Benzimidazole-oxindole hybrids as multi-kinase inhibitors targeting melanoma.

In the current study, a series of benzimidazole-oxindole conjugates 8a-t were designed and synthesized as type II multi-kinase inhibitors. They exhibited moderate to potent inhibitory activity against BRAFWT up to 99.61 % at 10 µM. Notably, compounds 8e, 8k, 8n and 8s demonstrated the most promising activity, with 99.44 to 99.61 % inhibition. Further evaluation revealed that 8e, 8k, 8n and 8s exhibit moderate to potent inhibitory effects on the kinases BRAFV600E, VEGFR-2, and FGFR-1. Additionally, compounds 8a-t were screened for their cytotoxicity by the NCI, and several compounds showed significant growth inhibition in diverse cancer cell lines. Compound 8e stood out with a GI50 range of 1.23 - 3.38 µM on melanoma cell lines. Encouraged by its efficacy, it was further investigated for its antitumor activity and mechanism of action, using sorafenib as a reference standard. The hybrid compound 8e exhibited potent cellular-level suppression of BRAFWT, VEGFR-2, and FGFR-1 in A375 cell line, surpassing the effects of sorafenib. In vivo studies demonstrate that 8e significantly inhibits the growth of B16F10 tumors in mice, leading to increased survival rates and histopathological tumor regression. Furthermore, 8e reduces angiogenesis markers, mRNA expression levels of VEGFR-2 and FGFR-1, and production of growth factors. It also downregulated Notch1 protein expression and decreased TGF-ß1 production. Molecular docking simulations suggest that 8e binds as a promising type II kinase inhibitor in the target kinases interacting with the key regions in their kinase domain.

Developing a rapid analytical method for simultaneous determination of apigenin and gallic acid: validation and application in a nanoliposomal formulation.

OBJECTIVE: Apigenin and gallic acid are natural compounds that are useful as antioxidant, anti-inflammatory and anticancer agents, especially when used together in combination. Therefore, the development and validation of a simultaneous method of analysis for both compounds in pure form and when encapsulated in an advanced delivery system such as liposomes would be useful. METHODS: Analysis was performed using C18 column under isocratic conditions. The mobile phase was acetonitrile: water containing 0.2% orthophosphoric acid at a ratio of 67:33, flow rate 1 ml/min, and detection wavelength 334 nm for apigenin and 271 nm for gallic acid. RESULTS: The assay method was linear at the concentration range (5-600 µg/mL) with R2 of 1 for both drugs. The method was also shown to be precise and robust with RSD less than 2% with LOD (0.12, 0.1 µg/mL) and LOQ (4.14, 3.58 µg/mL) for apigenin and gallic acid respectively. The method was also applicable for the determination of the entrapment efficiency of both drugs when co-loaded in a nanoliposomal formulation. CONCLUSION: The described HPLC method was shown to be suitable, sensitive, and reproducible for the simultaneous identification and quantification of apigenin and gallic acid. The analytical results were accurate and precise, with good recovery, low limit of detection, and the chromatographic assay was accomplished in less than 3 min, suggesting the suitability of the method for routine analysis of both drugs in pharmaceutical formulations.

Erratum to "Facile synthesis and in vitro anticancer evaluation of a new series of tetrahydroquinoline" [Heliyon 7(10) (October 2021) e08117].

[This corrects the article DOI: 10.1016/j.heliyon.2021.e08117.].

Ecofriendly HPLC Method for Simultaneous Determination of the Co-Prescribed Drugs in Chemotherapy Omeprazole, Ondansetron and Deflazacort in Spiked Human Plasma.

Green, selective and accurate high-performance liquid chromatography (HPLC) chromatographic method is presented for simultaneous separation and quantitation of the co-prescribed drugs in chemotherapy omeprazole, ondansetron and deflazacort in spiked human plasma. An isocratic HPLC separation was performed on X Bridge C18 (4.6 × 250 mm) column with 5 µm particle size using mobile phase consisting of methanol: ammonium acetate buffer pH 4 adjusted by acetic acid (60: 40, v/v). The injection volume was 20µL with UV detection wavelength at 237 nm at room temperature. Flow rate of the mobile phase was adjusted to be 2.0 ml/min. Dexamethasone was used as internal standard to correct the variation during sample pretreatment. FDA guidelines were followed to validate the developed method. Successful application of the developed method was revealed by simultaneous determination of omeprazole, ondansetron and deflazacort in spiked human plasma in ranges of 1-20, 0.1-8 and 0.2-8 µg mL-1 for omeprazole, ondansetron and deflazacort, respectively. Four greenness assessment tools were used to evaluate the greenness of the developed method and the results were accepted. This method permitted the accurate simultaneous determination of the studied drugs, thus it can be used during therapeutic drug monitoring in daily clinical practice.

Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.

Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed and synthesized. The anticancer potential of the new compounds was evaluated against hepatocellular carcinoma (HepG-2), colorectal carcinoma, colon cancer (HCT-116), and breast cancer (MCF-7) cell lines. Compounds 6d and 6o were the most potent derivatives with IC50 values ranging from 6.02 to 13.87 µM against HePG-2, HCT-116, and MCF-7 cell lines. Moreover, methyl analog of the fluoro-substituted indolizine derivative 6m revealed significant antiproliferative activity against HePG-2, HCT-116, and MCF-7 cancer cell lines with IC50 values of 11.97, 28.37, and 19.87 µM, respectively. The most active anticancer analogs, 6d, 6m, and 6o, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK 2) inhibitory activities. Thus, compound 6o displayed the most inhibitory activity against EGFR and CDK 2 with IC50 values of 62 and 118 nM, respectively. Additionally, the quantitative real-time PCR analysis for the P-glycoprotein effect of compounds 6d, 6m, and 6o was performed, in which compound 6o illustrated significant down-regulation of P-gp against the HepG-2 cell line by 0.2732 fold. Mechanistic studies for the most active compounds involving the reversal doxorubicin (DOX) effect of compounds 6d, 6m, and 6o were performed, which illustrated cytotoxic activity with IC50 22.27, 3.88, and 8.79 µM, respectively. Moreover, the apoptotic activity of the most active derivative 6o on HCT-116 cancer cells showed accumulation in the G1 and S phases of the cell cycle.

Discovery and optimization of 2,3-diaryl-1,3-thiazolidin-4-one-based derivatives as potent and selective cytotoxic agents with anti-inflammatory activity.

Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a-q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a-q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC50 = 0.02-17.02 µM). The cytotoxicity of 7a-q was also assessed against normal MRC5 cells (IC50 = 0.47-13.46 µM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 µM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 µM). On the other hand, compounds 7a-q inhibited the activity of COX-2 (IC50 = 0.42-29.11 µM) compared to celecoxib (IC50 = 0.86 µM). In addition, 7c, 7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate.

Chemomodulatory Effect of the Marine-Derived Metabolite "Terrein" on the Anticancer Properties of Gemcitabine in Colorectal Cancer Cells.

BACKGROUND: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and therefore, treatment failure. METHODS: The potential anticancer properties of terrein, its antiproliferative effects, and its chemomodulatory effects on GCB were assessed against various colorectal cancer cell lines (HCT-116, HT-29, and SW620) under normoxic and hypoxic (pO2 ≤ 1%) conditions. Further analysis via flow cytometry was carried out in addition to quantitative gene expression and 1HNMR metabolomic analysis. RESULTS: In normoxia, the effect of the combination treatment (GCB + Terr) was synergistic in HCT-116 and SW620 cell lines. In HT-29, the effect was antagonistic when the cells were treated with (GCB + Terr) under both normoxic and hypoxic conditions. The combination treatment was found to induce apoptosis in HCT-116 and SW620. Metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling. CONCLUSIONS: Terrein influenced GCB's anti-colorectal cancer properties which are reflected in different aspects such as cytotoxicity, cell cycle progression, apoptosis, autophagy, and intra-tumoral metabolism under normoxic and hypoxic conditions.

Dietary Frankincense (Boswellia serrata) Oil Modulates the Growth, Intestinal Morphology, the Fatty Acid Composition of Breast Muscle, Immune Status, and Immunoexpression of CD3 and CD20 in Broiler Chickens.

This investigation explored the impact of dietary frankincense resin oil (FO) on growth performance parameters, intestinal histomorphology, fatty acid composition of the breast muscle, and the immune status of broilers. We allotted 400, three-day-old, male chicks (Ross 308 broiler) into four treatment groups (ten replicates/group; ten chicks/replicate). They were fed a basal diet with different concentrations of FO (0, 200, 400, and 600 mg kg-1). FO supplementation increased the overall body weight (BW) and body weight gain (BWG) by different amounts, linearly improving the feed conversion ratio with the in-supplementation level. Total feed intake (TFI) was not affected. Growth hormones and total serum protein levels also linearly increased with the FO level, while albumin was elevated in the FO600 group. Moreover, total globulins increased linearly in FO400 and FO600 treatment groups. Thyroxin hormone (T3 and T4) levels increased in all FO treatment groups without affecting glucose and leptin serum values. Different concentrations of FO supplementation in the diet increased the activities of Complement 3, lysozyme, and interleukin 10 levels in the serum. Dietary FO in broilers increased the total percentage of n-3 and n-6 fatty acids. It also increased the ratio of n-3 to n-6 linearly and quadratically. Additionally, FO supplementation led to the upregulation of immune clusters of differentiation 3 and 20 (CD3 and CD20) in the spleen, along with improving most of the morphometric measures of the small intestine. In conclusion, FO up to 600 mg kg-1 as a feed additive in broiler chicken production is valuable for promoting their growth, intestinal histomorphology, and immune status along with enriching breast muscle with polyunsaturated fatty acids (PUFA).

Challenging breast cancer through novel sulfonamide-pyridine hybrids: design, synthesis, carbonic anhydrase IX inhibition and induction of apoptosis.

Background: Among the important key modulators of the tumor microenvironment and hypoxia is a family of enzymes named carbonic anhydrases. Herein, 11 novel sulfonamide-pyridine hybrids (2-12) were designed, synthesized and biologically evaluated for their potential use in targeting breast cancer. Methods & results: The para chloro derivative 7 reported the highest cytotoxic activity against the three breast cancer cell lines used. In addition, compound 7 was found to induce cell cycle arrest and autophagy as well as delaying wound healing. The IC50 of compound 7 against carbonic anhydrase IX was 253 ± 12 nM using dorzolamide HCl as control. Conclusion: This study encourages us to expand the designed library, where more sulfonamide derivatives would be synthesized and studied for their structure-activity relationships.

Design, Synthesis, Molecular docking, and biological evaluation of novel 2,3-diaryl-1,3-thiazolidine-4-one derivatives as potential anti-inflammatory and cytotoxic agents.

A new series of 2,3-diaryl-1,3thiazolidin-4-one derivatives was designed, synthesized, and evaluated for their cytotoxicity and COXs inhibitory activities. Among these derivatives, compounds 4 k and 4j exhibited the highest inhibitory activities against COX-2 at IC50 values of 0.05 and 0.06 µM, respectively. Compounds 4a, 4b, 4e, 4 g, 4j, 4 k, 5b, and 6b, which exhibited the highest inhibition% against COX-2, were evaluated for their anti-inflammatory activity in rats. Results showed 41.08-82.00 % inhibition of paw edema thickness by the test compounds compared to celecoxib (inhibition% = 89.51 %). In addition, compounds 4b, 4j, 4 k, and 6b exhibited better GIT safety profiles compared to celecoxib and indomethacin. The four compounds were also evaluated for their antioxidant activity. The results revealed the highest antioxidant activity for 4j (IC50 = 45.27 µM) comparable to torolox (IC50 = 62.03 µM). The antiproliferative activity of the new compounds was evaluated against HePG-2, HCT-116, MCF-7, and PC-3 cancer cell lines. The results showed the highest cytotoxicity for compounds 4b, 4j, 4 k, and 6b (IC50 = 2.31-27.19 µM), with 4j being the most potent. Mechanistic studies revealed the ability of 4j and 4 k by inducing marked apoptosis and cell cycle arrest at the G1 phase in HePG-2 cancer cells. These biological results may also suggest a role for COX-2 inhibition in the antiproliferative activity of these compounds. The results of the molecular docking study for 4 k and 4j into the active site of COX-2 revealed good fitting and correlation with the results of the in vitro COX­2 inhibition assay.

Computational Analysis of Deleterious SNPs in NRAS to Assess Their Potential Correlation With Carcinogenesis.

The NRAS gene is a well-known oncogene that acts as a major player in carcinogenesis. Mutations in the NRAS gene have been linked to multiple types of human tumors. Therefore, the identification of the most deleterious single nucleotide polymorphisms (SNPs) in the NRAS gene is necessary to understand the key factors of tumor pathogenesis and therapy. We aimed to retrieve NRAS missense SNPs and analyze them comprehensively using sequence and structure approaches to determine the most deleterious SNPs that could increase the risk of carcinogenesis. We also adopted structural biology methods and docking tools to investigate the behavior of the filtered SNPs. After retrieving missense SNPs and analyzing them using six in silico tools, 17 mutations were found to be the most deleterious mutations in NRAS. All SNPs except S145L were found to decrease NRAS stability, and all SNPs were found on highly conserved residues and important functional domains, except R164C. In addition, all mutations except G60E and S145L showed a higher binding affinity to GTP, implicating an increase in malignancy tendency. As a consequence, all other 14 mutations were expected to increase the risk of carcinogenesis, with 5 mutations (G13R, G13C, G13V, P34R, and V152F) expected to have the highest risk. Thermodynamic stability was ensured for these SNP models through molecular dynamics simulation based on trajectory analysis. Free binding affinity toward the natural substrate, GTP, was higher for these models as compared to the native NRAS protein. The Gly13 SNP proteins depict a differential conformational state that could favor nucleotide exchange and catalytic potentiality. A further application of experimental methods with all these 14 mutations could reveal new insights into the pathogenesis and management of different types of tumors.

Impact of Dietary Lavender Essential Oil on the Growth and Fatty Acid Profile of Breast Muscles, Antioxidant Activity, and Inflammatory Responses in Broiler Chickens.

This study aimed to investigate the impact of dietary addition of lavender essential oil (Lavandula angustifolia L.) (LEO) on the growth performance, tissue histoarchitecture, and fatty acid profile in breast muscles, as well as blood biochemistry and immune expression of pro-inflammatory cytokines of broiler chickens. A total of 200 three-day-old broiler chickens (average body weight 101.3 ± 0.24 g) were assigned to a completely randomized design consisting of four dietary treatments (n = 50 per treatment, each replicate consisting of 10 birds) that included lavender essential oil at concentrations of 0 (control group), 200, 400, and 600 mg Kg−1 diet. The experiment lasted for 35 days. The results revealed that supplementation of lavender essential oil at 200, 400, or 600 mg/kg in broiler diets had no effect (p > 0.05) on the growth performance throughout the experimental periods (3−10, 11−23, and 24−35 days of age). According to the broken line regression model, the optimal level for dietary LEO addition was the 460 mg kg−1 diet based on the total body weight gain and feed conversion ratio results. The diets supplemented with lavender essential oil had no effect (p > 0.05) on the percentages of carcass yield or internal organs. Dietary addition of LEO significantly increased the percentages of omega-3 polyunsaturated fatty acids PUFA (n-3), omega-6 polyunsaturated fatty acids (n-6), and the n-3/n-6 ratio (p < 0.05) in the breast muscles of chickens in a level-dependent manner. The blood concentration of alanine aminotransferase was significantly increased in lavender essential oil at 600 mg kg−1 compared with other treatments. The dietary addition of LEO at 200, 400, and 600 mg kg−1 significantly reduced the malondialdehyde level. Still, they significantly increased the serum enzyme activities of total antioxidant capacity, catalase, superoxide dismutase, and the pro-inflammatory cytokine (interleukine-1 beta and interferon γ) compared with the unsupplemented group. The LEO-supplemented groups showed normal liver histomorphology as in the control group. However, the immunoexpression of the pro-inflammatory cytokine transforming growth factor ß was significantly increased by increasing the level of LEO. It can be concluded that lavender essential oil can be included in broiler chicken diets up to 460 mg kg −1 with no positive effect on the bird's growth. It can improve the antioxidant capacity and enrich the breast muscles with PUFA. An increased level of supplementation (600 mg kg−1) increased the inflammatory responses in broiler chickens.

Design, synthesis, and molecular docking of novel pyrazole-chalcone analogs of lonazolac as 5-LOX, iNOS and tubulin polymerization inhibitors with potential anticancer and anti-inflammatory activities.

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with IC50 values of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with IC50 28.93 µM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (IC50 = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (IC50 = 5.13 µM) more than COX-1 (IC50 = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 IC50 = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (IC50 = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with IC50 values of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment.

Barrett's esophagus in a patient with bulimia nervosa: A case report.

BACKGROUND: Barrett's esophagus is a known complication of long-standing gastroesophageal reflux disease, and it is a potential risk factor of developing esophageal adenocarcinoma. CASE SUMMARY: Here, we present a case of a 47-year-old male patient referred to the gastroenterology clinic for upper endoscopy because he has a long-standing history of heartburn and vomiting after meals. On examination, he had characteristic findings of self-induced vomiting as abrasions and callosities on the dorsum of the right hand and dental erosions. A detailed history revealed that he had 17 years of binge eating with self-induced vomiting. His upper endoscopy showed gastroesophageal reflux grade D with salmon-red mucosal projections, and the biopsy revealed intestinal mucosal metaplasia. CONCLUSION: This case emphasized the importance of considering upper endoscopy screening for Barrett's esophagus in patients with eating disorders, especially those with self-induced vomiting, as in bulimia nervosa.

Modulating the Growth, Antioxidant Activity, and Immunoexpression of Proinflammatory Cytokines and Apoptotic Proteins in Broiler Chickens by Adding Dietary Spirulina platensis Phycocyanin.

This study investigated the dietary effect of Spirulina platensis phycocyanin (SPC) on growth performance (body weight (BW), body weight gain (BWG), feed intake (FI), feed conversion ratio (FCR)) at starter, grower, and finisher stages, intestinal histomorphology, serum biochemical parameters, inflammatory and antioxidant indices, and proinflammatory cytokines (tumor necrosis factor-α and caspase-3) immune expression in broiler chickens. In total, 250 one-day-old chicks (Ross 308 broiler) were randomly allotted to five experimental groups (5 replicates/group, 10 chicks/replicate) and fed basal diets supplemented with five levels of SPC (0, 0.25, 0.5, 0.75, and 1 g kg-1 diet) for 35 days. Compared with SPC0 treatment, different SPC levels increased the overall BW and BWG without affecting the total feed consumption. However, the FCR decreased linearly with an increase in supplementation level. The serum levels of total proteins, albumin, globulins, and growth hormone increased linearly by increasing levels of SPC supplementation. Further, SPC supplementation increased the thyroxin hormones without affecting serum glucose and leptin levels. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) values decreased in broilers fed SPC0.250 and SPC1 diets. Triglycerides (TG) decreased in SPC0.25-, SPC0.75-, and SPC1-treated groups. Though antioxidant enzyme activities (total antioxidant capacity, catalase, and superoxide dismutase) increased linearly and quadratically, malondialdehyde (MDA) decreased linearly by increasing the SPC level. There was no effect on serum proinflammatory cytokines IL1ß levels. Immunolabelling index of caspase-3 and tumor necrosis factor-α (TNF-α) were downregulated by SPC supplementation. The intestinal histomorphology is represented by increased villus height, the villus height to crypt depth ratio, and numbers of goblet cells in different sections of the small intestine. In conclusion, SPC supplementation is beneficial in broiler chicken diets due to its growth-promoting, antioxidant, and anti-inflammatory properties.

A Comprehensive Overview of Globally Approved JAK Inhibitors.

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

Potential Effects of Anthocyanin-Rich Roselle (Hibiscus sabdariffa L.) Extract on the Growth, Intestinal Histomorphology, Blood Biochemical Parameters, and the Immune Status of Broiler Chickens.

The potential effects of anthocyanin-rich roselle, Hibiscus sabdariffa L. extract (ARRE) on the growth, carcass traits, intestinal histomorphology, breast muscle composition, blood biochemical parameters, antioxidant activity, and immune status of broiler chickens were evaluated. In the present study, Hibiscus acidified ethanolic extract was reported to have a total anthocyanin content of about 359.3 mg cyanidin 3-glucoside/100 g DW, total polyphenol concentration (TPC) of about 598 mg gallic acid equivalent (GAE)/100 g DW, and total flavonoids (TFs) of about 100 mg quercetin equivalent (QE)/100 g DW. Two-hundred-fifty one-day-old chicks (Ross 308 broiler) (87.85 gm ± 0.32) were randomly allotted to five experimental groups and fed on basal diets supplemented with five levels of ARRE: 0, 50, 100, 200, and 400 mg Kg-1 for 35 days. Dietary ARRE addition did not improve the birds' growth and carcass traits. Supplemental ARRE increased the n-3 polyunsaturated fatty acids (PUFA) (ω-3) percentage in the breast muscle. Dietary ARRE increased the villous height, and the ARRE100 group raised the villus height to crypt depth ratio. Dietary ARRE increased the immunoexpression of immunoglobulin G (IgG) in the spleen. The serum thyroxine hormone (T4) level was higher in the ARRE200 group. The serum growth hormone level was increased by ARRE addition in a level-dependent manner. According to the broken-line regression analysis, the optimum inclusion level of ARRE was 280 mg Kg-1. All levels of supplemental ARRE decreased the serum triglyceride level. The serum total antioxidant capacity (TAC) was increased in the ARRE100-ARRE400 groups, the serum superoxide dismutase (SOD) level was increased in the ARRE200 group, and the serum malondialdehyde (MDA) level was decreased by increasing the ARRE level. Supplemental ARRE significantly increased the serum levels of lysozymes and IL10. The serum complement 3 (C3) level was increased in ARRE200 and ARRE400 groups. It can be concluded that dietary ARRE addition had many beneficial effects represented by the improvements in the bird's metabolic functions, blood biochemistry, intestinal morphology, antioxidant activity, immune status, and higher ω-3 content in the breast muscles. However, it had no improving effect on the birds' growth.

Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities.

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRAFV600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV600E. Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRAFV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRAFV600E active sites to clarify their binding modes.

Zinc and L-Ascorbic Acid Dietary Supplementation Affected Antioxidant Status, Heat Shock Protein 70, and Some Immunoglobulins in Japanese Quail Under Heat Stress Conditions.

This study assessed the impact of the dietary inclusion of L-ascorbic acid and organic zinc (Availa-Zn) on heat-stressed Japanese quails. Growth performance, antioxidant status, immune status, heat shock protein 70 (HSP70), and some blood biochemical parameters were assessed. One-day-old, unsexed Japanese quail chicks (n = 240) were randomly allocated into 4 dietary treatments (6 replicates per treatment; 10 birds per replicate). Birds were fed a basal corn-soybean meal diet (control treatment) with different supplemental levels of L-ascorbic acid and/or Availa-Zn (200 mg L-ascorbic acid/kg diet, 62 mg Availa-Zn/kg diet, and 200 mg L-ascorbic acid + 62 mg Availa-Zn/kg diet) from July to August 2020 for 35 days. The average minimum and maximum ambient temperatures varied from 85.4 to 98.8 °F, and the relative humidity was between 69 and 74%. Supplemented L-ascorbic acid and Availa-Zn, either as separate supplements or as combined supplements, increased bird growth performance, blood hemoglobin, thyroid hormones, total protein, globulin, total antioxidant capacity, HSP70, catalase, superoxide dismutase enzyme activity, and immunoglobulin A and G (P < 0.05), while heterophil/lymphocytes decreased (P < 0.01) during the entire rearing period (1-35 days). Most of the assessed parameters showed stronger responses when L-ascorbic acid and Availa-Zn were added together, which may suggest a synergistic effect. In conclusion, the combined supplementation of L-ascorbic acid and Availa-Zn at 200 and 62 mg/kg, respectively, could be considered an efficient dietary supplement to enhance Japanese quail growth performance, antioxidant capacity, immune status, and general health under heat stress conditions.

Docking studies of sesquiterpene lactones isolated from Ambrosia maritima L. reveals their potential anti-inflammatory and cytotoxic activities.

Five sesquiterpene lactones were isolated and identified from Ambrosia maritima L. Hymenin showed highest cytotoxic activity against HCT-116, A-549, and MCF-7 cell lines (IC50= 3.83 ± 0.2, 5.48 ± 0.3, 10.1 ± 0.6 µg/mL, respectively). Damsin has significant COX-2 inhibitory activity (IC50=33.97 ± 1.62 µg/mL) while hymenin showed highest selectivity to COX-1 (IC50 = 18.21 µg/mL) and significant inhibition of NO (IC50=18.19 ± 0.75 µg/mL). The docking study revealed nice fitting into COX-1/2 and a higher binding affinity for maritimolide towards human Src kinase compared to the native ligand, Bosutinib. Results suggested that both COXs/Src kinase inhibition could contribute even partially to the overall mechanism of cytotoxic activity of the five compounds. The structure-activity relationship revealed that α-methylene-γ-lactone moiety enhances the cytotoxic activity, OH group at C-1 increase activity of hymenin. However, the reduction of the double bond at C-2 as in damsin resulted in a significant decrease in activity against HCT-116 and MCF-7 cells.