). Diabetes was induced by 55 mg/kg of streptozotocin applied intraperitoneally. In TX and DTX groups, 150 mg/kg troxerutin was administered by oral gavage. Diabetic rats in DI group received 2-4 U NPH insulin subcutaneously. Troxerutin and insulin treatments were begun immediately on the day of diabetes confirmation. After 30 days, the testicular lipid peroxidation and antioxidant activity, apoptosis process, and stereology as well as serum glucose and insulin levels were assessed. RESULTS: The results showed that diabetes caused a significant increase in the blood glucose, the number of TUNEL positive cells and tubules, and the malondialdehyde level as well as a significant decrease in serum insulin level compared to controls. The stereological analysis also revealed various alterations in diabetic rats compared to controls. Troxerutin treatment improved these alterations compared to the diabetic group. CONCLUSION: Troxerutin-pretreatment may play an essential role in the management of the type-1 diabetes-induced testicular disorders by decreasing blood glucose and modulating apoptosis.

Bone marrow mesenchymal stem cells and condition media diminish inflammatory adhesion molecules of pulmonary endothelial cells in an ovalbumin-induced asthmatic rat model.

OBJECTIVES: Although excitements related to stem cell therapeutic outcomes have been highlighted enormously in asthma, the vast majority of works were conducted by researchers in animal models. Elucidating the mechanisms underlying the therapeutic effects of MSCs in asthmatic rats will provide a rational basis for assuring maximal safety of future clinical application of stem cells. In the current study, we sought to investigate the possible paracrine mechanism by which direct injection of MSCs and/or CM attenuate efficiently Th2-mediated inflammation in asthmatic lung tissues with the focus on ICAM-1 and VCAM-1 expression. METHODS: Male rats were divided into four experimental groups (n = 6); healthy rats received PBS intratracheally (group C), sensitized rats received PBS intratracheally (group S), sensitized rats received CM intratracheally (group S + CM), and sensitized rats received PBS intratracheally containing 2 × 106 rBMMSCs (group S + MSCs). Two weeks post-transplantation, the expression of interleukin (IL)-5, -12 and INF-γ, ICAM-1 and VCAM-1 were assessed along with pathological injuries and the homing of MSCs into the lung tissues. RESULTS: Our results showed CM, and notably rBMMSCs, returned the expression of IL-5, IL-12, INF-γ, ICAM-1, and VCAM-1 (p < 0.001 to p < 0.05) to the normal levels. Based on data, pathological injuries in pulmonary specimens of asthmatic rats were significantly attenuated (p < 0.001 to p < 0.05). Moreover, rBMMSCs had potential to successfully home to an asthmatic niche in cell-administrated rats. CONCLUSIONS: Our data noted the potency of CM and especially MSCs in ameliorating pathological changes via intra-tracheal route presumably by targeting ICAM-1 and VCAM-1 in lung tissues in rat asthma model.

Beneficial treatment effects of dietary nitrate supplementation on testicular injury in streptozotocin-induced diabetic male rats.

RESEARCH QUESTION: Do low doses of dietary nitrate help to attenuate the progression of diabetic reproductive disorders in streptozotocin-induced diabetic male rats? DESIGN: Fifty male Wistar rats were divided into five groups: controls receiving distilled water; controls receiving 100 mg/l nitrate in distilled water; diabetic rats receiving distilled water; diabetic rats receiving insulin 2-4 U/day of neutral protamine hagedorn insulin; and diabetic rats receiving 100 mg/l nitrate in distilled water. Diabetes was induced by 45 mg/kg streptozotocin. Nitrate and insulin treatment were started 4 weeks after diabetes induction for 8 weeks. Serum insulin, nitrogen oxide, stereology of testis, apoptosis, sperm parameters, and mRNA expression of Pdcd4, Pacs2, p53 and miR-449a were assessed at the end of the study. RESULTS: Blood glucose, apoptotic index of seminiferous tubules and expression of p53, Pdcd4, and Pacs2 mRNA were significantly higher in the diabetic rats (P < 0.001). Decreased body weight, serum insulin and nitrogen oxide level, and miR-449a were observed in the diabetic group (P < 0.01 for insulin; P < 0.001 for others). Most sperm parameters and stereological results differed between diabetic and control rats; nitrate recovered almost all these alterations, including dead spermatozoa, sperm motility grade, sperm deformity index, spermatozoa with damaged DNA, malformations in abnormal spermatozoa, total volume of seminiferous tubule, germinal epithelium, capsule, lumen, interstitial tissue, seminiferous tubule diameter, germinal epithelium height, the number of spermatogenic, Sertoli and Leydig cells. CONCLUSIONS: Treatment with sodium nitrate could modulate apoptosis, which is a major cause of diabetic testicular disorder. These experiments suggest that nitric oxide plays an important role in the function of the reproductive system.

Evaluation of ameliorative effect of sodium nitrate in experimental model of streptozotocin-induced diabetic neuropathy in male rats.

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.

Two months sodium nitrate supplementation alleviates testicular injury in streptozotocin-induced diabetic male rats.

NEW FINDINGS: What is the central question of this study? Can low-dose inorganic nitrate supplementation prevent testicular structural and functional alterations in streptozotocin-induced type 1 diabetic male rats? What is the main finding and it's important? Treatment with a low dose of inorganic nitrate for 2 months had protective effects on the male reproductive system in diabetic rats including improved body weight loss, sperm and testis parameters, spermatogenesis index and testicular histology as well as increased serum testosterone levels. These favourable effects may be associated with increased serum insulin and decreased serum glucose, and with modulation of apoptosis in testis. ABSTRACT: Inorganic nitrate supplementation is a possible therapeutic agent in diabetes. The aim of this study was to evaluate the effect of nitrate on the reproductive system in streptozotocin-induced diabetic male rats. Fifty male Wistar rats were allocated randomly to five groups: control (C), control plus nitrate (CN), diabetic (D), diabetic plus insulin (DI) and diabetic plus nitrate (DN). Sodium nitrate was administered for 2 months in the drinking water (100 mg l-1 ) of the CN and DN groups. Insulin was injected at 2-4 U daily in the DI group. Serum glucose level and body weight were measured at the beginning of the study and at regular intervals. At the end of the study, serum levels of glucose, insulin, nitrogen oxides (NOx), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were assessed as well as sperm parameters, testis morphometry and histology, and testicular miR-34b and p53 mRNA expression. Nitrate treatment in diabetic rats significantly improved sperm parameters, epididymal weight, spermatogenesis and testicular histology as well as decreasing serum glucose and testicular p53 gene and miR-34b expression, although it had no effect on serum LH and FSH levels. In diabetic rats, serum insulin and NOx, body weight, testicular and epididymal weight, sperm count and motility, testis morphology, spermatogenesis indices, Johnsen's score, and testosterone were significantly lower than in controls. Nitrate administration increased serum insulin, NOx and testosterone levels in the DN group. Consuming water supplemented with sodium nitrate could improve diabetes-induced testicular functional and structural disorders; these favourable effects may be related to increased serum insulin and decreased serum glucose, as well as modulation of apoptosis in testis.

Bone marrow mesenchymal stem cells modified pathological changes and immunological responses in ovalbumin-induced asthmatic rats possibly by the modulation of miRNA155 and miRNA133.

In the current experiment, we investigated the immune-modulatory potential of mesenchymal stem cells (MSCs) and conditioned media (CM) in attenuating of chronic asthmatic changes in a rat model. Male rats were divided into control (C) and ovalbumin-sensitized (S) groups, which further allocated into three subgroups; rats received systemically 50 µl volume of PBS (C and S groups), CM (CSV and SSV groups) and rats received intravenous infusion of 2 × 106 bone marrow-derived mesenchymal stem cells (rBMMSCs) (CCV and SCV groups). Two weeks later, the expression of interleukin (IL)-4, IL-13, and IL-10, miRNA133, and miRNA155 was measured by real-time PCR. Pathological changes and the recruitment of rBMMSCs into pulmonary parenchyma were evaluated by histopathological and immunofluorescence analyses, respectively. The systemic injection of rBMMSCs, but not CM, decreased the levels of IL-4, IL-13, IL-10, miRNA133, miRNA155 and reduced pathological changes in sensitized rats as compared with other sensitized groups (p < 0.001 to p < 0.05). rBMMSCs transmigrated to lung tissue in cell-administrated rats, albeit intensity of asthmatic changes, in turn, affected the amount of recruited cells. Collectively, our data suggest the potential role of MSCs, but not CM, in reducing pathological changes possibly via the modulation of miRNA133 and miRNA155 during asthmatic changes.

Increased Visfatin Expression Is Associated with Nuclear Factor-κB in Obese Ovalbumin-Sensitized Male Wistar Rat Tracheae.

OBJECTIVE: To investigate the effects of diet-induced obesity on the expression of nuclear factor-κB (NF-κB) and visfatin messenger RNA in male Wistar rats' tracheae after sensitization with ovalbumin (OVA). MATERIALS AND METHODS: Twenty male Wistar rats were divided into 4 groups (n = 5 for each group), which included a control group fed a normal diet (ND) and groups fed normal diet, OVA-sensitized (S+ND); high-fat diet (HFD) only (diet-induced obesity); and high-fat diet, OVA-sensitized (S+HFD). All animals were fed for 8 weeks with standard chow or a high-fat diet, and then were sensitized and challenged with OVA or saline for another 4 weeks as per the above groups. The rats were anesthetized, after which the necks were exposed and the tracheae isolated and examined for expression levels of NF-κB and visfatin mRNA with the real-time polymerase chain reaction method. Data were compared between the different groups using one-way analysis of variance. RESULTS: The expression level of NF-κB mRNA in the S+HFD group was 2.67, which was statistically higher than the levels in the ND (0.96; p = 0.001), S+ND (1.86; p = 0.05), and HFD (1.26; p = 0.001) groups. Also, the visfatin mRNA expression level in the S+HFD group was 4.21, which was higher than the levels in the ND (0.92), S+ND (1.79), and HFD (2.20) (p = 0.001) groups. CONCLUSION: In this study, the expression levels of NF-κB and visfatin were markedly higher in the S+HFD group in comparison to the other groups. These findings indicate that alternative signaling pathways might be activated in diet-induced obesity associated with the OVA-sensitized animal model and could be responsible for possible altered sensitization phenotype.

Effect of α-Hederin on IL-2 and IL-17 mRNA and miRNA-133a Levels in Lungs of Ovalbumin-Sensitized Male Rats.

α-hederin, a saponin that is a major constituent of English Ivy (Hedera helix) is effective in the treatment of asthma. In the present study, the effect of α-hederin on lung tissue pathology and the levels of the inflammatory mediators; IL-2 mRNA, IL-17 mRNA, and MicroRNAs (miRNA)-133a was evaluated in a rat ovalbumin (OVA)-sensitized model of asthma. Rats were divided randomly into control (C), OVA-sensitized (S), OVA-sensitized pretreated with the antioxidant, thymoquinone (3 mg/kg, S + TQ) or OVA-sensitized pretreated with α-hederin (0.02 mg/kg, S + AH) groups. Levels of IL-2 and IL-17 mRNA were higher in the OVA-sensitized group than controls while the level of miRNA-133a gene expression was lower. IL-2 mRNA and miRNA-133a gene expression in the S + TQ group was higher than in the control and OVA-sensitized groups while the level of IL-17 mRNA in the S + TQ group was lower than in the OVA-sensitized group. Pretreatment with α-hederin decreased IL-17 mRNA levels and increased miRNA-133a gene expression compared with OVA-sensitized animals. All pathological changes in pretreated groups were lower than the OVA-sensitized group. These results showed a beneficial effect of α-hederin in OVA-sensitized rats, suggesting that α-hederin affects the IL-2 and IL-17 secretion pathways, altering miRNA-133a expression.

The Protective Effect of α-Hederin, the Active Constituent of Nigella sativa, on Lung Inflammation and Blood Cytokines in Ovalbumin Sensitized Guinea Pigs.

In the present study, the preventive effect of two different concentrations of α-hederin, the active constituent of Nigella sativa, on lung inflammation and blood cytokines in ovalbumin sensitized guinea pigs was examined. Forty eight male adult guinea pigs were divided into control (C), sensitized (S) and sensitized pretreated groups; with thymoquinone (S+TQ), low dose (S+LAH) and high dose of α-hederin (S+HAH) and inhaled fluticasone propionate (S+FP). The lung histopathology and blood levels of IL-4, IFN-γ and IL-17 were assessed. Compared to sensitized animals, all pathological changes improved significantly in pretreated groups (p < 0.001 to p < 0.05). These improvements in α-hederin pretreated groups were similar to S+TQ and S+FP groups except cellular infiltration in S+LAH and S+HAH groups which was lower than S+TQ group (p < 0.05). The blood IL-4 and IL-17 levels in S+HAH groups showed a significant decrease compared to S group (p < 0.05) which were similar to S+TQ and S+FP groups. The level of IFN-γ in S+LAH and S+HAH groups increased significantly compared to S group (p < 0.05) which was higher than S+FP group (p < 0.05). Blood IL-4 in S+HAH group was significantly lower than S+LAH group (p < 0.05). In conclusion, α-hederin could attenuate the lung inflammation and improve the changes of cytokines like thymoquinone and fluticasone in used dosages.

Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation.

BACKGROUND: Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation. METHODS: Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium. RESULTS: Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group. CONCLUSION: Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium.

Caloric restriction prevents lead-induced oxidative stress and inflammation in rat liver.

The aim of the present study is to investigate the effects of caloric restriction on liver of lead-administered rat. Male Sprague-Dawley rats were randomly divided into two groups: Ad libitum fed group (AL, free access to normal rat chow) and caloric restriction group (CR, fed 65% of AL animals' food intake). After 6 weeks, half of the animals of each group were injected lead acetate and the other half were injected saline. Liver tissue samples were collected at the end of the experiments. Glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA), and tumor necrosis factor (TNF-α) were measured in the tissue extracts. Histological studies were also performed. Our results showed that lead administrations (not saline injections) reduced liver SOD and GPx and increased MDA and TNF-α in AL animals, but in the CR animals lead injections did not significantly change the measured parameters. The histological studies supported the biochemical findings. We concluded that 65% CR may prevent lead-induced oxidative stress and inflammation in rat liver.

AMPK Signaling Pathway as a Potential Therapeutic Target for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the loss of dopaminergic neurons. Genetic factors, inflammatory responses, oxidative stress, metabolic disorders, cytotoxic factors, and mitochondrial dysfunction are all involved in neuronal death in neurodegenerative diseases. The risk of PD can be higher in aging individuals due to decreased mitochondrial function, energy metabolism, and AMP-activated protein kinase (AMPK) function. The potential of AMPK to regulate neurodegenerative disorders lies in its ability to enhance antioxidant capacity, reduce oxidative stress, improve mitochondrial function, decrease mitophagy and macroautophagy, and inhibit inflammation. In addition, it has been shown that modulating the catalytic activity of AMPK can protect the nervous system. This article reviews the mechanisms by which AMPK activation can modulate PD.

The role of probiotics on microvascular complications of type-2 diabetes: Nephropathy and retinopathy.

Diabetes is a multifactorial disorder that involves several molecular mechanisms and is still one of the key global health challenges with increasing prevalence and incidence. Gut microbiome dysbiosis could activate and recognize receptors that trigger the inflammation response and modulation of insulin sensitivity. In addition, the intricate role of gut microbiota dysbiosis in the onset and development of T2D (Type 2 diabetes mellitus) and associated microvascular complications was identified. These complications include diabetic nephropathy (DN) and diabetic retinopathy (DR), diabetic neuropathy, cerebrovascular disorders, and coronary heart disease. A recent interesting strategy to improve these complications is probiotics administration. The safety and health effects of probiotics against various diseases have been validated by various in vitro, in vivo and clinical studies. In this review, the related mechanisms between the gut microbiome, initiation, and progression of T2D and its common microvascular complications (DN and DR) have been discussed.