Protective anti-inflammatory activity of tovophyllin A against acute lung injury and its potential cytotoxicity to epithelial lung and breast carcinomas.

Tovophyllin A (TA) is a xanthone isolated from Garcinia mangostana L. (GM, Guttiferae) pericarps that possesses various beneficial bioactivities. However, its protective effects on acute lung injury (ALI) and lung carcinoma have not yet been explored. The current work was designed to investigate the protective potential of TA against ALI and explore the possible mechanism of action. Two different doses of TA were tested against lipopolysaccharide (LPS)-induced ALI in mice. Moreover, the cytotoxic potential of TA was assessed in epithelial lung (A549 cells) and breast (MCF7 cells) carcinomas utilizing a sulforhodamine B (SRB) assay. The results revealed that TA possessed the ability to protect against LPS-induced acute lung damage. TA attenuated LPS-induced pulmonary edema, as it lowered the protein content in the bronchoalveolar lavage fluid (BALF) and the lung W/D ratio. In addition, TA counteracted inflammatory cell infiltration into the lung tissue, as shown by the total and differential cell counts in the BALF and histopathological examination of the lungs. The oxidative burden in the pulmonary tissue was ameliorated in TA-treated animals as there were reductions in the malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels in the lung tissue. TA increased the levels of antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in the lungs. Furthermore, TA inhibited the activation of nuclear factor-κB (NF-κB). In addition, TA had potent anti-inflammatory activity as it reduced the immunoexpression and levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6. Furthermore, TA showed significantly enhanced cytotoxic activity against the MCF-7 and A549 cell lines with IC50s of 6.1 and 2.2 µM, respectively, compared to doxorubicin (IC50s of 0.41 and 0.74 µM, respectively). In conclusion, TA ameliorates LPS-induced ALI through the suppression of oxidative stress and inflammation. These findings suggest the potential use of this compound as a future treatment for ALI.

Aspernolide F, as a new cardioprotective butyrolactone against doxorubicin-induced cardiotoxicity.

Endophytic fungi have known as a promising source of secondary metabolites. γ-Butyrolactones are a class of metabolites reported from Aspergillus genus, which attracted much attention for their bioactivities. This study aimed to assess the potential cardioprotective effects of aspernolide F (AF) separated from the endophytic fungus A. terreus against doxorubicin (DOX)-induced cardiotoxic effects in rats. Animals were treated with two different doses of AF for 10 days prior to DOX injection. Electrocardiographic (ECG), biochemical, histopathological and immunohistochemical analyses were performed. Results have shown that AF effectively protected against DOX-induced cardiac damage as AF counteracted DOX-induced ECG abnormalities and attenuated serum markers of cardiotoxicity (creatine kinase-MB, lactate dehydrogenase, troponin I, and troponin T). Histopathological examination of cardiac tissue revealed a remarkable improvement in DOX-induced lesions. In addition, AF ameliorated DOX-induced oxidative damage and increased the levels of antioxidants in cardiac tissues. AF treatment inhibited the activation of nuclear factor-κB (NF-κB) and decreased the immuno-expression of NF-κB in cardiac tissue. Furthermore, AF caused a marked lowering in the level of inflammatory cytokines (nitric oxide, tumor necrosis factor-α, and interleukin-6) in the cardiac tissue. Collectively, this study demonstrates the cardioprotective activity of AF against DOX-induced cardiac damage which may be due to its antioxidant and anti-inflammatory activities.

Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways.

BACKGROUND/PURPOSE: Pristimerin (Pris) is triterpenoid compound with many biological effects. Until now, nothing is known about its effect on doxorubicin (DOX)-induced cardiotoxicity. Hence, this study investigated the impact of Pris on DOX-induced cardiotoxic effects. MATERIALS AND METHODS: Rats were treated with Pris 1 week before and 2 weeks contaminant with repeated DOX injection. Afterwards, electrocardiography (ECG), biochemical, histopathological, PCR, and Western blot assessments were performed. RESULTS: Pris effectively alleviated DOX-induced deleterious cardiac damage. It inhibited DOX-induced ECG abnormities as well as DOX-induced elevation of serum indices of cardiotoxicity. The histopathological cardiac lesions and fibrosis were remarkably improved in Pris-treated animals. Pris reduced hydroxyproline content and attenuated the mRNA and protein expression of the pro-fibrogenic genes. The antioxidant activity of Pris was prominent through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, Pris enhanced the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway as it increased the mRNA and protein expression of Nrf2 and Nrf2-dependent antioxidant genes (GCL, NQO1, HO-1). Additionally, the anti-inflammatory effect of Pris was obvious through the inhibition of mitogen activated protein kinase (MAPK)/nuclear factor kappa-B (NF-kB) signaling and subsequent inhibition of inflammatory mediators. CONCLUSION: This study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways.

Protective effects of Ajwa date extract against tissue damage induced by acute diclofenac toxicity.

OBJECTIVES: To investigate the tissue-protective effects of Ajwa date fruits (a Prophetic medicinal remedy) against acute diclofenac toxicity. METHODS: Albino Sprague-Dawley rats were allocated to four experimental groups: a negative control group, an Ajwa-only group that received 2 g/kg of Ajwa date extract (ADE) orally, an acute diclofenac toxicity group that received 200 mg diclofenac once intraperitoneally, and a treatment group that received diclofenac and ADE after 4 h. Histological examinations of rat lung and liver tissues were performed. RESULTS: Acute diclofenac toxicity caused marked hepatic derangements, such as congested central veins, congested blood sinusoids, hyaline degeneration, and hepatocyte necrosis. Toxic diclofenac overdose resulted in markedly congested alveolar capillaries and alveolar haemorrhages, thick edematous alveolar walls, and edema fluid exudates in the alveoli. Upon treatment with ADE, significant reduction in diclofenac-induced hepatic and pulmonary derangements were observed. CONCLUSION: ADE is a safe, tissue-protective nutritional agent that alleviates cellular and tissue-damaging effects due to acute diclofenac toxicity. ADE relieved hepatic and pulmonary changes induced by acute diclofenac toxicity. The use of ADE is recommended for the treatment of acute diclofenac toxicity.

Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway.

Valproate is a widely used drug against epilepsy and several other neurological disorders although it has deleterious hepatotoxic side effects. The current study was designed to test if agmatine as nitric oxide modulator has protective effects against valproate-induced hepatic injury. Male Swiss albino mice were treated with sodium valproate (SVP) with or without agmatine for 7 days. Serum and liver samples were collected for analysis. Results have revealed that agmatine exerted hepatoprotective effects against SVP-associated hepatic injury. Agmatine ameliorated SVP-induced elevated serum biochemical markers of hepatic damage such as serum transaminases, alkaline phosphatase, γ-glutamyl transferase, and lactate dehydrogenase. Histopathological examination of the liver showed improvement of hepatic lesions in case of agmatine treatment. Furthermore, agmatine attenuated oxidative stress and enhanced antioxidants in liver tissue. Agmatine inhibited the activation of nuclear factor-κB and ameliorated the immunoexpression of inducible nitric oxide synthetase. This was accompanied by decrease in the level of inflammatory markers as nitrite/nitrate, tumor necrosis factor-α, and interleukin-6. These data provide new evidence of the hepatoprotective activity of agmatine against SVP-induced hepatotoxic effects.

Protective activity of tovophyllin A, a xanthone isolated from Garcinia mangostana pericarps, against acetaminophen-induced liver damage: role of Nrf2 activation.

Garcinia mangostana L. (GM, family Guttiferae) is one of the most widely recognized tropical fruits. GM is a wealthy pool of xanthones that exhibit a wide range of bioactivities. Tovophyllin A (TA) separated from GM pericarps was tested for its efficacy to ameliorate acetaminophen (APAP)-induced liver injury. Mice were injected with a single dose of APAP with or without TA pretreatment. The protective effects of TA against APAP-induced liver damage were evident through amelioration of serum indices of hepatotoxicity and improvement of hepatic histopathologic lesions. TA has antioxidant activity because it inhibited APAP-induced lipid peroxidation and improved the antioxidant capacity of the liver. Also, TA enhanced the mRNA expression of nuclear erythroid-related factor 2 (Nrf2) and its target genes. Protein expression of Nrf2 and heme oxygenase-1 was enhanced remarkably in TA-pretreated groups. TA suppressed activation of nuclear factor-kappa B (NF-κB) and the subsequent release of pro-inflammatory cytokines. In conclusion, TA has a marked protective activity against APAP-induced hepatotoxicity which may be linked to its ability to activate Nrf2 and inhibit the NF-κB signaling pathway.

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study.

BACKGROUND/AIMS: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. METHODS: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. RESULTS: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1ß genes and proteins in hepatic tissue. The activities of IL-1ß and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. CONCLUSIONS: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug's ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

Pristimerin as a Novel Hepatoprotective Agent Against Experimental Autoimmune Hepatitis.

Pristimerin (Pris) is bioactive natural quinonoid triterpene that has anti-inflammatory and anti-cancer activities. Meanwhile, its effect against hepatitis needs to be elucidated. This investigation aimed to evaluate the ability of Pris to protect against autoimmune hepatitis (AIH). A mouse model of AIH was established using single concanavalin A (Con A) intravenous injection. Mice were treated with Pris at two different doses (0.4 and 0.8 mg/kg) for 5 days prior to Con A challenge. Markers of hepatic injury, oxidative, inflammatory, and apoptotic damage were estimated. Results have revealed that Pris pretreatment ameliorated Con A-induced hepatic damage. There was decrease in the elevated serum indices of hepatic damage (ALT, AST, ALP, and LDH) and improvement of the histopathological picture of the liver. Pris effectively decreased Con A-induced neutrophil infiltration into the hepatic tissue as presented by amelioration of the level and immuno-expression of myeloperoxidase (MPO). Additionally, Pris attenuated Con A-induced increase in CD4+ T-cells in hepatic tissue. Lipid peroxidation was significantly depressed simultaneously with enhancement of the antioxidant capacity in Pris pretreated animals. Pris also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression and its binding capacity. In addition, Pris increased mRNA expression of heme-oxygenase-1 (HO-1) and restored its normal level. Furthermore, Pris decreased the level and immuno-expression of nuclear factor kappa-B (NF-κB) as well as the downstream inflammatory cascade (TNF-α, IL-6, and IL-1ß). Finally, Pris showed inhibitory effect on Con A-induced apoptotic alteration in liver as it decreased the mRNA expression and levels the apoptotic markers (Bax and caspase-3) and increased mRNA expression and level of the anti-apoptotic protein (Bcl2). In conclusion, this study demonstrates the potent hepatoprotective efficacy of Pris against Con A-induced hepatitis which may be related to anti-oxidative, anti-inflammatory, and anti-apoptotic pathways. Pris could serve as a new candidate for the management of hepatitis.

Lutein mitigates cyclophosphamide induced lung and liver injury via NF-κB/MAPK dependent mechanism.

This study targeted to test the potential protective role of lutein against lung and liver damage associated with cyclophosphamide (CP) administration. Lutein was given orally for 5days at two different doses both before and after CP injection. Results have shown that CP administration caused marked pulmonary and hepatic injurious effects in mice. Lung damage was evident through increased lung wet/dry ratio, elevated inflammatory cells infiltration into the pulmonary tissues, increased total protein content and lactate dehydrogenase (LDH) activity in the broncho-alveolar lavage fluid. Estimation of high levels of serum transaminases, alkaline phosphatase and LDH in serum revealed hepatic injury. Histopathological examination of both organs confirmed the biochemical analysis. Elevation of oxidative stress along with depressed anti-oxidant status of lung and liver were evident in CP-intoxicated animals. Furthermore, CP induced elevation of inflammatory cytokines (NOx, TNF-α, IL-6) contaminant with activation of nuclear factor kappa-B (NF-κB) and p38 mitogen activated protein kinase (p38-MAPK). On the other side, lutein treatment successfully protected the lung and the liver as indicated by improvement of the biochemical and histopathological parameters. These results suggest that lutein can ameliorate CP-induced pulmonary and hepatic oxidative injurious effects via inhibition of reactive oxygen species (ROS)/NF-κB/MAPK pathway.

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity.

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Modulation of cyclophosphamide-induced cardiotoxicity by methyl palmitate.

PURPOSE: Cyclophosphamide (CP) is a frequently used anticancer and immunosuppressant although its use has been associated with severe cardiotoxicity. The present study examined the ability of methyl palmitate (MP) to counteract CP-induced cardiotoxicity. METHODS: Adult male Wistar rats were divided into four groups. The first one served as control while the second received a single injection of CP (200 mg/kg, i.p.). The other two groups were administered MP at two different dose levels (300, 400 mg/kg) for 10 days before and 7 days after CP single injection. RESULTS: CP injection resulted in marked cardiac injury as presented by ECG abnormal changes, elevation of serum creatine kinase-MB (CK-MB), cardiac troponin I, troponin T and lactate dehydrogenase (LDH) and enormous histopathological lesions. Moreover, CP-induced oxidative stress as it elevated malondialdehyde (MDA) and diminished superoxide dismutase activity and glutathione content in heart tissue. Additionally, CP-induced overexpression of toll-like receptors-4 (TLR-4) and nuclear factor kappa-B (NF-κB) accompanied by overproduction of inflammatory cytokines (TNF-α, NO). CP activated cardiomyocyte apoptosis as it increased apoptosis parameters (Bax and caspase-3) and decreased anti-apoptotic marker (Bcl-2). On the other hand, MP treatment attenuated all of the measured parameters of CP-induced cardiotoxicity. MP counteracted CP-induced oxidative stress and suppressed TLR-4 and NF-κB overexpression. Also, levels of cytokines and apoptotic markers were declined while Bcl-2 was elevated in MP treated animals. CONCLUSIONS: MP may serve as a new cardioprotective candidate. The cardioprotective effects of MP may be attributed to its ability to suppress oxidative stress and interrupt TLR4/NF-κB signaling pathway with subsequent amelioration of apoptosis.

Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats.

There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo- and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factor-alpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicin-induced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis.

Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients.

OBJECTIVES: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67. METHODS: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters.   RESULTS: Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02), high tumor grade (p less than 0.01), lymph node metastasis (p less than 0.001), and Her-2/neu positivity (p less than 0.009). However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (p less than 0.04). CONCLUSION: The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

Molecular Profiling of Breast Carcinoma in Almadinah, KSA: Immunophenotyping and Clinicopathological Correlation.

PURPOSE: To subtype breast cancer (BC) in Saudi women according to the recent molecular classification and to correlate these subtypes with available clinicopathological parameters. MATERIALS AND METHODS: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (Her2/neu) immunostaining was semi-quantitatively assessed to define molecular subtypes of luminal A and B, HER-2 and triple negative (basal- like) in BC paraffin embedded sections from 115 Saudi female patients diagnosed between 2005 to 2015 at the Department of Pathology, King Fahd Hospital, Almadinah, Saudi Arabia. RESULTS: The most common subtypes were luminal A (47%), followed by luminal B (27.8%) and basal like subtypes (18.3%), whereas HER-2 was the least common subtype (6.9%). Luminal A was predominantly found in the old age group, with low tumor grade (p< 0.001) and small tumor size, whereas HER-2 and basal-like subtypes were significantly associated with young age, high tumor grade, lymph node metastasis and lymphovascular invasion (p< 0.03, 0.004, 0.05 and 0.04 respectively). All subtypes showed advanced clinical stage at the time of presentation. CONCLUSIONS: Molecular subtypes of Saudi BC patients in Almadinah region are consistent with most of the worldwide subtyping. The biological behaviour of each molecular subtype could be expected based on its characteristic clinicopathological features. Along with other prognostic indicators, molecular subtyping would be helpful in predicting prognosis and management of our BC patients. We recommend screening and early diagnosis of BC in our population.

High quality tissue miniarray technique using a conventional TV/radio telescopic antenna.

BACKGROUND: The tissue microarray (TMA) is widely accepted as a fast and cost-effective research tool for in situ tissue analysis in modern pathology. However, the current automated and manual TMA techniques have some drawbacks restricting their productivity. Our study aimed to introduce an improved manual tissue miniarray (TmA) technique that is simple and readily applicable to a broad range of tissue samples. MATERIALS AND METHODS: In this study, a conventional TV/radio telescopic antenna was used to punch tissue cores manually from donor paraffin embedded tissue blocks which were pre-incubated at 40oC. The cores were manually transferred, organized and attached to a standard block mould, and filled with liquid paraffin to construct TmA blocks without any use of recipient paraffin blocks. RESULTS: By using a conventional TV/radio antenna, it was possible to construct TmA paraffin blocks with variable formats of array size and number (2-mm x 42, 2.5-mm x 30, 3-mm x 24, 4-mm x 20 and 5-mm x 12 cores). Up to 2-mm x 84 cores could be mounted and stained on a standard microscopic slide by cutting two sections from two different blocks and mounting them beside each other. The technique was simple and caused minimal damage to the donor blocks. H and E and immunostained slides showed well-defined tissue morphology and array configuration. CONCLUSIONS: This technique is easy to reproduce, quick, inexpensive and creates uniform blocks with abundant tissues without specialized equipment. It was found to improve the stability of the cores within the paraffin block and facilitated no losses during cutting and immunostaining.

Role of hysteroscopy in the detection of endometrial pathologies in women presenting with postmenopausal bleeding and thickened endometrium.

OBJECTIVES: The goal of this study was to define the diagnostic value of hysteroscopy in evaluating uterine cavity compared to endometrial biopsy in women presenting with postmenopausal bleeding and thick endometrial mucosa with particular attention to endometrial hyperplasia and carcinoma. METHODS: Eighty-three consecutive women presenting with postmenopausal bleeding and endometrial thickness of 5 mm or more measured by transvaginal ultrasound (TVU) were enrolled in a prospective study between May 2008 and July 2010. They underwent diagnostic hysteroscopy and endometrial biopsy. Hysteroscopic data was compared with the final diagnosis established by histological examination. RESULTS: The women's mean age was 61.2 ± 5.2 years (range 44-80). The most frequent endometrial lesion was endometrial polyps (31.1%). Hyperplastic endometrium was confirmed in 23 (27.8%), only 13 cases were suspected by the hysteroscope. Out of the 14 (16.9%) proven cases of endometrial cancer, only half of the cases were suspected. In benign endometrial lesions, the sensitivity of the hysteroscopic view was 94.7%, specificity was 97.8%, positive (PPV) and negative (NPV) predictive values were 97.3 and 95.7%, respectively. On the other hand, hysteroscopy demonstrated an overall sensitivity, specificity, PPV, and NPV of 56.5, 91.6, 72.2, and 84.6%, respectively, in endometrial hyperplasia, whereas the same parameters for endometrial cancer were 50, 94.2, 63.6, and 90.2%. CONCLUSION: Hysteroscopy can be used as the first line diagnostic tool for evaluating the benign endometrial lesions, such as endometrial polyp and submucosal myoma, nonetheless hysteroscopy has poor validity for excluding endometrial hyperplasia and cancer in women presenting with the postmenopausal bleeding and thick endometrium.

Montelukast, a leukotriene receptor antagonist abrogates lipopolysaccharide-induced toxicity and oxidative stress in rat liver.

Endotoxemia-induced hepatotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) generation inducing DNA, proteins and membrane lipid damages. In the present study, the protective effects of montelukast (MNT) against Escherichia coli lipopolysaccharides (LPS)-induced oxidative stress were investigated in rat liver. LPS (10mg/kg, i.p.) was injected and the animals were sacrificed 6h after LPS challenge. MNT (10mg/kg) was administered orally for seven successive days before endotoxemia induction. Blood samples were withdrawn for assessing the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and levels of serum total bilirubin, total protein, tumor necrosis factor-alpha (TNF-α) and interleukin 1ß (IL-1ß). Livers were dissected out and used for histological examination or stored for the determination of malondialdehyde (MDA), protein carbonyl content (PCC), reduced glutathione (GSH) levels, enzymatic activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and myeloperoxidase (MPO). Sepsis significantly increased ALT, AST, ALP, LDH, total bilirubin, TNF-α and IL-1ß, MPO, MDA and PCC levels and decreased total protein, GSH and enzymatic antioxidants (CAT, SOD and GSH-Px). MNT decreased the markers of liver injury (AST, ALT, ALP, LDH, and total bilirubin), inflammatory biomarkers (TNF-alpha, IL-1ß), MDA, PCC and MPO after LPS challenge. In conclusion, MNT abrogates LPS-induced markers of liver injury and suppresses the release of inflammatory and oxidative stress markers via its antioxidant properties and enhancement enzymatic antioxidant activities.