Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives.

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

Network pharmacology-based screening of active constituents of Avicennia marina and their clinical biochemistry related mechanism against breast cancer.

Breast cancer is the second major cause of cancer death in women globally. Avicennia marina is a medicinal plant that belongs to the family Acanthaceae and is known as grey or white mangrove. It has antioxidant, antiviral, anticancer, anti-inflammatory, and antibacterial activity in the treatment of various diseases including cancer. The goal of the study is to use a network pharmacology method to identify the potential phenomena of bioactive compounds of A. marina in the treatment of breast cancer and explore clinical biochemistry related aspects. A total of 74 active compounds of A. marina were retrieved from various databases as well as a literature review and collectively 429 targets of these compounds were identified by STITCH and Swiss Target Prediction databases. Breast cancer related 15606 potential targets were retrieved from the GeneCards database. A Venn diagram was drawn to find common key targets. To check the biological functions, the GO enrichment and KEGG pathways analysis of 171 key targets were performed through the DAVID database. To understand the interactions among key targets, Protein-protein interaction (PPI) studies were completed using the STRING database, and the Protein-Protein Interaction (PPI) network, as well as the compound-target-pathway network, was constructed using Cytoscape 3.9.0. Finally, molecular docking analysis of 5 hub genes named tumor protein 53 (TP53), catenin beta 1 (CTNNB1), interleukin 6 (IL6), tumor necrosis factor (TNF), and RAC-alpha serine/threonine protein kinases 1 (AKT1) with the active constituent of A. marina against breast cancer were performed. Additionally, a molecular docking study demonstrates that active drugs have a higher affinity for the target that may be used to decrease breast cancer. The molecular dynamic simulation analysis predicted the very stable behavior of docked complexes with no global structure deviations seen. The MMGBSA further supported strong intermolecular interactions with net energy values as; AKT1_Betulinic_acid (-20.97 kcal/mol), AKT1_Stigmasterol (-44.56 kcal/mol), TNF_Betulinic_acid (-28.68 kcal/mol) and TNF_Stigmastero (-29.47 kcal/mol).Communicated by Ramaswamy H. Sarma.

The role of hesperidin as a cardioprotective strategy against doxorubicin-induced cardiotoxicity: The antioxidant, anti-inflammatory, antiapoptotic, and cytoprotective potentials.

Background: Doxorubicin (DOX), an anthracycline antibiotic, is a powerful chemotherapeutic agent effective against multiple types of cancer, particularly lung, breast, bladder and hematologic neoplasia (lymphomas and leukemia). However, its therapeutic usage is restricted by its known cardiotoxicity, which is associated with the production of oxidative stress. Enhancing antioxidant capacity represents a promising approach to mitigate DOX-induced cardiotoxicity. Hesperidin (HES), a citrus bioflavonoid, possesses several pharmacological effects, such as anti-inflammatory and antioxidant characteristics. Aim: This study was designed to evaluate the cardiotoxicity of DOX and assess the possible cardioprotective role of HES. Methods: Groups of Wistar rats were either treated with DOX (4 mg/kg. bw., once a week for five consecutive weeks, intraperitoneally) or received co-treatment with HES (100 mg/kg. bw./day in distilled water, 5 days in a week for five consecutive weeks, administered orally). Heart and blood samples were obtained for histological, immunohistochemical, and biochemical assessments. Results: DOX administration resulted in severe cardiotoxicity, as evidenced by significant elevations in cardiac biomarkers, including Troponin I (CTnI), Creatine kinase (CK-Total), Creatine kinase isoenzyme-MB (CK-MB), lactate dehydrogenase (LDH), and Aspartate aminotransferase (AST). DOX also elevated pro-inflammatory cytokines, such as Interferon γ (IFN-γ), Interleukin 1ß (IL-1ß), and Tumor necrosis factor α (TNF-α). Furthermore, DOX-induced oxidative stress and substantially reduced the levels of antioxidant enzymes, including Glutathione peroxidase (GPX), Superoxide dismutase (SOD), and Catalase (CAT). Histopathologically, DOX caused severe Zenker's necrosis, cardiomyocyte disarray, sarcoplasmic vacuolizations, cardiomyocyte congestion, and inflammatory cell infiltration. Immunohistochemically, DOX exhibited extensive apoptosis, as indicated by strong positive immuno-localization against anti-caspase-3 antibody. In contrast, co-treatment with HES protected cardiac tissues against cardiotoxicity of DOX, as indicated by the amelioration of histological abnormalities and the normalization of biochemical values. Conclusion: We can conclude that DOX induces severe cardiotoxicity characterized by oxidative stress, inflammation, pathological alterations, and apoptosis. Co-treatment with HES demonstrates significant cardioprotective effects by virtue of its potent anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic characteristics.

Integrated molecular modeling and dynamics approaches revealed potential natural inhibitors of NF-κB transcription factor as breast cancer therapeutics.

Breast cancer is a silent killer malady among women and a serious economic burden in health care management. A case of breast cancer is diagnosed among women every 19 s, and every 74 s, a woman dies of breast cancer somewhere in the world. Despite the pop-up of progressive research, advanced treatment approaches, and preventive measures, breast cancer remains amplifying ailment. The nuclear factor kappa B (NF-κB) is a key transcription factor that links inflammation with cancer and is demonstrated as being involved in the tumorigenesis of breast cancer. The NF-κB transcription factor family in mammals consists of five proteins; c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52). The antitumor effect of NF-κB has also been explored in breast cancer, however, the actual treatment for breast cancer is yet to be discovered. This study is attributed to the identification of novel drug targets against breast cancer by targeting c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52) proteins. To identify the putative active compounds, a structure-based 3D pharmacophore model to the protein active site cavity was generated followed by virtual screening, molecular docking, and molecular dynamics (MD) simulation. Initially, a library of 45000 compounds were docked against the target protein and five compounds namely Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 were selected for further analysis. The relative binding affinity of Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 with NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel proteins were -6.8, -8, -7.0, -6.9, and -7.2 kcal/mol, respectively which remained stable throughout the simulations of 200 ns. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with breast cancer, but, experimental validation is needed to ensure their safety.Communicated by Ramaswamy H. Sarma.

A field study on the anthelmintic resistance of Parascaris spp. in Arab foals in the Riyadh region, Saudi Arabia.

BACKGROUND: In the last decade, Parascaris spp. resistance to anthelmintics has been recorded in many countries. In Saudi Arabia, there are limited data available on Parascaris spp. resistance to anthelmintics. OBJECTIVE: To determine the current status of ivermectin, abamectin and praziquantel combined, and fenbendazole resistance to Parascaris spp. in horses in Saudi Arabia. METHODS: Three hundred and forty-one foals from eleven different farms were examined by faecal egg count (FEC). The foals were all Arab horses aged 17.2 ± 4.5 (SD) months. Ivermectin (n = 46 foals), abamectin and praziquantel combined (n = 46), and fenbendazole (n = 46) were administered on day 0 and faeces were collected on day 14. The study comprised 41 untreated foals as controls. Animals that have FEC of ≥100 eggs per gram (EPG) were used to measure anthelmintic efficacy. Parascaris spp. populations were considered susceptible when faecal egg count reduction (FECR) was ≥95% associated with a lower 95% confidence limit (LCL) >90%, suspected resistant when FECR ≤90% or LCL <90% and resistant when FECR <90% and LCL <90%. RESULTS: Prevalence of Parascaris spp. infection was 53% (179/341 horses). Anthelmintic resistance to Parascaris spp. were highest following fenbendazole (55% of farms and 65% of foals) and to a lower extent following ivermectin or the combination of abamectin and praziquantel which comprised 27% of farms (and 46% of foals) and 18% of farms (and 10% of foals), respectively. CONCLUSION: These data indicate that anthelmintics-resistant Parascaris spp. populations are present on horse farms in Saudi Arabia.

Protective effect of grape seed extract against cadmium-induced testicular dysfunction.

Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)­induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2­4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi­quantitative RT­PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B­cell lymphoma 2­associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co­treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B­cell lymphoma 2­associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side­chain cleavage enzyme, cytochrome P450 17A1, 3ß­hydroxysteroid dehydrogenase (3ß­HSD), 17ß­HSD, androgen receptor, steroidogenic acute regulatory protein, and follicle­stimulating hormone receptor. GSE administration exhibited a stimulatory effect on steroidogenesis­associated enzymes, and co­treatment with GSE and CdCl2 normalized and upregulated the mRNA expression levels of these examined genes. This study concluded that GSE has beneficial protective effects against the deleterious effects of CdCl2 on the testis.

Translin and Trax differentially regulate telomere-associated transcript homeostasis.

Translin and Trax proteins are highly conserved nucleic acid binding proteins that have been implicated in RNA regulation in a range of biological processes including tRNA processing, RNA interference, microRNA degradation during oncogenesis, spermatogenesis and neuronal regulation. Here, we explore the function of this paralogue pair of proteins in the fission yeast. Using transcript analysis we demonstrate a reciprocal mechanism for control of telomere-associated transcripts. Mutation of tfx1+ (Trax) elevates transcript levels from silenced sub-telomeric regions of the genome, but not other silenced regions, such as the peri-centromeric heterochromatin. In the case of some sub-telomeric transcripts, but not all, this elevation is dependent on the Trax paralogue, Tsn1 (Translin). In a reciprocal fashion, Tsn1 (Translin) serves to repress levels of transcripts (TERRAs) from the telomeric repeats, whereas Tfx1 serves to maintain these elevated levels. This reveals a novel mechanism for the regulation of telomeric transcripts. We extend this to demonstrate that human Translin and Trax also control telomere-associated transcript levels in human cells in a telomere-specific fashion.