Ameliorating effects of adropin on letrozole-induced polycystic ovary syndrome via regulating steroidogenesis and the microbiota inflammatory axis in rats.

Growing evidence supports the role of gut microbiota in chronic inflammation, insulin resistance (IR) and sex hormone production in polycystic ovary syndrome (PCOS). Adropin plays a pivotal role in the regulation of glucose and lipid metabolism and is negatively correlated with IR, which affects intestinal microbiota and sex hormones. However, the effect of adropin administration in PCOS has yet to be investigated. The present study aimed to assess the effects of adropin on letrozole (LTZ)-induced PCOS in rats and the potential underlying mechanisms. The experimental groups were normal, adropin, letrozole and LTZ + adropin. At the end of the experiment, adropin significantly ameliorated PCOS, as evidenced by restoring the normal ovarian structure, decreasing the theca cell thickness in antral follicles, as well as serum testosterone and luteinizing hormone levels and luteinizing hormone/follicle-stimulating hormone ratios, at the same time as increasing granulosa cell thickness in antral follicles, oestradiol and follicle-stimulating hormone levels. The ameliorating effect could be attributed to its effect on sex hormone-binding globulin, key steroidogenic genes STAR and CYP11A1, IR, lipid profile, gut microbiota metabolites-brain-ovary axis components (short chain fatty acids, free fatty acid receptor 3 and peptide YY), intestinal permeability marker (zonulin and tight junction protein claudin-1), lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B inflammatory pathway and oxidative stress makers (malondialdehyde and total antioxidant capacity). In conclusion, adropin has a promising therapeutic effect on PCOS by regulating steroidogenesis, IR, lipid profile, the gut microbiota inflammatory axis and redox homeostasis. KEY POINTS: Adropin treatment reversed endocrine and ovarian morphology disorders in polycystic ovary syndrome (PCOS). Adropin regulated the ovarian steroidogenesis and sex hormone-binding globulin in PCOS. Adropin improved lipid profile and decreased insulin resistance in PCOS. Adropin modulated the components of the gut-brain-ovary axis (short chain fatty acids, free fatty acid receptor 3 and peptide YY) in PCOS. Adropin improved intestinal barrier integrity, suppressed of lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B signalling pathway and oxidative stress in PCOS.

Trichinella spiralis: A new parasitic target for curcumin nanoformulas in mice models.

Trichinosis spiralis is a global disease with significant economic impact. Albendazole is the current-treatment. Yet, the world-widely emerging antimicrobial resistance necessitates search for therapeutic substitutes. Curcumin is a natural compound with abundant therapeutic benefits. This study aimed to evaluate the potential of crude-curcumin, chitosan and for the first time curcumin-nano-emulsion and curcumin-loaded-chitosan-nanoparticles against Trichinella spiralis adults and larvae in acute and chronic trichinosis models. Trichinosis spiralis was induced in 96 Swiss-albino mice. Infected mice were divided into 2 groups. Group I constituted the acute model, where treatment started 2 h after infection for 5 successive days. Group II constituted the chronic model, where treatment started at the 30th day-post-infection and continued for 10 successive days (Refer to graphical abstract). Each group contained 8 subgroups that were designated Ia-Ih and IIa-IIh and included; a; Untreated-control, b; Albendazole-treated (Alb-treated), c; Crude-curcumin-treated (Cur-treated), d; Curcumin-nanoemulsion-treated (Cur-NE-treated), e; Albendazole and crude-curcumin-treated (Alb-Cur-treated), f; Albendazole and curcumin-nanoemulsion-treated (Alb-Cur-NE-treated), g; Chitosan-nanoparticles-treated (CS-NPs-treated) and h; Curcumin-loaded-chitosan-nanoparticles-treated (Cur-CS-NPs-treated). Additionally, six mice constituted control-uninfected group III. The effects of the used compounds on the parasite tegument, in-vivo parasitic load-worm burden, local pathology and MDA concentration in small intestines of acutely-infected and skeletal muscle of chronically-infected mice were studied. Results showed that albendazole was effective, yet, its combination with Cur-NE showed significant potentiation against adult worms and muscle larvae and alleviated the pathology in both models. Cur-CS-NPs exhibited promising results in both models. Crude-curcumin showed encouraging results especially against muscle larvae on long-term use. Treatments effectively reduced parasite load, local MDA level and CD31 expression with anti-inflammatory effect in intestine and muscle sections.

The protective effects of topiramate and spirulina against doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX) is a widely used chemotherapy drug that can cause significant cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential protective effects of topiramate (TPM) and spirulina (SP), either alone or in combination, in preventing DOX-induced cardiotoxicity. Adult Sprague Dawley rats were divided into five groups, including a normal control group and groups receiving DOX alone, DOX with TPM, DOX with SP, or DOX with a combination of TPM and SP. Cardiotoxicity was induced by administering DOX intraperitoneally at a cumulative dose of 16 mg/kg over 4 weeks. TPM and/or SP administration started 1 week before DOX treatment and continued for 35 days. Body weight, serum markers of cardiac damage, oxidative stress and inflammatory parameters were assessed. Histopathological and immunohistochemical examinations were performed on cardiac tissues. Results showed that TPM and SP monotherapy led to significant improvements in serum levels of cardiac markers, decreased oxidative stress, reduced fibrosis-related growth factor levels, increased antioxidant levels, and improved histopathological features. SP demonstrated more prominent effects in comparison to TPM, and the combination of TPM and SP exhibited even more pronounced effects. In conclusion, TPM and SP, either alone or in combination, hold promise as therapeutic interventions for mitigating DOX-induced cardiotoxicity.

Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis.

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.

Anti-cancer effect of nano-encapsulated boswellic acids, curcumin and naringenin against HepG-2 cell line.

BACKGROUND: liver cancer is one of the most common cancers in the world. So far, there is no gold standard treatment for hepatocellular carcinoma. We conducted this in vitro study to assess the effect of three natural products: Boswellic acids, curcumin and naringin versus corresponding nanoparticles (NPs) on Hep G2 cells proliferation. METHODS: Boswellic acid, curcumin, naringin-loaded NPs were prepared using nanoprecipitation method. Human liver (HepG2) cell line was cultured in Dulbecco's modified Eagle's medium (DMEM). The cell growth inhibition and cytotoxicity were evaluated by MTT assay. RESULTS: Boswellic acid, curcumin, naringin were able to inhibit HepG2 cells proliferation. IC50 at 24 h, 48 h showed significant lower values in NPs versus Free herbs. IC50 values of free Boswellic acids and NPs at 24 h were (24.60 ± 1.89 and 7.78 ± 0.54, P < 0.001), at 48 h were (22.45 ± 1.13 and 5.58 ± 0.27, P < 0.001) respectively. IC50 values of free curcumin and NPs at 24 h were (5.89 ± 0.8 and 3.46 ± 0.23, P < 0.05), at 48 h were (5.57 ± 0.94 and 2.51 ± 0.11, P < 0.05), respectively. For free and naringenin NPs, IC50 values at 24 h were (14.57 ± 1.78 and 7.25 ± 0.17, P < 0.01), at 48 h were (11.37 ± 1.45 and 5.21 ± 0.18, P < 0.01) respectively. CONCLUSION: Boswellic acid, curcumin, naringin and their nanoprecipitation prepared nanoparticles suppressed Hep G2 cells proliferation.

Crocin lessens desipramine-induced phospholipidosis biomarker levels via targeting oxidative stress- related PI3K/Akt/mTOR signaling pathways in the rat liver.

Background and aim Crocin is a pharmacologically active chemical found in the spice saffron from Crocus sativus L. It possesses antioxidant and anti-radical properties that can minimize the hepatic phospholipidosis triggered using the tricyclic antidepressant desipramine. The aim of this study was to examine the effect of crocin on desipramine-induced hepatic phospholipidosis targeting the oxidative stress-related PI3K/Akt/mTOR signaling pathways. METHODS: Forty adult male rats were divided into 4 groups (n =10): control group, a group receiving intraperitoneal (IP) crocin (50 mg/kg/day), a group receiving IP desipramine (10 mg/kg/day), and a group receiving both IP crocin and desipramine. RESULTS: After 3 weeks of treatment, the combined treatment group showed diminished desipramine-induced hepatic phospholipidosis, along with significant reductions in total oxidant status (TOS) , the levels of inflammatory markers including interleukin 6 (IL6) and tumor necrosis factor α (TNF-α) and apoptotic markers including caspase3 and Bcl2 (B-cell lymphoma 2) while other markers including total antioxidant capacity (TAC), superoxide dismutase (SOD), phosphoinositide 3-kinases (PI3K), and mammalian target of rapamycin (mTOR) were increased. The gene expression of lysosomal enzymes including ELOVL6, SCD1 and HMGR was notably downregulated, while AP1S1 was upregulated in the combined treatment group compared to the desipramine group. No ultrastructural signs of hepatic phospholipidosis, in the form of multilamellar bodies, were apparent in the combined treatment group. CONCLUSIONS: These data collectively suggest that crocin has a protective effect against desipramine-induced phospholipidosis. (www.actabiomedica.it).

Possible mitigating effect of adropin on lung injury in diabetic rats: Targeting the role of Rho A/Rho-associated kinase pathway.

This study evaluated possible mitigating effect of adropin on lung injury in diabetic rats, targeting role of Rho A/Rho-associated kinase pathway. Rats were allocated into four groups: control, adropin, diabetic, and diabetic+adropin groups. At the termination of the experiment, serum fasting glucose, insulin and adropin levels and insulin resistance were calculated. Wet/dry ratio, histopathological, immunohistochemical analyses, and relative real time gene expression of lung tissue was determined. Interleukin-6, tumor necrosis factor alpha, malondialdehyde, 8-Oxo-2'-deoxyguanosine, reduced glutathione, superoxide dismutase, Bcl-2, BAX, myeloperoxidase, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and transforming growth factor-ß were determined in lung tissue. Adropin treatment in diabetic rats notably attenuated hyperglycemia and insulin resistance. Also, it mitigated diabetic lung injury via suppressing effect on Rho A/ROCK pathway, apoptosis, inflammatory reactions, oxidative stress, and fibrosis of lung tissue. Adropin can be considered as a promising therapeutic agent for treating diabetic lung injury.

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice.

AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.

Effect of spexin on renal dysfunction in experimentally obese rats: potential mitigating mechanisms via galanin receptor-2.

This study declared effect of spexin (SPX) on renal dysfunction in obese rats and its potential mitigating mechanisms which could mediated via galanin receptor-2 (GALR-2). Thirty two 32 Wistar male rats were arranged into four groups: control, high fat/fructose diet (HFFD), HFFD + SPX and HFFD + M871 (galanin receptor 2 antagonist)+SPX. At the termination of the experiment, urine volume, body mass index, Lee index and mean arterial blood pressure were assessed. Renal function was evaluated. Lipid profile, fasting glucose, insulin, insulin resistance and SPX levels were estimated. Also, renal histopathological, immunohistochemical and relative gene expression of renal tissue were done. Also, renal protein carbonyl, reduced glutathione, interferon gamma, monocyte chemoattractant protein-1, interleukin-10 and hydroxyproline were determined.Our results explored that SPX treatment prominently mitigated the metabolic changes and renal dysfunction induced by HFFD via GALR-2. SPX improved insulin resistance, dyslipidemia, renal oxidative stress, inflammation, apoptosis, and fibrosis. So, SPX can be considered as prospective therapeutic agent for treating renal dysfunction.

Fisetin ameliorates oxidative glutamate testicular toxicity in rats via central and peripheral mechanisms involving SIRT1 activation.

OBJECTIVES: This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. METHODS: Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H2O2), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT-PCR in testicular tissues. RESULTS: After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H2O2, NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. DISCUSSION: Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.

Effect of atorvastatin with or without prednisolone on Freund's adjuvant induced-arthritis in rats.

Rheumatoid arthritis is a chronic systemic inflammatory disease where cardiovascular diseases have been recognized as major determinants of early morbidity and mortality. Recently, there has been renewed interest in medication with glucocorticoids to decrease joint damage, but in long-term they incur substantial increase in the risk of cardiovascular diseases and their overall risk/benefit ratio is deemed unfavorable. So, the proposed role of statins in treatment of rheumatoid arthritis when corticosteroids indicated as traditional therapy needs to be investigated. Fifty albino rats were divided into 5 equal groups; normal control group, Freund's adjuvant induced arthritis group, group of induced arthritis treated with atorvastatin, group of induced arthritis treated with prednisolone, and group of induced arthritis treated with atorvastatin and prednisolone. The change in paw volume, serum levels of malondialdehyde (MDA), paraoxonase1 (PON1) activity, nitrites, C-reactive protein (CRP) and lipid profile was determined. The results revealed that treatment by atorvastatin in combination with prednisolone produced better satisfactory results than in either remedy alone evidenced by significant decrease in volume of hind paw, levels of MDA, nitrites, CRP, significant increase in PON1 activity and HDL and amelioration of other lipid profile parameters that were impaired by prednisolone. The present work demonstrated that statins exert beneficial anti-inflammatory and antioxidant effects beyond their basic cholesterol-lowering activity. Thus, we suggest that if corticosteroid therapy is indicated in rheumatoid arthritis, atorvastatin could be added to get benefit from its pleiotropic effects. However, further studies are needed to verify to what extent statin therapy contribute to clinical benefits in human.