Preparation and characterization of vitamin E/calcium/soy protein isolate nanoparticles for soybean milk beverage fortification.

Soybean milk is a rich plant-based source of protein, and phenolic compounds. This study compared the nutritional value of soybean milk, flour, soy protein isolate (SPI) and evaluated the impact of prepared vitamin E/calcium salt/soy protein isolate nanoparticles (ECSPI-NPs) on fortification of developed soybean milk formulations. Results indicated that soybean flour protein content was 40.50 g/100 g, that fulfills 81% of the daily requirement (DV%), the unsaturated fatty acids (USFs), oleic and linoleic content was 21.98 and 56.7%, respectively, of total fatty acids content. In soybean milk, essential amino acids, threonine, leucine, lysine achieved 92.70, 90.81, 77.42% of amino acid scores (AAS) requirement values respectively. Ferulic acid was the main phenolic compound in soybean flour, milk and SPI (508.74, 13.28, 491.78 µg/g). Due to the moisture content of soybean milk (88.50%) against (7.10%) in soybean flour, the latest showed higher nutrients concentrations. The prepared calcium (20 mM/10 g SPI) and vitamin E (100 mg/g SPI) nanoparticles (ECSPI-NPs) exhibited that they were effectively synthesized under transmission electron microscope (TEM), stability in the zeta sizer analysis and safety up to IC50 value (202 ug/mL) on vero cell line. ECSPI-NPs fortification (NECM) enhanced significantly phenolic content (149.49 mg/mL), taste (6.10), texture (6.70) and consumer overall acceptance (6.54). Obtained results encourage the application of the prepared ECSPI-NPs for further functional foods applications.

Autophagy and exosomes; inter-connected maestros in Alzheimer's disease.

Autophagy is a crucial process involved in the degradation and recycling of cytoplasmic components which are transported to the lysosomal compartment by autophagosomes. Exosomes are an important means of communication and signaling in both normal and diseased states, and they have a significant role in the transmission and propagation of proteins, especially proteins implicated in neurodegenerative disorders. Autophagy may affect exosomal processing, but whether autophagy controls the release of aggregated ß-amyloid and tau proteins in exosomes of Alzheimer disease (AD) is unclear. Therefore, our study aimed to investigate how modulating autophagy affects the exosomal release of these proteins in animal models of AD. Isolated exosomes from brain tissues of 48 male albino mice were divided into four groups (Negative control, LPS, rapamycin (RAPA), and chloroquine (CQ). LC3 I and LC3 II as well as Aß and Tau proteins levels were determined. All mice undergone Neuro-behavioral tests (Morris Water maze test, Y-maze test, and Novel Object Recognition). Both LPS and CQ groups showed reduced expression levels of LC3 II and LC3 II/LC3 I ratio. In contrast, RAPA group showed a significant increase in both LC3-II expression and LC3-II/LC3-I ratio. The levels of both Aß & Tau in exosomes of CQ & LPS groups were higher. While RAPA group showed a significant diminished levels of tau & Aß proteins. In conclusion, our findings suggest that autophagy alterations in AD can influence the release of Aß and tau proteins through exosomes, which may impact the spread of misfolded proteins in AD. These results highlight a potential innovative therapeutic approach for combating AD.

Bioactive metabolites identified from Aspergillus terreus derived from soil.

Aspergillus terreus has been reported to produce many bioactive metabolites that possess potential activities including anti-inflammatory, cytotoxic, and antimicrobial activities. In the present study, we report the isolation and identification of A. terreus from a collected soil sample. The metabolites existing in the microbial ethyl acetate extract were tentatively identified by HPLC/MS and chemically categorized into alkaloids, terpenoids, polyketides, γ-butyrolactones, quinones, and peptides. In addition, a new triglyceride (1) and a diketopiperazine derivative namely asterrine (4), together with two known butyrolactone (2-3) were purified from the extract. The chemical skeleton of the purified compounds was established by comprehensive analysis of their ESI/MS, 1 and 2D-NMR data. The extract and compounds 3,4 exhibited a strong inhibitory activity for the binding of ACE2 to SARS-CoV-2 spike-protein receptor with IC50 7.4, 9.5, and 8.5 µg/mL, respectively. In addition, the extract, 1 and 2 displayed a potent anti-inflammatory effect with IC50 51.31 and 37.25 pg/mL (Il-6) and 87.97, 68.22 pg/mL (TNF-α), respectively, in comparison to LPS control. In addition, the extract and compound 4 displayed an antimicrobial effect towards S. aureus by MIC 62.5 and 125 µg/mL, while the extract exhibited a potent effect against C. albicans (MIC of 125 µg/mL). Collectively, our data introduce novel bioactivities for the secondary metabolites produced by the terrestrial fungus Aspergillus terreus.

Extender Supplementation with Glutathione (GSH) and Taurine Improves In Vitro Sperm Quality and Antioxidant Status of New Zealand Rabbits during Chilled Storage for up to 72 hours.

This study assessed the influence of supplementing the rabbit semen extender with various concentrations of glutathione (GSH) and taurine at 24, 48, and 72 h postchilling at 5°C. Semen samples were collected from 20 New Zealand bucks, and ejaculates with standard color, motility (>85%), about 0.5 mL volume, and ∼400 × 106/mL concentration were used and diluted with extenders supplemented with 0.5, 1, and 2 mM of GSH and 1, 5, and 10 mM of taurine and chilled at 5°C. Nonsupplemented samples were used as a control. Sperm's progressive motility, acrosome reaction, and extracellular oxidative stress biomarkers such as MDA contents and GPx, SOD, and CAT concentrations and intracellular transcriptomic levels of SOD and CAT genes were assessed. GSH and taurine supplementation improved the sperm's kinetics by reducing cooling-associated stress, which was ascertained by lowering MDA concentration and increasing SOD, CAT, and GPx concentrations (P < 0.05). Increasing the levels of antioxidant enzymes in the extender was due to the increasing mRNA copies of the SOD and CAT genes (P < 0.05). Furthermore, GSH and taurine maintained the fructose levels in the extender and lowered the GPT levels, which implies sperm membrane stability is maintained through GSH and taurine supplementation. GSH and taurine supplementation to the extender had protective influences on the in vitro rabbit semen quality during chilled storage for up to 72 h, which were remarkable with increasing supplementation dose and cooling time at 5°C.

Zinc Oxide Nanoparticles (ZnO-NPs) Induce Cytotoxicity in the Zebrafish Olfactory Organs via Activating Oxidative Stress and Apoptosis at the Ultrastructure and Genetic Levels.

Nanotechnology has gained tremendous attention because of its crucial characteristics and wide biomedical applications. Although zinc oxide nanoparticles (ZnO-NPs) are involved in many industrial applications, researchers pay more attention to their toxic effects on living organisms. Since the olfactory epithelium is exposed to the external environment, it is considered the first organ affected by ZnO-NPs. Herein, we demonstrated the cytotoxic effect of ZnO-NPs on the olfactory organ of adult zebrafish after 60 days post-treatment. We opted for this period when fishes stop eating their diet from the aquarium, appear feeble, and cannot swim freely. Our study demonstrated that ZnO-NPs induced significant malformations of the olfactory rosettes at histological, ultrastructural, and genetic levels. At the ultrastructure level, the olfactory lamellae appeared collapsed, malformed, and twisted with signs of degeneration and loss of intercellular connections. In addition, ZnO-NPs harmed sensory receptor and ciliated cells, microvilli, rodlet, crypt, and Kappe cells, with hyper-activity of mucous secretion from goblet cells. At the genetic level, ZnO-NPs could activate the reactive oxygen species (ROS) synthesis expected by the down-regulation of mRNA expression for the antioxidant-related genes and up-regulation of DNA damage, cell growth arrest, and apoptosis. Interestingly, ZnO-NPs affected the odor sensation at 60 days post-treatment (60-dpt) more than at 30-dpt, severely damaging the olfactory epithelium and irreparably affecting the cellular repairing mechanisms. This induced a dramatically adverse effect on the cellular endoplasmic reticulum (ER), revealed by higher CHOP protein expression, that suppresses the antioxidant effect of Nrf2 and is followed by the induction of apoptosis via the up-regulation of Bax expression and down-regulation of Bcl-2 protein.

Corrigendum: Essential oils of Psidium cattleianum Sabine leaves and flowers: anti-inflammatory and cytotoxic activities.

[This corrects the article DOI: 10.3389/fchem.2023.1120432.].

Bladder preservation by neoadjuvant chemotherapy followed by concurrent chemoradiation for muscle-invasive bladder cancer.

Introduction: In Egypt, bladder cancer (BC) represents about 8.7% of cancers in both sexes. In Egyptian men, it accounts for over 30% of all cancers, which makes it the second most frequent cancer. The standard curative treatment for patients with muscle-invasive bladder cancer (MIBC) has been radical cystectomy (RC) with urinary diversion and pelvic lymphadenectomy. Concomitant chemoradiation therapy (CCRT) in MIBC appears to produce results that are comparable to those of RC. Material and methods: Between January 2018 and March 2021, 34 BC- diagnosed patients, who refused RC, were enrolled. They received transurethral resection of the bladder tumour (TURBT) followed by 3 cycles of neoadjuvant chemotherapy (NACT) with gemcitabine, cisplatin, and CCRT. Concomitant chemoradiation therapy with cisplatin, as a chemosensitizer, was administered to patients who experienced a complete response (CR) and a partial response (PR) ≥ 50%. Results: Following NACT, CCRT was given to 27 patients (79.45%) who had either a PR > 50% or CR. Seven patients (20.5%) showed PR below 50%, stable disease, or progressive disease; 4 of them underwent RC followed by postoperative radiation. The average follow-up period was 46 months (range: 6-52 months). Twenty-three patients (67.6%) were still alive at the last check-up. Disease-free survival and 3-year overall survival were 70.8% and 65.1%, respectively. Conclusions: Bladder preservation provides survival rates comparable to those of MIBC patients, but with a higher quality of life. The findings show good survival rates without metastasis; nevertheless, more multicentre trials with larger sample sizes and longer follow-up periods are required to confirm these findings.

Essential oils of Psidium cattleianum Sabine leaves and flowers: Anti-inflammatory and cytotoxic activities.

Introduction: Psidium cattleianum Sabine is a Brazilian native shrub cultivated for its edible fruit araçá (strawberry guava). P. cattleianum is recognized for health and food applications, although the essential oils (EOs) from the Egyptian inhabitant are not fully explored. The current study investigated the anti-inflammatory and cytotoxic activities of EOs from P. cattleianum leaves and flowers. Materials and methods: The EOs were obtained by three different methods viz; the conventional hydro-distillation, microwave assisted hydro-distillation, and supercritical fluid extraction, while their analysis was accomplished using GC/MS. The derived EOs were screened for their anti-inflammatory activity in the 5-lipoxygenase, COX-1, and COX-2 enzyme based assays, while the anticancer potential was deduced from MTT cytotoxic assay, cell cycle, and western blotting analysis. Results and discussion: Among other methods, supercritical fluid extraction offered the highest EO yield, 0.62% (leaves) and 1.4% (flowers). GC/MS identified ß-caryophyllene and α-humulene in both organs with high but variable percentages. The leaves demonstrated strong activity in inhibiting the 5-lipoxygenase enzyme (IC50 2.38), while the flowers, in inhibiting COX-2 (IC50 2.575). Moreover, the leaves showed potent, selective cytotoxicity to MCF-7 cells (IC50 5.32) via apoptosis by modulating the p53/Bax/Bcl2 axis. The deduced activities are possible due to the synergism between the volatile components that endorses P. cattleianum leaves' EOs in the management of breast cancer and inflammatory disorders.

Outcome of docetaxel in treatment of metastatic hormone-sensitive prostate cancer and correlation with hemoglobin, albumin, lymphocyte and platelets score.

Introduction: We aimed to evaluate the outcome of treatment with docetaxel plus androgen deprivation therapy (ADT) in newly diagnosed patients with metastatic high tumor burden hormone-sensitive prostate cancer (mHSPC) and correlated the outcome with hemoglobin, albumin, lymphocyte and platelets (HALP) score. Material and methods: Six cycles of docetaxel plus ADT were given to 50 patients with high burden mHSPC. Baseline HALP score was calculated and disease outcome was tabulated; moreover, the prognostic impact of the HALP score in response to treatment and survival was calculated. Results: We found a significant association between high HALP score and response to treatment where a higher rate of complete response occurred in patients with a high HALP score than in patients with a low HALP score (53.8% vs. 5.4% respectively, p-value = 0.001). Patients with ≥ 12-month-duration castration-resistant prostate cancer (CRPC) had a significantly higher HALP score compared to patients with a lower HALP score (84.6% vs. 35.1% respectively, p-value = 0.002); 18-month-duration CRPC-free survival was significantly greater in patients with higher HALP score than patients with a lower HALP score (23.1% and 5.4% respectively, p-value < 0.001). Patients with a high HALP score had insignificantly higher mean overall survival than patients with a low HALP score (mean: 22.91 and 20.66 months respectively, p-value = 0.230). Conclusions: Our results confirmed the benefits of treatment with docetaxel plus ADT in high-burden mHSPC with accepted tolerance. HALP score was found to be an independent predictive factor for benefit from therapy; we can apply it as an easy way to stratify patients for appropriate selection of treatment for better tolerance and outcome.

Phylogenetic comparative analysis: Chemical and biological features of caseins (alpha-S-1, alpha-S-2, beta- and kappa-) in domestic dairy animals.

Caseins determine the physicochemical, physiological, and biological characteristics of milk. Four caseins-alpha-S-1, alpha-S-2, beta, and kappa-were analyzed phylogenetically and in silico and characterized regarding chemical, antimicrobial, and antioxidant features in five dairy animals: Arabian camels, sheep, goats, cattle, and water buffalos. The sequence of full-length amino acids of the four caseins for the five species was retracted from the NCBI GenBank database. Multiple sequence alignment is used to examine further the candidate sequences for phylogenetic analysis using Clustal X and NJ-Plot tools. The results revealed that sheep and goats possess strong similarities (98.06%) because of their common ancestor. The same was observed with cattle and water buffalos (96.25%). The Arabian camel was located in a single subclade due to low similarity in casein residues and compositions with other dairy animals. Protein modeling showed that alpha-S1- and alpha-S2-caseins possess the highest number of phosphoserine residues. The in silico computed chemical properties showed that ß-casein recorded highest hydrophobicity index and lowest basic amino acid content, while α-S2-casein showed the opposite. The computed biological parameters revealed that α-S2-casein presented the highest bactericidal stretches. Only Arabian camel ß-casein and k-casein showed one bactericidal stretches. The analysis also revealed that ß-casein, particularly in Arabian camels, possesses the highest antioxidant activity index. These results support the importance of the bioinformatics resources to determine milk casein micelles' chemical and biological activities.

Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19.

DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP-4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti-inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.

Genetic and Morphological Diversity Assessment of Five Kalanchoe Genotypes by SCoT, ISSR and RAPD-PCR Markers.

Determining the appropriate parents for breeding programs is the most important decision that plant breeders must make to maximize the genetic variability and produce excellent recombinant genotypes. Several methods are used to identify genotypes with desirable phenotypic features for breeding experiments. In this study, five kalanchoe genotypes were morphologically characterized by assessing plant height, number of inflorescences, number of flowers, flower length, flower diameter and number of petals. The analysis showed the distinction of yellow kalanchoe in the plant height trait, while the orange kalanchoe was distinguished in the number of inflorescences, the number of flowers and flower length traits, whereas the violet kalanchoe possessed the largest flower diameter and the highest number of petals. The molecular profiling was performed by random amplified polymorphism DNA (RAPD), inter-simple sequence repeats (ISSR) and start codon targeted (SCoT)-polymerase chain reaction (PCR) tools. Genomic DNA was extracted from young leaves and the PCR reactions were performed using ten primers for each SCoT, ISSR and RAPD marker. Only four out of ten primers showed amplicon profiles in all PCR markers. A total of 70 bands were generated by SCoT, ISSR and RAPD-PCR with 35 polymorphic bands and 35 monomorphic bands. The total number of bands of RAPD, ISSR and SCoT was 15, 17 and 38, respectively. The polymorphism percentages achieved by RAPD, ISSR and SCoT were 60.25%, 15% and 57%, respectively. The cluster analysis based on morphological data revealed two clusters. Cluster I consisted of violet and orange kalanchoe, and cluster II comprised red, yellow and purple kalanchoe. Whereas the cluster analysis based on molecular data revealed three clusters. Cluster I included only yellow kalanchoe, cluster II comprised orange and violet kalanchoe while cluster III comprised red, and purple kalanchoe. The study concluded that orange, violet and yellow kalanchoe are distinguished parents for breeding economically valued traits in kalanchoe. Also, the study concluded that SCoT and RAPD markers reproduced reliable banding patterns to assess the genetic polymorphism among kalanchoe genotypes that consider the basis stone for genetic improvements in ornamental plants.

Prognostic significance of lymphocyte-to-monocyte ratio in patients with classical Hodgkin lymphoma before and after receiving first-line chemotherapy.

Introduction: Despite the presence of a prognostic risk stratification sco-ring system for Hodgkin lymphoma (HL), the lymphocyte-to-monocyte ratio (LMR) is a simple and low-cost test that has been investigated as a prognostic marker to evaluate the clinical course and survival outcomes. Material and methods: We prospectively enrolled 92 patients with classical HL (CHL), who were diagnosed and treated in the period from April 2017 to April 2020. Lymphocyte monocyte ratio cut-off values were estimated using receiver operating characteristic curves. Results: We found that patients with LMR < 1.4 at the time of diagnosis had poorer progression-free survival (PFS) and overall survival (OS) than those with LMR > 1.4. Patients with increased LMR values after the first 2 cycles of chemotherapy had better PFS and OS; meanwhile, patients who had low LMR after the end of chemotherapy had poorer PFS and OS in comparison to patients who gained higher value after the completion of all cycles of chemotherapy. Conclusions: A rise of LMR value indicated better outcome and better survival rate, so it can be an independent prognostic factor for survival and to predict outcome in patients with CHL.

Clinical significance of cytokeratin 19 and OCT4 as survival markers in non-metastatic and metastatic breast cancer patients.

Introduction: Cytokeratin 19 (CK19) is highly expressed in epithelial tumours such as breast cancer (BC). Octamer-binding transcription factor 4 (OCT4), a transcription factor of the POU (Pit-Oct-UNC) family, plays a criti-cal role in the self-renewal and maintenance of pluripotency of embryonic stem cells; therefore, it has been used as a promising CSC marker. Material and methods: CK19 was assessed in peripheral blood using flow-cytometric analysis while OCT4 was evaluated in breast tissue samples by immunohistochemistry from 70 patients (non-metastatic BC, meta-static BC, and non-malignant breast tumours). Results: CK19 and OCT4 were significantly associated with BC patients compared to control (p < 0.001). CK19 was detected in 38 patients with BC (62.2%); meanwhile, OCT4 was positive in 37 BC patients (60.6%). CK19 was positively associated with grade (p = 0.002), HER2 (p = 0.009), metastasis (p = 0.026), molecular subtypes and LN (p < 0.001), and stage (p = 0.001) while OCT4 expression was positively associated with BMI (p < 0.023), aggressive molecular subtype (p < 0.019), ER expression (p = 0.025), presence of LN metastases (p < 0.017), and distant metastasis (p < 0.018). A non-significant relation was found between the expression of CK19 and OCT (p = 0.291). The positive expression of CK19 and OCT4 was significantly and inversely associated with both 3-year OS and 3-year PFS. Conclusions: CK19 and OCT4 are associated with BC, so they can be considered as prognostic and predictive markers for poor OS and PFS in non-metastatic as well as metastatic BC patients.

Identification of a promising hit from a new series of pyrazolo[1,5-a]pyrimidine based compounds as a potential anticancer agent with potent CDK1 inhibitory and pro-apoptotic properties through a multistep in vitro assessment.

A new series of sixteen new 2-arylamino-5,7-disubstituted-N-aryl-pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives was designed and synthesized. The antitumor activities of the new compounds were initially screened through the developmental therapeutics program at NCI-USA 60 cell line panel. 2-((2,4-dimethoxyphenyl)amino)-5,7-diphenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7a) was identified as a potential hit with a mean percentage of growth inhibition of 48.5% over the 60-NCI cancer cell lines whereas the other fifteen compounds ranged from 0.5 to 10.72%. In MTT assay, compound 7a exhibited IC50 of 6.28 ± 0.26 µM and 17.7 ± 0.92 µM against HCT-116 colorectal cancer and WI-38 human lung fibroblast normal cell lines, respectively. In cell cycle analysis, compound 7a arrested cell cycle at G2/M phase. It was able to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyc B (Cyclin B) complex at IC50 161.2 ± 2.7 nM. The apoptosis-inducing ability of compound 7a was assessed through apoptosis detection flow-cytometry and gene expression analysis of apoptosis markers and caspase cascade which revealed that compound 7a exerts pro-apoptotic effect and increased expression of p53, Bax, cytochrome c, caspases (-3,-8, and-9), and decreased expression of Bcl-2. This suggests that the pro-apoptotic effect is exerted through the intrinsic pathway. The molecular docking study revealed a unique binding mode at the ATP binding pocket of CDK1/Cyc B/Cks2 through its 2,4-dimethoxyphenyl-amino. These results suggest that compound 7a could be a promising hit as a targeted protein kinase inhibitor which exerts its antitumor effect through CDK1 inhibition and pro-apoptotic action.

Choosing the Appropriate Individualized Adjuvant Chemotherapy in Stage III Colon Cancer Patients Under and Over 70 Years.

BACKGROUND: Colon cancer is one of the leading causes of cancer-related deaths worldwide. The increased incidence of comorbid diseases in elderly patients above 70 leads to the need of less aggressive strategies to be used in the adjuvant setting of stage III colon cancer. METHOD: Our prospective cohort study was performed in the period from April 2017 to March 2020. Seventy-five patients with newly diagnosed stage III colon cancer received adjuvant chemotherapy after surgery. Patients who either received adjuvant chemotherapy less than 3 months due to intolerability or toxicity from medications or who have more than one type of cancers or metastatic disease from the start were excluded from the study. Patients' clinicopathological characteristics in relation to oxaliplatin- and non-oxaliplatin-based chemotherapeutic regimens were analyzed with survival assessment. RESULTS: In our study, patients above 70 had better overall survival (OS) in the non-oxaliplatin chemotherapy group (p-value = 0.032) in contrast to OS in patients under 70 which was better in the oxaliplatin group (p-value < 0.001). By comparing the OS between the two age groups, the OS was better in patients < 70 years (p-value = 0.001). Additionally, we found that the DFS in patients above 70 was better in oxaliplatin-based regimens than in the non-oxaliplatin group (p-value = 0.011) with better survival rates (81.8% vs 15.7%), and markedly high DFS in patients under 70 for oxaliplatin based regimens (p-value < 0.001), with survival rates (31.1% vs 0%). By comparing the DFS between the two age groups, the DFS was better in patients < 70 years (p-value < 0.001). The disease recurrence was in favor of the non-oxaliplatin group with significant p-value = 0.003, while mortality occurred more in the oxaliplatin group (p-value < 0.001). CONCLUSIONS: The appropriate selection of a personalized strategy for treatment of stage III colon cancer plays an important role in the outcome of the disease. Our findings supported the use of oxaliplatin-based chemotherapy as a standard treatment option in the adjuvant management of stage III colon cancer patients in all age groups. The benefit of non-oxaliplatin-based chemotherapy was limited to patients above 70 which might be an effective option for elderly patients.

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking.

In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds 6b,d-g, and 7b showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound 6e displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, 6e was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound 6e endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

Circular RNAs 0064286 and 0000475: Potential Diagnostic Biomarkers in Hepatocellular Carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is considered the highest recorded malignancy in Egypt. The shortage of appropriate biomarkers for early detection often results in the late diagnosis of the HCC. Circular RNAs (CircRNAs) are presented as long stranded non-coding RNA that combine covalently to make a sealed circular form which make them very stable. CircRNAs are known to have interpretative role in cancer development and metastasis. AIM: To examine the dysregulation of two new CircRNAs obtained from Circbase database (hsa_circ_0064286 and hsa_circ_0000475) in the serum of HCC patients as predictable diagnostic biomarkers of HCC and their correlation with some liver biochemical parameters. METHODS: Sixty clinically diagnosed HCC Egyptian patients and 25 healthy volunteers were enrolled in the study. Expression levels of the selected CircRNAs was evaluated in subjects' serum. Moreover, correlation with liver biochemical parameters, sensitivity, and specificity of studied CircRNAs were estimated. RESULTS: Both circular RNAs were significantly down regulated in HCC patients, which was negatively correlated with ALP, ALT, AST, AFP, and bilirubin levels. Circ_0064286 showed more sensitivity and specificity (88.3% and 96%, respectively). CONCLUSION: As far as we know, this is the first study that shed light on the expression levels of both circRNAs in Egyptian HCC patients. They may serve as potential biomarkers for HCC diagnosis. Moreover, those circRNAs draw attention as therapeutic targets for HCC through targeting their sponge miRNAs.

Neuroprotective effect of green and roasted coffee bean extracts on cerebral ischemia-induced injury in rats.

Stroke is a lethal event with a high incidence in Egypt. Quick early intervention can be lifesaving. Transient global ischemia (TGI), a type of ischemic stroke, is mainly instigated by cardiac arrest. Ischemia followed by reperfusion causes further neuronal cell damage. In this study, we aimed to evaluate the potential apoptotic, anti-inflammatory, and neuroprotective effects of green (GCBE) and roasted (RCBE) coffee bean water extract against transient global ischemia-induced via a bilateral common carotid artery occlusion (CAO) in rats. Before CAO, 1.5 ml/kg body weight/day of GCBE or RCBE was administered for 14 days by oral gavage. Ischemia/reperfusion (I/R) and sham groups were treated with a vehicle. Oxidative stress biomarkers and antioxidant enzyme activities, such as MDA, NO, GSH, SOD, CAT, GR, GPx, inflammatory markers TNF-α, IL-1ß, and NF-κB, and BDNF were investigated. Quantitative real-time PCR analysis of mitogen-activated protein kinase pathways, in addition to heme oxygenase 1, and nuclear factor erythroid 2-related factor 2 were determined. Apoptotic markers, including Bcl-2, Bax, and caspase 3, in addition to the vascular endothelial growth factor-a, were investigated, followed by an examination of hippocampal histopathology. Pre-administration of GCBE and RCBE improved neurological function and neuronal survival, suppressed the spread of oxidative stress, inflammation, and apoptosis, and reversed most of the pathological changes. However, green coffee bean extract was more effective than roasted coffee bean extract, perhaps due to the roasting process, which may affect active compounds. In conclusion, GCBE and RCBE represent a potential clinical strategy for pre-ischemic conditioning.

Immune response and susceptibility of Nile tilapia fish to Aeromonas hydrophila infection following the exposure to Bifenthrin and/or supplementation with Petroselinum crispum essential oil.

Bifenthrin (BF) is a widely used 3rd generation type I pyrethroid with a potential toxic effect in fish. Nevertheless, its effect on the immune system remains unclear. In the present study, Oreochromis niloticus was exposed to BF at 0.68 µg/L for 60 days, followed by evaluating the hematological, biochemical, and immunological responses. Additionally, the potential of parsley (Petroselinum crispum) essential oil (PEO) to ameliorate the BF-induced toxic insults was explored. Our data have shown reductions in the growth performance with alterations observed in the hematological variables, protein profile and serum biomarkers of stress. DNA oxidative damage was evidenced by elevation of serum 8-hydroxy-2-deoxyguanosine (8-OHdG) content. BF-exposed fish presented also decline in serum lysozyme activity and levels of immunoglobulins (IgG and IgM) and nitric oxide (NO), with diminished resistance to Aeromonas hydrophila challenge. Furthermore, the RT-PCR analysis showed an upregulated expression pattern of immune -related genes including interleukin 1ß (IL-1ß), interferon - γ (IFN-γ) and tumor necrosis factor - α (TNF-α) genes in the liver tissue. Dietary co-supplementation of PEO at 1 or 2 mL/kg diet with concomitant BF exposure, alleviated the adverse effects of the insecticide in a dose-dependent manner. The observations from this study demonstrate the immunomodulation by BF and provide further insight into the protective properties of PEO and strengthen its applicability as a promising feed supplement to fish.