Peripheral Blood B-Cell Subsets Frequency and Distribution and the BSF-2(IL-6) to CSIF:TGIF(IL-10) Ratio as Severity-Associated Signatures in Primary Open-Angle Glaucoma: A Case-Controlled Study.

Although primary open-angle glaucoma (POAG) is a major cause of blindness worldwide, patients' immune response and its relation to the disease course have not been fully unraveled in terms of analyses of circulating B-cell subsets, as well as the association of these subsets with the severity of POAG clinical features. SUBJECTS AND METHODS: Flow cytometry was used to determine B-cell subset frequencies from 30 POAG patients grouped by hierarchical cluster analysis or the mean deviation (MD) of the visual field (VF) and correlated with the patients' clinical and pathological data, as well as with BSF-2(IL-6) and CSIF:TGIF(IL-10), which were quantified in peripheral blood samples of patients and controls by ELISA. RESULTS: The total B-cell frequency was increased in the POAG group in comparison to the control group (n = 30). Frequencies of specific B-cell subsets, such as double-negative (DN) and naïve B-cell subsets, were increased in relation to the severity of the POAG disease. However, the unswitched memory B compartment subset decreased in the POAG group. Other non-typical B-cell subsets such as DN B cells also showed significant changes according to the POAG disease severity course. These differences allow us to identify POAG severity-associated inflammatory clusters in patients with specifically altered B-cell subsets. Finally, ocular parameters, biomarkers of inflammation, and other glaucoma-related or non-clinical scores exhibited correlations with some of these B-cell subpopulations. CONCLUSION: The severity of the POAG disease course is accompanied by changes in the B-cell subpopulation, namely, DN B cells. Furthermore, the existing relationship of the B-cell subset frequencies with the clinical and the inflammatory parameters BSF-2(IL-6), CSIF:TGIF(IL-10), and the BSF-2(IL-6) to CSIF:TGIF(IL-10) ratio suggests that these B lymphocyte cells could serve as potential molecular bio-markers for assessing POAG disease severity and/or progression.

Chrysin promotes angiogenesis in rat hindlimb ischemia: Impact on PI3K/Akt/mTOR signaling pathway and autophagy.

Limb ischemia occurs due to obstruction of blood perfusion to lower limbs, a manifestation that is associated with peripheral artery disease (PAD). Angiogenesis is important for adequate oxygen delivery. The present study investigated a potential role for chrysin, a naturally occurring flavonoid, in promoting angiogenesis in hindlimb ischemia (HLI) rat model. Rats were allocated into four groups: (1) sham-operated control, (2) HLI: subjected to unilateral femoral artery ligation, (3) HLI + chrysin: received 100 mg/kg, i.p. chrysin immediately after HLI, and (4) HLI + chrysin + rapamycin: received 6 mg/kg/day rapamycin i.p. for 5 days then subjected to HLI and dosed with 100 mg/kg chrysin, i.p. Rats were killed 18 h later and gastrocnemius muscles were collected and divided into parts for (1) immunohistochemistry detection of CD31 and CD105, (2) qRT-PCR analysis of eNOS and VEGFR2, (3) colorimetric analysis of NO, (4) ELISA estimation of TGF-ß, VEGF, ATG5 and Beclin-1, and (5) Western blot analysis of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, mTOR, and HIF-1α. Chrysin significantly enhanced microvessels growth in HLI muscles as indicated by increased CD31 and CD105 levels and decreased TGF-ß. Chrysin's proangiogenic effect is potentially mediated by increased VEGF, VEGFR2 and activation of PI3K/AKT/mTOR pathway, which promoted eNOS and NO levels as it was reversed by the mTOR inhibitor, rapamycin. Chrysin also inhibited autophagy as it decreased ATG5 and Beclin-1. The current study shows that chrysin possesses a proangiogenic effect in HLI rats and might be useful in patients with PAD.

Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids.

Uterine fibroids (UFs) are the most prevalent gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as myomectomy and hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate tumor development. Several risk factors for UFs have been identified including vitamin D deficiency, inflammation, DNA repair deficiency, and environmental exposures to endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and in utero EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-fibroid landscape and altered the DNA repair and inflammation pathways. Notably, Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal biological pathways and ameliorated the developmental exposure-induced DNA damage and pro-inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis D at the MMSCs level and provides proof-of-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.

CoQ10 augments candesartan protective effect against tourniquet-induced hind limb ischemia-reperfusion: Involvement of non-classical RAS and ROS pathways.

Tourniquet is a well-established model of hind limb ischemia-reperfusion (HLI/R) in rats. Nevertheless, measures should be taken to alleviate the expected injury from ischemia/ reperfusion (I/R). In the present study, 30 adult male Sprague-Dawley rats were randomly divided into 5 groups (n = 6): control, HLI/R, HLI/R given candesartan (1 mg/kg, P.O); HLI/R given Coenzyme Q10 (CoQ10) (10 mg/kg, P.O); HLI/R given candesartan (0.5 mg/kg) and CoQ10 (5 mg/kg). The drugs were administered for 7 days starting one hour after reperfusion. Candesartan and CoQ10 as well as their combination suppressed gastrocnemius content of angiotensin II while they raised angiotensin-converting enzyme 2 (ACE2) activity, angiotensin (1-7) expression, and Mas receptor mRNA level. Consequently, candesartan and/or CoQ10 reversed the oxidative stress and inflammatory changes that occurred following HLI/R as demonstrated by the rise of SOD activity and the decline of MDA, TNF-α, and IL-6 skeletal muscle content. Additionally, candesartan and/or CoQ10 diminished gastrocnemius active caspase-3 level and phospho-p38 MAPK protein expression. Our study proved that CoQ10 enhanced the beneficial effect of candesartan in a model of tourniquet-induced HLI/R by affecting classical and non-classical renin-angiotensin system (RAS) pathway. To our knowledge, this is the first study showing the impact of CoQ10 on skeletal muscle RAS in rats.

Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-ß, TGF-ß, and FOXL-2.

Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-ß and FOXL-2 with downregulation of TGF-ß expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females' cancer survivors.

Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.

Early-life exposure of the myometrium to endocrine-disrupting chemicals (EDCs) has been shown to increase the risk of uterine fibroid (UF) prevalence in adulthood. Vitamin D3 (VitD3) is a unique, natural compound that may reduce the risk of developing UFs. However, little is known about the role and molecular mechanism of VitD3 on exposed myometrial stem cells (MMSCs). We investigated the role of, and molecular mechanism behind, VitD3 action on DNA damage response (DDR) defects in rat MMSCs due to developmental exposure to diethylstilbestrol (DES), with the additional goal of understanding how VitD3 decreases the incidence of UFs later in life. Female newborn Eker rats were exposed to DES or a vehicle early in life; they were then sacrificed at 5 months of age (pro-fibroid stage) and subjected to myometrial Stro1+/CD44+ stem cell isolation. Several techniques were performed to determine the effect of VitD3 treatment on the DNA repair pathway in DES-exposed MMSCs (DES-MMSCs). Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01). VitD3 treatment significantly decreased the DNA damage levels in DES-MMSCs. Concomitantly, the levels of key DNA damage repair members, including the MRN complex, increased in DES-MMSCs following treatment with VitD3 (p < 0.01). VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR. This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers. Moreover, VitD3 targets primed MMSCs, suggesting a novel therapeutic approach for the prevention of UF development.

Sitagliptin attenuates intestinal ischemia/reperfusion injury via cAMP/PKA, PI3K/Akt pathway in a glucagon-like peptide 1 receptor-dependent manner.

AIMS: This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism. MAIN METHODS: Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment. KEY FINDINGS: Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-κB, TNF-α, IL-1ßand MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP-1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt. SIGNIFICANCE: Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor.

The growth inhibitory effect of gambogic acid on pancreatic cancer cells.

Pancreatic cancer, the fourth most common cause of cancer-related deaths, is one of the most aggressive and devastating human malignancies with increasing incidence worldwide. To date, surgical resection is the only potentially curative therapy available for pancreatic cancer patients. Early diagnosis of pancreatic tumors is difficult, and hence, nearly 80% of patients cannot receive surgical resection. Natural products have always been a vital source for novel compounds for cancer treatment. The naturally occurring prenylated xanthone, gambogic acid, has been previously shown to exert potent anticancer, anti-inflammatory, apoptotic, antiangiogenic, and antioxidant activities. However, to our knowledge, there have been no specific studies showing its effect on the whole-genome expression in pancreatic cancer cells. Here, the anticancer activity of gambogic acid toward a panel of pancreatic cancer cells with different differentiation stages has been evaluated. Additionally, a whole-genome transcription profiling study was performed in order to identify possible candidate players modulating the antitumor effect of gambogic acid on pancreatic cancer cells. Expression analysis results showed that the pancreatic adenocarcinoma signaling pathway was specifically affected upon gambogic acid treatment. Moreover, the growth inhibitory effect of gambogic acid on pancreatic cancer cells was modulated through up-regulation of DDIT3, DUSP1, and DUSP5 and down-regulation of ALDOA, TOP2A, and ATG4B. The present work is a starting point for the generation of hypotheses on significantly regulated candidate key player genes and for a detailed dissection of the potential role of each individual gene for the activity of gambogic acid on pancreatic cancer.

Diallyl sulfide alleviates cisplatin-induced nephrotoxicity in rats via suppressing NF-κB downstream inflammatory proteins and p53/Puma signalling pathway.

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo-sulfide, present in garlic, in cisplatin-induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno-protective effect of DAS in cisplatin-induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis-induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co-treated with DAS. In addition, DAS significantly restored Cis-depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis-elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis-increased renal expression of nuclear factor kappa B (NF-κB) and subsequent pro-inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co-treatment with DAS significantly inhibited Cis-increased caspase-8 and -9 levels. Additionally, DAS significantly mitigated Cis-induced protein expression of p53, Puma, and Bax while, it significantly restored Cis-reduced protein expression of Bcl-xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin-induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.

Attenuating effects of coenzyme Q10 and amlodipine in ulcerative colitis model in rats.

CONTEXT: Ulcerative colitis is a chronic inflammatory bowel disease. Recent studies reported a pivotal role of elevated intracellular calcium in this disorder. Coenzyme Q10 (CoQ10) and amlodipine are known to maintain cellular energy, decrease intracellular calcium concentration in addition to their antioxidant and anti-inflammatory properties. OBJECTIVE: The aim of this study was to evaluate the possible protective effects of CoQ10, amlodipine and their combination on ulcerative colitis. MATERIALS AND METHODS: Colitis was induced in rats by intracolonic injection of 3% acetic acid. CoQ10 (10 mg/kg), amlodipine (3 mg/kg) and their combination were administered for 8 consecutive days before induction of colitis. RESULTS: Our results showed that administration of CoQ10, amlodipine and their combination decreased colon tissue malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), prostaglandin E2 (PGE2), myeloperoxidase (MPO) and heat shock protein (HSP70) levels induced by intracolonic injection of acetic acid and restored many of the colon structure in histological examination. On the other hand, they increased superoxide dismutase (SOD) activity, adenosine-5'-triphosphate (ATP) and interleukin-10 (IL-10) colonic contents. DISCUSSION AND CONCLUSION: Administration of either CoQ10 or amlodipine was found to protect against acetic acid-induced colitis. Moreover, their combination was more effective than individual administration of either of them. The protective effect of CoQ10 and amlodipine may be in part via their antioxidant, anti-inflammatory and energy restoration properties.

Protective effect of artichoke leaf extract against paracetamol-induced hepatotoxicity in rats.

CONTEXT: Paracetamol overdose is a predominant cause of hepatotoxicity in both humans and experimental animals. OBJECTIVE: In this study, we investigated the protective effect of aqueous artichoke leaf extract (ALE) against paracetamol-induced liver injury in rats using N-acetylcysteine (NAC) as a reference drug. MATERIALS AND METHODS: Rats were divided into five groups: negative control, paracetamol (2 g/kg, single oral dose), ALE (1.5 g/kg, orally for 14 d), ALE + paracetamol, and NAC (100 mg/kg) + paracetamol. Indices of liver damage (serum alanine aminotransferase and aspartate aminotransferase) were measured. Liver homogenates were analyzed for oxidative stress biomarkers (MDA, malondialdehyde; SOD activity, superoxide dismutase activity; NO, nitric oxide; GSH content, reduced glutathione), glutathione cycling (GR, glutathione reductase), and utilization (GST, glutathione-S-transferase). Apoptosis was assessed using the comet assay. RESULTS: Paracetamol caused marked liver damage as noted by significant increased activities of serum aminotransferases (p < 0.05) as well as a significant increase in hepatic MDA and NO levels (p < 0.001) compared with the negative control group. GSH content, GR, GST, and SOD activities were decreased significantly (p < 0.001). Comet assay parameters (tail length, percentage of tailed cells, percentage of migrated DNA, and tail moment) were increased (p < 0.05), indicating apoptosis. Histopathological examination showed necrotic areas. Pre-treatment with ALE replenished hepatic GSH, reversed oxidative stress parameters, DNA damage, and necrosis induced by paracetamol. DISCUSSION AND CONCLUSION: These results suggest that ALE may protect from paracetamol-induced liver toxicity via its antioxidant and anti-apoptotic properties.

Hepatoprotective effect of methylsulfonylmethane against carbon tetrachloride-induced acute liver injury in rats.

This study evaluated the effect of methylsulfonylmethane (MSM) on carbon tetrachloride (CCl4)-induced acute liver injury in rats. A single injection of CCl4 (2 ml/kg, i.p.) increased serum aminotransferases (ALT and AST) activities. In addition, CCl4 treatment led to elevation of hepatic malondialdehyde (MDA) content as well as decrease in superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, cytochrome P450 2E1 (CYP2E1) content was suppressed while proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels increased in liver tissue after CCl4 administration. We showed that acute CCl4-induced damage was accompanied by a rise in Bax/Bcl2 ratio indicating apoptosis. Pre-treatment with MSM (400 mg/kg) inhibited the increases of serum ALT and AST activities, decreased hepatic MDA, TNF-α, IL-6 and Bax/Bcl2 ratio compared to CCl4 treated group. On the other hand, MSM raised SOD and CAT activities as well as CYP2E1 level in liver tissues. The present study shows that MSM possesses a hepatoprotective effect against CCl4-induced liver injury in rats. This protective effect might be through its antioxidant, anti-inflammatory and antiapoptotic properties.

Immunomodulatory effect of candesartan on indomethacin-induced gastric ulcer in rats.

Non steroidal anti-inflammatory drugs (NSAIDs) induce gastric mucosal lesions in part by induction of oxidative stress as well as the activation of inflammatory cells and the production of proinflammatory cytokines. In this study, we examined the protective effect of candesartan (2 and 5 mg/kg) on indomethacin-induced gastric mucosa damage. Pretreatment with candesartan for 10 days reduced significantly the ulcer index induced by indomethacin injection. The preventive index of 2 mg/kg (76.74%) was higher than that of 5 mg/kg (65.11%). Both doses of candesartan were able to reduce significantly the stomach malondialdehyde content compared to indomethacin-treated group. Myeloperoxidase, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant gastric levels were significantly reduced by 2 mg/kg of candesartan more than 5 mg/kg. The Th1 cytokine interferon γ was also significantly reduced by both doses of candesartan compared to indomethacin injected group. On the other hand, indomethacin significant decreased the anti-inflammatory cytokine IL-10 gastric level. Pretreatment with candesartan (2 and 5 mg/kg) reversed this effect. In conclusion, the present study indicates that pretreatment with candesartan, can protect against the stomach injury induced by indomethacin through its antioxidant and immunomodulatory effects.

Synthesis of new pyrroles of potential anti-inflammatory activity.

We herein disclose a series of novel pyrrole derivatives 1-4 and pyrrolo[2,3-d]pyrimidine derivatives 6-11 as novel potent anti-inflammatory compounds. The structures were confirmed by IR, (1) H-NMR, and MS. Some newly synthesized compounds were examined for their in-vivo anti-inflammatory activity. Several derivatives showed a promising anti-inflammatory activity compared to ibuprofen. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

Effect of thymoquinone on hepatorenal dysfunction and alteration of CYP3A1 and spermidine/spermine N-1-acetyl-transferase gene expression induced by renal ischaemia-reperfusion in rats.

OBJECTIVES: Renal ischaemia-reperfusion (I/R) is a well-characterised model of acute renal failure that causes both local and remote organ injury. The aim of this work was to investigate the effect of thymoquinone, the main constituent of the volatile oil extracted from Nigella sativa seeds, on renal and hepatic changes after renal ischaemia-reperfusion. METHODS: Male Sprague-Dawley rats were divided into sham I/R vehicle-treated groups, and I/R thymoquinone-treated groups. Thymoquinone (10 mg/kg, p.o.) was administered for ten consecutive days to the I/R thymoquinone group before injury. I/R and I/R thymoquinone groups were subjected to 30-min ischaemia followed by 4-h reperfusion. KEY FINDINGS: I/R resulted in a significant increase in malondialdehyde (MDA) level and decreases in glutathione-S-transferase (GST) and superoxide dismutase (SOD) activity in liver and kidney tissues. Thymoquinone treatment caused the reversal of I/R-induced changes in MDA as well as GST and SOD activity. Moreover, I/R caused a significant rise in creatinine and alanine aminotransferase serum levels. CYP3A1 mRNA expression was induced significantly by I/R in both liver and kidney tissues compared with sham group. Thymoquinone reduced significantly this increase. I/R caused induction of mRNA expression of spermidine/spermine N-1-acetyl-transferase (SSAT), a catabolic enzyme that participates in polyamine metabolism, in liver and kidney tissues. Thymoquinone reduced SSAT mRNA expression significantly in liver and markedly in kidney. CONCLUSIONS: These findings suggested that thymoquinone protected against renal I/R-induced damage through an antioxidant mechanism as well as the decrease of CYP3A1 and SSAT gene expression.

New condensed pyrroles of potential biological interest syntheses and structure-activity relationship studies.

The Pyrrole derivatives Ia-d were prepared and utilized for the preparation of pyrrolo[2,3-d]pyrimidine derivatives IIa-c, III, IVa-e, V and VIIIa-c; pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine VI and pyrrolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidine derivative derivatives VIIa-c. These some newly synthesized compounds were examined for their in vitro antimicrobial activity and in vivo anti-inflammatory. Result indicated that these compounds showed promising anti-inflammatory activity in comparison to ibuprofen (the standard anti-inflammatory drug). The structure-activity relationships (SAR) and anti-inflammatory activities of these compounds are also discussed in this paper.

WITHDRAWN: Synthesis and biological evaluation of some novel Pyrrolo[2, 3-d]pyrimidine derivatives.

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Synthesis and biological evaluation of some thio containing pyrrolo [2,3-d]pyrimidine derivatives for their anti-inflammatory and anti-microbial activities.

The pyrroles Ia-c were used as precursor for the preparation of pyrrolo [2, 3-d] pyrimidine-2 and/or 4 thione derivatives IIa-f. A series of 8-Aryl-pyrrolo [2, 3-d] thiazolo[3,2-a]pyrimidine VI and VII were prepared. Alkylation of the thione compounds in basic medium afforded the pyrrolo [2, 3-d] pyrimidine IV. Also, some 2-amino pyrrolo [2, 3-d]pyrimidines V were obtained. Some newly synthesized compounds were examined for their in vitro anti-inflammatory. Also, all new compounds were examined for their in vivo anti-microbial activity. Several derivatives, showed a promising anti-inflammatory activity in compared to ibuprofen. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

Effect of rosuvastatin on cholestasis-induced hepatic injury in rat livers.

Recent studies reported that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have pleotropic effects independent of their lipid-lowering properties. The present study was undertaken to determine whether treatment with rosuvastatin (RO) would be beneficial in a rat model of bile duct ligation (BDL). Animals were divided into three groups: a sham group (group I), a BDL group treated with vehicle (group II), and a BDL group treated with RO (10 mg/kg) (group III). Serum levels of total bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase decreased significantly in group III when compared to group II. Lipid peroxides and NO levels of group III were found to be significantly lower than those of group II. Antioxidant enzymes (superoxide dismutase, glutathione-S-transferase, and catalase) activity in liver tissues markedly decreased in group II, whereas treatment with RO preserved antioxidant enzyme activity. DT-diaphorase activity in group II was significantly higher than that in group III. The histopathological results showed multiple numbers of newly formed bile ductules with inflammatory cells infiltration in group II. These pathological changes were improved in group III. Our data indicate that RO ameliorates hepatic injury, inflammation, lipid peroxidation and increases antioxidant enzymes activity in rats subjected to BDL. RO may have a beneficial effect on treatment of cholestatic liver diseases.

Immunomodulation by maternal autoantibodies of the fetal serotoninergic 5-HT4 receptor and its consequences in early BALB/c mouse embryonic development.

BACKGROUND: The presence of functional 5-HT4 receptors in human and its involvement in neonatal lupus erythematosus (NLE) have prompted us to study the receptor expression and role during embryogenesis. Earlier we managed to demonstrate that female BALB/c mice immunized against the second extracellular loop (SEL) of the 5-HT4 receptor gave birth to pups with heart block. To explain this phenomenon we investigated the expression of 5-HT4 receptors during mouse embryogenesis. At the same time we looked whether the consequence of 5-HT4 receptor immunomodulation observed earlier is in relation to receptor expression. We studied the expression of 5-HT4 receptor at the mRNA level and its two isoforms 5-HT4(a) and 5-HT4(d) at the protein level in embryos from BALB/c mice, at 8th, 12th, 18th gestation days (GD) and 1 day post natal (DPN). Simultaneously the receptor activity was inhibited by rising antibodies, in female mice against SEL of the receptor. The mice were mated and embryos were collected at 8th, 12th, 18th GD and 1 DPN. RESULTS: 5-HT4 receptor mRNA increased in brain from 12th GD to 1 DPN. Its expression gradually decreased in heart and disappeared at birth. This was consistent with expression of the receptor isoforms 5-HT4(a) and (d). Abnormalities like decreased number of embryos, growth delay, spina bifida and sinus arrhythmia from 12th GD were documented in pups of mice showing anti-5-HT4 receptor antibodies. CONCLUSION: serotoninergic 5-HT4 receptor plays an important role in mouse foetal development. In BALB/c mice there is a direct relation between the expression of receptor and the deleterious effect of maternal anti-5-HT4 receptor autoantibodies in early embryogenesis.