Azza A. Ali

Insights into the Protective Mechanisms of Tamoxifen in Radiotherapy-Induced Ovarian Follicular Loss: Impact on Insulin-Like Growth Factor 1

Radiotherapy is one of the most common and effective cancer treatments. However, it has a profound impact on ovarian function, leading to premature ovarian failure. With the hope of preserving fertility in cancer survivors, the need for an effective radioprotective therapy is evident. The present study investigated the mechanism of the potential radioprotective effect of tamoxifen (TAM) on γ-irradiation-induced ovarian failure on experimental rats and the impact of the IGF-1 in the underlying protective mechanisms. Female Sprague Dawley rats were either exposed to single whole-body irradiation (3.2 Gy; lethal dose [LD₂₀]) and/or treated with TAM (1 mg/kg). γ-Irradiation caused an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (proliferating cell nuclear antigen), and oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1 receptor axis expression was assessed using real-time RT-PCR and immunolocalization techniques. Furthermore, fertility assessment was performed. TAM significantly enhanced follicular development and restored the anti-Mullerian hormone level. Moreover, it ameliorated the deleterious effects of irradiation on oxidative stress, proliferating cell nuclear antigen expression, and apoptosis. Interestingly, TAM was shown to enhance the ovarian IGF-1 but not IGF-1 receptor, a property that contributed significantly to its radioprotective mechanisms. Finally, TAM regained the fertility that was lost after irradiation. In conclusion, TAM showed a radioprotective effect and saved the ovarian reserve and fertility through increasing anti-Mullerian hormone and the local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Doxorubicin (DOX) has limited efficacy in colorectal cancer due to multi-drug resistance. Resveratrol (RES) and didox (DID) are polyhydroxyphenols with potential chemosensitizing effects. Herein, we assessed the chemomodulatory effects of RES and DID to DOX in colorectal cancer cells. Equitoxic combination of DOX with RES and DID in HCT 116 reduced the IC50 of DOX from 0.96 ± 0.02 μM to 0.52 ± 0.05 μM and 0.4 ± 0.06 μM, respectively. Similarly, combination of DOX with RES and DID in HT-29 decreased the IC50’s of DOX from 0.88 ± 0.03 μM to 0.47 ± 0.02 μM and 0.29 ± 0.04 μM, respectively. The expressions of p53 and Bax genes were markedly elevated in HCT 116 cells after exposure to DOX/DID. In HT-29 cells, the expression of Bcl-XL gene was significantly decreased after exposure to DOX/DID. In addition, combination of DOX with RES significantly increased the expression of Bax gene in HCT 116 cells. RES treatment induced significant S-phase arrest in DOX-treated HCT 116 cells, while DID induced G2/M- and S-phase arrest in HCT 116 and HT-29, respectively. Both RES and DID significantly enhanced the intracellular entrapment of DOX due to blocking the efflux activity of p-glycoprotein pump. In conclusion, RES and DID sensitize colorectal cancer cells to DOX via facilitating apoptosis and enhancing intracellular entrapment of DOX.

Protective effect of cardamonin against acetic acid-induced ulcerative colitis in rats

BACKGROUND Ulcerative colitis (UC) is an inflammatory bowel disease with significant morbidity. Cardamonin is a natural chalcone derivative with considerable anti-inflammatory activity. Herein, the potential protective effect of cardamonin against UC was tested in a rat model. METHODS Rats were given 10 or 30mg/kg/day of cardamonin orally for 14days before induction of UC. On the 14th day of treatment, UC was induced by intrarectal instillation of 2ml 3% acetic acid. Twenty four h after acetic acid instillation, rats were sacrificed and colons were analyzed by macroscopic and histopathological examination. Colon lipid peroxidation was examined by biochemical evaluation of malondialdehyde (MDA). Myeloperoxidase (MPO), iNOS, NF-κB, TNFα levels were measured by ELISA. Moreover, caspase-3 and COX-2 were assessed by immunohistochemical analysis. RESULTS Cardamonin at 10 and 30mg/kg decreased the disease activity index and macroscopic damage index scores, and significantly reduced histopathological deterioration. Additionally, cardamonin reduced levels of MPO, iNOS, NF-κB, TNFα and MDA (p<0.05). Immunohistochemistry revealed down-regulation of COX-2 and caspase-3 in groups treated with cardamonin. CONCLUSION Cardamonin has a protective effect against acetic acid-induced colitis. This effect may be due to reducing inflammation, oxidative stress and apoptosis.

Effect of low-protein diet on anthracycline pharmacokinetics and cardiotoxicity.

Objectives  Anthracyclines are broad spectrum anticancer drugs with dose‐dependent cardiotoxicity. Protein malnutrition commonly occurs in cancer patients and is considered a risk factor for development of cardiotoxicity. This study was designed to assess the modulatory effect of protein malnutrition on the pharmacokinetics and drug disposition properties of a single dose of doxorubicin and epirubicin and how these possible changes will affect the degree of cardiotoxicity of these drugs.

Molecular modeling, enzyme activity, anti-inflammatory and antiarthritic activities of newly synthesized quinazoline derivatives

AIM 16 thioxoquinazolines were evaluated in vivo for anti-inflammatory activity using carrageenan-induced paw edema assay. RESULTS In particular, out of the targets (1-16), compounds 4 and 6 displayed the highest anti-inflammatory activity (≥80%) and furtherly tested against complete Freunds adjuvant-induced arthritic rats. Significant reduction in the serum level of IL-1β, COX-2 and prostaglandin E2 in the complete Freunds adjuvant rats is demonstrated by compounds 4 and 6. Furthermore, compound 4 showed non-selective activity against COX-1 and COX 2, however, compound 6 was specific toward COX-2. Molecular docking study has demonstrated the possible binding modes of the active quinazolines 4 and 6 in the COX-2 active site. CONCLUSION These targets could be used as templates for further development of new derivatives with potent anti-inflammatory activity.

Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis.

Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.

Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives

The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure–activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity against rheumatoid arthritis. The obtained results indicate promising anti-arthritic activity for compounds 9 and 15 as significant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats.

Study on Social Isolation as a Risk Factor in Development of AlzheimerâÂÂs Disease in Rats

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that leads to memory loss. It is characterized by deposition of Beta-amyloid peptides (Aβ), accumulation of neurofibrillary tangles and cell loss. Social isolation may exacerbate memory deficits. The risk of cognitive decline and the onset of AD may be lower by maintaining social connections and keeping mentally active. The relationship between frequent social activity and enhancing cognitive functions has been established. Objective: Study the influence of complete social isolation for a long period on biochemical and histopathological changes as well as DNA fragmentation in the brain of normal rats. In addition, investigate the possible interaction between social isolation and development of AD using isolation-associated AD rat model. Methods: Four groups of rats were used; 2 groups socialized and 2 isolated for four weeks. One of each socialized and isolated groups were served as control and the other served as AD groups and injected by ALCl3 (70 mg/kg, IP) every day during four weeks of isolation or socialization. Isolated rats were housed individually in cages covered with black plastic while socialized rats were randomly paired and housed in transparent covered cages. Biochemical changes in the brain as acetyl cholinesterase (ACHE), Aβ, brain derived neurotrophic factor (BDNF), monoamins (Dopamine, Serotonin, Norepinephrine), inflammatory mediators (TNF-α, IL-1β), oxidative parameters (MDA, SOD, TAC) and DNA fragmentation were estimated for all groups. Histopathological changes in the brain were also evaluated. Results: Complete social isolation for a long period resulted in brain neurological damage indicated by significant increase in Aβ, ACHE, MDA, TNF-α, IL-1β as well as decreases in SOD, TAC, BDNF, and monoamines and confirmed by histopathological changes in different brain regions. Brain neurological damage was more severe in isolation-associated AD than in socialized condition. Isolation also enhanced the DNA fragmentation induced by AD. Conclusion: Complete social isolation for a long period induces brain neuronal degenerations. It represents a risk factor especially when associated with AD; it increases DNA fragmentation and enhances the severity of AD development. Thus, socialization is advised especially with AD to avoid worsen or deterioration of the disease.

Comparative Study on the Influence of Vinpocetine Alone or in Combination with different drugs against Aluminum-induced Alzheimers disease in Rats

Neurosurg, an open access journal ISSN: 2471-9633 Statement of the Problem: Neonatal encephalopathy (NE), a clinically defined syndrome of disturbed neurologic function in new born babies, is a serious public health concern. This condition often results in serious health consequences including death, cerebral palsy, developmental delay and seizure disorder. However, the underlying causes of NE are often poorly understood, and its treatment is primarily focused on the management of its risk factors. The purpose of the study was to identify intrapartum risk factors that influence the occurrence of neonatal encephalopathy at Yaounde Gynaeco-Obstetric and Pediatric Hospital.The present study was designed to study anxiolytic property of aqueous extracts of Mercurialis annua, an important and commonly used medicinal plant for its medicinal properties. The anxiolytic activity was evaluated in adult mice by hole board test and light/dark box test and motor coordination by rotarod test. The efficacy of the plant extract (100 - 600 mg/kg) was compared with the standard anxiolytic drug diazepam (1 mg/kg). The extract increased the time spent in the brightly lit chamber of the light/dark box, as well as in the number of times the animal crossed from one compartment to the other. Performance on the rotarod was unaffected. In the hole board test, the extract significantly increased head dip counts. Mercurialis annua, in contrast to diazepam, had no effect on locomotion. These results provide support for anxiolytic activity of Mercurialis annua, in line with its traditional medical use, and may also suggest a better side effect profile of Mercurialis annua relative to diazepam.

The Role of Mental and Physical Activities against Development of Alzheimer âÂÂs Disease in Socialized and Isolated Rats

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder; lifestyle changes may slow its onset. Mental and physical activities have been related to better cognitive function in older adults. Cognitive engagement and physical activities have been associated with decreased risk of AD. Social isolation refers to a complete absence of or insufficient contact with other members of society and can exacerbate memory deficits. Objective: To study the influence of mental and physical activities in normal socialized conditions as well as to evaluate their role in social isolated conditions on normal and AD rat models. Methods: Rats were divided into two main groups; Group I socialized and Group II isolated. Both socialized and isolated groups were subdivided into four subgroups; two received saline and served as control, while two served as AD subgroups and received ALCl3 (70 mg/kg IP) every day for four weeks. One of the control and AD subgroups was exposed to mental and physical activities but the other not exposed. Mental and physical activities were performed using Swimming test and Y-maze (each for one time/week) during four weeks. Isolated rats were housed individually in cages covered with black plastic while socialized rats randomly paired and housed in transparent covered cages. Histopathological changes in different brain regions and biochemical changes in Aβ, ACHE, brain monoamins (DA, NE, 5-HT), inflammatory mediators (TNF-α, IL-1β), oxidative parameters; (MDA, SOD, TAC) as well as brain derived neurotrophic factor (BDNF) were also measured for all groups. Results: Brain neurological damage characterizing isolation was more pronounced in isolation-associated AD rats. Mental and physical activities significantly decreased Aβ, ACHE, MDA, TNF-α, IL-1β together with increased SOD, TAC, DA, NE, 5-HT and BDNF. The protective effect of mental and physical activities against brain neuronal degenerations was more marked in isolated rats especially in isolated-associated AD rats. These results were confirmed by histopathological examinations of different brain regions. Conclusion: Mental and physical activities can protect from brain neuronal degenerations either induced by isolation or that associated with AD in both socialized and isolated rat models. The protection using mental and physical activities is more pronounced in isolation-associated AD model.