LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced testicular toxicity in rats: Role of neprilysin inhibition and lncRNA TUG1 in ameliorating apoptosis.

Cyclophosphamide (CP) is widely used as chemotherapy in various cancers; however, testicular atrophy has been encountered as an associated adverse effect. Oxidative stress, enhanced endoplasmic reticulum (ER) stress, and subsequent apoptosis are involved in the molecular mechanisms of CP-induced testicular toxicity. In addition to the cardiovascular benefits of LCZ696 (sacubitril/valsartan (VAL)), neprilysin inhibition was shown to mediate Ca2+ sequestration inside the ER. Furthermore, long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) was shown to ameliorate apoptosis in various diseases. This tempted us to investigate the possible benefit of LCZ696 against CP-induced testicular dysfunction in rats through neprilysin inhibition axis, and the downstream apoptotic cascade, with highlighting the impact of lncRNA TUG1 in regulating testicular toxicity. Sixty adult male Wistar rats were randomly allocated as control, LCZ696, VAL, CP, CP + LCZ696, and CP + VAL. Testicular atrophy was induced by single-dose injection of CP (200 mg/kg; i.p.). LCZ696 treated group received LCZ696 (30 mg/kg; p.o.) for 6 days, with CP (200 mg/kg; i.p.) single-dose on day 5. LCZ696 increased lncRNA TUG1 expression, improved sperm characteristics, hormonal profile, testicular function, antioxidant defences, and Bcl-2. The histopathological picture and reduced oxidative and ER stress markers, aligned with declined Bax, caspase-3 and the expression of CHOP, PUMA, Noxa, Bim, and p53, with a subtle superior effect over VAL-treated group. In conclusion, the current study highlights the promising impact of LCZ696 in ameliorating chemotherapy-induced testicular atrophy; yet, further investigation regarding longer duration and different doses of LCZ696 is warranted.

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.