The cardioprotective effects of secoisolariciresinol diglucoside (flaxseed lignan) against cafeteria diet-induced cardiac fibrosis and vascular injury in rats: an insight into apelin/AMPK/FOXO3a signaling pathways.

Introduction: Fast food is a major risk factor for atherosclerosis, a leading cause of morbidity and mortality in the Western world. Apelin, the endogenous adipokine, can protect against cardiovascular disease via activating its receptor, APJ. Concurrently, secoisolariciresinol diglucoside (SDG), a flaxseed lignan extract (FLE), showed a therapeutic impact on atherosclerosis. The current study aimed to examine the effect of SDG on cafeteria diet (CAFD)-induced vascular injury and cardiac fibrosis via tracking the involvement of the apelin/APJ pathway. Methods: Thirty male rats were allocated into control, FLE-, CAFD-, CAFD/FLE-, and CAFD/FLE/F13A-treated rats, where F13A is an APJ blocker. All treatments lasted for 12 weeks. Results and discussion: The CAFD-induced cardiovascular injury was evidenced by histological distortions, dyslipidemia, elevated atherogenic indices, cardiac troponin I, collagen percentage, glycogen content, and apoptotic markers. CAFD increased both the gene and protein expression levels of cardiac APJ, apelin, and FOXO3a, in addition to increasing endothelin-1, VCAM1, and plasminogen activator inhibitor-1 serum levels and upregulating cardiac MMP-9 gene expression. Moreover, CAFD reduced serum paraoxonase 1 and nitric oxide levels, cardiac AMPK, and nuclear Nrf2 expression. FLE attenuated CAFD-induced cardiovascular injury. Such effect was reduced in rats receiving the APJ blocker, implicating the involvement of apelin/APJ in FLE protective mechanisms. Conclusion: FLE supplementation abrogated CAFD-induced cardiac injury and endothelial dysfunction in an apelin/APJ-dependent manner.

The expression profiling of circulating miR-204, miR-182, and lncRNA H19 as novel potential biomarkers for the progression of peptic ulcer to gastric cancer.

Deregulation of noncoding RNAs, microRNAs (miRNAs) and long noncoding RNA (lncRNA), are implicated in the initiation and progression of gastric cancer (GC). This study is a pilot case-control study carried out on 75 subjects, 40 of them were Helicobacter pylori-gastric ulcer patients and 35 were GC patients recruited from the Gastrointestinal Endoscopy Unit in Al-Kasr Al-Aini Hospital, Cairo University in Egypt. Real-time PCR was performed to evaluate the expression level of serum miR-204, miR-182, and lncRNA H19 in patients with peptic ulcer-progressed GC vs nonprogressed peptic ulcer patients. Fibroblast growth factor 18 (FGF-18)/FGF receptor 2 (FGFR2) expression and their downstream immunological and inflammatory signaling markers were assessed and their association with the addressed noncoding RNAs investigated. As regards miR-204 and miR-182, they were significantly increased (12.5 and 2.6 folds, respectively) in GU samples, compared with those of healthy control levels. The elevated levels of these miRNAs were significantly de-escalated in GC samples compared with GU and the fold decrease valued 2.2 fold for miR-204 and 1.8 folds for miR-182. On the other hand, the significant escalation in the level of lnRNA H19 in GU recorded a 16.6 fold increase and further elevation in its levels was evident in GC samples. The herein assessed miRNAs are correlated with disease duration and FGFR2 with miR-182 being significantly correlated with all inflammatory markers, TAC, INF-γ, matrix metallopeptidase 9, and FGF-18. In terms of diagnostic accuracy of assessed miRNAs (stages III to IV), the receiver operating characteristic analysis indicated that serum lncRNA H19 showed the highest diagnostic accuracy (95.5%), specificity (100%), and sensitivity (90.9%), compared with miR-204 and miR-182, which showed the same specificity (60%), sensitivity (72.7%), and diagnostic accuracy (68.8%). Our findings conclude that lnRNA H19, miR-204, and miR-182 may function as novel prospective plasma biomarkers to detect GC and its progression from H. pylori-peptic ulcer, which would be helpful to improve the theranostics of GC.

Ameliorative effect of taurine-chloramine in azathioprine-induced testicular damage; a deeper insight into the mechanism of protection.

BACKGROUND: The male reproductive system is a sensitive and intricate process that can be distressed following exposure to various toxicants. Therapeutic drugs, especially chemotherapeutics, can also adversely affect male fertility by instigating hormonal changes leading to testicular cells injury. Azathioprine (AZA) is an effective anticancer drug, but some cases of testicular toxicity have been reported. The aim of this work was to investigate the protective effects of taurine chloramine (TAU-Cl), a reported antioxidant and antiinflammtory peptide, against AZA-induced testicular dysfunction in male rats and ascertain the contributing mechanisms. METHODS: Forty male rats were allocated into four equal groups; (i) normal control rats, (ii) TAU-Cl group (100 mg/kg b.w/day for 10 weeks, (iii) AZA group (5 mg/day for 4 weeks); (iv) TAU-Cl/AZA group. RESULTS: AZA caused increased DNA damage in the testes, and alterations in sex hormones and sperm quality, including sperm count, viability, and motility. Moreover, testicular tissue from the AZA-treated group had increased levels of oxidative stress indicator, MDA, and decreased activity of the antioxidant enzymes as superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) levels. These deleterious events were accompanied by upregulated levels of the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and protein expression of iNOS and NFκB-p65, interleukin-1beta (IL-1ß), and proapoptotic marker; caspase-9, together with decreased Bcl-2, NrF2 and hemeoxygenase (HO-1) expression. In contrast, TAU-Cl pretreatment significantly abrogated these toxic effects which were confirmed histologically. CONCLUSION: Pretreatment with TAU-Cl exerts a protective effect against AZA-induced male reproductive testicular atrophy. This finding could open new avenues for the use of TAU-Cl as a complementary approach to chemotherapy supportive care.

Synergistic effect of carnosine on browning of adipose tissue in exercised obese rats; a focus on circulating irisin levels.

The recent appreciation of the energy burning capacity of brown adipose tissue turns it to an attractive target for anti-obesity therapy. We sought to evaluate the effect of L-carnosine on browning of white adipose tissue in exercised obese rats. Sixty adult male Wistar albino rats, 7-8 week-old weighing 130-150 g, were allocated into six groups; with 10 rats in each, for an experimentation period of 12 weeks: (i) normal control rats fed a standard fat diet (SFD/control), (ii) normal control rats fed a standard diet and injected with L-carnosine (250 mg/kg, i.p,) for 6 weeks (SFD/CAR), (iii) high-fat diet (HFD)-induced obese rats for 12 weeks, (iv) HFD rats subjected to exercise training (HFD/EXE) for 6 weeks, (v) HFD rats injected with L-carnosine (250 mg/kg,i.p.) for 6 weeks (HFD/CAR) and, (vi) HFD rats subjected to exercise training and L-carnosine (HFD/EXE/CAR). At the end of the 12-week-experiment, the body weights and the serum levels of lipid profile, oxidative stress, and inflammatory markers as well as circulating myokines were investigated. Gastrocnemius muscles and inguinal adipose tissues were excised for the measurement of gene expression of muscle irisin, adipose tissue uncoupling protein1 (UCP1), CD137 and the protein level of p38MAPK. In addition, histopathological examination for the studied groups was performed. Both exercise training for 6 weeks and carnosine treatment significantly decreased body weight gain, ameliorated obesity-induced dyslipidemia, reduced the thiobarbituric acid reactive species (TBARS) and TNF-α, while increased total antioxidant capacity and IL-10. Furthermore, increases in serum irisin levels and the expression of adipose uncoupling protein-1 (UCP-1), adipose CD137, p38 MAPK, and muscular fibronectin type III domain-containing protein 5(FNDC5), the precursor of irisin gene expression, were correlated with these carnosine- and exercise-induced physiological improvements. The highest improvement was evident in the combined exercise and carnosine group which indicates that their beneficial effects in obese animals were synergistic. These findings suggest that L-carnosine may induce browning of adipose tissue through irisin stimulation, a phenomenon that could be related to its antioxidant, anti-inflammatory, and anti-obesity effects.

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the alarmingly rising clinical problems in the 21st century with no effective drug treatment until now. Taurine is an essential amino acid in humans that proved efficacy as a non-pharmacological therapy in a plethora of diseases; however, its impact on NAFLD remains elusive. The aim of the current study is to evaluate the protective mechanism of taurine in experimental steatohepatitis induced by junk food given as cafeteria-diet (CAF-D) in male albino rats. METHODS: Forty adult male albino rats of local strain between 8-10 weeks old, weighing 150 ± 20 g, were divided into four equal groups: Group I (control group), Group II (Taurine group), Group III (CAF-D for 12 weeks) and Group IV (CAF-D +Taurine). CAF-D was given in addition to the standard chow for 12 weeks, where each rat was given one piece of beef burger fried in 15 g of sunflower oil, one teaspoonful of mayonnaise, and one piece of petit pan bread, weighing 60g/ piece. In the serum, liver function tests; ALT, AST, ALP, GGT and the lipid profile; TG, TC, HDL-C added to reduced glutathione (GSH) were assessed colorimetrically, while fibroblast growth factor (FGF)-21, adiponectin & interleukin (IL)-6 via ELISA. The same technique was used for the assays of the hepatic levels of FGF-21, silent information regulator (SIRT1), malondialdehyde (MDA),IL-10, tumor necrosis factor-α (TNF-α) as well as the apoptotic markers; caspase-3 and B-cell lymphoma (Bcl-2). RESULTS: The cafeteria-diet induced steatohepatitis was reflected by significantly increased body and liver weight gain, elevation of liver enzymes; ALT, AST, ALP and GGT added to the dyslipidemic panel, presented as increased TC, TG, LDL-C and decreased HDL-C levels. The steatosis-induced inflammatory milieu, marked by elevated serum levels of FGF-21, IL-6, hepatic TNF-α, as well as reduced IL-10 and adiponectin, was associated with steatosis- induced hepatic oxidative stress, reflected by increased hepatic MDA and decreased GSH levels, along with stimulated caspase-3 and decline in BcL-2 hepatic levels. These pathological disturbances were significantly ameliorated by taurine supplementation and evidenced histopathologically. The cross talk between hepatic FGF-21 and SIRT1 and their association to the induced perturbations are novel findings in this study. Taurine's efficacy in restoration of hepatic structure and function is partially via the increase in SIRT1 and associated reduction of FGF-21. CONCLUSION: The findings of the current study prove the protective role of taurine in NAFLD via a novel role in the amelioration of FGF-21/ SIRT1 axis, which could be considered a new therapeutic target.

Hypoglycemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats.

BACKGROUND: Diabetes is a major public health concern. In spite of continuous new drug development to treat diabetes, herbal remedies remain a potential adjunct therapy to maintain better glycemic control while also imparting few side-effects. Portulaca oleracea has been traditionally used to manage several diseases due to the anti-oxidant and anti-atherogenic effects it imparts. To better understand the mechanisms associated with potential protective effect of P. oleracea extract against diabetes, alloxan-induced diabetic rats were used in this study. METHODS: Forty Wistar rats (male, 7-8-wk-old, 140-160 g) were divided into four groups (n = 10/group): Group I (control), Group II (P. oleracea-treated; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks), Group III (diabetic control; daily IP injection of alloxan [at 75 mg/kg] for 5 days) and Group IV (P. oleracea-pre-treated diabetic; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks and then daily IP injection of alloxan [at 75 mg/kg] for 5 days). Body weight, food consumption, blood (serum) levels of glucose, C peptide, Hb A1C, insulin, tumor necrosis factor (TNF)-α and interleukin (IL)-6 were determined for all groups. RESULTS: The results indicated that while Hb A1C, serum levels of glucose, TNF-α and IL-6 were all significantly decreased in the P. oleracea-pre-treated diabetic rats, these hosts also had significant increases in C peptide and insulin compared to levels in the counterpart diabetic rats. These results were confirmed by the histopathological assessments which showed marked improvement of the destructive effect on pancreatic islet cells induced by alloxan. CONCLUSION: P. oleracea extract is a general tissue protective and regeneartive agent, as evidenced by increasing ß-cell mass and therefore improved the glucose metabolism. Thus, stimulation of Portulaca oleracea signaling in ß- cells may be a novel therapeutic strategy for diabetes prevention.

Tc-99 m diethylenetriamine-pentaacetic acid (DTPA): is it reliable for assessment of methotrexate-induced cumulative effect on renal filtration in rheumatoid arthritis patients?

Methotrexate (MTX) is commonly employed as the initial DMARD used for the treatment of rheumatoid arthritis (RA). We aimed to contribute to the safety profile of MTX by assessing its cumulative effect on renal filtration. A total of 52 RA adult female patients with normal baseline serum creatinine and GFR at the initial diagnosis of the disease were included. Group 1 (G1) included 30 patients (mean age 40.4 ± 4.4 years) on MTX and NSAIDS, while 22 RA patients (mean age 38.5 ± 8.2 years) who received NSAIDs only served as control group (G2). Renal function was assessed by GFR measurement using technetium diethylenetriamine-pentaacetic acid (Tc-99 m DTPA) at a point of the study time corresponding to disease duration. Twenty-one out of thirty (70 %) in G1 showed reduced GFR compared to 6/22 (27.3 %) in G2 (P = 0.007), with 3.3 ± 0.5 % annual reduction in GFR. Reduced GFR in G1 showed significant negative correlation with age (r = -0.396, P = 0.005), MTX cumulative dose (r = -0.263, P = 0.049), MTX-intake duration (r = -0.293, P = 0.031) and NSAIDs-intake duration (r = -0.344, P = 0.014). Low-dose MTX has a slow cumulative effect on renal filtration manifested by GFR reduction overtime that could be monitored by Tc-99 m DTPA.