L-Arginine-induced acute pancreatitis and its associated lung injury in rats: Down-regulation of TLR-4/MAPK-p38/JNK signaling pathway via Ginkgo biloba extract EGb 761.

Objectives: Acute pancreatitis (AP) is an abrupt inflammatory condition characterized by a storm of inflammatory cytokines leading to high morbidity and mortality. The current study aimed to examine the efficacy of Ginkgo biloba extract EGb 761 (GBE) in the treatment of L-arginine-induced AP and its associated lung injury. Materials and Methods: Forty rats were randomly assigned into four groups. The normal group received only saline intraperitoneally while the other groups received two intraperitoneal L-arginine injections (250 mg/100 g b.wt) separated by a 1-hour interval to provoke AP. GBE (200 and 400 mg/kg/day, PO) was administered for 2 weeks post-induction of pancreatitis. Sera and pancreatic tissues were isolated. Results: The outcome of the present study revealed that GBE ameliorated the elevated levels of serum amylase, lipase, and pancreatic inflammatory mediators viz., tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase P38 (MAPK-P38), c-Jun N-terminal kinase 1 (JNK1), and nuclear factor-kappa B (NF-κB). Moreover, GBE restored the pancreatic gene expression of Toll-like receptor 4 (TLR4) and prostatic acid phosphatase-2 (PAP-2). Pancreatic and lung histopathological examinations confirmed the aforementioned parameters. Conclusion: GBE interfered with the mechanistic pathway of L-arginine-induced acute pancreatic and its associated lung injury. Due to its anti-inflammatory properties, GBE can be used as a novel therapeutic candidate for the treatment of AP through down-regulating TLR-4/MAPK-p38/JNK and MAPK- p38/NF-κB signaling cascades.

Eugenol alleviates acrylamide-induced rat testicular toxicity by modulating AMPK/p-AKT/mTOR signaling pathway and blood-testis barrier remodeling.

This study aimed to investigate the effects of eugenol treatment on reproductive parameters in acrylamide (ACR)-intoxicated rats. The study evaluated alterations in relative testes and epididymides weights, sperm quality, serum hormonal status, seminal plasma amino acids, testicular cell energy and phospholipids content, oxidative and nitrosative stress parameters, adenosine monophosphate-activated protein kinase/ phosphoinositide 3-kinase/phosphor-protein kinase B/mammalian target of rapamycin (AMPK/PI3K/p-AKT/mTOR) signaling pathway, blood-testis barrier (BTB) remodeling markers, testicular autophagy and apoptotic markers, as well as histopathological alterations in testicular tissues. The results revealed that eugenol treatment demonstrated a significant improvement in sperm quality parameters, with increased sperm cell concentration, progressive motility live sperm, and a reduction in abnormal sperm, compared to the ACR-intoxicated group. Furthermore, eugenol administration increased the levels of seminal plasma amino acids in a dose-dependent manner. In addition, eugenol treatment dose-dependently improved testicular oxidative/nitrosative stress biomarkers by increasing oxidized and reduced glutathione levels and reducing malondialdehyde and nitric oxide contents as compared to ACRgroup. However, eugenol treatment at a high dose restored the expression of AMPK, PI3K, and mTOR genes, to levels comparable to the control group, while significantly increasing p-AKT content compared to the ACRgroup. In conclusion, the obtained findings suggest the potential of eugenol as a therapeutic agent in mitigating ACR-induced detrimental effects on the male reproductive system via amelioration of ROS-mediated autophagy, apoptosis, AMPK/p-AKT/mTOR signaling pathways and BTB remodeling.

Pylorus ligation-induced hyperacidity: synergistic prophylactic effects of linagliptin and L-arginine via up-regulation of EP4 receptor subtype and improvement of vascular endothelial damage.

Gastric hyperacidity and ulceration are chronic diseases characterized by repeated healing followed by re-exacerbation. The study aims to protect against gastric hyperacidity without interfering with gastric acid secretion. Pylorus ligation-induced hyperacidity is commonly utilized in the induction of gastric ulcers.Forty-two rats were distributed into seven groups (n = 6). Group I comprised sham-operated group. Group II served as pylorus-ligation group. Groups III-VII were given oral Linagliptin (LN; 3 and 6 mg/kg), L-arginine (LA; 150 and 300 mg/kg) and their combination (LN 3 + LA 150 mg/kg), respectively for 7 days. On the 8th day, groups II-VII were subjected to pylorus-ligation.Treatment of pylorus-ligated rats with LN, LA and their combination improved the gastric hyperacidity as exhibited by a marked reduction in the gastric juice volume, total and free acidities and pepsin contents with a noticeable increase in pH. Pre-treatment with LN, LA and their combination showed a marked alleviation in the gastric inflammatory indicators evidenced by reduction in the gastric levels of MCP-1and Il-1ß as well as elevation of eNOS levels versus the sham-operated group. A marked up-regulation in the gastric gene expression of PGE, EP4 and VEGF accompanied by an improvement of the histopathologic pictures/scores, and TNF-α and caspase-3 immuno-staining were also recorded.By estimating the combination-index, it can be concluded that combining LN with LA exhibited prophylactic synergistic effects in ameliorating pylorus ligated-induced hyperacidity, mainly via up-regulation of EP4 receptor and improvement of vascular endothelial damage through VEGF expression in gastric mucosa.

Uro-protective role of chrysin against cyclophosphamide-induced hemorrhagic cystitis in rats involving the turning-off NF-κB/P38-MAPK, NO/PARP-1 and STAT-3 signaling cascades.

BACKGROUND: Chemotherapeutic agents are used to treat a wide range of cancer types, but they cause serious side effects which must be managed after treatment. Cyclophosphamide (CYP) is one of chemotherapeutic drugs that causes hemorrhagic cystitis (HC) induced by acrolein. OBJECTIVE: The current investigation intended to uncover the role of chrysin (CHR) in CYP-induced HC in rats and explore the signaling pathway beyond this effect. ANALYSIS: process: A single dose of CYP (200 mg/kg/IP) was injected, meanwhile CHR (25, 50 and 100 mg/kg, P.O) was administered respectively for 7 days prior to CYP administration and resume for 7 days afterwards. Urinary bladder tissue was then isolated from all rats to assess oxidative stress and inflammatory biomarkers. Moreover, histopathological examinations were performed. RESULTS: Treatment with CHR showed a marked alleviation in oxidative stress biomarkers induced by CYP. Furthermore, CHR treatment presented a dose-dependent boost in the anti-inflammatory; IL-10 levels and a drop in the pro-inflammatory biomarkers; IL-1ß, IL-6, and TNF-α. Additionally, stabilization of the PARP-1 protein expression was also detected thus preventing DNA damage. Similarly, CHR restored the urinary bladder cGMP levels. Notably, CHR treatment was accompanied with inhibition in NF-κB/p38-MAPK, NO/PARP-1 and STAT-3 signaling pathways inflammatory cascades. All these findings conformed with the histopathological examinations as well as iNOS immunostaining in the urinary bladder tissue. CONCLUSION: Co-administration of CHR and CYP attained uro-protective therapeutic potential to guard against HC as well as spot the tangled mechanism of CHR in attenuating the HC induced by CYP.

The Reversed Flow Hemisoleus Propeller Muscle Flap.

BACKGROUND: Soleus muscle flap can be used in different modifications to reconstruct lower limb defects. It can be proximally based, distally based, island or reversed flow flap. The first description of the soleus muscle as an island flap supplied by one distal perforator was reported by Yajima et al (Plast Reconstr Surg. 1995;96:1162-1168). However, its use as a propeller flap supplied by the distal perforators and rotated for more than 90 degrees was not described yet. OBEJECTIVES: The aims of the study are to study the detailed vascular anatomy of the distal perforators of the soleus muscle flap and to demonstrate the applicability of using it as a propeller flap. PATIENTS AND METHODS: A total number of 42 patients were included in this study. These patients had various distal leg and foot defects. All patients were assessed preoperatively by Doppler study and computed tomography angiography to define the vascular status of the leg. The muscle was raised as a reversed flow flap, based on 1 or more distal perforators and its feeding vessel (posterior tibial artery) after being dissected and divided proximally. The muscle was rotated for more than 90 degrees to reach distal leg defects and approximately 180 degrees to reach the foot defects. RESULTS: All flaps survived completely with good and durable coverage. The vascularity of the limb was not affected in all patients. There was no functional donor site morbidity. CONCLUSIONS: The reversed flow hemisoleus muscle flap supplied by the distal perforators and the posterior tibial artery has a great arc of rotation that can cover all distal leg, ankle, and foot defects. Therefore, it can be used as alternative to free flap in lower extremity reconstruction. A new nomenclature is suggested for this flap which is the propeller hemisoleus muscle flap.

Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3ß axis modulation.

Doxorubicin (DOX), a common antibiotic used to treat a variety of tumors, has several substantial adverse effects that limit its clinical use. As a result, finding effective protective agents to combat DOX-induced organ damage is a necessity. The current study was set to delineate the hepatoprotective role of omega-3 fatty acids (ω-3FA) against DOX-mediated acute liver damage in rats and the underlined mechanism of GSK-3ß inhibition. Five groups of rats were orally received either saline (groups 1 & 2) or ω-3FA (25, 50 and 100 mg/kg/day; groups 3, 4 & 5, respectively) for 28 consecutive days. Single DOX intraperitoneal injection (20 mg/kg) was used to induce hepatic toxicity in all groups except group 1 (negative control). Blood samples and liver tissues were collected 48-hr after injection. Our results revealed that pre-administration of ω-3FA (25, 50 and 100 mg/kg) to DOX-induced hepatic injured rats showed a significant reduction in serum hepatic injury biomarkers (ALT, AST, total and direct bilirubin) as well as hepatic contents of MDA, GSH, Nrf2 and HO-1. Additionally, hepatic PI3K, pAkt and GSK-3ß have been restored significantly in a dose-dependent manner. Furthermore, all the hepatic histopathological features have been retained upon ω-3FA treatment together with the immunostaining intensity of tumor necrosis factor-α and caspase-3. These results suggest that ω-3FA have shown a marked activation of the Nrf2/HO-1 signaling pathway and modulation of the PI3K/pAkt/GSK-3ß axis against DOX-induced hepatotoxicity.

Phytochemical profiling and anti-fibrotic activities of Plumbago indica L. and Plumbago auriculata Lam. in thioacetamide-induced liver fibrosis in rats.

This study aimed at investigating the chemical composition and the hepatoprotective activities of Plumbago indica L. and P. auriculata Lam. LC-MS/MS analyses for the hydroalcoholic extracts of the aerial parts of the two Plumbago species allowed the tentative identification of thirty and twenty-five compounds from P. indica and P. auriculata, respectively. The biochemical and histopathological alterations associated with thioacetamide (TAA)-induced liver fibrosis in rats were evaluated in vivo where rats received the two extracts at three different dose levels (100, 200 and 400 mg/kg p.o, daily) for 15 consecutive days with induction of hepatotoxicity by TAA (200 mg/kg/day, i.p.) at 14th and 15th days. Results of the present study showed a significant restoration in liver function biomarkers viz. alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase and total bilirubin. The liver homogenates exhibited increased levels of antioxidant biomarkers: reduced glutathione (GSH) and catalase (CAT), accompanied with decline in malondialdehyde (MDA). Furthermore, treated groups exhibited a significant suppression in liver inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6), and fibrotic biomarker: alpha smooth muscle relaxant. Histopathological examination of the liver showed normality of hepatocytes. Noteworthy, P. indica extract showed better hepatoprotective activity than P. auriculata, particularly at 200 mg/kg. To sum up, all these results indicated the hepatoprotective properties of both extracts, as well as their antifibrotic effect was evidenced by reduction in hepatic collagen deposition. However, additional experiments are required to isolate their individual secondary metabolites, assess the toxicity of the extracts and explore the involved mechanism of action.

Curcumin nanoemulsion ameliorates brain injury in diabetic rats.

Diabetes mellitus has been implicated in the exacerbation of cerebral ischemic injuries. Among the most promising therapeutic approaches is the combination of nutraceuticals and nanotechnology. Curcumin has been termed "the magic molecule", and it was proven to exert several therapeutic actions. Therefore, the aim of the presented work was to investigate the therapeutic effects of curcumin nanoemulsion (NC) administered orally on the middle cerebral artery occlusion and reperfusion (MCAO/Re)-induced cerebral damage in rats with streptozotocin-induced diabetes. The cerebral injury was induced in rats by MCAO/Re 6 weeks after single intraperitoneal STZ injection (50 mg/kg; i.p.). MCAO/Re diabetic rats were then treated with NC (50 and 100 mg/kg; bw; p.o.) for two consecutive weeks. The results of the present study showed that oral treatment of MCAO/Re diabetic rats with NC was associated with a marked attenuation of the neurological deficit score as well as the brain imbalance of the redox homeostasis. NC treatment was also associated with decline in the brain expression of tumor necrosis factor, interleukin-1ß, COX-2, cleaved caspase-3, and nuclear factor kappa B. In addition, the expression of glucose transporter 1 proteins upon treatment was restored. PRACTICAL APPLICATIONS: From all these results, it can be concluded that oral supplementation of curcumin nanoemulsion (NC) in diabetic rats reduced the brain injury via augmentation of the expression of glucose transporter 1, as well as its antioxidant and anti-inflammatory properties. Therefore, NC could be delineated as a promising treatment option for cerebral ischemia in diabetic patients.

Effect of a Novel Hybrid Nanocomposite of Cisplatin-Chitosan on Induced Tissue Injury as a Suggested Drug by Reducing Cisplatin Side Effects.

The self-assembly of cisplatin (Cis-Pt) and chitosan nanoparticles (Cs NPs) has been synthesized and characterized successfully by different analyses and techniques, such as scanning electron microscopy, ultraviolet-visible spectrophotometry, and Fourier transform infrared spectroscopy. The efficiency of loading Cis-Pt on Cs NPs for decreasing the side effects of Cis-Pt by loading it on Cs NP surface was revealed through histopathological and physiological measurements for the liver, testis, and kidney cells. Self-assembly hybrid nanocomposite (Cis-Pt@Cs) could improve spermatogenic cells, seminiferous tubules, and Leydig cells in the interstitial tissue. Kidney examination showed intact glomeruli with a mild increase in capsular space in addition to the intact renal tubular epithelial lining, and liver findings showed improvement in dilation and congestion of the central vein besides mild dilation of blood sinusoids in addition to a mild degree of hepatocyte vacuolation. The serum levels of hepatic, renal, and testicular marker analysis were measured, where Cis-Pt increased the serum levels of alanine aminotransferase, aspartate aminotransferase activity, urea, creatinine, and decreased testosterone levels, while synthesized self-assembly appeared normalized levels. From the results, the self-assembly hybrid nanocomposite decreases and improves the side effects of Cis-Pt.

Our Strategy in Management of Maxillonasal Dysplasia in Pediatric Patients.

ABSTRACT: Maxillonasal dysplasia or Binder syndrome is an uncommon condition. It is a congenital disease characterized by undergrowth of the central face and may include elements of the nose and upper jaw. The hallmark of the deformity is a retruded mid-face and an extremely flat nose. The timing and the surgical approaches for management of such deformity are still controversial. In this paper, we are going to present our experience in management of Binder syndrome in children. Seven children ranging in age from 6 to 13 years with classic features of Binder syndrome were operated upon in this study. The surgical approach was done at an early age and included 3 main components; nasal dorsum augmentation by costal cartilage graft, maxillary augmentation by rib grafts and columellar reconstruction by VY-plasty and strut grafts. Patients were followed for up to 6 years. Excellent results were obtained in all patients with this surgical procedure. Half of our patients required more than 1 surgery but none of them required any secondary orthognathic surgery. Therefore, we recommend that children with Binder syndrome should be managed at an early age at least for correction of their nasal deformities. Maxillary augmentation can also be done simultaneously or delayed for a second stage. During the second stage, further nasal augmentation can be accomplished. Definitive orthognathic surgeries have to be postponed to adolescence. This strategy can dramatically improve the patient aesthetic and alleviate the psychological upset without much disturbance of the facial growth.

In silico proteolysis and analysis of bioactive peptides from sequences of fatty acid desaturase 3 (FAD3) of flaxseed protein.

Flaxseed (Linum usitatissimum), commonly known as linseed is an oilseed crop, emerging as an important and functional ingredient of food and has been paid more attention due to its nutritional value as well as beneficial effects. It is mainly rich in is α-linolenic acid (ALA, omega-3 fatty acid), fibres and lignans that have potential health benefits in reducing cardiovascular diseases, diabetes, osteoporosis, atherosclerosis, cancer, arthritis, neurological and autoimmune disorders. Due to its richness in omega-3 fatty acid, a group of enzymes known as fatty acid desaturases (FADs) mainly introduce double bonds into fatty acids' (FAs) hydrocarbon chains that produce unsaturated fatty acids. Fatty acid desaturase 3 (FAD3), the commonest microsomal enzyme of omega-3 fatty acid, synthesizes linolenic acid (C18:3) from linoleic acid located in endoplasmic reticulum (ER) facing towards the cytosol. The emerging field of bioinformatics and large number of databases of bioactive peptides, helps in providing time-saving and efficient method for identification of potential bioactivities of any protein. In this study, 10 unique sequences of FAD3 from flaxseed protein have been used for in silico proteolysis and releasing of various bioactive peptides using three plant proteases, namely ficin, papain and stem bromelain, that are evaluated with the help of BIOPEP database. Overall, 20 biological activities were identified from these proteins. The results showed that FAD3 protein is a potential source of peptides with angiotensin-I-converting enzyme (ACE) inhibitory and dipeptidyl peptidase-IV (DPP-IV) activities, and also various parameters such as ∑A, ∑B, AE, W, BE, V and DHt were also calculated. Furthermore, PeptideRanker have been used for screening of novel promising bioactive peptides. Various bioinformatics tools also used to study protein's physicochemical properties, peptide's score, toxicity, allergenicity aggregation, water solubility, and drug likeliness. The present work suggests that flaxseed protein can be a good source of bioactive peptides for the synthesis of good quality and quantity of oil, and in silico method helps in investigating and production of functional peptides.

Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: Targeting oxidative stress, energy deficit and spermatogenesis.

Methotrexate (MTX) is commonly used as a therapeutic agent in the treatment of malignancies and autoimmune disorders. Risk of subsequent infertility following MTX administration has been reported as a significant side effect due to testicular toxicity. The aim of the study was to evaluate the modulatory effects of Ginkgo biloba (standardized extract, EGb 761) on MTX-induced testicular oxidative stress, energy deficits and spermatogenic status in rats. All groups received intraperitoneal injection of MTX (0.5 mg/kg) twice weekly for four weeks except the control group that received the corresponding vehicles. Other groups received oral EGb761, at doses 25, 50 or 100 mg/kg/day, for four weeks, concurrently with MTX. Blood and semen sampling followed by testis dissection were performed 24 h after last EGb 761 treatment. Semen was examined for sperm progressive motility, percent of normal spermatozoa and sperm cell concentration as well as seminal plasma essential and non-essential amino acids. Serum LH, FSH and testosterone were detected as well as testicular MDA, GSH, GSSG, TNF-α, IL-1ß, IL-6, NF-κB and the nuclear, cytoplasmic and mRNA expression levels of Nrf-2 besides the testicular cell energy; AMP, ADP and ATP. Histopathological studies of interstitial fibrosis and the severity of germ cell degeneration were also conducted. MTX induced significant decline in sperm quality along with decreased essential and non-essential amino acids in seminal plasma. MTX reduced serum FSH, LH and testosterone as well as testicular ATP, GSH and Nrf2, while increased levels of testicular ADP, AMP, MDA, GSSG and TNF-α. Results were confirmed by prominent interstitial fibrosis and severe germ cell degeneration in MTX group. Concurrent treatment with EGb 761 alleviated MTX-induced testicular insult evidenced by amelioration of oxidative stress biomarkers, energy functions, seminal sperms abnormalities and spermatogenesis status. The present study suggests a beneficial role of EGb 761 in MTX-induced testicular injury and subsequent distortion of spermatogenesis.

New pyridine and chromene scaffolds as potent vasorelaxant and anticancer agents.

Based on studies that have reported the association between cancer and cardiovascular diseases, new series of pyridine- (3a-o) and/or chromene- (4a-e) carbonitrile analogous were designed, synthesized and screened for their vasodilation and cytotoxic properties. The majority of the new chemical entities demonstrated significant vasodilation efficacies, compounds 3a, 3h, 3j, 3m, 3o, 4d and 4e exhibited the most promising potency with IC50 = 437.9, 481.0, 484.5, 444.8, 312.1, 427.6 and 417.2 µM, respectively, exceeding prazosin hydrochloride (IC50 = 487.3 µM). Compounds 3b-e, 3k and 3l also, revealed moderate vasodilation activity with IC50 values ranging from 489.7 to 584.5 µM. In addition, the anti-proliferative activity evaluation of the experimental compounds at 10 µM on the MCF-7 and MDA-MB 231 breast cancer cell lines illustrated the excellent anti-proliferative properties of derivatives 3d, 3g and 3i. Compound 3d was the most potent analogue with IC50 = 4.55 ± 0.88 and 9.87 ± 0.89 µM against MCF-7 and MDA-MB 231, respectively. Moreover, compound 3d stimulated apoptosis and cell cycle arrest at the S phase in MCF-7 cells in addition to its capability in accumulation of cells in pre-G1 phase and activating caspase-3. Furthermore, the molecular docking of 3d was performed to discover the binding modes within the active site of caspase-3. 3d, as the only common bi-functional agent among the tested hits, demonstrated that new pyridine-3-carbonitrile derivatives bearing cycloheptyl ring systems offer potential as new therapeutic candidates with combined vasodilation and anticancer properties.

Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.

Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 â†’ 6)-ß-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 â†’ 6)-ß-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 â†’ 6)-ß-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.

Omega-3 fatty acids ameliorate doxorubicin-induced cardiorenal toxicity: In-vivo regulation of oxidative stress, apoptosis and renal Nox4, and in-vitro preservation of the cytotoxic efficacy.

This study examines the protective effects of omega-3 fatty acids (OMG), a frequently used nutritional therapy in cancer patients, against doxorubicin (DOX)-induced acute cardiorenal toxicity in rats, and evaluates the cytotoxic activity of DOX when used with OMG against breast cancer cell line. Five groups of rats were treated for 4 consecutive weeks with vehicle (groups I & II), or OMG (25, 50 or 100 mg/kg/day, po; groups III, IV & V, respectively). After twenty-four hours, the last four groups were injected with DOX (200 mg/kg, ip). In DOX-treated rats, the altered ECG, serum cardiac and renal function biomarkers, and histopathological features indicated the induction of cardiorenal toxicity. Increased oxidative and apoptotic markers in both organs was observed, with elevated renal contents of NADPH-oxidase-4 (Nox4) and renin. OMG pretreatment improved those DOX-induced impairments in a dose-dependent manner, and showed antioxidant and antiapoptotic effects with regulation of renal Nox4 expression. The in-vitro study showed preservation of the cytotoxic activity of DOX on MCF7 cell line in the presence of OMG. The data suggests OMG for protection against acute DOX-induced cardiorenal damage without affecting the latter antitumor activity. It proposes regulation of oxidative stress, Nox4 activity and apoptosis as contributing protective mechanisms.

Rosuvastatin and simvastatin attenuate cisplatin-induced cardiotoxicity via disruption of endoplasmic reticulum stress-mediated apoptotic death in rats: targeting ER-Chaperone GRP78 and Calpain-1 pathways.

Cisplatin (CP) is a powerful antineoplastic chemotherapeutic agent with broad-spectrum properties. Acute and cumulative cardiotoxicity are major limiting factors for CP therapy. Various pathogenic pathways have been suggested to CP-induced cardiotoxicity; oxidative damage, ER stress, and programmed cell death/apoptosis. The present study aimed to assess the signaling mechanisms related to the advantageous effects of rosuvastatin (RSV) and simvastatin (SMV) against CP-related cardiac ER stress dependent apoptotic death in rats. Acute cardiotoxicity was induced by a single dose of CP (10 mg/kg, i.p.) on the 10th day of the experiment. RSV (10 mg/ kg/day) and SMV (10 mg/kg/day) were orally administered for 15 days. CP-treated rats showed significant alterations in electrocardiographic recordings and elevation in serum cardiac function biomarkers; troponin T content, lactate dehydrogenase and creatine kinase-MB levels as well as boost in the cardiac oxidative stress biomarkers. In addition, CP exposure resulted in GRP78 induction; an ER stress and elevation marker at calpain-1 content as well as activation of activated caspase-3 (ACASP3) and caspase-12 were reflected on CP-triggered apoptosis evidenced by elevation in the Bax/Bcl-2 ratio. However, RSV and SMV administration mitigate those adverse CP effects. Statins administration prominently alleviated CP-induced cardiac abnormalities exerting improvement in the ECG pattern and cardiac enzyme biomarkers. Interestingly, statins; RSV and SMV, disrupted CP-induced ER stress and the consequent apoptotic cell death evidenced by downregulation of ER-chaperone GRP78, calpain-1, ACASP3 and caspase-12 as well as decline in the Bax/Bcl-2 ratio. From all the previous findings, it can be suggested that statins namely; RSV and SMV, play protective role against CP-induced cardiac injury by regulating ER stress-mediated apoptotic pathways.

Melatonin regulates neurodegenerative complications associated with NAFLD via enhanced neurotransmission and cellular integrity: a correlational study.

Nonalcoholic fatty liver disease (NAFLD) is recognized globally as the leading cause of chronic liver diseases whose patients are asymptomatic and are diagnosed incidentally. It increases the rate of mortality which is usually related to cardiovascular events; however, scarce attention has been addressed to brain damage. This study was designed to investigate the impact of melatonin (MEL; 10 mg/kg) on overcoming the hepato and neuro-complications associated with high fat, high fructose (HFHF) diet induced-NAFLD in rats. NAFLD was induced by HFHF diet for 8 consecutive weeks. MEL was given orally for the last 10 days. Rats' general behavior was assessed by; open field test (OFT) and forced swimming test (FST). On biochemical level; serum levels of glucose, insulin, alanine transaminase and aspartate transaminase as well as the hepatic levels of triglycerides and total cholesterol were evaluated. Monoamines' brain levels, their metabolites in addition to the brain level of 8-hydroxyguanosine (8-OHdG) were evaluated. Moreover, the levels of tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NOx) were measured in both the liver and brain tissues. Oral treatment of NAFLD induced rats with MEL for ten consecutive days managed to increase the activity of the rats in the OFT and decrease the immobility period in the FST. Moreover, MEL reduced monoamines turnover and elevated brain 8-OHdG level. It also had the ability to counteract the elevated levels of GSH, NOx, MDA, and TNF- α in liver and brain tissues. MEL can be suggested to be a promising candidate for treating the neuronal side effects related to NAFLD.

Impact of type III collagen on monosodium iodoacetate-induced osteoarthritis in rats.

Osteoarthritis (OA) is a degenerative chronic disease that affects various tissues surrounding the joints, such as the subchondral bone and articular cartilage. The purpose of the study was to investigate the impact of collagen type III (CIII; 10 mg/kg; p.o.) on OA evidenced by restoration of articular cartilage structural changes as well as inflammatory responses using an established rat model of OA. OA was induced in rats by a single intra-articular injection of monosodium iodoacetate (MIA) through the right knee of the rats. Oral administration of CIII was undergone for 14 consecutive days. Changes in joint volume were measured throughout the experiment period with one-week intervals. At the end of the experiment, the rats were placed in the activity cage, and their activities were counted. Oxidative stress and nitrosative biomarkers were assessed by measuring the serum levels of malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NOx). Moreover, inflammatory markers viz. interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis nuclear factor-alpha (TNF-α) were measured. In addition, radiographic analysis and histopathological examination of the rat's knee were performed. The results of the current study revealed that oral treatment of MIA-induced osteoarthritic rats with CIII (10 mg/kg) for two weeks showed a marked decrease in the joint volume which led eventually to a prominent increase in the motor activity. Furthermore, treatment with CIII restored the serum levels of MDA, GSH, NOx, IL-6, IL-1ß and the TNF-α. Furthermore, CIII succeeded to ameliorate the detrimental effect of MIA on radiographic images and histopathological alterations of the joint. From these findings, it can be concluded that CIII has regenerative and anti-inflammatory properties, thus has the ability to counteract MIA-induced OA in rat. Finally, CIII is said to be a potential anti-osteoarthritic candidate.

Melatonin suppresses the brain injury after cerebral ischemia/reperfusion in hyperglycaemic rats.

BACKGROUND AND PURPOSE: Diabetes mellitus is a disorder accompanied by oxidative and inflammatory responses, that might exacerbate vascular complications. The purpose of this study was to investigate the potential antioxidant and anti-inflammatory effects of melatonin (MLN) on streptozotocin (STZ)-induced diabetic rats subjected to middle cerebral artery occlusion followed by reperfusion (MCAO/Re). EXPERIMENTAL APPROACH: Diabetes was induced in rats by a single injection of STZ (55 mg/kg; i.p.). The cerebral injury was then induced by MCAO/Re after six weeks. After 24 h of MCAO/Re the MLN (10 mg/kg) was administered orally for 14 days. Serum and tissue samples were extracted to determine malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), interleukin-1ß (IL-1ß), and the tumor necrosis factor- α (TNF-α). Part of the brain tissue was kept in formalin for pathological and immunohistochemical studies to determine nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2) immune reactivity. FINDINGS/RESULTS: MCAO/Re in STZ-induced hyperglycaemic rats caused a decrease in brain GSH, an increase in brain MDA, and NO was increased in both serum and brain tissue. Rats showed a prominent increase in the serum and brain inflammatory markers viz. IL-1ß and TNF-α. Oral treatment with MLN (10 mg/kg) for two weeks reduced the brain levels of MDA, NO, IL-1ß, and TNF-α. Impressive amelioration in pathological findings, as well as a significant decrease in NF-kB and COX2 immune stained cells of the cerebral cortex, hippocampus, and cerebellum, occurred after treatment with MLN. It also succeeded to suppress the exacerbation of damage in the brain of hyperglycaemic rats. CONCLUSION AND IMPLICATIONS: Daily intake of MLN attenuates the exacerbation of cerebral ischemic injury in a diabetic state.

Heamatococcus pluvialis ameliorates bone loss in experimentally-induced osteoporosis in rats via the regulation of OPG/RANKL pathway.

BACKGROUNDS: Osteoporosis prevailing in elderly involves a marked increase in bone resorption showing an initial fall in bone mineral density leading to a significant reduction in bone formation. AIM: The present study aimed to investigate the effect of Heamatococcus pluvialis microalgae on osteoporosis in D-galactose-treated rats. The underlying mechanism was tracked targeting the osteoprotegerin (OPG)/ nuclear factor-κß ligand (RANKL) pathway using micro-computed tomography scanning. METHODS: Osteoporosis was induced in rats by intraperitoneal injection of D-galactose (200 mg/kg/day) for eight consecutive weeks. Osteoporotic rats were orally treated with H. pluvialis biomass (BHP; 450 mg/kg), its polar (PHP; 30 mg/kg) and carotenoid (CHP; 30 mg/kg) fractions for the last 2 weeks of D-Gal injection. Twenty four hours after the last dose of the treatments, tibia bones of the rats were scanned using micro-computed tomography scanning for bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness/separation/number (Tb.Th, Tb.Sp, Tb.N) evaluation, blood samples were withdrawn and sera were used for biochemical assessment. Moreover, femur bones were examined histopathologically using several stains. RESULTS: Induction of osteoporosis was associated with a marked reduction in BMD, BV/TV, Tb.Th, Tb.Sp, Tb.N and in serum levels of phosphorus and catalase. On the other hand, a significant elevation in serum levels of calcium, bone alkaline phosphatase (BALP) and interleukin-6 was observed. Moreover, up-regulation of OPG was detected in osteoporotic rats. Oral treatment with BHP, and PHP incremented tibia BMD and serum phosphorus level along with the decrease in serum levels of calcium, BALP, interleukin-6, OPG and RANKL. However, treatment with CHP almost restored all the fore mentioned parameters to normal values. Furthermore, the histopathological evaluation emphasized the biochemical outcomes. CONCLUSION: H. pluvialis fractions rich in astaxanthin ameliorated bone loss in experimentally-induced osteoporosis in rats probably through the down-regulation of serum OPG in concurrence with up-regulation of serum RANKL.