Therapeutic effects of genistein in experimentally induced ulcerative colitis in rats via affecting mitochondrial biogenesis.

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the mucosa of the colon, resulting in severe inflammation and ulcers. Genistein is a polyphenolic isoflavone present in several vegetables, such as soybeans and fava beans. Therefore, we conducted the following study to determine the therapeutic effects of genistein on UC in rats by influencing antioxidant activity and mitochondrial biogenesis and the subsequent effects on the apoptotic pathway. UC was induced in rats by single intracolonic administration of 2 ml of 4% acetic acid. Then, UC rats were treated with 25-mg/kg genistein. Colon samples were obtained to assess the gene and protein expression of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-gamma coactivator (PGC-1), mitochondrial transcription factor A (TFAM), B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3, caspase-8, and caspase-9. In addition, colon sections were stained with hematoxylin/eosin to investigate the cell structure. The microimages of UC rats revealed inflammatory cell infiltration, hemorrhage, and the destruction of intestinal glands, and these effects were improved by treatment with genistein. Finally, treatment with genistein significantly increased the expression of PGC-1, TFAM, Nrf2, HO-1, and BCL2 and reduced the expression of BAX, caspase-3, caspase-8, and caspase-9. In conclusion, genistein exerted therapeutic effects against UC in rats. This therapeutic activity involved enhancing antioxidant activity and increasing mitochondrial biogenesis, which reduced cell apoptosis.

WRH-2412 alleviates the progression of hepatocellular carcinoma through regulation of TGF-ß/ß-catenin/α-SMA pathway.

Hepatocellular carcinoma is considered one of the most lethal cancers, which is characterised by increasing prevalence associated with high level of invasion and metastasis. The novel synthetic pyrazolo[3,4-b]pyridine compound, WRH-2412, was reported to exhibit in vitro antitumor activity. This study was conducted to evaluate the antitumor activity of WRH-2412 in HCC induced in rats through affecting the TGF-ß/ß-catenin/α-SMA pathway. Antitumor activity of WRH-2412 was evaluated by calculating the rat's survival rate and by assessment of serum α-fetoprotein. Protein expression of TGF-ß, ß-catenin, E-cadherin, fascin and gene expression of SMAD4 and α-SMA were determined in hepatic tissue of rats. WRH-2412 produced antitumor activity by significantly increasing the rats' survival rate and decreasing serum α-fetoprotein. WRH-2412 significantly reduced an HCC-induced increase in hepatic TGF-ß, ß-catenin, SMAD4, fascin and α-SMA expression. In addition, WRH-2412 significantly increased hepatic E-cadherin expression.

QNZ alleviated hepatocellular carcinoma by targeting inflammatory pathways in a rat model.

The pathogenicity of HCC could be enhanced by TNF-α and NFκB, which are crucial parts of the inflammatory pathway inside the HCC microenvironment. Therefore, we aimed to discover the therapeutic effects of QNZ, an inhibitor of both TNF-α and NFκB, in an experimental model of HCC in rats. HCC was experimentally induced in rats by thioacetamide, and some of the rats were treated with QNZ. The expression levels of nuclear factor (NF)κB, tumor necrosis factor (TNF)-α, apoptosis signal regulating kinase (ASK)-1, ß-catenin, glycogen synthase kinase (GSK)-3 and TNF receptor-associated factor (TRAF) were examined in hepatic samples. In addition, hepatic tissues were stained with hematoxylin/eosin and anti-TNF-α antibodies. QNZ blocked HCC-induced expression of both NFκB and TNF-α. It significantly reduced both α-fetoprotein and the average number of nodules and increased the survival rate of the HCC rats. Moreover, hematoxylin and eosin liver sections from the HCC rats showed vacuolated cytoplasm and necrotic nodules. All of these effects were alleviated by QNZ treatment. Finally, treating HCC rats with QNZ resulted in a reduction in the expression of TRAF, ASK-1 and ß-catenin, as well as increased expression of GSK-3. In conclusion, inhibition of the inflammatory pathway in HCC with QNZ produced therapeutic effects, as indicated by an increased survival rate, reduced serum α-fetoprotein levels, decreased liver nodules and improved the hepatocyte structure. In addition, QNZ significantly reduced the expression of TRAF, ASK-1 and ß-catenin that were associated with increased expression of GSK-3.

Fucoidan Ameliorates Hepatocellular Carcinoma Induced in Rats: Effect on miR143 and Inflammation.

Fucoidan is sulfated polysaccharide of brown seaweed. It offers various pharmacological actions like anti-inflammatory, anti-bacterial and anti-tumor activities. Therefore, we aimed to investigate the effect of targeting microRNA-143 and inflammatory pathway by Fucoidan on experimentally induced hepatocellular carcinoma (HCC) in rats. HCC is experimentally induced in Sprague Dawley by thioacetamide. Rats were treated with 100 mg/kg and 200 mg/kg Fucoidan. Hepatic sections were stained with hematoxylin/esosin for investigation of cell integrity. Moreover, hepatic sections were immunohistochemically stained with antibodies for ki67, TNF-α, and IL-1ß. Finally, hepatic tissues were investigated for expression of miR-143, NF-κB, TNF-α, and IL-1ß. We found that treating HCC with Fucoidan significantly reduced HCC-induced elevation in oxidative stress. Moreover, Fucoidan reduced HCC-induced in expression of miR-143, NF-κB, TNF-α, and IL-1ß. Finally, Fucoidan attenuated pseudohepatic lobules, broad fibrous septa and vacuolar to ballooning degeneration associated with reduction of immunostaining of ki67, TNF-α, and IL-1ß. Fucoidan elevated the survival of HCC rats and reduced their serum AFP. In addition, Fucoidan treatment revealed reduction in the expression of miR-143 associated with antioxidant and anti-inflammatory activities in HCC rats.

Measuring the appropriateness of carbamazepine and valproic acid prescribing and utilization using a newly implemented online system in the Tabuk Region of Saudi Arabia.

Epilepsy is a common neurologic disorder, which is efficiently treated with carbamazepine and valproic acid. Moreover, Saudi Ministry of Health implemented a new E-system for Poison Control Centers called Awtar to enhance technology utilization in ensuring patients' satisfaction and to improve treatment outcomes. Therefore, we conducted this study to assess appropriateness of indication of requests and therapeutic levels of carbamazepine and valproic acid in Tabuk area, North West Saudi Arabia. This is a retrospective observational study conducted in Poison Control & Forensic Chemistry Center, Tabuk, Saudi Arabia. Patients' data were obtained for years 2018 and 2019. The blood levels of carbamazepine and valproic acid were measured by Therapeutic Drug Monitoring (TDM) Unit. We selected patients treated with either valproic acid or carbamazepine alone without any history of drug allergy. Data of 264 patients were extracted from Awtar E-system. Serum carbamazepine levels were within therapeutic range in 114 patients (75.50%), above-therapeutic range in 13 patients (8.61%) and sub-therapeutic levels in 24 patients (15.89%). Regarding serum valproic acid, it is within therapeutic range in 62 patients (54.87%), above-therapeutic range in 11 patients (9.73%) and sub-therapeutic levels in 40 patients (35.40%). In conclusion, this study gives information about partial appropriateness of usage of carbamazepine and low level of appropriateness of valproic acid. However, more efforts are needed to improve results of appropriateness of indication of antiepileptic drugs.

Clinical significance of the TNF-α receptors, TNFRSF2 and TNFRSF9, on cell migration molecules Fascin-1 and Versican in acute leukemia.

In human hematologic malignancies, some of the TNF receptor family members are up-regulated and have the ability to evoke reactions favoring tumor progression. Moreover, cell migration molecules, Fascin-1 and Versican are involved in proliferation, migration and invasion of cancer cells. They are linked to many human cancers. Therefore, we conducted this study to evaluate both the plasma and leukocytes concentrations of tumor necrosis factor receptor super family 2 (TNFRSF2), TNFRSF9, Fascin-1 and Versican in patients with acute leukemia, as well as to correlate these values with clinical features and treatment outcome. Therefore, forty-eight patients with acute myeloid leukemia (AML), thirty-two patients with acute lymphoblastic leukemia (ALL) and fifteen control subjects were included. TNFRSF2, TNFRSF9, Fascin-1 and Versican were measured in plasma and leukocytes of all subjects by enzyme-linked immunosorbent assay. We found that plasma TNFRSF9 was highly elevated in ALL and AML as compared with the control group. In addition, AML patients who failed to achieve complete remission showed a significant increase in leukocytes TNFRSF9 level. TNFRSF2 is significantly increased in plasma and leukocytes of ALL patients when compared with the control group and AML patients. Fascin-1 significantly increased in AML, but not in ALL cases. Plasma and leukocytes levels of Versican significantly increased in AML compared to both control and ALL subjects. Plasma Versican correlated with poor response to induction of chemotherapy in AML cases. In conclusion, TNFRSF2 and TNFRSF9 could act as a possible prognostic biomarkers for the outcomes of ALL patients and TNFRSF9 could be a potential target in AML. Versican may be used as a diagnostic biomarker and as a predictor of the response to chemotherapy in AML. In addition, plasma Fascin-1 is a potential biomarker for AML.

Chemopreventive and hepatoprotective roles of adiponectin (SULF2 inhibitor) in hepatocelluar carcinoma.

Sulfatase 2 (SULF2) is an extracellular enzyme that catalyzes the removal of 6-O-sulfate groups from the heparan sulfate (HS). As elevated SULF2 activity has been correlated with hepatocellular carcinoma (HCC), this study was conducted to evaluate the chemoprotective and the hepatoprotective roles of adiponectin, as a SULF2 inhibitor, against hepatocellular carcinoma both in vivo and in vitro. HCC was induced in rats using thioacetamide (200 mg/kg). Treated rats received adiponectin (5 µg/kg) once a week. Moreover, human hepatocellular carcinoma (HepG2) cell line was used as an in-vitro model. In both in-vivo and in-vitro models, adiponectin completely blocked HCC-induced SULF2 elevation. The antitumor activity of adiponectin was confirmed by 80% increased the survival rate, 73% reduction in the average number of nodules per nodule-bearing liver and 46% reduction in serum AFP. In addition, adiponectin ameliorated HCC-induced expression of tumor invasion markers, MMP9, syndecan-1 and FGF-2. Moreover, adiponectin attenuated HCC-induced elevation of nfκb and TNF-α levels. Moreover, treatment of HepG2 cell line with adiponectin showed dose-dependent reduction of HepG2 cell viability and elevation of cellular cytotoxicity. Besides, Adiponectin yielded the same results in HepG2 cells in a dose-dependent manner. Adiponectin achieved both hepatoprotective and chemoprotective effects against HCC through blocking of SULF2.

Thymoquinone ameliorated elevated inflammatory cytokines in testicular tissue and sex hormones imbalance induced by oral chronic toxicity with sodium nitrite.

Scientific evidence illustrated the health hazards of exposure to nitrites for prolonged time. Nitrites affected several body organs due to oxidative, inflammatory and apoptosis properties. Furthermore, thymoquinone (TQ) had curative effects against many diseases. We tried to discover the impact of both sodium nitrite and TQ on inflammatory cytokines contents in testicular tissues and hormonal balance both in vivo and in vitro. Fifty adult male SD rats received 80mg/kg sodium nitrite and treated with either 25 or 50mg/kg TQ daily by oral-gavage for twelve weeks. Testis were removed for sperms' count. Testicular tissue homogenates were used for assessment of protein and gene expression of IL-1ß, IL-6, TNF-α, Nrf2 and caspase-3. Serum samples were used for measurement of testosterone, LH, FSH and prolactin. Moreover, all the parameters were measured in human normal testis cell-lines, CRL-7002. Sodium nitrite produced significant decrease in serum testosterone associated with raised FSH, LH and prolactin. Moreover, sodium nitrite significantly elevated TNF-α, IL-1ß, IL-6, caspase-3 and reduced Nrf2. TQ significantly reversed all these effects both in vivo and in vitro. In conclusion, TQ ameliorated testicular tissue inflammation and restored the normal balance of sex hormones induced by sodium nitrite both in vivo and in vitro.

The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment.

Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.

Renal protective effects of arjunolic acid in a cisplatin-induced nephrotoxicity model.

Cisplatin is the first platinum-containing anti-cancer drugs. Cisplatin notable side effect of nephrotoxicity limits its use in clinic. Meanwhile, arjunolic acid possesses anti-inflammatory properties and plays protective roles against chemically induced organ pathophysiology. This study was conducted to find out whether arjunolic acid could attenuate kidney damage in rats, and to elucidate its possible mechanism of action. Fifty rats were treated with cisplatin (10mg/kg) in the presence/absence of 100 or 250mg/kg arjunolic acid. Arjunolic acid is given 1h after cisplatin. Morphological changes were assessed in kidney sections stained with Hematoxylin/Eosin and Masson Trichrome. Kidney samples were used for measurements of transforming growth factor (TGF)-ß1 and its type 1 receptor (TGF-ßR1), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß by ELISA. Gene expression NFκB was determined by real time-PCR. Kidney tissue apoptosis was assessed by measuring the activities of caspase-3/8/9. The renal protective effect of arjunolic acid was confirmed by approximately normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. Furthermore, arjunolic acid showed dose dependent reduction in cisplatin-induced elevation in renal levels of TGF-ßR1, TGF-ß1, TNF-α, IL-1ß and caspases. These findings demonstrated that arjunolic acid attenuates cisplatin nephrotoxicity either indirectly by enhancing body antioxidant activity or directly through several mechanisms, including inhibition of pro-inflammatory cytokines, blocking activation of TGF-ß1, and anti-apoptotic effects.

Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats.

Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.

The Effect of a Vegan Diet on the Health Indicators and Outcomes of P atients with Type 2 Diabetes Mellitus.

INTRODUCTION/OBJECTIVES: Recently, there has been a notable increase in interest in various forms of vegetarianism, which may be due to the growing prevalence of health issues, such as Type 2 Diabetes Mellitus (T2DM). Adhering to a vegan diet may have positive health outcomes. As a result, we conducted a review article to gather data from previous research studies on the effects of a vegan diet on different aspects of managing patients with T2DM. METHODS: We searched the PubMed website for research studies on how a vegan diet affects the outcomes of patients with T2DM. The research studies were categorized according to the type of data collected, such as prevalence, incidence, body weight, insulin resistance, glycemic control, and lipid profile. RESULTS: It was found that following a vegetarian diet can significantly reduce the risk of mortality from heart disease. Additionally, studies have demonstrated that a vegetarian diet is linked to several improvements in T2DM. However, long-term weight loss plans and managing T2DM is a comprehensive intervention that includes caloric restriction, exercise, and behavioral modification. CONCLUSION: Incorporating a vegan diet can be a valuable factor to consider in managing T2DM, as it can offer numerous benefits, such as increased insulin sensitivity, weight loss, and reduced blood sugar levels. It helps to reduce cholesterol levels, LDL, and triglyceride levels, which are all risk factors associated with T2DM. By reducing these risk factors, the vegan diet can improve the overall health of T2DM patients.

Echinacoside ameliorates hepatic fibrosis and tumor invasion in rats with thioacetamide-induced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) affects approximately 800,000 individuals globally each year. Despite advancements in HCC treatments, there is still a pressing need to identify new drugs that can combat resistance. One potential option is echinacoside, a natural caffeic acid glycoside with antioxidant, anti-inflammatory, antidepressant, and antidiabetic properties. Therefore, we aimed to investigate the ability of echinacoside to exhibit antitumor activity against HCC in rats through ameliorating hepatic fibrosis and tumor invasion. Rats were given thioacetamide to induce HCC, and some were given 30 mg/kg of echinacoside twice a week for 16 weeks. The liver impairment was assessed by measuring serum α-fetoprotein (AFP) and examining liver sections stained with Masson trichrome or anti-transforming growth factor (TGF)-ß1 antibodies. The hepatic expression of mRNA and protein levels of TGF-ß1, ß-catenin, SMAD4, matrix metalloproteinase-9 (MMP9), phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR), connective tissue growth factor 2 (CCN2), E-Cadherin, platelets derived growth factor (PDGF)-B and fascin were also analyzed. Echinacoside improved the survival rate of rats by decreasing serum AFP and the number of hepatic nodules. Examination of micro-images indicated that echinacoside can reduce fibrosis. It also significantly decreased the expression of TGF-ß1, ß-catenin, SMAD4, MMP9, PI3K, mTOR, CCN2, PDGF-B, and fascin while enhancing the expression of E-Cadherin. In conclusion, echinacoside exhibits a protective effect against HCC by increasing survival rates and decreasing tumor growth. It also acts as an inhibitor of the hepatic tissue fibrosis pathway by reducing the expression of TGF-ß1, ß-catenin, SMAD4, PI3K, CCN2, PDGF-B and mTOR. Additionally, it prevents tumor invasion by suppressing MMP9 and fascin, and increasing the expression of E-Cadherin.

Effects of Cycloastragenol on Alzheimer's Disease in Rats by Reducing Oxidative Stress, Inflammation, and Apoptosis.

BACKGROUND: As individuals age, they may develop Alzheimer's disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer. OBJECTIVES: This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis. METHODS: Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed. RESULTS: Cycloastragenol significantly improved rats' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1. CONCLUSION: Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.

Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by early blood-retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75(NTR)), suggesting a possible pathological role of the proNGF-p75(NTR) axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75(NTR) would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown. METHODS: Diabetes was induced by streptozotocin in wild-type and p75(NTR) knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75(NTR) short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Müller glial cell line (rMC-1) and primary Müller cells. RESULTS: Deletion of p75(NTR) blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75(NTR) also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75(NTR) blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75(NTR)-dependent production of inflammatory mediators in primary wild-type Müller and rMC-1 cultures, but not in p75KO Müller cells. CONCLUSIONS/INTERPRETATION: The proNGF-p75(NTR) axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75(NTR) as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.

Hepatoprotective effects of cod liver oil against sodium nitrite toxicity in rats.

CONTEXT: Exposure to high levels of nitrites for a prolonged time have adverse health effects on several organs especially the liver due to oxidative properties. Meanwhile, cod liver oil has been reported to ameliorate organ dysfunction in animal models that involve oxidative stress. OBJECTIVE: Examine the impact of dietary cod liver oil on sodium nitrite-induced liver damage. MATERIALS AND METHODS: Thirty-two adult male Sprague-Dawely rats were daily treated with sodium nitrite (80 mg/kg) in presence or absence of cod liver oil (5 ml/kg). Morphological changes were assessed in liver sections. Oxidative stress and antioxidant markers were measured in serum and liver homogenates. Liver samples were used for measurements of MCP-1, DNA fragmentation and mitochondrial function. RESULTS: The hepatoprotective effect of cod liver oil was proved by significant reduction of elevated liver enzymes and normal appearance of hepatocytes. Cod liver oil significantly reduced hepatic malondialdehyde, hydrogen peroxide and superoxide anion (224.3 ± 18.9 nmol/g, 59.3 ± 5.1 and 62.5 ± 5.1 µmol/g, respectively) compared with sodium nitrite (332.5 ± 25.5 nmol/g, 83.1 ± 8.1 and 93.9 ± 6.5 µmol/g, respectively). Cod liver oil restored hepatic cytochrome c oxidase activity after 38% reduction by sodium nitrite. Furthermore, cod liver oil significantly reduced hepatic MCP-1 (79.8 pg/mg) and DNA fragmentation (13.8%) compared with sodium nitrite (168.7 pg/mg and 41.3%, respectively). DISCUSSION AND CONCLUSION: Cod liver oil ameliorates sodium nitrite induced hepatic impairment through several mechanisms including attenuation of oxidative stress, blocking MCP-1, reactivation of mitochondrial function and reduction of DNA fragmentation.

Curative effects of crocin in ulcerative colitis via modulating apoptosis and inflammation.

Ulcerative colitis (UC) is an inflammatory bowel disease with characteristic inflammation to mucosal cells in rectum and colon leading to lesions in mucosa and submucosa. Moreover, crocin is a carotenoid compound among active constituents of saffron with many pharmacological effects as antioxidant, anti-inflammatory and anticancer activities. Therefore, we aimed to investigate therapeutic effects of crocin against UC through affecting the inflammatory and apoptotic pathways. For induction of UC in rats, intracolonic 2 ml of 4% acetic acid was used. After induction of UC, part of rats was treated with 20 mg/kg crocin. cAMP was measured using ELISA. Moreover, we measured gene and protein expression of B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3/8/9, NF-κB, tumor necrosis factor (TNF)-α and IL-1ß/4/6/10. Colon sections were stained with hematoxylin-eosin and Alcian blue or immune-stained with anti-TNF-α antibodies. Microscopic images of colon sections in UC group revealed destruction of intestinal glands associated with infiltration of inflammatory cell and severe hemorrhage. While images stained with Alcian blue showed damaged and almost absent intestinal glands. Crocin treatment ameliorated morphological changes. Finally, crocin significantly reduced expression levels of BAX, caspase-3/8/9, NF-κB, TNF-α, IL-1ß and IL-6, associated with increased levels of cAMP and expression of BCL2, IL-4 and IL-10. In conclusion, protective of action of crocin in UC is proved by restoration of normal weight and length of colon as well as improvement of morphological structure of colon cells. The mechanism of action of crocin in UC is indicated by activation of anti-apoptotic and anti-inflammatory effects.

Genistein ameliorated experimentally induced gastric ulcer in rats via inhibiting gastric tissues fibrosis by modulating Wnt/ß-catenin/TGF-ß/PKB pathway.

OBJECTIVES: Gastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein is a legume flavonoid with antioxidants, anti-inflammatory and antibacterial activities. Therefore, we aimed to investigate the ability of genistein to reduce experimentally induced GU in rats by affecting gastric tissue fibrosis Wnt/ß-catenin/TGF-ß/SMAD4 pathway. METHODS: Thirty rats were used. Ten rats served as control, and GU was induced in twenty rats using a single dose of indomethacin (80 mg/kg) orally. Following induction of GU, ten were treated with genistein 25 mg/kg orally. The gastric tissues were isolated to investigate markers of gastric fibrosis, Wnt, ß-catenin, transforming growth factor (TGF)-ß, SMAD4, and Protein kinase B (PKB). In addition, gastric sections were stained with PAS and anti-TGF-ß antibodies. RESULTS: Investigation GU micro-images revealed degeneration in both surface cells and glandular epithelial cells, which was improved by genistein. In addition, treatment with genistein significantly reduced the expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB. CONCLUSION: Besides antioxidant activity, genistein improves experimentally induced GU in rats, at least in part, via reduction of gastric tissue fibrosis as indicated by reduction in expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB.

Electroporation-mediated gene delivery of cleavage-resistant pro-nerve growth factor causes retinal neuro- and vascular degeneration.

PURPOSE: Neurotrophins, including nerve growth factor (NGF), are secreted by glia as a pro-form (proNGF) that is normally cleaved into the mature ligand. Increases of proNGF has been well documented in retinal neurodegenerative diseases. Since systemic overexpression of proNGF exhibits embryonic lethality, we aimed to establish a model that specifically and stably overexpresses a cleavage-resistant mutant of proNGF (proNGF123) plasmid in the retina using electroporation. METHODS: Male Sprague-Dawley rats were injected intravitreally with pGFP or pGFP-proNGF123 plasmids, then electroporated with various settings for optimization. Retinal cell death and ganglion cell count were assessed by TUNEL and immunostaining with anti-Brn3. Expression of proNGF, NGF, and their receptors was examined by western blot. Retinal vascular permeability was assessed by extravasation of bovine serum albumin-fluorescein. Development of acellular capillaries was assessed by periodic acid-Schiff and hematoxylin staining. RESULTS: Successful pGFP-proNGF123 gene delivery and expression of proNGF was demonstrated by western blot and extensive proNGF immunostaining in retina sections. Overexpression of proNGF reduced NGF expression while inducing the expression of neurotrophin receptors, including p75(NTR) and tyrosine receptor kinase A, but not sortilin. Overexpression of proNGF resulted in ~50% reduction in ganglion cell count and fivefold increase in TUNEL-positive cells in rat retina. In addition, overexpression of proNGF induced breakdown of the blood-retina barrier evident by twofold increase in extravasation of bovine serum albumin-fluorescein after 1 week and induced the development of acellular capillaries after 4 weeks. CONCLUSIONS: Electroporation can successfully incorporate and express biologically active cleavage-resistant proNGF locally in rat retinas. Overexpression of cleavage-resistant proNGF can be a useful tool to investigate specific molecular mechanisms by which proNGF causes neurodegeneration and vascular injury in the retina.

Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in Egypt, in parallel with increasing obesity. NAFLD can lead to liver inflammation, fibrosis and cirrhosis. NAFLD appears tightly linked with metabolic syndrome (MetS). OBJECTIVE: Examine the impact of dietary fish oil on human patients with MetS and NAFLD. MATERIALS AND METHODS: One hundred and forty patients were enrolled in the current study and classified into two groups: patients with both MetS and NAFLD and patients with MetS alone. Sixty-four patients were treated with daily supplementation of 2 g of fish oil for 6 months. Markers of hyperlipidemia and oxidative stress, hydrogen peroxide (H(2)O(2)) and malondialdhyde (MDA), as well as proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were analyzed. RESULTS: Patients without fish oil exhibited significant increases in triglycerides (TGs), low-density lipoprotein (LDL), H(2)O(2) and MDA that were associated with significantly elevated TNF-α and IL-6 compared to controls. Furthermore, patients with both NAFLD and MetS showed significant increase in H(2)O(2), MDA, TNF-α and IL-6 levels compared with MetS group (p < 0.05). Treatment with fish oil reduced serum level of TG, LDL-cholesterol (LDL-C), H(2)O(2), MDA, TNF-α and IL-6 levels in patients and did not affect the control levels. DISCUSSION AND CONCLUSION: Patients with NAFLD had bad lipid profile through a mechanism that involved developed redox imbalance, characterized by boosted free-radical activity and lipid peroxidation enhancing the release of proinflammatory cytokines leading to increased MetS risk and liver damage. However, daily treatment of patients with fish oil for 6 months improved lipid profile and blocked the oxidative stress and cytokines release.