Nanoemulsions of Phoenix dactylifera L. (Decaffeinated) and Coffea arabica L. Extracts as a Novel Approach for the Treatment of Carbon Tetrachloride-Mediated Liver Fibrosis.

Liver fibrosis is a condition characterized by the excessive buildup of scar tissue in the liver. This scarring occurs as a result of chronic liver damage, often caused by conditions such as hepatitis, alcohol abuse, certain metabolic disorders, genetic abnormalities, autoimmunity, and noninfectious diseases such as fatty liver which leads to liver fibrosis. Nanoparticles have gained attention in recent years as potential therapeutic agents for liver fibrosis. They offer unique advantages due to their small size, large surface area, and ability to carry drugs or target specific cells or tissues. Studies have suggested that nanoemulsions may enhance drug delivery systems, enabling targeted drug delivery to specific sites in the liver and improving therapeutic outcomes. In this study, we explore the protective and therapeutic values with phytochemical profiling of the used agro-wastes decaffeinated palm date seeds (Phoenix dactylifera L., PSC) coffee and caffeinated Arabic coffee seeds (Coffea arabica L.; ACS). Both ACS and PSC extracts were converted into nanoemulsion (NE) forms using the oleic acid/Tween 80 system, which was recruited for the purpose of treating a rat model with liver fibrosis. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to record the sizes, morphologies, hydrodynamic diameters, and ζ-potentials of the prepared NE-ACSE and NE-PSCE. Accordingly, the NE-ACSE and NE-PSCE imaged via TEM and their ζ-potentials were recorded at 20.7, 23.3 nm and -41.4, -28.0 mV, respectively. The antioxidant properties were determined with a DPPH scavenging assay. The synthesized NE-PSCE and NE-ACSE were employed to treat a rat model with CCl4-induced liver fibrosis, to estimate the role of each emulsion-based extract in the treatment of liver fibrosis through recording inflammatory parameters, liver functions, antioxidant enzymes, and histopathological analysis results. The nanoemulsion forms of both ACSE and PSCE provided significant increases in antioxidant enzymes, reducing inflammatory parameters, compared to other groups, where liver functions were decreased with values close to those of the control group. In conclusion, both nanoemulsions, ACSE and PSCE, provided a new avenue as therapeutic approaches for liver diseases, and further studies are encouraged to obtain maximum efficiency of treatment via the combination of both extracts.

Antitumor activity and targeting p53-PUMA mRNA expression by 5-flurouracil PLGA-lipid polymeric nanoparticles in mouse mammary carcinomas: comparison to free 5-flurouracil.

Polymeric poly (lactic-co-glycolic acid) (PLGA)-lipid hybrid nanoparticles (PNPs)-based therapy are powerful carriers for various therapeutic agents. This study was conducted to evaluate the chemotherapeutic potential of free 5-flurouracil (5FU) and synthetized 5FU-PNPs and impact on p53-dependent apoptosis in mammary carcinomas (MCs) grown in mice. Breast cancer cells were injected in Swiss albino female mice and 2 bilateral masses of MC were confirmed after one week. Mice were distributed to five experimental groups; Group 1: MC control group. Groups 2 and 3: MC + free 5FU [5 or 10 mg per kg] groups. Groups 4 and 5: synthetized MC+ 5FU-PNPs [5 or 10 mg per kg] groups. Medications were administered orally, twice weekly for 3 weeks. Then, tumors were dissected, and sections were stained with hematoxylin-eosin (HE) while the other MC was used for measuring of cell death and inflammatory markers. Treatment with 5FU-PNPs suppressed the MC masses and pathologic scores based on HE-staining. Similarly, greater proapoptotic activity was recorded in 5FU-PNPs groups compared to free 5FU groups as shown by significant upregulation in tumoral p53 immunostaining. The current results encourage the utility of PNPs for improving the antitumor effect of 5FU. The chemotherapeutic potential was mediated through enhancement of tumoral p53-mediated p53 up-regulated modulator of apoptosis (PUMA) genes. Additional studies are warranted for testing the antitumor activity of this preparation in other mouse models of breast cancer.

Arthrospira platensis nanoparticles defeat against diabetes-induced testicular injury in rat targeting, oxidative, apoptotic, and steroidogenesis pathways.

Varieties of studies have been used to investigate the health benefits of Spirulina (Arthrospira platensis); however, more research is needed to examine if its nano form may be utilized to treat or prevent several chronic diseases. So, we designed this study to explore the effect and the cellular intracellular mechanisms by which Arthrospira platensis Nanoparticles (NSP) alleviates the testicular injury induced by diabetes in male Wistar rats. Eighty Wistar male rats (n = 80) were randomly allocated into eight groups. Group 1 is untreated rats (control), Group 2 including STZ-induced diabetic rats with 65 mg/kg body weight STZ (STZ-diabetic), Group 3-5: including diabetic rats treated with NSP1, NSP2, and NSP3 at 0.25, 0.5, and 1 mg/kg body weight, respectively, once daily orally by the aid of gastric gavage for 12 consecutive weeks and groups 6-8 include normal rats received NSP (0.25, 0.5, and 1 mg/kg body weight once daily orally. The identical volume of normal saline was injected into both control and diabetic rats. After 12 weeks of diabetes induction, the rats were killed. According to our findings, NSP administration to diabetic rats enhances the total body weight and the weight of testes and accessory glands; in addition, NSP significantly reduced nitric oxide and malondialdehyde in testicular tissue improved sperm parameters. Intriguingly, it raises testicular GSH and SOD activity by a significant amount (p < 0.05). As well, Oral administration of NSP to diabetic rats resulted in a decrease in the blood glucose levels, HA1C, induced in the diabetic group, which overcame the diabetic complications NSP caused down-regulation of apoptotic genes with upregulation of BCL-2 mRNA expression (p < 0.05) and prominent up-regulation of steroidogenesis genes expression level in testes in comparison to the diabetic rats which resulted in improving the decreased levels of testosterone hormone, FSH, and LH induced by diabetes. In the same way, our histopathological findings support our biochemical and molecular findings; in conclusion, NSP exerted a protective effect against reproductive dysfunction induced by diabetes not only through its high antioxidant and hypoglycemic action but also through its down-regulation of Apoptotic genes and up-regulation of steroidogenesis regulatory genes expression level in diabetic testes.

Anti-Alzheimer's disease potential of Arabian coffee versus Date palm seed extract in male rats.

Coffee is among the most commonly consumed beverage all over the world. Studies have increasingly suggested caffeine and coffee as effective therapeutic interventions against Alzheimer's disease (AD). We have therefore utilized the aluminum chloride rat model for AD to compare the influence of moderately caffeinated (Arabian) and decaffeinated (Date palm seed) coffee on cognitive impairment and pathological events in AD. AD rats given Arabian or Date palm seed coffee were protected against memory impairment and had lower serum levels of the abnormal protein (amyloid-beta; Aß1-42), the central pathogenic contributor to AD, and transforming growth factor-beta (TGF-ß). Interestingly, Date palm seed (decaffeinated) coffee seems to provide more pronounced protection against AD than Arabian (moderately caffeinated) coffee as evidenced by the greater decrease in serum Aß levels. These results suggest a surprising therapeutic potential of moderate caffeine intake in Arabian coffee to ameliorate AD through decreasing serum Aß levels. However, Date palm seed (decaffeinated) coffee, rich in flavonoids, appears to provide a better AD-modifying ability through a direct reduction of Aß production. PRACTICAL APPLICATIONS: Consumption of moderately caffeinated Arabian coffee attenuated AD-induced cognitive impairment via its anti-amyloidogenic potential, decreasing Aß levels. Moreover, intake of decaffeinated Date seed extract, rich in flavonoids, exerted a superior anti-AD potential through a direct reduction of Aß production. Both of them were also safe and maintained hepatic and renal functions in a rat model of AlCl3 -induced AD. Further clinical studies are warranted to confirm current results and to recommend the regular drinking of Arabian coffee or Date seed extract as a protective approach to delay AD progression in vulnerable individuals or in early disease stages.

Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma.

In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.

Clopidogrel or prasugrel reduces mortality and lessens cardiovascular damage from acute myocardial infarction in hypercholesterolemic male rats.

AIMS: Hypercholesterolemia is a hazard for increasing susceptibility of the heart to myocardial infarction (MI) by inducing platelet hyperaggregability. Clopidogrel and prasugrel have documented cardioprotective effects in clinical studies. Herein, we investigated whether clopidogrel and prasugrel could protect against isoproterenol-induced acute MI (A-MI) under hypercholesterolemic conditions in rats. MAIN METHODS: Dietary hypercholesterolemic rats were subjected to acute doses of isoproterenol. Serum lipids, inflammatory markers, aortic endothelin1 and endothelial nitric oxide synthase (eNOS) mRNAs expression and immunexpression of BCL2 were determined. KEY FINDINGS: Hypercholesterolemic rats showed infiltration of inflammatory cells and reduction in aortic wall thickness, deposition of fibrous tissue between cardiac muscle fibers. Protective doses of prasugrel or clopidogrel for 28 days before A-MI increased survival, amended the ECG parameters -including ST segment elevation- and improved the histopathological picture in hypercholesterolemic rats. This was coupled with reductions in platelet aggregation, creatine kinase-MB activity, endothelin 1, systemic inflammation and cardiac lipid peroxidation and increment in aortic eNOS expression. Clopidogrel and prasugrel groups showed enhanced BCL2 expression in cardiac fibers and aortic wall. SIGNIFICANCE: Prasugrel and clopidogrel protected against A-MI via anti-aggregatory and anti-inflammatory effects. These results add to the value of these drugs in correcting cardiovascular dysfunction in patients vulnerable to A-MI after confirmation by appropriate human studies.

Potential therapeutic roles of 10-dehydrogingerdione and/or pentoxifylline against calcium deposition in aortic tissues of high dietary cholesterol-fed rabbits.

The present study aimed to investigate the inhibitory effects of 10-dehydrogingerdione (10-DHGD) and pentoxifylline (PTX) either individually or in combined form on calcium deposition in high cholesterol diet (HCD)-fed rabbits as compared to atorvastatin (ATOR), and to clarify the underlying mechanisms. Three-months-old male New Zealand white rabbits received either normal chow or HCD for 12 weeks. The latter group was subdivided into five groups and concurrently treated either with vehicle (dyslipidemic control), ATOR, 10-DHGD, PTX or combined 10-DHGD and PTX. Blood samples and aortic tissue were collected for biochemical and histological analyses. HCD-fed rabbits displayed dyslipidemia, inflammation, atherosclerotic lesions, and calcium deposition in aortas as compared to normal group. This was associated with up-regulation of bone morphogenetic protein-2 (BMP-2), wingless-type MMTV integration site family 3A (Wnt3a) mRNA levels and osteopontin expression in their aortic tissue, along with higher serum alkaline phosphatase and osteocalcin levels. Furthermore, a marked decrease in osteoprotegerin, along with a significant increase in receptor activator of NF-κB(RANK) levels, was found in aortic tissue of dyslipidemic rabbits. 10-DHGD and PTX monotherapy significantly modulated the afore-mentioned calcification markers and attenuated aortic calcification to greater extent than ATOR. Combination of 10-DHGD and PTX exerted more anti-calcifying effect than either individual drug. Our findings suggested therapeutic roles of 10-DHGD and PTX against aortic calcium deposition in dyslipidemic rabbits, likely mediated by HDL-raising effect and attenuation of associated inflammation. Combination of 10-DHGD and PTX may represent a promising therapeutic strategy for aortic calcification associated with atherosclerosis.

Evening Primrose Oil Ameliorates Hyperleptinemia and Reproductive Hormone Disturbances in Obese Female Rats: Impact on Estrus Cyclicity.

Obesity is a public health burden disturbing all body functions and reproductive hormones. As obesity increases among females, there will be a rising challenge to physicians in care from fertility problems. Evening primrose oil (EPR oil) contains essential fatty acids including omega-6 linoleic acid with strong anti-inflammatory activity. Since EPR oil has utility in alleviating dysmenorrhea, this study aimed to ascertain its modulatory effect on systemic inflammation, reproductive hormones and estrus cycle irregularity in female obese rats. Thirty-two female rats were distributed to 4 groups: (i) normal, (ii) dietary obese-control female rats, and (iii and iv) dietary obese female rats treated with EPR oil (5 or 10 g/kg). Rats were examined for estrus regularity by taking vaginal smears daily during the last 2 weeks of the experiment. Serum level of insulin, leptin, adiponectin, and inflammatory cytokines was measured. In addition, serum lipid profile, and liver enzyme activities were estimated. Adipose tissues were taken for histopathologic examination as well as determination of gene expression for leptin, leptin receptors, adiponectin, and visfatin. Obese rats exhibited significant weight gain (90.69 ± 8.9), irregular prolonged estrus cycles (83.33%), increased serum levels of insulin, leptin, prolactin and testosterone and decreased gonadotropin levels. EPR oil exhibited a curative effect on obesity-related irregularity in estrus cycle and ovarian pathology. The underlying molecular mechanism may be related to reduction of systemic inflammation, alleviating insulin resistance and modulation of adipokine expression. EPR oil may be considered as a promising therapeutic intervention against obesity-related female hormonal disturbances and estrus irregularity.

Inhibition of Aortic Calcification by Policosanol in Dyslipidemic Rabbits Is Enhanced by Pentoxifylline: Potential Role of PCSK9.

Policosanol (POL) is a hypocholesterolemic drug of natural origin and has been shown to reduce circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy participants. Recently, we have reported that POL can attenuate aortic calcification in diabetic dyslipidemic rats; however, the underlying mechanism is not fully elucidated. We aimed to investigate the effect of POL on aortic calcification and whether PCSK9 has a contributory role and also to examine whether the combination of POL with pentoxifylline (PTX) as anti-tumor necrosis factor α would offer additional benefits. Thirty adult male New Zealand rabbits weighing 1.5 to 2 kg were randomly assigned to 5 groups. One group received standard chow diet and served as normal control group (NC). The other 4 groups received 0.5% wt/wt cholesterol-rich diet for 12 weeks and concurrently treated with placebo, POL, PTX, or a combination of POL and PTX. Sera samples and aortic tissue were collected for biochemical measurements and histological assessment. Rabbits fed a cholesterol-rich diet demonstrated dyslipidemia, increased inflammatory state, and elevated serum levels of PCSK9, compared to the NC group. Aortic calcification was evident in dyslipidemic rabbits, represented by increased calcium deposition and osteopontin expression in aortic tissue, along with elevated serum levels of alkaline phosphatase and osteocalcin. Dyslipidemic rabbits showed a significant upregulation of wingless-type MMTV integration site family 3A and bone morphogenetic protein 2 genes in their aortic tissue. Policosanol significantly reduced circulating PCSK9 levels, suppressed calcification markers, and attenuated aortic calcification. Combination of POL with PTX alleviated aortic calcification to a greater extent than either monotherapy, which may be attributed to further suppression of PCSK9 and calcification markers. These findings suggested that POL exerted anticalcifying effect partly via inhibition of PCSK9. Combination of POL and PTX offered additional benefits and might represent a promising therapeutic option for aortic calcification.

Asymmetric dimethylarginine and heart-type fatty acid-binding protein 3 are risk markers of cardiotoxicity in carbon monoxide poisoning cases in Zagazig university hospitals.

Carbon monoxide (CO) poisoning is a leading cause of toxicity-related mortality and morbidity worldwide. Recent studies focused on CO-induced cardiovascular toxicity. Oxidative stress plays an important role in the pathophysiology of CO toxicity. The aim of this study was to elucidate the relationship between cardiac damage biomarkers and oxidative stress biomarkers in patients with CO-induced cardiotoxicity. This study was carried out on 36 CO-poisoned patients admitted to Zagazig University Hospitals. Forty healthy individuals (age- and sex-matched) were selected as a control group. Clinical examination and electrocardiography (ECG) were performed for CO-poisoned patients. These patients have been investigated for carboxyhaemoglobin percent (COHB%) and cardiac damage biomarkers; cardiac troponin I (cTn-I), heart-type fatty acid-binding protein 3 (H-FABP3). Oxidative stress biomarkers comprising malondialdehyde (MDA), asymmetric dimethylarginine (ADMA), and total antioxidant capacity (TAC) have been also assessed. All biomarkers have been assessed on admission (0 h) and 6 h after treatment of CO-poisoned patients with high-flow oxygen and compared with those of the control groups. ECG findings were abnormal in 31 patients (86.11%), where sinus tachycardia was the commonest finding (58.33%). There was a statistically significant increase of COHB%, MDA, ADMA, and H-FABP3 levels, and a significant decrease of TAC level in CO-poisoned patients compared to controls with no significant changes in cTn-I. Six hours following treatment, all measured parameters were significantly improved except for cTn-I, which was significantly increased when compared with admission status (0 h). Furthermore, H-FABP3 showed a significant positive correlation with COHB%, MDA, ADMA, and a negative correlation with TAC, while cTn-I was significantly correlated with COHB% only. ADMA and MDA seem to be the strongest determinants for the prediction of H-FABP3 changes and hence cardiovascular toxicity. Thus, cardiac damage in patients with CO poisoning could be partially mediated by CO-induced oxidative stress, where H-FABP3 level was directly and strongly associated with MDA and ADMA levels.

Sildenafil citrate attenuates the deleterious effects of elevated ammonia.

Ammonia is a bi-product of protein metabolism in the body. It is able to cross the blood-brain barrier and elevated ammonia levels are toxic to the brain. Rats with hyperammonemia showed impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanosine monophosphate (glutamate-NO-cGMP) pathway in the brain. Chronic treatment with sildenafil restored learning ability. We therefore tested the hypothesis that sildenafil has a protective effect on the brains of hyperammonemic rats. Hyperammonemia was induced in male rats by daily intraperitoneal (i.p.) injection of ammonium chloride (100 mg/kg body weight) for 8 weeks. Sildenafil citrate was administered intraperitoneally (10 mg/kg body weight/3 days) for 8 weeks. Treatment with sildenafil resulted in a significant reduction in plasma liver enzymes, lipid profile as well as brain lipid peroxidation and caspase-3 mRNA. Meanwhile, plasma NO as well as cGMP, antioxidants and endothelial nitric oxide synthase (eNOS) gene expression were significantly elevated in the brains of hyperammonemic rats. Our results showed that sildenafil exerts a protective effect on the brain by reversing oxidative stress during hyperammonemia and this could be due to (i) cytoprotective, antioxidant and anti-apoptotic effects (ii) increasing cGMP and enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus preventing oxidative damage in the brain. The exact protective mechanism of sildenafil has to be still investigated and further studies are warranted. Consequently, therapeutic modulation of the NO/cGMP pathway might have important clinical applications to improve brain functions in patients with hyperammonemia or clinical hepatic encephalopathy.

Nicotine and vascular endothelial dysfunction in female ovariectomized rats: role of estrogen replacement therapy.

OBJECTIVES: The protective effects of estrogen replacement therapy (ERT) against oxidative injury and endothelial dysfunction in the aortic tissues induced with nicotine in ovariectomized (OVX) rats were investigated. METHODS: Female rats were divided into a sham-operated group (n = 8) and four groups in which OVX rats received either vehicle (0.1 ml sesame oil, i.m., n = 8), or nicotine (0.1 mg/kg, s.c., n = 8), or estradiol benzoate (0.1 mg/kg, i.m., n = 8), or both nicotine and estradiol benzoate (n = 8) starting at week 5 after the surgery and continuing for the following 6 weeks. KEY FINDINGS: ERT was effective in preventing the rise in plasma lipid profile, atherogenic index and the level of induced endothelin-1 (ET-1) in nicotine-treated OVX rats. It also reduced aortic malondialdehyde, hydroxyproline levels, calcium content and caspase-3 expression induced in nicotine-treated OVX rats. ERT increased serum estradiol, high-density lipoprotein cholesterol and nitric oxide levels in nicotine-treated OVX rats. Furthermore, ERT was effective in restoring reduced glutathione and cyclic guanosine monophosphate contents and endothelial nitric oxide synthase expression in aortic tissues of nicotine-treated OVX rats. CONCLUSIONS: Short-term ERT could be a promising therapeutic strategy to minimize nicotine-induced oxidative stress and vascular endothelial dysfunction in menopausal women subjected to environmental smoke.