Complementary Medicine and Alternative Medicine             No Of Abstract is : 13  
Coordinator : Prof. Dr. Sahar El-Haggar
Faculty : Vice Dean of the College of Pharmacy for Community Service and Environmental Development
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  Rational use of drugs and pharmacoeconomics can be achieved by strategies for optimization of bioavailabilty of drugs, minimization of microbial resistance to antibiotics, drug therapy monitoring , traditional use and safety of herbal medicines, complementary natural remedies, improving the drug delivery systems and targeted immunotherapy, cancer nanotechnology & immunotherapy, new uses of old drugs, design to decrease adverse drug reactions and enhance drug action  
Effect of Educational Program regarding Hyperemesis Gravidarum on Nurses′ Performance and Women's Outcomes   
  Mona Mohamed Gomaa Abd Elaal 1, Fatma Ahmed abou Romia 2, Azza Fouad El-Adham3, and Alya Mohamed El-Refaey 4   
  Faculty of Nursing Tanta University   
Abstract: Hyperemesis gravidarum referes to prolonged and excessive nausea and vomiting resulting in undesirable maternal and fetal health outcomes, which require hospital admission and extensive medical and nursing care. So, there is an urgent need to increase nurses' performance regarding hyperemesis gravidarum. Aim: The present study aimed to determine the effect of educational program regarding hyperemesis gravidarum on nurses′ performance and women′s outcomes. Subjects and method: This study was conducted at antenatal units of obstetric departments of Tanta University hospital affiliated to Ministry of High Education, El-Menshawy hospital affiliated to Ministry of Health and Population and EL-Mabara hospital affiliated to Health Insurance. The study included all nurses (48 nurses) who are working in the previously mentioned settings, and 144 pregnant women diagnosed with hyperemesis gravidarum during the first trimester of their pregnancy. The studied pregnant women were divided randomly into 3 groups (48 women in each group) pre, immediately post and three months post implementation of the educational program. Three tools were used to collect the data of this study: Tool I: Structured interview schedule for nurses and women, Tool II: An observational checklist for nurses′ practice, and Tool III: Women′s outcomes assessment sheet. Results: The studied nurses' knowledge and practice regarding hyperemesis gravidarum as well as women′s outcomes were improved immediately and three months post implementation of the educational program. Conclusion: The findings of the present study revealed significant improvement in the nurses' performance immediately and three months post implementation of the educational program regarding hyperemesis gravidarum. Recommendations: the study recommended developing continuous educational programs for nurses to enhance and update their performance regarding hyperemesis gravidarum.      

Fascia Lata Allograft versus Subepithelial Connective Tissue Grafts in the Peri-Implant Mucosal Thickness Enhancement (Histological Evaluation).   
  Mohamed H. Helal a, Hoda M. Elguindy a, Sahar F. Ghoraba a, Malak Y. Shoukheba a, Sarah Yasser b   
  Affiliation Mohamed H. Helal1, Hoda M. Elguindy2, Sahar F. Ghoraba3, Malak Y. Shoukheba4, Sarah Yasser5 1. Assistant Lecturer of Oral Medicine, Periodontology, Oral Diagnosis and Radiology Dep., Faculty of Dentistry, Tanta University, Egypt. DDS, MS, PHD Email: 2. Professor of Oral Medicine, Periodontology, Oral diagnosis and Radiology Department, Faculty of Dentistry, Tanta University, Egypt. DDS, MS, PHD. Email: 3. Professor of Oral Medicine, Periodontology, Oral diagnosis and Radiology Department, Faculty of Dentistry, Tanta University, Egypt. DDS, MS, PHD. Email: 4. Professor of Oral Medicine, Periodontology, Oral diagnosis and Radiology Department, Faculty of Dentistry, Tanta University, Egypt. DDS, MS, PHD. Email: 5. Ass. professor of Oral Biology, Faculty of Dentistry, Tanta University, Egypt. DDS, MS, PHD. Email: 0000-0001-6098-4812   
Abstract Purpose: the current study was conducted to evaluate the effect Subepithelial Connective Tissue Grafts SCTGs versus Fascia Lata Allograft FLA in increasing the peri- implant mucosal thickness when placed simultaneously with dental implant histologically and histomorphometrically in human. Materials and Methods: A total of sixteen patients who met the inclusion criteria were selected to be included in this study. They were randomly classified into two treatment groups: a control group (SCTGs), and the test group (FLA); with eight implantation sites in each group. Three months after implantation, the augmented sites were located, soft tissue biopsies(n=16) (punch biopsy) were collected for histological and histomorphometry analysis. Results: Both grafts were integrated well into the surrounding soft tissues. Regarding percentage of fibro vascular tissues (FVT) at 3 months post-surgery showed a significant increase in FLA graft in comparison with SCTGs it was (36.52 in the FLA group and 24.17 in the SCTGs group). A significant difference in the vimentin expression percentage in favor of FLA grafts in comparison with SCTGs; it was (24.95% for FLA) where it was (7.24% for SCTGs). Conclusions: FLA was found to be clinically save with no adverse reactions and integrated well into the surrounding soft tissues and organized by newly formed connective tissue, and provided results are comparable to SCTGs (the gold standard). Keywords: Subepithelial Connective Tissue Grafts, Fascia Lata Allograft, Peri-Implant Mucosal Thickness, gingival biotype.      

In vivo anti-tumor effect of the Egyptian Scorpion Leiurus quinquestriatus venom in Ehrlich ascites carcinoma bearing mice   
  Wesam M Salama1,*, Sabry Ali El-Naggar1 ,and Barakat M. ALRashdi2   
  1Zoology Department, Faculty of Science, Tanta University, Egypt. 2Biology Department, College of Science, Jouf University, Sakaka, Saudi Arabia   
The current study addressed the anti-tumor effects of the Leiurus quinquestriatus venom (LQV) in Ehrlich ascitic carcinoma (EAC) bearing mice. Methodes:Thirty-two CD1 female albino mice were used and divided into four groups equally. Group 1 (Gp1) was served as a negative control. Groups 2, 3, and 4 were inoculated with 1 x 106 EAC cells/mouse intraperitoneal (i.p.); Gp2 was served as untreated EAC-bearing mice. After 24 h, Gp3 and Gp4 were injected with cisplatin (Cis) (2mg/kg) and LQV (0.025mg/kg) i.p., respectively, for 7 days. Post 14 days of EAC inoculation, body weight changes, tumor profile, hematological parameters, liver, kidney functions, and antioxidant biomarkers were determined. Results: The treatment of EAC-bearing mice with LQV was associated with decreased tumor volume (P< 0.05) and viable tumor cells compared to untreated EAC bearing mice. The results reported that the treatment of EAC-bearing mice with LQV induced necrosis, apoptosis of EAC-cells, and arrest them in G0 and S-phases. RT-PCR analysis showed that LQV treatment upregulated the apoptotic genes Bax and caspase-3 expressions, and down-regulated the anti-apoptotic gene, bcl-2 expression , in EAC cells.      

New insights into arsenic, lead, and iron neurotoxicity: Activation of MAPK signaling pathway and oxidative stress   
  Naglaa F. Khedr*, Ola F. A. Talkan**   
  *Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt **Chemistry Department, Animal Health Research Institute‐Shiben El‐Kom Lab., Agriculture Research Center, Menofia, Shiben El‐Kom, Egypt   
Toxic metals cause neurodegeneration via formation of toxic complexes with the cellular compounds and production of highly reactive oxygen species. The present study aimed to investigate the role of mitogen‐activated protein kinase (MAPK) signaling pathway in iron, lead, and arsenic induced neurotoxicity. Also, to explore their effect on brain enzymes, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF‐κB) in rat brains. Rats were divided into four groups (n = 8): Control group, lead group (30 mg/kg lead acetate), arsenic group (5 mg/kg sodium arsenite), and iron group (100 mg/kg ferric hydroxide). Treatments were given three times/ week orally for 2 months. Brain tissues were assessed for reduced glutathione and malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), alkaline phosphatase (ALP), acid phosphatase (ACP), Na+ /K+ activated adenosine 5′‐triphosphatase (Na+ /K+ ‐ATPase) and acetylcholinesterase (AChE) activities, expression of iNOS and NF‐κB, and Western blot analysis of c‐Jun NH(2)‐terminal kinase (JNK) and extracellular signal‐regulated protein kinase (ERK) proteins. Levels of arsenic, iron, and lead were significantly (p = 0.000) increased in blood and brain tissues. Levels of MDA, SOD, CAT, iNOS, and NF‐κB gene expression, phosphorylated JNK and phosphorylated ERK proteins were increased significantly in lead, arsenic, and iron treated rat groups compared to control. ALP, ACP, AChE, and ATPase activities in brain were significantly altered in metal‐treated rat groups compared to control. Iron, lead, and arsenic induced neurotoxicity activated the pro‐ inflammatory mediators NF‐κB, iNOS, and MAPK pathway and altered the activity of brain ALP, ACP, Na+      

Antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis   
  Tarek Mohamed Mostafa1 · Sahar Kamal Hegazy1 · Salwa El‑morsy Abd El‑Ghany2 · Fedaa Abd El‑Monem Kotkata1   
  1 Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt 2 Rheumatology & Rehabilitation Department, Faculty of Medicine, Tanta University, Tanta, Egypt.   
Purpose: This study aimed at Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA). Methods: From December 2018 to December 2019, 75 patients with RA were enrolled in this randomized parallel controlled study. The patients were randomized into three groups (n=25 in each group); methotrexate (MTX) group which received MTX 15-25 mg/week subcutaneous (Control group); MTX/RUP group which received MTX plus RUP 10 mg once daily and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was three months. At baseline and three months after treatment, blood samples were collected for biochemical analysis of high sensitivity C-reactive protein (hs-CRP), interleukins 8 & 17 (IL-8, IL-17), E-selectin and clusterin (CLU) levels. Clinical & functional assessments using disease activity score-CRP (DAS28-CRP) and multidimensional health assessment questionnaire (MDHAQ) were performed. Results: Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (p<0.05) except for IL-17 & clusterin. Montelukast significantly decreased all measured variables (p<0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 & clusterin (CLU), while hs-CRP was positively correlated with E-selectin & body mass index (BMI). Both drugs were well tolerated; somnolence was the most common side effect for RUP. No neuropsychiatric events were reported with MON.      

Blocking of The Prostaglandin E2 Receptor as a Therapeutic Strategy for Treatment of Breast Cancer: Promising Findings in a Mouse Model   
  Nahla E. EL-Ashmawy*, Enas A. EL-Zamarany**, Eman G. Khedr*, Hend M. Selim*, Naglaa F. Khedr   
  * Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31511 ** Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt. Postal code: 31511 Corresponding author: Hend Selim, E-mail: Address: Al Geesh Street, Medical Campus, Faculty of Pharmacy, Tanta University, Egypt. Postal code: 31511   
Objective: The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB)® in mice bearing solid Ehrlich carcinoma (SEC). Methods: The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and β 1 integrin. Results: Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and β1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. Conclusion: EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.      

Clinical Study Evaluating the Impact of Nitazoxanide on Portosystemic Encephalopathy Index   
  Khadija A.M. Glal1, Sherief M. Abd-Elsalam2, Tarek M. Mostafa1   
  1Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt 2Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt   
Aim: The study aimed at evaluating the safety and the efficacy of Nitazoxanide (NTZ) compared to Rifaximin (RFX) in preventing recurrence of HE and to assess its impact on QOL. Patients and Methods: This randomized, controlled study included sixty patients who were randomly assigned to receive either Rifaximin 550 mg twice daily (Group 1; n=30) or Nitazoxanide 500 mg twice daily (Group 2; n=30) for six months. All eligible patients underwent detailed physical, neurological, psychometric assessment with making note of their mental status and the severity of asterixis. Serum levels of ammonia, tumor necrosis factor-α (TNF-α), and octopamine (OPM), Model of End-Stage Liver Disease (MELD), Child-Pugh score, clinical hepatic encephalopathy staging score (CHESS) and chronic liver disease quality of life (CLDQ) score were assessed at baseline and six months after intervention. Furthermore, patients were followed-up every month at clinic and every two weeks by telephone to assess patients’ compliance, and to report any treatment related adverse events. Results: : Six-months after treatment, patients on NTZ therapy showed more enhanced remission from HE than those on RFX therapy. Furthermore, patients on NTZ drug showed a statistically significant decrease in serum level of ammonia, TNF-α and octopamine. Both groups showed a statistically significant reduction in CHESS. Regarding QOL, NTZ group showed an improvement in fatigue, worry, abdominal symptoms, activity domains, and total CLDQ score. Both groups were tolerated and showed mild and controllable side effects.      

Prevalence of SARS-CoV-2 Delta Variant B.1.617.2 among Covid-19 Egyptian Patients   
  Maisra M. El-Bouseary1, Thanaa A. El-Masry2, Reem Binsuwaidan3, Badriyah Alotaibi3, Mohamed G. Seadawy4, Bassem E. El-Harty4, Ahmed F. Gad4   
  1 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Tanta University, Tanta, Egypt 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt 3 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia 4 Biological Prevention Department, Egypt Army, Egypt   
In December 2019, a mysterious viral pneumonia first appeared in Wuhan, China, resulting in a huge number of fatal cases. This pneumonia, which was named coronavirus disease 2019 (COVID-19), was attributed to a novel coronavirus, SARS-CoV-2. The emerging SARS-CoV-2 mutations pose the greatest risk to human health because they could result in an increase in the severity of diseases or the failure of vaccines currently in development. One of these notable mutations is the SARS-CoV-2 Delta variant, known as B.1.617, which was first detected in India and has since spread to 115 countries worldwide. Consequently, in this study, we performed whole genome sequencing and phylogenetic analysis of SARS-COV-2 during the third wave of the pandemic to determine the prevalence of the SARS-CoV-2 Delta variant (B 1.617.2) in Egypt. We observed several mutational patterns, revealing that SARS-CoV-2 evolution has been expanded in Egypt with a significant increase in the number of variants of concern (VOC). Therefore, the Egyptian authorities must take all appropriate measures to investigate the compatibility of already employed vaccines with this VOC and to examine the efficacy of the existing treatment protocol against new SARS-CoV-2 variants.      

Modulatory Effect of Silymarin on Apoptosis in Testosterone -Induced Benign Prostatic Hyperplasia in Rats   
  Nahla E. El-Ashmawy, Eman G. Khedr, Hoda A. El-Bahrawy, Nada N. Helmy   
  Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527   
Background: Benign prostatic hyperplasia (BPH) is considered a normal part of the aging process in men and is characterized by an imbalance between cell proliferation and apoptosis. Our study aimed to investigate the potential protective role of silymarin (SIL) against testosterone-induced BPH in rats and to elucidate the molecular mechanisms underlying SIL pro-apoptotic and anti-proliferative effects. Methods: Forty adult male Wistar rats were divided equally into four groups: control group, BPH group (3 mg/kg testosterone propionate, s.c. for 14 days, SIL group (50 mg/kg SIL, orally, once daily concomitantly with 3 mg/kg testosterone propionate s.c.) and inhibitor group (50 mg/kg SIL orally concomitantly with 3 mg/kg testosterone, s.c. and 0.5 mg/rat Z-VAD-FMK, i.p.). Results: Silymarin induced caspase-dependent apoptosis in BPH as SIL significantly reduced prostatic Bcl-2 protein and increased Bax protein concentration. Also, SIL down-regulated survivin (Inhibitor of apoptosis protein (IAPs) gene expression assisting mainly caspase-dependent pathway. Silymarin significantly increased caspase 3 activity compared to BPH group. Silymarin significantly increased the content of p27/kip1 (Cyclin dependent kinase inhibitor (CDKIs) promoting cell cycle arrest. Conclusion: Silymarin showed a significant anti-proliferative and pro-apoptotic role in BPH and it could be effectively and safely used as a treatment tool in BPH or prostatic disorders.      

Tailoring Dexamethasone Loaded BSA/PEI NPs: A Full Factorial Design Approach Enhanced Anti-inflammatory Activity   
  Suleiman S. El Tokhya,c, Sanaa A. Elgizawya, Mohammed A. Osmana, Ahmed E. Godab and Larry D Unsworthc   
  a Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Egypt b Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Egypt c Department of Chemical and Material Engineering, Faculty of Engineering, Alberta University, Canada.   
Protein-based nanoparticles (NPs) are biodegradable, biocompatible, and easily amenable to chemical modifications to allow for the incorporation of bioactive compounds. In the current study, we adopted a full factorial design to optimize dexamethasone disodium phosphate (Dex) encapsulation within NPs formed with bovine serum albumin (BSA) and stabilized using polyethylenimine (PEI). The optimized NP size (<200 nm dia.), zeta potential (-23.3 mV), and entrapment efficiency (67.4%) were occurred at 0.652 mg, 0.04, 5%, and 8.3 for solution concentration of Dex, PEI/BSA molar ratio, BSA solution concentration, and solution pH, respectively. Incorporation of Dex resulted in a decrease in alpha helix content of BSA indicating a change in its secondary structure. Dex loaded NPs yielded a bimodal release of Dex over an extended period of time via a quasi-Fickian diffusion mechanism. The in vivo anti-inflammatory activity of BSA/PEI Dex NPs surpassed that of free Dex in carrageenan-induced hind paw edema in rats as evidenced by enhanced suppression of oxidative stress, abrogation of NF-κB-p65 expression, as well as reduced myositis and inflammatory cell infiltration. The extended-release profile of BSA/PEI Dex NPs is crucial for achieving a significantly significant anti-inflammatory activity.      

Clinical and Biochemical Study Evaluating the Effect of L-arginine and Sildenafil in Children with Beta Thalassemia Major Associated with High Tricuspid Regurgitant Jet Velocity   
  Tarek Mohamed Mostafa1, Sahar Mohamed El-Haggar1, Osama El- Razaky2, Mohamed Ramadan El-Shanshory2, Eman El-Khateeb1   
  1 Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta. Egypt 2 Paediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt   
Aim: We aimed at evaluating the possible clinical and biochemical effects of L-arginine and sildenafil in children with pulmonary hypertension. Method: This comparative, randomized parallel controlled clinical trial involved 60 children with β-thalassemia major and PHT. The participants were randomized into three groups; the control group (not received any new medication), L- arginine group (received 0.1 mg/kg/day oral L- arginine), and sildenafil group (received 0.25 mg/kg twice daily oral sildenafil) for two months. Biochemical assessment included the measurement of nitric oxide (NO), ferritin, interleukin- 1 β (IL-1β), E-selectin, asymmetric dimethylarginine (ADMA) and visfatin levels at baseline, one and two months after treatment along with evaluation of Tricuspid Regurgitation Jet Velocity (TRJV) using Doppler echocardiography. Results: Both L- arginine and sildenafil improved pulmonary hypertension (PHT) and reduced the TRJV. L-arginine significantly increased serum nitric oxide (NO) and reduced ADMA and visfatin levels after 2 months of therapy as compared to baseline data. Although, sildenafil did not show these significant changes, it prevented the gradual rise in IL-1β, and ADMA levels as compared to the control group. Both E-selectin and ferritin levels did not show any significant change among the three study groups. Significant negative correlations between nitric oxide (NO) and TRJV were observed in both L- arginine and sildenafil groups. Conclusion: Impaired nitric oxide pathway in children with β-thalassemia can be mitigated by L-arginine and sildenafil in order to ameliorate chronic pulmonary hypertension. Both interventions seem clinically useful; however, L-arginine was superior to sildenafil regarding its effect on the biochemical parameters.      

Identification, Propagation and Molecular Characterization of SARS-CoV-2 Delta Variant Isolated from Egyptian COVID-19 Patients   
  Thanaa A. El-Masry1, Badriyah Alotaibi2, Maisra M. El-Bouseary3, Mohamed G. Seadawy4, Bassem E. El-Harty4, Ahmed F. Gad4   
  Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt 2 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia 3 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Tanta University, Tanta, Egypt 4 Biological Prevention Depart Egypt Army, Egypt   
The etiologic agent of the coronavirus disease 2019 pandemic is the newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global disease has led to large numbers of cases and deaths, which emphasizes the urgent need to develop new therapeutic and preventive approaches to contain this pandemic. Recently, more than 285,000 cases and 16,500 deaths were confirmed in Egypt. In order to conduct virological and vaccine studies in Egypt, it is essential to isolate, propagate, and inactivate SARS-CoV-2 from Egyptian patients. Here, we isolated SARS-CoV-2 from oropharyngeal and nasopharyngeal swabs taken from Egyptian patients with COVID-19 symptoms. We used a specific RT-qPCR kit to identify positive specimens. The virus was propagated in Vero E6 cells, where replication and propagation were confirmed by RT-qPCR and the cytopathic effect (CPE). SARS-CoV-2 was completely inactivated chemically using beta propiolactone. The full genome of the propagated virus from some samples was sequenced and submitted to NCBI and GISAID. All sequenced viruses isolated in 2020 (n=18) have at least 99% identity to Wuhan-Hu-1. These variants were clade 20A and B.1 PANGO lineage. While, the sequenced viruses isolated in 2021 (n=2) were clade 21J and Delta (B.1.617.2-like) variant. The two isolates recovered in our study are considered the first recorded Delta variant in Egypt. This study provides a methodology reference for isolation, propagation and inactivation of SARS-CoV-2, and have aided in understanding of COVID-19 evolution and tracking mutational patterns in Egypt which is valuable for researchers working on vaccine development against SARS-CoV-2      

The mechanistic perspective of Bilobetin protective effects against cisplatin-induced testicular toxicity: Role of Nrf-2/Keap-1 signaling, inflammation, and apoptosis.   
  Walaa A. Negm 1,*, Aya H. El-Kadem 2,* Ismail A. Hussein 3 and Moneerah J. Alqahtani 4,5   
  1 Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt 3 Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy (Boys), Al‐Azhar University, Cairo 11884, (I.A.H.) 4. Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.J.A.) 5 Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, MS 38677, U.S.A   
Abstract: Cisplatin (CP) is a productive anti-tumor used to treat numerous tumors. However, multiple toxicities discourage prolonged use, especially toxicity on the reproductive system. This experiment was mapped out to determine the potential therapeutic impact of Bilobetin on CP‐induced testicular damage. Herein, Bilobetin was isolated from Cycas thouarsii leaves R. Br ethyl acetate fraction for the first time. A single dose of CP (7 mg/kg, IP) is used to evoke testicular toxicity on the third day. Rats were classified into five groups; Normal control, Bilobetin 12 mg/kg, Untreated CP, and CP treated with Bilobetin (6 and 12 mg/kg, respectively) orally daily for ten days. Bilobetin treatment ameliorated testicular injury. In addition, it boosted serum testosterone levels considerably and restored relative testicular weight. Nevertheless, apoptosis biomarkers such as P53, Cytochrome-C, and caspase-3 were decreased significantly. Additionally, it enhanced the testes' antioxidant status via activation of Nrf-2, inhibition of Keap-1, and significant elevation of SOD activity alongside reducing lipid peroxidation. Histopathologically, Bilobetin preserved testicular architecture and improved testicular immunostaining of Ki67 substantially, showing evidence of testicular regeneration. Bilobetin beneficial effects on CP-induced testicular damage are associated with enhancing antioxidant effects, lowering apoptotic signals, and restoring testes' regenerative capability. In addition, bilobetin may be used in combination with CP in treatment protocols to mitigate CP-induced testicular injury.      

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