The deleterious effects of sofosbuvir and ribavirin (antiviral drugs against hepatitis C virus) on different body systems in male albino rats regarding reproductive, hematological, biochemical, hepatic, and renal profiles and histopathological changes.

Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.

Neuroprotective effects of vitamin D in an Alzheimer's disease rat model: Improvement of mitochondrial dysfunction via calcium/calmodulin-dependent protein kinase kinase 2 activation of Sirtuin1 phosphorylation.

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl3 + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl3 + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aß), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aß aggregation, and elevated p-Tau levels in the AlCl3 + D-gal-induced AD rat model. In AlCl3 + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca2+ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl3 + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation.

Monitoring the effects of fungi isolated from archival document on model albumen silver prints.

Fungi are a common problem in the photographic collection, so the aim of this study focused on isolating and molecular identification of fungi from old albumen prints dating to an archive of Dr. Francis and belonging to the Al-Hagar Family and dating back to 1880-1890. The isolated fungi were identified according to their morphological traits and PCR sequencing. The ability of these isolates to cause deterioration was evaluated on model samples (2 × 2 cm) of albumen silver prints. The effect of these fungi on the morphology and structure of the tested samples were examined by SEM, ATR-FTIR, and chromatic alternations. Four fungal species Aspergillus sydowii, A. flavus, Talaromyces atroroseus, and Penicillium chrysogenum were identified. All isolates were able to grow on the surface of the model Albumen silver print and were capable of causing damage to the binder and able to extend their growth to the paper fibers. A. sydowii, A. flavus, and P. chrysogenum caused hydrolysis and oxidation to the albumen prints, while no significant chemical damage to the albumen was detected for the photographic sample infected with T. atroroseus. All the inoculated samples were significantly affected in terms of color change and the high-light areas have become darker. ATR-FTIR spectra showed the degradation of the protein content in Albumen silver prints inoculated with A. sydowii, A. flavus, and P. chrysogenum.

Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity in Rats.

Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3ß, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism.

Recent developments in alginate-based adsorbents for removing phosphate ions from wastewater: a review.

The huge development of the industrial sector has resulted in the release of large quantities of phosphate anions which adversely affect the environment, human health, and aquatic ecosystems. Naturally occurring biopolymers have attracted considerable attention as efficient adsorbents for phosphate anions due to their biocompatibility, biodegradability, environmentally-friendly nature, low-cost production, availability in nature, and ease of modification. Amongst them, alginate-based adsorbents are considered one of the most effective adsorbents for removing various types of pollutants from industrial wastewater. The presence of active COOH and OH- groups along the alginate backbone facilitate its physical and chemical modifications and participate in various possible adsorption mechanisms of phosphate anions. Herein, we focus our attention on presenting a comprehensive overview of recent advances in phosphate removal by alginate-based adsorbents. Modification of alginate by various materials, including clays, magnetic materials, layered double hydroxides, carbon materials, and multivalent metals, is addressed. The adsorption potentials of these modified forms for removing phosphate anions, in addition to their adsorption mechanisms are clearly discussed. It is concluded that ion exchange, complexation, precipitation, Lewis acid-base interaction and electrostatic interaction are the most common adsorption mechanisms of phosphate removal by alginate-based adsorbents. Pseudo-2nd order and Freundlich isotherms were figured out to be the major kinetic and isotherm models for the removal process of phosphate. The research findings revealed that some issues, including the high cost of production, leaching, and low efficiency of recyclability of alginate-based adsorbents still need to be resolved. Future trends that could inspire further studies to find the best solutions for removing phosphate anions from aquatic systems are also elaborated, such as the synthesis of magnetic-based alginate and various-shaped alginate nanocomposites that are capable of preventing the leaching of the active materials.

Protective effects of Folic acid against reproductive, hematological, hepatic, and renal toxicity induced by Acetamiprid in male Albino rats.

Acetamiprid (ACP) is a widespread used insecticide belonging to neonicotinoids (NNs) that are introduced for controlling pests, and for domestic use to control fleas on cats and dogs. The current experiment pertains to a comprehensive overview of the toxic effects of acetamiprid and the protective role of folic acid against reproductive, hematological, histopathological and biochemical toxicity induced by ACP during 5 weeks. Male Albino rats were divided into four groups of seven each: First group served as control rats (CL group); Second group received acetamiprid (ACP group) (10 mg/Kg body weight) by oral gavage. Third group received both acetamiprid and folic acid (ACP + FA group) (2 mg/Kg body weight); Fourth group received folic acid (FA group) (2 mg/Kg body weight). Exposure of rats to acetamiprid caused significant changes in the reproductive indices as it cause a significant decrease in the sperm count, viability and motility. Furthermore, reproductive hormones such as testosterone and gonadotropin-releasing hormones (GnRH) were found significantly decreased in acetamiprid treated group. In addition, acetamiprid administration causes significant changes of some hematological and immunological parameters (red blood cells (RBC), hemoglobin (Hb), platelet (Plt), white blood cells (WBCs), lymphocyte, monocyte, neutrophil, eosinophil, IgG, IgM and IgA) in treated rats compared to controls. Significant increases in the levels of hepatic markers enzymes (aspartate transaminase (AST), Alanine transaminase (ALT), alkaline phosphatase (ALP) in acetamiprid treated group, as well as severe toxic effect was found on the liver and kidney after acetamiprid delivery according to the histopathological examinations which were confirmed after applying histological, histochemical, and Immunohistochemistry tests. The most conspicuous histopathological changes occurred on the liver and kidney of the acetamiprid treated group represented in the liver by fatty liver cells, leukocytic infiltration, and hemorrhage while in kidney tissues revealed tubular atrophy, dense eosinophilic cytoplasm and dilated congested blood vessels. Both liver and kidney tissues showed an increase in the amount of collagenous fibers and immune reactivity of fatty acid synthase. Moreover, other markers such as uric acid and total antioxidant capacity (TAC) were significantly decreased in acetamiprid treated rats. Co-administration of folic acid to the third group restored all the parameters cited above to near-normal values. Therefore, our investigation revealed that acetamiprid induce severe toxicity on different body systems and parameters and folic acid appeared to be a promising agent for protection against acetamiprid-induced toxicity.

Inhibition of boldenone-induced aggression in rats by curcumin: Targeting TLR4/MyD88/TRAF-6/NF-κB pathway.

The illicit abuse of anabolic steroids is associated with brutal aggression, which represents a serious health hazard and social threat. Boldenone is commonly used for doping by athletes and adolescents for esthetic purposes and to enhance performance and endurance during competitions. However, the mechanistic pathways underlying boldenone-induced behavioral deviations and neuronal toxicity have not yet been elucidated. On the other hand, the natural polyphenol curcumin is appreciated for its relative safety, potent antioxidant activity, and anti-inflammatory properties. Therefore, the present study was initiated to explore the signaling pathways underlying boldenone-induced anxiety and aggression in rats, and the protective effects of curcumin. To achieve this aim, male Wistar albino rats were randomly distributed into control, curcumin (100 mg/kg in sesame oil, p.o., once daily), boldenone (5 mg/kg, intramuscular, once weekly), and combination groups. Rats were challenged across the open field, irritability, defensive aggression, and resident-intruder tests. The prefrontal cortex was used to assess serotonin level, oxidative stress markers, and mRNA expression of myeloid differentiation primary response gene (MyD88), TNFR-associated factor 6 (TRAF-6), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), protein expression of toll-like receptor 4 (TLR4), and phosphorylated nuclear factor-κB transcription factor (NF-κB p65). Unprecedented, the current results showed that boldenone elicited aggression in rats accompanied by depleted serotonin, enhanced oxidative stress, and exaggerated inflammatory response via upregulation of TLR4/MyD88/TRAF-6/NF-κB pathway. Interestingly, curcumin mitigated boldenone-induced neurobehavioral disturbances in rats, normalized the oxidant/antioxidant balance, and suppressed TLR4/MyD88/TRAF-6/NF-κB pathway and its downstream proinflammatory signaling molecules TNF-α and IL-1ß.

Nano-ivabradine averts behavioral anomalies in Huntington's disease rat model via modulating Rhes/m-tor pathway.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

pH-Sensitive Alginate/Carboxymethyl Chitosan/Aminated Chitosan Microcapsules for Efficient Encapsulation and Delivery of Diclofenac Sodium.

To develop an effective pH-sensitive drug carrier, alginate (Alg), carboxymethyl chitosan (CMCs), and aminated chitosan (AmCs) derivatives were employed in this study. A simple ionic gelation technique was employed to formulate Alg-CMCs@AmCs dual polyelectrolyte complexes (PECs) microcapsules as a pH-sensitive carrier for efficient encapsulation and release of diclofenac sodium (DS) drug. The developed microcapsules were characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analyzer (TGA), and scanning electron microscope (SEM). The results clarified that formation of dual PECs significantly protected Alg microcapsules from rapid disintegration at colon conditions (pH 7.4), and greatly reduced their porosity. In addition, the dual PECs microcapsules can effectively encapsulate 95.4% of DS-drug compared to 86.3 and 68.6% for Alg and Alg-CMCs microcapsules, respectively. Higher DS-release values were achieved in simulated colonic fluid [SCF; pH 7.4] compared to those obtained in simulated gastric fluid [SGF; pH 1.2]. Moreover, the drug burst release was prevented and a sustained DS-release was achieved as the AmCs concentration increased. The results confirmed also that the developed microcapsules were biodegradable in the presence of the lysozyme enzyme. These findings emphasize that the formulated pH-sensitive microcapsules could be applied for the delivery of diclofenac sodium.

Mechanistic insights into the protective effects of chlorogenic acid against indomethacin-induced gastric ulcer in rats: Modulation of the cross talk between autophagy and apoptosis signaling.

BACKGROUND: This study aimed to investigate the gastroprotective effect of chlorogenic acid (CGA) against Indomethacin (IND)-induced gastric ulcer (GU) in rats and its underlying mechanism, especially through autophagic and apoptotic pathways. METHODS: Seventy-five rats were divided into five groups; control, IND (50 mg/kg, p.o.), CGA (100 mg/kg, p.o., 14 days), IND pretreated with CGA (50 mg/kg or 100 mg/kg, p.o., 14 days). The stomach tissues were examined to calculate the ulcer index and analyze markers of autophagy (beclin-1, LC3-II/LC3-I and p62), lysosomal function (cathepsin-D) and apoptosis (Bcl-2, Bax and caspase-3), along with expression of Akt/mTOR pathway using western blot or ELISA techniques. In addition, viability of gastric mucosal cells was detected by flowcytometry. Structural changes were assessed histologically, while autophagic and apoptotic changes of gastric mucosa were observed by transmission electron microscopy. RESULTS: CGA exhibited a dose-dependent gastroprotective effect by reversing IND-induced accumulation of autophagic vacuoles, significant reduction in beclin-1, LC3-II/LC3-I, and p62 levels, and down-regulation of p-Akt/p-mTOR expression. CGA100 also restored normal autolysosomal function by modulation of cathepsin-D levels. Furthermore, pretreatment with CGA100 was significantly associated with an increase in antiapoptotic protein Bcl-2 along with a decrease in proapoptotic Bax and caspase-3 proteins in such a way that impairs IND-induced apoptosis. This was confirmed by CGA-induced significant decrease in annexin V+ cells. CONCLUSIONS: The natural compound CGA offers a novel gastroprotective intervention against IND-induced GU through restoration of normal autophagic flux, impairment of apoptosis in a crosstalk mechanism mediated by Akt/mTOR pathway reactivation, and alleviation of IND-induced lysosomal dysfunction.

CRISPR/Cas9 mediated knock-out of VPREB1 gene induces a cytotoxic effect in myeloma cells.

BACKGROUND: Multiple Myeloma (MM) is a heterogeneous, hematological neoplasm that accounts 2% of all cancers. Although, autologous stem cell transplantation and chemotherapy are currently the most effective therapy, it carries a notable hazards, in addition for being non curative. Recently, the Clustered Regular Interspaced Short Palindromic Repeats (CRISPR-cas9) has been successfully tried at the experimental level, for the treatment of several hematological malignancies. OBJECTIVES: We aimed to investigate the in-vitro effect of CRISPR-cas9-mediated knock-out of V-set pre B-cell surrogate light chain 1"VPREB1" gene on the malignant proliferation of primary cultured myeloma cells. METHODS: Bioinformatics' analysis was performed to explore the gene expression profile of MM, and the VPREB1 gene was selected as a target gene for this study. We knocked-out the VPREB1 gene in primary cultured myeloma cells using CRISPR-cas9, the VPREB1 gene editing efficacy was verified by determining VPREB1 gene expression at both the mRNA and protein levels by qPCR and immunofluorescence, respectively. Furthermore, the cytotoxic effect on primary myeloma cells proliferation was evaluated using cytotoxicity assay. RESULTS: There was a statistically significant reduction of both VPREB1 mRNA and protein expression levels (p<0.01). knock-out of VPREB1 gene in myeloma cell line resulted in a statistically significant reduction of myeloma cell proliferation. CONCLUSION: CRISPR-cas9-mediated knock-out of VPREB1 gene is effective for inhibiting the proliferation of primary myeloma cells. This would provide a basis for a promising therapeutic strategy for patients with multiple myeloma.

Liraglutide mends cognitive impairment by averting Notch signaling pathway overexpression in a rat model of polycystic ovary syndrome.

AIMS: Polycystic ovary syndrome (PCOS), the rifest endocrine disorder in women, is involved in disrupting many metabolic processes. However, the impact of PCOS on cognitive deficits is still uncertain. Recently, Notch signaling pathway was identified as a key modifier in regulating the pathological process in the ovary and various neurodegenerative disorders. Liraglutide has favourable neuroprotective effects that may protect against the possible cognitive dysfunction in PCOS. MAIN METHODS: PCOS was induced in rats by administrating Letrozole orally for 21 successive days. Then, Liraglutide (LIR) was administered intraperitoneally for 30 days. Memory was examined using Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests. Western blotting, enzyme immunoassay, and quantitative real-time PCR were used to examine Notch signaling downstream targets, as well as assessing the expression of the components of various pathways cross talked with Notch signaling in memory impairment. Furthermore, histopathological examination was performed to examine neuronal changes. KEY FINDINGS: Notch signaling was overexpressed in PCOS rats, which increased Aß aggregation, apoptosis, and neuroinflammation. Additionally, histopathological examination showed neuronal degeneration, which was marked by diminished acetylcholine levels in the PCOS rats' hippocampi. Finally, serum levels of insulin and testosterone were elevated while estradiol was reduced. Treatment with LIR repaired Notch signaling-attributed changes and improved the PCOS-induced memory impairment in rats. SIGNIFICANCE: The obtained findings confirm that Notch signaling activation in the hippocampus of rats impairs cognitive functions in PCOS, which is mitigated by LIR. Therefore, LIR may offer a novel therapeutic intervention to impede PCOS-induced dementia.

Acetyl-11-keto-ß-boswellic acid prevents testicular torsion/detorsion injury in rats by modulating 5-LOX/LTB4 and p38-MAPK/JNK/Bax/Caspase-3 pathways.

AIMS: Testicular torsion/detorsion (T/D) is a critical medical condition that necessitates prompt surgical intervention to avoid testicular atrophy and infertility. The use of natural compounds may protect against the associated detrimental oxidative stress and inflammatory responses. Interestingly, acetyl-11-keto-ß-boswellic acid (AKBA), the main active constituent of Boswellia resin, has shown potent inhibitory effect on 5-lipoxygenase enzyme which converts arachidonic acid into inflammatory mediators. Therefore, this study was conducted to assess the protective mechanisms by which AKBA may protect against testicular T/D injury in rats. MAIN METHODS: Male rats were randomly distributed into five groups: Sham, AKBA (50 mg/kg, p.o.), unilateral testicular T/D, AKBA at two dose levels (25 or 50 mg/kg for 15 successive days) followed by T/D. Histological examination and Johnsen's score were performed to assess testicular injury and perturbations in spermatogenesis. Biochemical parameters included markers of testicular function (serum testosterone), oxidant/antioxidant status (malondialdehyde, glutathione), inflammation (5-lipoxygenase, leukotriene-B4, myeloperoxidase, interleukin-1ß, interleukin-6), apoptosis (Bax, Bcl2, caspase-3), DNA integrity (quantitative DNA fragmentation, DNA laddering, PARP-1), energy production (ATP), in addition to p38 MAPK and JNK protein expression. KEY FINDINGS: In a dose dependent manner, AKBA significantly inhibited testicular T/D-induced upregulation of 5-LOX/LTB4 and p38-MAPK/JNK/Bax pathways and their associated downstream inflammatory and apoptotic cascades. These effects were accompanied with ATP replenishment and DNA preservation, resulting ultimately in salvage of the testis. SIGNIFICANCE: Unprecedentedly, the present mechanistic study revealed the pathways by which AKBA may inhibit testicular T/D injury and offered a novel protective approach that may attenuate the severity of this condition.

Carvedilol attenuates l-arginine induced acute pancreatitis in rats through modulation of oxidative stress and inflammatory mediators.

Acute pancreatitis (AP) is a sudden pancreatic inflammation accompanied by an excessive reactive oxygen species production that provokes inflammation. The present study investigated whether carvedilol can protect against l-arginine induced AP in a rat model and studied the mechanisms associated with its protection. Rats were divided into four groups: a control group, an AP group (injected with 2 doses of l-arginine 250 mg/100 g body weight at 1 h interval, intraperitoneally) on the 22nd day of the experiment, a carvedilol group (10 mg/kg, orally) for 21 successive days, and finally a carvedilol + AP group. It was found that pretreatment with carvedilol decreased α-amylase and lipase activities as well as C-reactive protein (CRP) and malondialdehyde levels; on the other hand, it improved the reduced glutathione (GSH) level and catalase (CAT) activity. In addition, carvedilol markedly decreased all of the following biomarkers: nuclear factor kappa B (NF-κB p65), p38 mitogen-activated protein kinases (P38-MAPK), signal transducer and activator of transcription 1 (STAT1-α), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), myeloperoxidase (MPO), and phospholipase A2 (PLA2) levels that was induced by l-arginine. Finally, carvedilol noticeably down regulated the pancreatitis associated protein (PAP2) and the pancreas platelets activating factor (PAF) genes expression. In conclusion: carvedilol protected against l-arginine induced AP in rats, via the inhibition of cellular oxidative stress and inflammatory pathways that contributed to pancreas injury.

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet-fed streptozotocin-treated diabetic rats.

Dapagliflozin (DAPA) is used for treating type 2 diabetes, whereas lansoprazole (LPZ) is used as a traditional antiulcer drug. The present study investigated the possible antidiabetic effects of LPZ on fortified diet-fed streptozotocin (FDF/STZ)-induced insulin-resistant diabetic rats. On the basis of the current results, it can be concluded that LPZ could be used as an add-on drug along with the conventional treatment for T2D as it showed beneficial effects in the current experimental model of insulin resistance.

Association Between Obesity-Mediated Atrial Fibrillation and Therapy With Sodium Channel Blocker Antiarrhythmic Drugs.

Importance: The association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear. Objective: To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF. Design, Setting, and Participants: An observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019. Main Outcomes and Measures: Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride. Results: A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P = .001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P = .001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P = .03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P = .02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P < .001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P < .01). Conclusions and Relevance: Results suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.

Knowledge of and Attitudes Toward the Use of Anabolic-Androgenic Steroids among the Population of Jeddah, Saudi Arabia.

PURPOSE: The aim of this study was to investigate the correlation between the use of anabolic-androgenic steroids (AASs) among the population of Jeddah, Saudi Arabia, and their knowledge and attitudes. METHODS: This was a community-based, cross-sectional observational study. This study was conducted using a questionnaire that was distributed among the population during the period from February 3, 2018, to February 25, 2018. This questionnaire comprised 31 questions, designed to evaluate the knowledge and attitudes toward using AASs. RESULTS: A total of 300 participants were enrolled in the study. The mean age of the population was 30.66 ± 9.2 years. Fourteen participants admitted using AASs, with a percentage of 4.7%, among whom 85.7% were male (P = 0.0005). Seventy-eight percent of AAS users believed that AASs do not cause tolerance when taken for a longtime (P = 0.023). However, the majority of both AAS users and nonusers did not agree on taking AASs for a longtime. Our results showed a strong correlation between not taking AASs and not consuming energy drinks (P = 0.0023). Half of our respondents exhibited poor knowledge regarding the side effects of AASs. The level of knowledge did not correlate with the use of AAS, gender, exercising, or consuming energy drinks. CONCLUSION: The results showed poor knowledge regarding using AASs among the population of Jeddah. Thus, we recommend having a national awareness program in order to prevent the possible side effects of misusing AASs.

Protective effects of febuxostat against paraquat-induced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades.

AIMS: The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms. MAIN METHODS: Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated. KEY FINDINGS: Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of ß-catenin protein expression and its downstream inflammatory mediators. SIGNIFICANCE: The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.

Interleukin-6 promotor gene polymorphisms and susceptibility to chronic hepatitis B virus in Egyptians.

AIM: To investigate the association between IL-6 polymorphisms (-174G/C, -572G/C and -597G/A) and susceptibility to chronic hepatitis B virus (CHB) infection. METHOD: Total 108 subjects with CHB infection and 102 healthy controls were enrolled in this study. IL-6 (-174G/C) was genotyped using Mutagenically separated Polymerase Chain Reaction (MS-PCR) while sequence specific primers-PCR (SSP-PCR) was used for studying -572G/C and -597G/A. IL-6 plasma level was measured using Enzyme-linked immunosorbent assay (ELISA). RESULTS: A significant increase (P < 0.01, P < 0.01, P < 0.001) in -174GG, -572GC and -597GA; respectively in the CHB group compared to control group, while -572GG genotype was significantly decreased (P < 0.01) in CHB patients. A significant increase (p < 0.01, p < 0.01) in -174 G and -597A alleles was observed in the CHB patient group; respectively. GGA haplotype is significantly increased (P < 0.05) while GCA haplotype is significantly decreased (P < 0.001) in the patient group. A moderate linkage disequilibrium (LD) (D' = 0.719, r2 = 0.474; P < 0.001) between IL-6 (-572G/C and -597G/A) was observed. A significant reduction (P < 0.01) in IL-6 plasma level in CHB patients compared to healthy controls (22.28 ±â€¯1.93 versus 32.08 ±â€¯2.41), which was negatively correlated (r = -0.216; P < 0.01) with HBV infection. CONCLUSIONS: This study pointed to the potential role of IL-6 (-174G/C, -572 G/C and -597G/A) gene polymorphisms in the susceptibility to HBV infection. Our results allow for only preliminary conclusions due to relatively small sample size. There is a need for further larger scale studies to fully examine the possible relationship between these cytokine gene polymorphisms and the development of CHB.

Montelukast attenuates rotenone-induced microglial activation/p38 MAPK expression in rats: Possible role of its antioxidant, anti-inflammatory and antiapoptotic effects.

Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were split into four groups: vehicle control (0.2 ml/kg/48 h, sc), MK (10 mg/kg/day, ip), rotenone (1.5 mg/kg/48 h, sc.) and rotenone pretreated with MK. Rotenone treatment led to significant reduction in motor functioning and elevation in oxidative stress markers. Additionally, upregulation of p38 mitogen-activated protein kinase (p38 MAPK) and CysLT1 receptor expressions were anchored with enhanced striatal microglial activation generating a severe neuro-inflammatory milieu. Furthermore, an augmentation in p53 expression and cleaved caspases-3 activity increased apoptotic neurodegeneration synchronized with reduction of striatal tyrosine hydroxylase (TH) content. Changes in neuronal morphology was also noted. MK administration significantly mitigated motor impairment and rise in oxidative stress mediators. As well, the anti-inflammatory activity of MK was manifested by hindering the principal controller of inflammatory pathway, nuclear factor-kappa B, followed by its downstream pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta), by attenuating striatal microglial activation and hampering the expression of both p38 MAPK and CysLT1. Moreover, MK revealed a decline in p53 expression with its downstream cleaved caspases-3 which resulted in preservation of striatal TH terminals as verified by increased striatal TH content and improvement in the histopathological changes incited by rotenone. In conclusion, MK endowed neuroprotective effects in rotenone-induced PD animal model via attenuation of microglial cell activation and p38 MAPK expression.