Zinc oxide-Ulva lactuca nanocomposite is a robust dietary immunostimulant in the red swamp crayfish (Procambarus clarkii).

Aquaculture industry suffers significant limitations such as low resistance to diseases and expensive feed. This study investigated the antibacterial and immunostimulatory activities of ZnO-Ulva lactuca nanocomposite (ZnO-Ul NC) in the Procambarus clarkii. Zinc oxide nanoparticles (ZnO NPs) and ZnO-Ul NC were synthetized and characterized by electron microscopies as well as Fourier transform infrared spectroscopy. ZnO NPs and ZnO-Ul NC inhibited the growth of the isolated species Citrobacter freundii and Enterobacter hormaechei. For immunostimulatory evaluation, six crayfish groups (control, U. lactuca, ZnO L, ZnO H, ZnO-Ul L, and ZnO-Ul H) were fed on commercial diet, Ulva lactuca powder, and low or high dose of ZnO NPs or ZnO-Ul NCs, respectively for 90 days. The highest levels of total hemocyte count, granular cells%, phenoloxidase (PO) activity in hemolymph, and NO, superoxide dismutase (SOD), and GSH in hepatopancreas were all reported in the ZnO-Ul groups. The expression of proPO, SOD, and lysozyme exhibited the highest upregulation in the ZnO-Ul H group. Taken together, dietary ZnO-Ul NC significantly improved the non-specific immunity and antioxidant milieu of the crayfish at the genomic and proteomic levels. ZnO-Ul NC is cost effective, easily synthesized, and a promising immunostimulant for Procambarus clarkii that could be used in the aquaculture.

Zinc Oxide Nanoparticles Induced Testicular Toxicity Through Inflammation and Reducing Testosterone and Cell Viability in Adult Male Rats.

Zinc oxide nanoparticles (ZnO NPs) have wide applications in daily life. Therefore, there is growing interest in the potential harmful impacts of these particles on human health. The present study was conducted to investigate the potential toxic effects of ZnO NPs (40 and 70 nm) compared to ZnO on the testes of rats. ZnO NPs were synthesized and characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). Adult male rats were randomly divided into four groups (n = 8): Group I (control), Group II (ZnO) received daily oral administration of ZnO (50 mg/kg), and Groups III and IV received daily oral administration of ZnO NPs of 40 nm or 70 nm at 50 mg/kg, respectively. All treatments continued for 50 consecutive days. ZnO and ZnO NPs reduced body and testis weights, sperm count and motility, serum luteinizing hormone (LH) and testosterone levels, testicular cytochrome p450 17A1 (CYP17A1) and cytochrome p450 1B1 (CYP1B1) concentrations, and the expression of p53 and cdk1. These treatments elevated testicular myeloperoxidase and serum acid phosphatase activities as well as sperm abnormalities. ZnO NPs reduced LH levels, which decreased CYP17A1 and CYP1B1, resulting in reduced synthesis of testosterone. ZnO NPs enhanced testicular inflammation and reduced cell viability. All these effects were manifested as reduced sperm motility and increased sperm deformities. Compared to macromolecules, nanoparticles exhibited significantly higher toxicity. The larger diameter ZnO NPs had more profound toxicity than the smaller-sized particles.

Taurine and enzymatically modified isoquercitrin protected against methotrexate-induced deteriorations in the conductivity and rhythmicity of the heart in rats: Antioxidant, anti-inflammatory, and histological architecture approach.

Cardiotoxicity is one of the most devastating complications of cancer treatment by methotrexate (MTX). The present study aimed to investigate the potential anti-cardiotoxic efficacy of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ) alone or combined against MTX-induced cardiotoxicity in adult male rats. A total of 36 rats were randomly divided into six groups (six animals each): control, MTX (a single i.p. dose of 20 mg/kg), EMIQ + MTX (26 mg/kg of EMIQ, p.o. for 16 days), Tau + MTX (500 mg/kg of Tau, p.o. for 16 days), EMIQ + Tau + MTX at the same previous doses, and (EMIQ + Tau)½ + MTX. MTX reduced the percentage of body weight change, the expression of dihydrofolate reductase (DHFR) and folypolyglutamyl synthetase (FPGS), the cleaved tumor necrosis factor alpha (TNF-α) level in the cardiac tissue, and the elevated serum TNF-α level. MTX extensively deteriorated the electrocardiography (ECG), inducing tachycardia with shortening of the time intervals between successive heartbeats (R-R interval), associated with elongation of ventricular depolarization (QRS interval), and the corrected total time for ventricular de- and repolarization (QTc) duration. Treatment with MTX resulted in a significant reduction in atrial depolarization (P amplitude) and rapid repolarization (T amplitude) and a significant elevation in plateau phase (ST height). MTX treatment resulted in swelling of cardiomyocytes with extensive vacuolization of sarcoplasm with numerous variably sized vacuoles in addition to apoptotic cells. Tau and EMIQ protected against MTX-induced deteriorations in the conductivity and rhythmicity of the heart through antioxidative, anti-inflammatory, and antiapoptotic activities. Treatment with tau and EMIQ combined at high or low doses offered superior protection to the heart than using each agent alone.

Therapeutic effects of a new bithiophene against aluminum -induced Alzheimer's disease in a rat model: Pathological and ultrastructural approach.

Alzheimer's disease (AD) remains of unknown etiology and lacks a cure. This study aimed to evaluate the therapeutic potential of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. Adult male rats (Rattus norvegicus) were divided into six groups (n=6): Group one consisted of naïve animals, group two received bithiophene (1 mg/kg) every other day for 30 days, and groups 3-6 were subjected to AlCl3 (100 mg/kg, equivalent to 20.23 mg Al3+) for 45 consecutive days. Groups four and five received low (0.5 mg/kg) or high (1 mg/kg) doses of bithiophene, respectively. Group six received memantine (20 mg/kg) daily for 30 days. All treatments were administered orally. Aluminum exposure resulted in severe degeneration of both histological and ultrastructural aspects of cells. Administration of the low dose of bithiophene significantly restored the number of CA1 pyramidal cells and the thickness of the stratum granulosum of the dentate gyrus. However, the high dose of bithiophene increased viable CA1 pyramidal cell numbers significantly without restoring the thickness of the stratum granulosum or reducing vacuolization or pyknotic changes. The low dose of bithiophene restored the normal histological and cytological structure of both cortical and hippocampal neurons affected by dementia. Further investigation is required to explore the molecular mechanisms underlying the ameliorative effects on Alzheimer's disease-induced deteriorations in the cortex and hippocampus.

New bithiophene derivative attenuated Alzheimer's disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission.

BACKGROUND: One of the hypotheses that leads to an increased incidence of Alzheimer's disease (AD) is the accumulation of aluminum in the brain's frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. METHODOLOGY: Adult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3-6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. MAIN FINDINGS: Al disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-ß plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. CONCLUSION: Taking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-ß plaques and phosphorylation of tau.

Azafuramidines as potential anticancer Agents: Pro-apoptotic profile and cell cycle arrest.

The current study aimed to test the antiproliferative activity of three azafuramidines (X, Y, and Z) against three different human cell lines; liver HepG2, breast MCF-7, and bone U2OS. And to explore the molecular mechanism(s) of the antiproliferative activity of these derivatives. The three new azafuramidines demonstrated a potent cytotoxicity at < 2 µM against the three cell lines investigated. The azafuramidines were highly selective with selectivity index âˆ¼ 47 - 61 folds indicating safety to the normal cells. In the scratch assay, azafuramidines significantly reduced the percentage of wound healing indicating ability to prevent or reduce metastasis. Derivatives X and Z arrested the HepG2 cells at S and G2/M phases detected by the flow cytometry. Derivatives X, Y, and Z elevated the apoptosis of HepG2 cells by âˆ¼ 71 %, 66 %, and 59 %, respectively. Derivatives X and Z were superior to derivative Y. The potent antiproliferative, cell cycle arrest, and pro-apoptotic efficacy of these chlorophenyl derivatives could be attributed to their ability of inducing the overexpression of p53, p21, and p27. These derivatives had the potential to act as anticancer agents and merit further investigations.

Quercetin and L-Arginine Ameliorated the Deleterious Effects of Copper Oxide Nanoparticles on the Liver of Mice Through Anti-inflammatory and Anti-apoptotic Pathways.

The widespread use and applications of copper oxide nanoparticles (CuO NPs) in daily life make human exposure to these particles inevitable. This study was carried out to investigate the deteriorations in hepatic and serum biochemical parameters induced by CuO NPs in adult male mice and the potential ameliorative effect of L-arginine and quercetin, either alone or in combination. Seventy adult male mice were equally allocated into seven groups: untreated group, L-arginine, quercetin, CuO NPs, arginine + CuO NPs, quercetin + CuO NPs, and quercetin + arginine + CuO NPs. Treating mice with CuO NPs resulted in bioaccumulation of copper in the liver and consequent liver injury as typified by elevation of serum ALT activity, reduction in the synthetic ability of the liver indicated by a decrease in the hepatic arginase activity, and serum total protein content. This copper accumulation increased oxidative stress, lipid peroxidation, inflammation, and apoptosis as manifested by elevation in malondialdehyde, nitric oxide, tumor necrosis factor-α, the expression level of caspase-3 and bax quantified by qPCR, and the activity of caspase-3, in addition to the reduction of superoxide dismutase activity. It also resulted in severe DNA fragmentation as assessed by Comet assay and significant pathological changes in the liver architecture. The study proved the efficiency of quercetin and L-arginine in mitigating CuO NPs-induced sub-chronic liver toxicity due to their antioxidant, anti-inflammatory, and anti-apoptotic properties; ability to inhibit DNA damage; and the potential as good metal chelators. The results of histopathological analysis confirmed the biochemical and molecular studies.

New 1,3,4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile.

A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N-(5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer agents. The chemical structures of these derivatives were fully elucidated using various spectral and elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 µM and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1 percent of cells probably through induction of necrosis. These results were confirmed by the annexin V-PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19 significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket. Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate Lipinski's rule of five. In silico studies showed that these derivatives have a low blood-brain barrier penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve as potential anticancer agents and merit further investigations.

miRNome of Child A hepatocellular carcinoma in Egyptian patients.

Introduction: Hepatocellular carcinoma (HCC) has different etiologies that contribute to its heterogeneity. In regards to the number of HCC patients, Egypt ranks third in Africa and fifteenth worldwide. Despite significant advancements in HCC diagnosis and treatment, the precise biology of the tumor is still not fully understood, which has a negative impact on patient outcomes. Methods: Advances in next-generation sequencing (NGS) have increased our knowledge of the molecular complexity of HCC. Results & discussion: In this research, 16 HCC and 6 tumor adjacent tissues (control) of Child A Egyptian patients were successfully profiled for the expression profile of miRNAs by NGS. Forty-one differentially expressed miRNAs (DEMs) were found by differential expression analysis, with 31 being upregulated and 10 being downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then conducted on these differentially expressed miRNAs revealing that Sensitivity and specificity analysis showed that hsa-miR-4488, hsa-miR-3178, and hsa-miR-3182 were unique miRNAs as they are expressed in HCC tissues only. These miRNAs were all highly involved in AMPK signaling pathways. However, hsa-miR-214-3p was expressed in control tissues about eight times higher than in cancer tissues and was most abundant in "pathways in cancer and PI3K-Akt signaling pathway" KEGG terms. As promising HCC diagnostic markers, we here suggest hsa-miR-4488, hsa-miR-3178, hsa-miR-3182, and hsa-miR-214-3p. We further urge future research to confirm these markers' diagnostic and prognostic potential as well as their roles in the pathophysiology of HCC.

1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, a natural product as a potential inhibitor of COVID-19: Extraction, crystal structure, and virtual screening approach.

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C15H24O2, have been probed by a Cremer-Pople puckering analysis. C-H···O hydrogen bonds generate chains in the crystal that stretch along the c-axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of -12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2.

New thiophene derivative augments the antitumor activity of γ-irradiation against colorectal cancer in mice via anti-inflammatory and pro-apoptotic pathways.

BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer worldwide and the second cause of cancer-related deaths. It usually starts as an inflammation that progresses to adenocarcinoma. The goal of the present study was to investigate the antitumor efficacy of a new thiophene derivative against CRC in mice and explore the possible associated molecular pathways. The potential of this thiophene derivative to sensitize the CRC tumor tissue to a low dose of gamma irradiation was also investigated. METHODS: Adult male mice were divided into seven groups; control, group treated with dimethylhydrazine (DMH) for the induction of CRC. The DMH-group was further divided into six groups and treated with either cisplatin, thiophene derivative, γ-irradiation, cisplatin + γ-irradiation, thiophene derivative + γ-irradiation, or left untreated. RESULTS: DMH induced CRC as evidenced by the macroscopic examination of colon tissues and histopathology, and elevated the activities of cyclooxygenase2 (COX2) and nitric oxide synthase (iNOS). DMH also elevated kirsten rat sarcoma (KRAS) and downregulated the peroxisome proliferator activated receptor (PPARγ) as shown by RT-PCR and Western blotting. DMH exerted anti-apoptotic activity by reducing the expression of phosphorylated p53 and cleaved caspase3 at the gene and protein levels. The flow cytometry analysis showed that DMH elevated the necrosis and reduced the apoptosis compared to the other groups. The colon tissue from DMH-treated mice showed hyperplasia, aberrant crypt foci, loss of cell polarity, typical CRC of grade 4 with lymphocytes and macrophages infiltrating mucosa, muscularis mucosa, and submucosa score 3. Treatment with thiophene derivative or γ-irradiation ameliorated most of these deleterious effects of DMH. The concomitant action of thiophene derivative + γ-irradiation was typified by the better amelioration of tumor incidence and multiplicity, iNOS, PPARγ, p53, caspase 3, and histopathology of colon. CONCLUSION: Taken together, the new thiophene derivative is a promising therapeutic candidate for treatment of colorectal cancer in mice. It also sensitizes the CRC tumor to the ionizing radiation through anti-inflammatory and pro-apoptotic pathways.

New fluorobenzamidine exerts antitumor activity against breast cancer in mice via pro-apoptotic activity.

BACKGROUND: Breast cancer is one of the leading causes of cancer-related morbidities. The present study aimed to evaluate the efficacy of bithiophene-fluorobenzamidine (BFB) against breast cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) in female Swiss mice and reveal the underlining mechanisms. METHODS: The mice were randomly divided into five groups; control, BFB-treated group, DMBA-treated group, and the last two groups received DMBA then tamoxifen or BFB. RESULTS: BFB reduced the tumor incidence by ~ 88% versus 30% after TAM. DMBA significantly increased the expression of CDK1 and HER2 and reduced the expression of p53, p21 (CDKN1A), ESR-α, and CAS3. BFB caused significant down-regulation of CDK1 and HER2 and upregulation of p53, p21, ESR-α, and CAS3. In the DMBA-treated mice, cancerous cells metastasized to several organs. This was prevented by the administration of BFB. The antimetastatic and proapoptotic activities were confirmed in MCF7 cells in vitro by the wound healing and annexin V assays, respectively. Kaplan-Meier analysis showed that the BFB increased survival. In the DMBA group, tumors showed invasive carcinoma of grade III with central necrosis, polymorphism, mitotic activity, and numerous newly formed ductules, and colloidal mucinous secretions within adenoid cysts. BFB administration restored the normal structure of the mammary glands. CONCLUSION: Taken together, BFB has antitumor, pro-apoptotic, and anti-metastatic activities against breast cancer in mice and therefore, it merits further investigations.

Synthesis of new thienylnicotinamidines: Proapoptotic profile and cell cycle arrest of HepG2 cells.

Fourteen new thienylnicotinamidines and their analogs 5a-5k, 12, 13a, and 13b were prepared and their antiproliferative potential was evaluated against the growth of 60 cancer cell lines. The tested compounds had a strong antiproliferative efficacy against almost all cancer cell lines, with the average GI50 at ~2.20 µM. The effect of the thienylnicotinamidines on the growth of normal lung fibroblast cells (WI-38) indicated that these derivatives are safe to the normal cells. The selectivity index (SI) ranges from 5.5- to 42.0-fold. The conceivable mechanisms of action of the effective compounds 5d, 5f, 5g, 5i, 5j, and 5k with high SI were investigated. Although the thienylnicotinamidines are similar in structure, they could be divided into three groups as per their effects on gene expression: The first group (5d and 5f) elevated p53 and caspase 3 expression, the second group (5g and 5i) elevated p53 expression, and the last group (5j and 5k) elevated p53 and reduced topoII expression. Many thienylnicotinamides inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) in cell lysates at concentrations comparable to or better than pazopanib. The data of caspase 3 expression were confirmed by measuring the protein level by Western blot and the activity of the cleaved active enzyme. The ability to arrest the cell cycle and induce apoptosis was confirmed by flow cytometry. Taken together, two derivatives, 5d and 5f, with a distinctive VEGFR-2 inhibitory activity and a proapoptotic and cell cycle arrest profile merit further investigations.

Novel Azine Linked Hybrids of 2-Indolinone and Thiazolodinone Scaffolds as CDK2 Inhibitors with Potential Anticancer Activity: In Silico Design, Synthesis, Biological, Molecular Dynamics and Binding Free Energy Studies.

Molecular hybrid of 2-indolinone-thiazolidinone is a well known scaffold for variable biological activities including anticancer activity. Accordingly, in the current work aided with structure-based molecular modeling studies, a library of novel twenty-six hybrids, 4(a-z), was designed and synthesized. Docking studies in the active site of CDK2, one of the key checkpoints enzymes, revealed that the binding scores of the designed molecules are comparable to the reference enzyme's inhibitors Sunitinib, Nintedanib, and Semaxanib. Variable antiproliferative activities are shown for these molecules against human liver (HepG2), breast (MCF7), and colon (HCT-29) cell lines considering Doxrubacin as a refrence drug. Compared to cytotoxic activities on the normal fibroblasts (WI-38), the tested molecules had better selectivity against the cancerous cells, expressed by their selectivity index (SI), than Doxrubacin and compound 4i was the safest compound. CDK2 inhibitory results of compounds 4f, 4g, 4h, and 4w showed IC50 at 59.43, 143.6, 27.42, and 61.63 nM respectively, while that of Sunitinib was 23.8 nM. To clarify the obtained biological activities of these molecules, broad docking and molecular dynamic simulations studies were undertaken and confirmed the consistency between the computational and the in vitro CDK2 inhibitory activities. Furthermore, in silico ADME/Tox profiles were done for the most active molecules using SwissADME and pkCSM-pharmacokinetics web-based methods predicted good pharmacokinetics, bioavailability, and toxicity profiles for the tested compounds.

miR-370 is better than miR-375 as a non-invasive diagnostic biomarker for pediatric acute myeloid leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by heterogeneity in phenotypic, genotypic, and clinical traits. miRNAs play an important role in pathogenesis and diagnosis of adult AML. Such information is not available about miRNA expression role in pediatric AML. OBJECTIVE: We aimed to investigate the expression of miR-370 and miR-375 as new diagnostic biomarkers to discriminate pediatric AML patients and to predict their roles in the disease molecular basis. METHODS: The expression of both miR-370 and miR-375 in peripheral blood (PB) of pediatric AML patients was assessed by QPCR; their impact for diagnosis was evaluated by ROC curve and their roles in pediatric AML development were predicted by bioinformatics analysis. RESULTS: The expression of miR-370 and miR-375 levels was significantly decreased in pediatric AML patients, suggesting them as tumor suppressor miRNAs as supported by bioinformatics analysis. miR-370 showed better potential and sensitivity toscreen pediatric AML patients and more significant correlation with AML risk than miR-375. This is the first study to report the positive correlation between both miR-370 and miR-375. CONCLUSION: miR-370 level in peripheral blood can serve as a potential non-invasive diagnostic biomarker and was significantly correlated with AML risk. We strongly recommend PB miRNAs as diagnostic biomarkers for pediatric AML.

N-Acetylcysteine and Safranal prevented the brain damage induced by hyperthyroidism in adult male rats.

Background: Hyperthyroidism is associated with impairment in the neurotransmission and severe tissue damage in the brain. The present study explored the potential deleterious effects of experimentally-induced hyperthyroidism on the neurotransmitters, oxidative homeostasis, apoptosis and DNA fragmentation in cerebral cortex, thalamus & hypothalamus, and hippocampus in rats.Methods and Results: The ameliorative effects of N-acetylcysteine (NAC; 50 mg/kg, oral) and safranal (50 mg/kg, intraperitoneal) against hyperthyroidism (L-T4 500 µg/kg, subcutaneous) were investigated. All treatments continued daily over three weeks. Hyperthyroidism was manifested by significant elevations in serum fT3 and fT4 levels and a decline in serum TSH level and body weight. It was also characterized by significant elevations in the levels of dopamine, serotonin, and 5-hydroxyindole acetic acid, and monoamine oxidase activity to varying degrees in the brain regions examined and a significant reduction in norepinephrine in hippocampus only. Hyperthyroidism resulted in a significant oxidative stress in brain typified by elevations in malondialdehyde and nitric oxide content and reductions in glutathione level and SOD and catalase activities. This led to elevations in Caspases 9 and 3 and a reduction in Bcl2 resulting in DNA damage and confirmed by the histopathology of brain tissue. The administration of NAC or safranal with L-T4 prevented these deleterious effects by reducing the oxidative load and improving the brain antioxidant status.Conclusions: Hyperthyroidism disrupted the neurotransmitters in the brain which aggravated the oxidative stress and resulted in apoptosis. N-Acetylcysteine and safranal prevented these deleterious effects by enhancing the poor antioxidant milieu of the brain.

The Antitumor Activity of Ginger against Colorectal Cancer Induced by Dimethylhydrazine in Rats.

BACKGROUND: Bowl or colorectal cancer (CRC) is the third most common type of cancer with about two million new cases every year. CRC is the second leading cause of cancer related mortalities. OBJECTIVE: The study aims to evaluate the anticancer activity of ethanolic Ginger Extract (GE) in HCT-116 colon cells and colorectal tumors induced by dimethylhydrazine (DMH). METHODS: The antiproliferative activity was measured by MTT assay and the gene expression was assessed by q-RTPCR. For the antitumor study, rats were divided into five groups in random; control, group two was orally treated with 300 mg/kg of GE for 21 weeks, group three was s.c. injected with DMH (20 mg/kg) for 9 weeks, and groups four and five were treated with DMH and then treated with cisplatin (2.5 mg/kg, i.p) or GE, respectively, for 21 weeks. RESULTS: GE had a significant antiproliferative activity with IC50~ 12.5 µg/ml. GE induced both extrinsic and intrinsic apoptotic pathways. GE induced the expression of FasL, TRAIL, p53, and caspase-8 and downregulated Bcl-2 and survivin genes. Treatment of rats with DMH resulted in 100% tumor incidence and 2.3 tumors/rat. DMH significantly elevated the serum ALT, urea, and creatinine and significantly decreased the body weight gain. DMH also caused significant reductions in the hepatic GSH level, and the activities of catalase, SOD, GST, and GR in the liver as well as the renal GSH content and γ-GT activity. The colon from rats insulted with DMH showed adenomatous polyps with polymorphism and mitosis. The mucosa and submucosa were infested with inflammatory cells while serosa and muscularis were devoid from these cells. However, the muscularis was infiltrated with cystic formation, anaplastic changes, and hemorrhage. GE was able to alleviate all the previous deleterious effects of DMH and it was superior to cisplatin in its ameliorative effects. It did so without eliciting hepatotoxicity or nephrotoxicity which were shown in the group treated with DMH and cisplatin. CONCLUSION: This study proved that the antitumor activity of GE against the DMH induced-CRC is superior to cisplatin. GE was also safer than cisplatin and did not elicit hepatotoxicity or nephrotoxicity. GE induced apoptosis and has carcinostatic activity.

Synthesis, Antiproliferative Activity, and Apoptotic Profile of New Derivatives from the Meta Stable Benzoxazinone Scaffold.

BACKGROUND: Cancer exerts a huge strain on the health system. The emerging resistance to the current chemotherapies demands the continuous development of new anticancer agents with lower cost, higher efficacy, and greater specificity. OBJECTIVE: This study aimed at developing selective small molecules as targeted anticancer agents. METHODS: The behavior of benzoxazinone 2 towards nitrogen nucleophiles, such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemicarbazide, was described. The behavior of the amino quinazolinone 3 towards carbon electrophiles and P2S5 was also investigated. The antiproliferative activity of 17 new benzoxazinone derivatives was examined against the growth of three human cancer cell lines; liver HepG2, breast MCF-7, and colon HCT-29, in addition to the normal human fibroblasts WI-38, and the selectivity index was calculated. The possible molecular pathways, such as the cell cycle and apoptosis, were investigated. RESULTS: Derivatives 3, 7, 8, 10, 13, and 15 had a significant (less than 10 µM) antiproliferative activity against the three cancer cell lines investigated. Derivative 7 showed the best antiproliferative profile comparable to that of doxorubicin. The selectivity index for all the effective derivatives ranged from ~5-12 folds, indicating high selectivity against the cancer cells. Derivative 15 caused ~ 7-fold and 8-fold inductions in the expression of p53 and caspase3, respectively. It also caused a ~ 60% reduction in the expression of both topoisomerase II (topoII) and cyclin-dependent kinase 1 (cdk1). Derivatives 3, 7, and 8 had a similar profile; ~ 6-8-fold increased in the expression of p53 and caspase3 but these compounds were devoid of any significant effect on the expression of topoII and cdk1. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression ofcaspase3, and more than 60% downregulation in the expression of topoII. The results of the gene expression of topoII and caspase3 were confirmed by the measurement of the topoII concentration and caspase3 activity in the HepG2 cells. CONCLUSION: Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing cdk1), preventing the DNA duplication (downregulating topo II), and inducing apoptosis (inducing p53 and caspase3). One common feature in all the six active derivatives is the presence of a free amino group. These compounds have merit for further investigations.

New N-(1,3,4-thiadiazol-2-yl)furan-2-carboxamide derivatives as potential inhibitors of the VEGFR-2.

The present study reports the synthesis and biological evaluation of a new series of novel N-(1,3,4-thiadiazol-2-yl)furan-2-carboxamide derivatives. The reactions were executed under both conventional and microwave irradiation conditions. An enhancement in the synthetic yields and rates was observed when the reactions were carried out under the microwave compared with the classical conditions. The structures of the products were ascertained by different analytical and spectral analyses. The antiproliferative activities were evaluated against three human epithelial cell lines; breast (MCF-7), colon (HCT-116), and prostate (PC-3) using MTT assay technique and doxorubicin was utilized as a reference drug. Besides, molecular docking studies were also performed and the vascular endothelial growth factor recptor-2 (VEGFR-2) was identified as a potential molecular target. Compounds 6, 7, 11a, 11b, 12, 14, and 16 showed promising antiproliferative activity against the three cancer cell lines investigated. Compounds 2 and 15b had significant antiproliferative activities against only colon and breast cells but not against the prostate cells. All the active antiproliferative compounds were highly selective. All the active antiproliferative compounds were good inhibitors of the VEGFR-2 at 7.4-11.5 nM compared with Pazopanib. Compound 7 with the most favorable orientation to the VEGFR-2 from the docking studies, was also the best inhibitor of the receptor. The antiproliferative activity of these compounds is in partial caused by their ability to inhibit the VEGFR-2 and since other molecular targets were not examined, other possibilities cannot be ruled out.