Ameliorative effect of nano-pregabalin in gastrocnemius muscle of gamma irradiated rats with an experimental model of fibromyalgia: Crosstalk of Sirt3, IL-1ß and PARP1 pathways.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome with somatic symptoms connected to the operational state of muscles. Although radiotherapy is a cornerstone in cancer treatment, it is implicated in the aggravation of FM. Lately, formulation of medicines in nano-forms become of great prominence due to their prospective applications in medicine. So, this study aimed to assess possible therapeutic benefits of formulating pregabalin in a nono-form (N-PG) for managing FM during exposure to gamma radiation. METHODS: Gamma rays administered in fractionated doses (2 Gy/day) to male rats after one hour of s.c. injection of reserpine (1 mL/kg per day) to induce FM, then treated with single daily dose of (30 mg/kg, p.o.) PG or N-PG for ten successive days. Rats were subjected to behavioral tests, then sacrificed to obtain serum and gastrocnemius muscles. RESULTS: N-PG significantly antagonized reserpine-induced FM as proved by; the immobility and performance times in forced swim and rotarod performance tests, respectively were restored near to the normal time, serum IL-8 and MCP-1 chemokines were nearby the normal levels, mitigated oxidative stress through increasing total thiol, Sirt3, CAT enzyme and decreasing COX-1, inhibition of inflammation via IL-1ß and MIF significant reduction, it possessed anti-apoptotic effect verified by decreasing PARP-1 and increasing Bcl-XL, gastrocnemius muscles had minimal fibrosis levels as seen after Masson trichrome staining. Histopathological results were coincidence with biochemical inspection. CONCLUSION: This study identifies N-PG as a novel drug that could be of a value in the management of FM particularly in cancer patients undergoing radiotherapy.

Enhancing the Sustainability of Eco-Friendly Potentiometric Ion-Selective Electrodes for Stability-Indicating Measurement of Ethamsylate: Application in Bulk and Pharmaceutical Formulations.

BACKGROUND: Through the use of sustainable and green chemistry concepts, scientists need to decrease waste, conserve energy, and develop safe substitutes for hazardous compounds, all for protecting and benefiting society and the environment. OBJECTIVE: Four novel eco-friendly ion selective electrodes (ISE) were generated to determine Ethamsylate (ETM) in bulk powder and different pharmaceutical formulations. The present electrodes were fabricated to clearly distinguish ETM from a variety of inorganic, organic ions, sugars, some common drug excipients and the degradation product, hydroquinone (HQ) of ETM, and thus used for stability-indicating methods. METHODS: The electrodes fabrication was based on 2-nitrophenyl octyl ether (NPOE) that was employed as a plasticizer in electrodes 1, 2, and 3 within a polymeric matrix of polyvinyl chloride (PVC) except for electrode 4, in which dibutyl sebacate was used as a plasticizer. Electrodes 1 and 2 were fabricated using tetradodecylammonium bromide as an anionic exchanger, adding 4-sulfocalix-8-arene as an ionophore only to electrode 2 and preparing electrode 1 without incorporation of an ionophore. The fabrication of electrodes 3 and 4 was based on ethamsylate-tetraphenylborate (ETM-TPB) as an ion-association complex in a PVC matrix. The environmental sustainability was assessed using the green analytical procedure index (GAPI), and analytical greenness metric for sample preparation (AGREEprep). RESULTS: Electrodes 1 and 2 had linear dynamic ranges of 10-1-10-5 mol/L and 10-1-10-4 mol/L, respectively, with a Nernstian slope of 49.6 and 53.2 mV/decade, respectively. Electrodes 3 and 4 had linear dynamic ranges of 10-1-10-4 mol/L, with a Nernstian slope of 43.9 and 40.2 mV/decade, respectively. CONCLUSION: The electrodes' selectivity coefficients showed good selectivity for ETM. The utility of 4-sulfocalix-8-arene as an ionophore had a significant influence on increasing the membrane sensitivity and selectivity of electrode 2 compared to other electrodes. HIGHLIGHTS: Four novel eco-friendly ISEs were used for determination of ETM in bulk powder and different pharmaceutical formulations. Different experimental parameters were performed to optimize the determination conditions such as solvent mediators, dynamic response time, effect of pH, and temperature. Stability-indicating measurement of ETM in the presence of its degradate HQ and co-formulated drug tranexamic acid. Using new ecological assessment tools to determine whiteness and greenness profiles.

Human leukocyte antigen - B27 and antibodies to Klebsiella pneumoniae in Ankylosing Spondylitis: associations and clinical outcome.

Ankylosing spondylitis (AS) is a chronic disabling rheumatic disease with indefinite etiology. Human leukocyte antigen-B27 (HLA-B27) carriage and Klebsiella pneumoniae (K. pneumoniae) infections may contribute to the etiopathogenesis of AS. The objective of this study was to determine the association of HLA-B27 carriage, serum immunoglobulin G (IgG) to K. pneumoniae with AS, and its clinical outcome. In a case-control study, HLA-B27 carriage was detected by polymerase chain reaction, serum IgG to K. pneumoniae was measured by ELISA, and K. pneumoniae was isolated from the stool of 40 AS patients who were compared to age and sex-matched 40 normal individuals. Clinical findings, disease activity, and functional ability were evaluated for all AS patients. HLA-B27, serum IgG to K. pneumoniae, and fecal carriage of Klebsiella were significantly higher in AS patients when compared to controls (p < 0.001 for all). Disease activity and functional score categories were significantly higher in HLA-B27 positive AS patients with an elevated titer of K. pneumoniae IgG than in HLA-B27 negative patients with low titer of K. pneumoniae IgG (p < 0.012 and p < 0.001, respectively). In conclusion, HLA-B27 carriage and K. pneumoniae infections could play a significant role in the development and clinical outcome of AS patients.

Nano-Emulsion Based Gel for Topical Delivery of an Anti-Inflammatory Drug: In vitro and in vivo Evaluation.

Introduction: Arthritic disorder is a common disease in elderly patients and the most common cause of joint dysfunction. This study aims to design Piroxicam-loaded nanoemulsion (PXM-NE) formulations to enhance the analgesic and anti-inflammatory activity of the drug for topical use. Methods: The nanoemulsion preparations were designed based on a high-pressure homogenization technique and were characterized for particle size (PS), poly dispersity index (Pi), zeta potential (ZP), drug content, and the selected formula was investigated for its topical analgesic activity and pharmacokinetic parameters. Results: The characterizations showed that the PS was 310.20±19.84 nm, Pi was 0.15±0.02, and ZP was -15.74±1.6 mV for the selected formula. A morphology study showed that the PXM-NE droplets were spherical with a uniform size distribution. The in vitro release study showed a biphasic release pattern with a rapid release within the first 2 hours followed by a sustained release pattern. The analgesic activity for optimal formula was 1.66 times higher than the commercial gel with a double duration of analgesic activity. The Cmax was 45.73±9.95 and 28.48±6.44 ng/mL for the gel form of the selected formula and the commercial gel respectively. The relevant bioavailability of the selected formula was 2.41 higher than the commercial gel. Conclusion: The results showed good physicochemical properties, higher bioavailability, and a longer analgesic effect of PXM from nanoemulsion gel, as compared to the commercial product.

Mechanistic approach of the therapeutic potential of mesenchymal stem cells on brain damage in irradiated mice: emphasis on anti-inflammatory and anti-apoptotic effects.

BACKGROUND AND OBJECTIVES: Brain damage which has been induced by radiation generally occurs in radiotherapeutics patients. Stem cell transplantation represents a vital applicant for alleviating neurodegenerative disorders. This work aims at exploring the potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) on brain injury induced by γ radiation in mice and the possible underlying mechanisms were elucidated. MATERIALS AND METHODS: Mice were allocated into three groups; Group I (Control), Group II (Irradiated control) where mice submitted to 5 Gy of whole-body γ radiation, Group III (Irradiated + BM-MSCs) where mice were intravenously injected of BM-MSCs at a dose of 106 cells/mice 24 h following irradiation. Animals were sacrificed 28 d following exposure to γ radiation. RESULTS: It was observed that BM-MSCs therapy provided a valuable tissue repair as evidenced by a reduction in inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), nuclear factor kappa (NF-κß), phosphorylated NF-κß-p65 (P-NF-κß-p65), interferon-gamma (IFNγ) and monocyte chemoattractant protein-1 (MCP-1) associated with decreased levels of transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor (VEGF) in brain tissues of irradiated mice. Furthermore, neuronal apoptosis was declined in brain tissues of the BM-MSCs group as remarkable inhibition of caspase-3 and Bax accompanied by elevation of Bcl-2 proteins expression. These results were supported by histopathological investigation. CONCLUSIONS: In conclusion, BM-MSCs could display a vital rule in alleviating brain injury in radio-therapeutic patients.

Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB/TGF-ß/MMP-9 pathways.

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-ß1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-ß1/MMP-9 signaling pathway.

Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-ß, and PPAR-ϒ pathways.

Radiotherapy is one of the principal approaches employed in the treatment of pelvic cancers. Nevertheless, testicular dysfunction and infertility are among the most common adverse effects in young adult cancer survivors. Clinically, alpha-lipoic acid (LA) has been applied to improve the quality of sperm with a satisfactory effect. Therefore, the present study investigated the underlying mechanisms of the radioprotective effects of LA against testicular damage. Male Sprague-Dawley rats were exposed to 10 Gy of whole-body ϒ-radiation and LA (50 mg/kg, P.O.) was administered one week before and three days post-irradiation. LA showed remarkable capacity in preserving testicular tissue against radiation damage by improving histological and ultrastructural changes of disorganized seminiferous tubules, besides enhancing its diameter, germinal epithelial thickness, and Johnsen's score. Radiation instigated a significant decrease in sperm quality and quantity associated with depletion of serum testosterone levels, while the LA administration maintained spermatogenesis. Strikingly, LA exhibited antioxidant properties by restoring reduced glutathione levels and antioxidant enzyme activities such as catalase and glutathione-s-transferase, besides diminishing malondialdehyde levels in the testis of irradiated group. Furthermore, LA alleviated testicular inflammation through downregulation of nuclear factor-ĸB (NF-ĸB) expression with a subsequent reduction in interleukin (IL)-6 and cyclooxygenase-2 expression, accompanied by the augmented expression of the anti-inflammatory cytokine IL-10. Additionally, testicular fibrosis markers including Masson's trichrome and transforming growth factor (TGF)-ß expression were noticeably declined in LA-treated irradiated rats, together with the upregulation of peroxisome proliferator-activated receptor-ϒ expression. Collectively, LA ameliorates radiation-mediated spermatogenesis-defects and testicular-damage via suppression of oxidative stress/NF-ĸB/TGF-ß signaling.

Metal complexes as a promising source for new antibiotics.

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.

Correction: Metal complexes as a promising source for new antibiotics.

[This corrects the article DOI: 10.1039/C9SC06460E.].

Coenzyme Q10 mitigates ionizing radiation-induced testicular damage in rats through inhibition of oxidative stress and mitochondria-mediated apoptotic cell death.

Radiotherapy is a common treatment modality for cancer patients; however, its use is limited by decreasing the probability of fertility in male cancer survivors. Therefore, this study aimed to define the capability of coenzyme Q10 (CoQ10), a potent stimulator of mitochondrial function, in attenuating ionizing radiation (IR)-induced spermatogenesis impairments. Male Sprague Dawley rats were exposed to a single dose of ϒ-rays (10 Gy) and/or treated with CoQ10 (10 mg/kg, orally, for 2 consecutive weeks). IR mediated irregular seminiferous tubules, which were emerged with typical morphological characteristics of apoptosis, and nuclear condensation, while CoQ10 significantly preserved the testicular structure and maintained spermatogenesis, which was displayed by higher levels of serum estradiol and testosterone. CoQ10 remarkably augmented sperm count, motility, and viability while diminished the rate of sperm-defects relatively to their counterparts after IR exposure. CoQ10 modulations in reproductive parameters were underpinned by attenuating IR-induced oxidative stress as evidenced by decreasing lipid peroxidation and increasing the antioxidant enzymes glutathione peroxidase and glutathione-s-transferase activities, and glutathione level. Supporting the involvement of CoQ10 in the anti-apoptotic response, the reduced mRNA expression levels of p53, Puma, and Bax accompanied by the increased Bcl-2 mRNA expression were observed. Subsequently, CoQ10 ameliorated the mitochondria dependent apoptotic pathway through diminishing Bax/Bcl-2 ratio, caspase-3 protein expression, and DNA fragmentation in testes of irradiated rats. Taken together, our findings showed that CoQ10 conserved against IR-induced steroidogenesis disruption through subsiding mitochondria-mediated oxidative stress injury in germinal cells.

68Ga-PSMA-11 PET/CT in newly diagnosed prostate cancer: diagnostic sensitivity and interobserver agreement.

PURPOSE: To determine the diagnostic sensitivity and interobserver agreement of Gallium 68-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) imaging for diagnosis and staging of patients with newly diagnosed prostate cancer (PC). MATERIALS AND METHODS: One hundred and seventy-three men (mean age, 68 ± 7.7 years; range 46-84 years) with newly diagnosed, untreated PC were enrolled in this prospective study between January 2017 and August 2018. All patients underwent a 68Ga-PSMA-11 PET/CT examination. For each patient, we determined the disease stage, the Gleason score, and the maximum standardized uptake value (SUVmax) for primary prostatic tumor and extraprostatic metastases. The diagnostic sensitivity and interobserver agreement of 68Ga-PSMA-11 PET/CT for diagnosis and staging of PC were established by histopathology as the reference standard. RESULTS: 68Ga-PSMA-11 PET/CT examinations were interpreted as positive for PC in 166 of 173 patients (101 patients had primary prostatic tumor only, two patients had extraprostatic metastases only and 63 patients had combined lesions). The sensitivity of 68Ga-PSMA-11 PET/CT examination in the diagnosis of PC was 96%. 68Ga-PSMA-11 PET/CT produced a significant change of stage in 28.6% patients with an upstage in 17.9% patients and a downstage in 10.7% patients. The interobserver agreements were almost good to perfect (k = 0.63-0.89) for visual image interpretation, SUVmax measurement, and tumor staging. CONCLUSION: 68Ga-PSMA-11 PET/CT is a valuable tool with high diagnostic sensitivity (96%) and high reproducibility for diagnosis and staging of patients with newly diagnosed PC.

Gynecology Imaging Reporting and Data System (GI-RADS): diagnostic performance and inter-reviewer agreement.

OBJECTIVE: To evaluate diagnostic performance and inter-reviewer agreement (IRA) of the Gynecologic Imaging Reporting and Data System (GI-RADS) for diagnosis of adnexal masses (AMs) by pelvic ultrasound (US). PATIENTS AND METHODS: A prospective multicenter study included 308 women (mean age, 41 ± 12.5 years; range, 15-73 years) with 325 AMs detected by US. All US examinations were analyzed, and AMs were categorized into five categories according to the GI-RADS classification. We used histopathology and US follow-up as the reference standards for calculating diagnostic performance of GI-RADS for detecting malignant AMs. The Fleiss kappa (κ) tests were applied to evaluate the IRA of GI-RADS scoring results for predicting malignant AMs. RESULTS: A total of 325 AMs were evaluated: 127 (39.1%) were malignant and 198 (60.9%) were benign. Of 95 AMs categorized as GI-RADS 2 (GR2), none was malignant; of 94 AMs categorized as GR3, three were malignant; of 13 AMs categorized as GR4, six were malignant; and of 123 AMs categorized as GR5, 118 were malignant. On a lesion-based analysis, the GI-RADS had a sensitivity, a specificity, and an accuracy of 92.9%, 97.5%, and 95.7%, respectively, when regarding only those AMs classified as GR5 for predicting malignancy. Considering combined GR4 and GR5 as a predictor for malignancy, the sensitivity, specificity, and accuracy of GI-RADS were 97.6%, 93.9%, and 95.4%, respectively. The IRA of the GI-RADS category was very good (κ = 0.896). The best cutoff value for predicting malignant AMs was >GR3. CONCLUSIONS: The GI-RADS is very valuable for improving US structural reports. KEY POINTS: • There is still a lack of a standard in the assessment of AMs. • GI-RADS is very valuable for improving US structural reports of AMs. • GI-RADS criteria are easy and work at least as well as IOTA.

Design, Synthesis, Anti-Proliferative Evaluation and Cell Cycle Analysis of Hybrid 2-Quinolones.

BACKGROUND: Quinolones are a significant group of nitrogen heterocyclic compounds that exist in therapeutic agents, alkaloids, and synthetic small molecules that have important biological activities. A wide range of quinolones have been used as antituberculosis, antibacterial, anti-malarial, antifungal, anticonvulsant, anticancer agents and urease inhibitors. METHODS: Ethyl 3,3-disubstituted-2-cyano propionates containing hybride quinolones derivatives were synthesized by the reaction of 1-amino-7-hydroxy-4-methylquinolin-2(1H)-one and its dibromo derivative with α, ß-unsaturated carbonyl in ethanol. RESULTS: A novel series of hybrid 2-quinolone derivatives was designed and synthesized. The compounds structures were confirmed using different spectroscopic methods and elemental analysis. The cytotoxic activities of all the compounds were assessed against HepG2 cell line in comparison with doxorubicin as a standard drug. CONCLUSION: Most compounds revealed superior anti-proliferative activity than the standard. Compound 4b, is the most active compound (IC50 = 0.39mM) compared with doxorubicin (IC50 = 9.23mM). DNA flow cytometric analysis of compound 4b showed cell cycle arrest at G2/M phase with a concomitant increase of cells in apoptotic phase. Dual annexin-V/ propidium iodide staining assay of compound 4b revealed that the selected candidate increased the apoptosis of HepG-2 cells more than control.

The utility of diffusion-weighted imaging in improving the sensitivity of LI-RADS classification of small hepatic observations suspected of malignancy.

PURPOSE: We investigated the added value of diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) in the categorization of small hepatic observation (≤ 20 mm) detected in patients with chronic liver disease in reference to LI-RADS (liver imaging reporting and data system) classification system. METHODS: We prospectively evaluated 165 patients with chronic liver disease with small hepatic observations (≤ 20 mm) which were previously categorized as LI-RADS grade 3-5 on dynamic contrast-enhanced CT (DCE-CT). All patients were submitted to a functional MRI including DCE and DWI. Using LI-RADS v2017, two radiologists independently evaluated the observations and assigned a LI-RADS category to each observation using DCE-MRI alone and combined DCE-MRI and DWI/ADC. In the combined technique, the radiologists assigned a LI-RADS category based on a modified LI-RADS criteria in which restricted diffusion on DWI was considered a major feature of HCC. We evaluated the inter-reader agreement with Kappa statistics and compared the diagnostic performance of the LI-RADS with two imaging techniques by Fisher's exact test using histopathology as the reference standard. RESULTS: Combined technique in LI-RADS yielded better sensitivities (reader 1, 97% [65/67]; reader 2, 95.5% [64/67]) for HCC diagnosis than DCE-MRI alone (reader 1, 80.6% [54/67], p = 0.005; reader 2, 83.6% [56/67], p = 0.04). The specificities were insignificantly lower in combined technique (reader 1, 88.4% [107/121]; reader 2, 77.7% [94/121]) than in DCE-MRI alone (reader 1, 90.9% [110/121], p = 0.67; reader 2, 79.3% [96/121], p = 0.88). The inter-reader agreement of the LI-RADS scores between combined technique and DCE-MRI was good (κ = 0.765). CONCLUSION: The use of DWI/ADC as an additional major criterion, improved the sensitivity of LI-RADS in the diagnosis of HCC while keeping high specificity.

Radiation preparation of L-arginine/acrylic acid hydrogel matrix patch for transdermal delivery of propranolol HCl in hypertensive rats.

In the present study, L-arginine/acrylic acid (Arg/AAc) batch hydrogel was successfully prepared by gamma irradiation for transdermal delivery of propranolol HCl in hypertensive rats. The resulted system has been characterized by FTIR to confirm the hydrogel formation. The swelling behavior of the prepared hydrogels was investigated as a function of time and pH. The kinetics of swelling has been investigated. In vivo pharmacokinetics evaluation, skin irritation test, and histopathological studies were investigated. Furthermore, the antihypertensive efficacy of transdermal propranolol-loaded Arg/AAc hydrogel on methyl prednisolone acetate-induced hypertensive rats was evaluated. It was found that the prepared patches exhibited a sustained release of the drug into systemic circulation over oral route which is subjected to hepatic first-pass metabolism, coupled with a short plasma half-life. Transdermal administration displayed a prolonged antihypertensive effect in spontaneously hypertensive rats. Moreover, the skin irritation test and histopathological examination indicated that the prepared patches are not irritant and can be safely applied on the skin. These results indicated that the hydrogel system composed of Arg and AAc has potential as a transdermal delivery system.

Nigella sativa oil modulates the therapeutic efficacy of mesenchymal stem cells against liver injury in irradiated rats.

Stem cell transplantation is a novel strategy for regenerative medicine in liver disease. This study was conducted to explore the modulatory effect of Nigella sativa oil (NSO) on the therapeutic potential of mesenchymal stem cells (MSCs) against irradiation-induced liver damage in rats. Liver damage was induced by a total body exposure to a single dose of 7Gy. NSO (2mg/kg/day) was then given orally for 4 consecutive weeks starting 24h after irradiation with or without a single intravenous MSCs administration, then rats were sacrificed four weeks after exposure to γ radiation. Data revealed that irradiation elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum, increased hepatic malondialdehyde (MDA) content and reduced hepatic superoxide dismutase (SOD) activity. Furthermore, it caused elevation in pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) associated with reduction in anti-inflammatory cytokine interleukin-10 (IL-10) and it increased fibrogenic marker transforming growth factor-ß (TGF-ß) in liver tissues. It was observed that combined NSO/MSCs therapy provided more beneficial tissue repair comparable to MSCs alone as demonstrated by modulating the tested parameters. Finally, these results were confirmed by histopathological examination. In conclusion, dual therapy with NSO and MSCs could serve as a promising approach for alleviating radiation-induced liver injury in patients with radiotherapy.

Antifungal activity of oral (Tragacanth/acrylic acid) Amphotericin B carrier for systemic candidiasis: in vitro and in vivo study.

In an effort to increase the oral bioavailability of Amphotericin B (AmB), a pH-sensitive drug carrier composed of Tragacanth (Trag) and acrylic acid (AAc) was prepared using γ-irradiation. The swelling behavior of (Trag/AAc) hydrogels was characterized as a function of pH and ionic strength of the swelling medium. The obtained swelling indices revealed the ability of the prepared hydrogel to protect a loaded drug in stomach-simulated medium (Fickian behavior) and to release such drug in intestinal-simulated medium (non-Fickian behavior). In vitro release studies of the antifungal (AmB) were performed to evaluate the hydrogel potential as a drug carrier. The antifungal activity of the prepared oral formulation was investigated in a mouse model of systemic candidiasis. Data revealed that (Trag/AAc)-AmB has a potent antifungal efficacy as demonstrated by prolonging the survival time and reducing the tissue fungal burden, serum antibody titers, as well as inflammatory cytokines in kidney and liver tissues. Furthermore, in vivo toxicity of (Trag/AAc)-AmB was assessed via measuring kidney and liver functions, and results displayed the safety of this novel AmB formulation which was confirmed by histopathological examination. Overall, results indicated that the prepared (Trag/AAc)-AmB is an effective oral delivery system for AmB with better bioavailability and minimal toxicity and could represent a promising approach for improving the therapeutic index of the drug.

New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation.

New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half-lives between 50 and 120min, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-containing enzymes and heme-containing proteins in a similar fashion to other acyloxy nitroso compounds. HNO released from these acyloxy nitroso compounds inhibits activated platelet aggregation. These acyloxy nitroso compounds augment the range of release for this group of HNO donors and should be valuable tools in the further study of HNO biology.

Synthesis and anticancer activity of silver(I)-N-heterocyclic carbene complexes derived from the natural xanthine products caffeine, theophylline and theobromine.

A new library of silver(I)-N-heterocyclic carbene complexes prepared from the natural products caffeine, theophylline and theobromine is reported. The complexes have been fully characterised using a combination of NMR spectroscopy, mass spectrometry, elemental analysis and X-ray diffraction analysis. Furthermore, the hydrophobicity of the complexes has been measured. The silver(I)-N-heterocyclic carbenes have been evaluated for their antiproliferative properties against a range of cancer cell lines of different histological types, and compared to cisplatin. The data shows different profiles of response when compared to cisplatin in the same panel of cells, indicating a different mechanism of action. Furthermore, it appears that the steric effect of the ligand and the hydrophobicity of the complex both play a role in the chemosensitivity of these compounds, with greater steric bulk and greater hydrophilicity delivering higher cytotoxicity.

Aminoglycoside resistance rates, phenotypes, and mechanisms of Gram-negative bacteria from infected patients in upper Egypt.

With the re-emergence of older antibiotics as valuable choices for treatment of serious infections, we studied the aminoglycoside resistance of Gram-negative bacteria isolated from patients with ear, urinary tract, skin, and gastrointestinal tract infections at Minia university hospital in Egypt. Escherichia coli (mainly from urinary tract and gastrointestinal tract infections) was the most prevalent isolate (28.57%), followed by Pseudomonas aeruginosa (25.7%) (mainly from ear discharge and skin infections). Isolates exhibited maximal resistance against streptomycin (83.4%), and minimal resistance against amikacin (17.7%) and intermediate degrees of resistance against neomycin, kanamycin, gentamicin, and tobramycin. Resistance to older aminoglycosides was higher than newer aminoglycosides. The most common aminoglycoside resistance phenotype was that of streptomycin resistance, present as a single phenotype or in combination, followed by kanamycin-neomycin as determined by interpretative reading. The resistant Pseudomonas aeruginosa strains were capable of producing aminoglycoside-modifying enzymes and using efflux as mechanisms of resistance. Using checkerboard titration method, the most frequently-observed outcome in combinations of aminoglycosides with ß-lactams or quinolones was synergism. The most effective combination was amikacin with ciprofloxacin (100% Synergism), whereas the least effective combination was gentamicin with amoxicillin (53.3% Synergistic, 26.7% additive, and 20% indifferent FIC indices). Whereas the studied combinations were additive and indifferent against few of the tested strains, antagonism was never observed. The high resistance rates to aminoglycosides exhibited by Gram-negative bacteria in this study could be attributed to the selective pressure of aminoglycoside usage which could be controlled by successful implementation of infection control measures.