New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors.

Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRß, and VEGFR-2 kinases, with IC50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRß active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.

Correction: Ammar et al. Protective Effects of Naringenin from Citrus sinensis (var. Valencia) Peels against CCl4-Induced Hepatic and Renal Injuries in Rats Assessed by Metabolomics, Histological and Biochemical Analyses. Nutrients 2022, 14, 841.

In the original publication [...].

Ameliorative effects of androstenediol against acetic acid-induced colitis in male wistar rats via inhibiting TLR4-mediated PI3K/Akt and NF-κB pathways through estrogen receptor ß activation.

5-androstenediol (ADIOL) functions as a selective estrogen receptor ß (ERß) ligand with a protective effect against many diseases. So, we conducted a novel insight into its role in acetic acid (AA)-induced colitis and investigated its effect on TLR4-Mediated PI3K/Akt and NF-κB Pathways and the potential role of ERß as contributing mechanisms. METHODS: Rats were randomized into 5 Groups; Control, Colitis, Colitis + mesalazine (MLZ), Colitis + ADIOL, and Colitis + ADIOL + PHTPP (ER-ß antagonist). The colitis was induced through a rectal enema of acetic acid (AA) on the 8th day. At the end of treatment, colons were collected for macroscopic assessment. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor kappa b (NF-κB), toll-like receptor (TLR4), and phosphorylated Protein kinase B (pAKT) were measured. Besides, Gene expression of interleukin-1beta (IL-1ß), metalloproteases 9 (Mmp9), inositol 3 phosphate kinase (PI3K), Neutrophil gelatinase-associated lipocalin (NGAL), ERß and NLRP6 were assessed. Histopathological and immunohistochemical studies were also investigated. RESULTS: Compared to the untreated AA group, the disease activity index (DAI) and macroscopic assessment indicators significantly decreased with ADIOL injections. Indeed, ADIOL significantly decreased colonic tissue levels of MDA, TLR4, pAKT, and NF-κB immunostainig while increased SOD activity and ß catenin immunostainig. ADIOL mitigated the high genetic expressions of IL1ß, NGAL, MMP9, and PI3K while increased ERß and NLRP6 gene expression. Also, the pathological changes detected in AA groups were markedly ameliorated with ADIOL. The specific ERß antagonist, PHTPP, largely diminished these protective effects of ADIOL. CONCLUSION: ADIOL could be beneficial against AA-induced colitis mostly through activating ERß.

Quinazolin-4-one/3-cyanopyridin-2-one Hybrids as Dual Inhibitors of EGFR and BRAFV600E: Design, Synthesis, and Antiproliferative Activity.

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

Telmisartan and candesartan promote browning of white adipose tissue and reverse fatty liver changes in high fat diet fed male albino rats.

Obesity is a key risk factor for many diseases, as cardiovascular disorders, diabetes, infertility, osteoarthritis, sleep apnea, non-alcoholic fatty liver disease (NAFLD) as well as increased risk for many cancers. Telmisartan and Candesartan cilexetil are angiotensin II receptor blockers which had proven to involve in pathogenesis of obesity and NAFLD. AIMS: This work is designed to explore the possible mitigated effects of Telmisartan and Candesartan cilexetil on weight gain and fatty liver in high fat diet (HFD) fed rats. MAIN METHODS: The HFD rat model was achieved with induction of NAFLD. For Seven weeks either telmisartan or candesartan were orally administered at doses of 5 and 10 mg/kg respectively once daily. The effects of both drugs were evaluated by measurements of rat's body weight, food intakes, length, body mass index (BMI), liver weight, inguinal and interscapular fat weights. In addition, we assayed lipid profile, liver functions tests, serum inflammatory cytokines, adipokine and leptin. Lastly, liver and adipose tissue histopathological structures were evaluated. KEY FINDINGS: at end of experiment, telmisartan and candesartan were highly effective in decreasing rat's body weight from (213.1±2.68 to 191.2±2.54 and 203.5±5.89 gm , respectively), BMI, liver weight, fat weights in addition reduced serum levels of lipid and liver enzymes. Also, inflammatory cytokines were reduced with repaired histopathological insults in liver by significantly damped NAFLD score from (6.5 ±0.17 to 1±0 and 4 ±0, respectively) and decreased areas of adipocytes from (21239.12 to 5355.7 and 11607.1 um2 , respectively). SIGNIFICANCE: Telmisartan and candesartan have therapeutic potential against obesity and NAFLD induced by HFD in rats. All the previous indices showed more improvement in telmisartan than candesartan group.

Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a-j, 8a-j, 9a-c, and 10a-c. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

Design, Synthesis, and Antiproliferative Activity of Quinazolin-4-One/Chalcone Hybrids via the EGFR Inhibition Pathway.

BACKGROUND: Quinazolinone scaffolds have drawn international attention due to their potent anticancer activity and therapeutic applications. Furthermore, Chalcone and Oxime are special chemical templates with a wide range of biological activities, including anti-cancer activity. As a result, the purpose of this research is to synthesize and develop a new series of 2-thioxo-3-substituted quinazolin-4-one/chalcone analogues and 2-thioxo-3-substituted quinazolin-4-one/oximes analogues in order to obtain a new cytotoxic agent that can target epidermal growth factor (EGFR) and/or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAFV600E) oncogene. OBJECTIVE: All synthesised compounds were tested for anticancer activity against four human cancer cell lines. The new hybrids' potential anti-cancer mechanism was evaluated using EGFR and BRAF enzymatic tests. The most active molecules within the target enzyme's active site were studied using molecular docking. Apoptosis and cell cycle analysis were also investigated. METHODS: The target compounds 7a-j (series I) are obtained in high yields by alkylation of 2-mercapto-3-ethyl-(3H)- quinazolin-4-one 3a with acylated chalcones 6a-j. Alkylation of compounds 3b-c with N-(4-acetylphenyl)-2- bromoacetamide 8, the corresponding ketones intermediates 9b-c was produced in high yields. Compounds 7a-j, 9b-c, and 10b-c were tested for their antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as a control drug. The EGFR and BRAF assay tests were used to assess the inhibitory potency against EGFR and BRAF. RESULTS: Compounds 7c, 7d, 7f and 10c exhibited high proliferative activity and inhibited EGFR, which could serve as a potential target for antiproliferative activity. The most active hybrid, 7c, primarily caused cell cycle arrest in G0/G1 phase and S phase as well as cell apoptosis. Finally, the most active hybrids were docked well to the EGFR active site. CONCLUSION: 2-thioxo-3-substituted quinazolin-4-one/chalcone derivatives have significant apoptotic and antiproliferative properties.

Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.

Repurposing of carvedilol to alleviate bleomycin-induced lung fibrosis in rats: Repressing of TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions.

Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation ß-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. AIMS: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. MAIN METHODS: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. KEY FINDINGS: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. SIGNIFICANCE: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.

New antiproliferative 3-substituted oxindoles inhibiting EGFR/VEGFR-2 and tubulin polymerization.

New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a-j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC50 value of 14.77 µM compared to 5-fluorouracil (5FU) (IC50 = 2.02 µM). Notably, compound 6f hampered receptor tyrosine EGFR fundamentally with an IC50 value of 1.38 µM, compared to the reference sunitinib with an IC50 value of 0.08 µM. Moreover, compound 6f afforded anti-tubulin polymerization activity with an IC50 value of 7.99 µM as an outstanding observable activity compared with the reference combretastatin A4 with an IC50 value of 2.64 µM. In silico molecular-docking results of compound 6f in the ATP-binding site of EGFR agreed with the in vitro results. Besides, the investigation of the physicochemical properties of compound 6f via the egg-boiled method clarified good lipophilicity, GIT absorption, and blood-brain barrier penetration properties.

Metabolomics approach of Symphyotrichum squamatum ethanol extract and its nano-Ag formulation protective effect on gastric ulcer via bio-chemical and pathological analyses.

ContextGastric ulcer (GU) a widely distributed ailment is associated with many causes, including alcohol consumption.Materials and MethodsChemical profiling of Symphyotrichum squamatum ethanol extract (SSEE) was established via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-qTOF-MS) and employed in a silver nano-formulation (SSEE-N-Ag). SSEE and SSEE-N-Ag antiulcer activities were estimated against ethanol-induced rats by biochemical, histological, and metabolomics assessments. Reduced glutathione, total antioxidant capacity and prostaglandin E2 levels and gastric mucosa histopathological examination were analysed. The rats' metabolome changing alongside action pathways were elucidated via metabolite profile coupled to multivariate data analysis.ResultsUPLC-MS profiling of SSEE identified 75 components belonging to various classes. Compared with control, EtOH-treated rats showed decreased of tissue GSH, TAC and PGE2 by 62.32%, 51.85% and 47.03% respectively. SSEE and SSEE-N-Ag administration mitigated biochemical and histopathological alterations. Serum metabolomics analysis revealed for changes in several low molecular weight metabolites with ulcer development. These metabolites levels were restored to normal post-administration of SSEE-N-Ag. SSEE-N-Ag as mediated via modulating numerous metabolic pathways such as lipids, pyrimidine, energy metabolism and phosphatidylinositol signalling. This study provides novel insight for metabolic mechanisms underlying gastric ulcer relieving effect.ConclusionPresent results revealed potential antiulcer effect of SSEE and SSEE-N-Ag by decreasing ulcer-associated syndromes, supporting their anti-ulcerogenic action.

Insights on attenuating autophagy cellular and molecular pathways versus methotrexate-induced toxicity via liposomal turmeric therapy.

BACKGROUND: Methotrexate (MX), a competitive inhibitor of dihydrofolate reductase, can inhibit DNA and RNA production and is a powerful anticancer agent widely utilized in clinical practice for treating nonneoplastic maladies, as psoriasis and rheumatoid arthritis; meanwhile, its probable prescription dose and interval of administration are strictly limited due to dose-related organ damage. Former studies verified that kidney, brain, liver, and lung harms are prospective obstacles of methotrexate administration. To understand the machinery of methotrexate-prompt toxicity, various mechanisms were investigated. The former is an autophagy defense mechanism; autophagy is a self-digesting mechanism responsible for the removal of damaged organelles and malformed proteins by lysosome. The contemporary article hypothesized that turmeric or its liposomal analog could defeat autophagy of MX-induced acute toxicity. Methotrexate, in a dose of 1.5 mg/kg, was administered intravenously followed by turmeric and liposomal turmeric treatment in a dose of 5 mg/kg for 30 days in rats. RESULTS: Increment in autophagy (AUTP) consent by MX administration was attenuated by concurrent treatment via turmeric and liposomal turmeric that was reliable on the alteration in apoptotic markers. The assembly of FOXO-3 in serum post methotrexate administration was suppressed by concurrent treatment via liposomal turmeric. Apoptosis/autophagic marker investigation was evaluated through the gene expression of Bax (BCL2-associated X protein)/Bcl2 (B-cell lymphoma 2)/P53 (tumor protein P53)/SiRT-1 (sirtuin silent mating-type information regulation 2 homolog 1) and FOXO-3 (forkhead box transcription factor-3)/ERDJ-4 (endoplasmic reticulum localized DnaJ homologs)/BNP (brain natriuretic peptide B) signaling. The cell death of all cells was categorized to achieve autophagy. Interestingly, Bax/Bcl2/P53/SiRT-1 signaling pathways were downregulated, contributing to inhibiting the initiation of autophagy. Meanwhile, FOXO-3/BNP/ERDJ-4 reduction-implicated noncanonical autophagy pathways were involved in methotrexate-induced autophagy, whereas this change was suppressed when turmeric was administered in liposomal form. CONCLUSION: These outcomes recommended that liposomal turmeric prevents MX-induced acute toxicity through its autophagy, antioxidant, and antiapoptotic properties.

Design and Synthesis of New Hydantoin Acetanilide Derivatives as Anti-NSCLC Targeting EGFRL858R/T790M Mutations.

Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFRL858R/T790M inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which 5a and 5f were the most potent. Compounds 5a and 5f possessed potent anticancer activity on H1975 cells with IC50 values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, 5a and 5f showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of 5a. Besides, active hydantoin derivative 5a strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that 5a could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy.

The protective and therapeutic effects of 5-androstene3ß, 17ß-diol (ADIOL) in abdominal post-operative adhesions in rat: Suppressing TLR4/NFκB/HMGB1/TGF1 ß/α SMA pathway.

Neurosteroid, 5-androstenediol (ADIOL) had been experimentally applied to protect against many diseases as it had anti-oxidant, anti-inflammatory, and anti-apoptotic effects. In our study, we investigate its role in abdominal postoperative adhesion (APA) formations. Our results demonstrate that ADIOL alleviates APA formation after induction by cecal abrasion (CA) model in the male rat. Interestingly, per administration of ADIOL before APA induction leads to inhibit oxidative stress by increasing superoxide dismutase (SOD) and decreasing Malondialdehyde (MAD) levels to a similar level to the sham group, in addition inhibiting inflammatory pathway by decreasing toll-like receptor 4 (TLR4), nuclear factor kappa-B (NFκB), and High mobility group box 1 (HMGB1) to a similar level to the sham group, furthermore decreasing Transforming growth factor beta 1 (TGFß1) and alpha Smooth muscle -actin (α SMA) levels to similar levels in the sham group. While administration of ADIOL after APA induction lead to decrease adhesions formation by decreasing oxidative stress (↓MDA and ↑SOD levels), inflammatory markers (↓TLR4, ↓NFκB, and ↓HMGB1levels), and collagen deposition by (↓TGF1 ß and↓α SMA levels) is the highly significant manner to those levels in CA model but also significant to those levels in the sham group. Concluded that, pre-administration of ADIOL before APA induction was more effective than its administration after adhesions formations.

ß-Sitosterol Glucoside-Loaded Nanosystem Ameliorates Insulin Resistance and Oxidative Stress in Streptozotocin-Induced Diabetic Rats.

ß-Sitosterol glucoside (SG), isolated from Senecio petasitis (Family Asteraceae), was loaded in self-nanoemulsifying drug delivery systems (SEDDS) in a trial to enhance its solubility and biological effect. Various co-surfactants were tested to prepare a successful SEDDS. The selected SG-loaded SEDDS had a droplet size of 134 ± 15.2 nm with a homogenous distribution (polydispersity index 0.296 ± 0.02). It also demonstrated a significant augmentation of SG in vitro release by 4-fold compared to the free drug suspension. The in vivo insulin sensitivity and antidiabetic effect of the prepared SG-loaded SEDDS were further assessed in streptozotocin-induced hyperglycemic rats. The hypoglycemic effect of SG-loaded nanosystem was evidenced by decreased serum glucose and insulin by 63.22% and 53.11%, respectively. Homeostasis model assessment-insulin resistance (HOMA-IR) index demonstrated a significant reduction by 5.4-fold in the diabetic group treated by SG-loaded nanosystem and exhibited reduced glucagon level by 40.85%. In addition, treatment with SG-loaded nanosystem significantly decreased serum MDA (malondialdehyde) and increased catalase levels by 38.31% and 64.45%, respectively. Histopathological investigations also supported the protective effect of SG-loaded nanosystem on the pancreas. The promising ability of SG-loaded nanosystem to ameliorate insulin resistance, protect against oxidative stress, and restore pancreatic ß-cell secretory function warrants its inclusion in further studies during diabetes progression.

Protective Effects of Naringenin from Citrus sinensis (var. Valencia) Peels against CCl4-Induced Hepatic and Renal Injuries in Rats Assessed by Metabolomics, Histological and Biochemical Analyses.

Citrus fruits are grown worldwide for their special nutritive and several health benefits. Among citrus bioactives, naringenin, a major flavanone, exhibits a potential hepatoprotective effect that is not fully elucidated. Herein, serum biochemical parameters and histopathological assays were used to estimate the hepatoprotective activity of naringenin, isolated from Citrus sinensis (var. Valencia) peels, in CCl4-induced injury in a rat model. Further, GC-MS-based untargeted metabolomics was used to characterize the potential metabolite biomarkers associated with its activity. Present results revealed that naringenin could ameliorate the increases in liver enzymes (ALT and AST) induced by CCl4 and attenuate the pathological changes in liver tissue. Naringenin decreased urea, creatinine and uric acid levels and improved the kidney tissue architecture, suggesting its role in treating renal disorders. In addition, naringenin increased the expression of the antiapoptoic cell marker, Bcl-2. Significant changes in serum metabolic profiling were noticed in the naringenin-treated group compared to the CCl4 group, exemplified by increases in palmitic acid, stearic acid, myristic acid and lauric acids and decrease levels of alanine, tryptophan, lactic acid, glucosamine and glucose in CCl4 model rats. The results suggested that naringenin's potential hepato- and renoprotective effects could be related to its ability to regulate fatty acids (FAs), amino acids and energy metabolism, which may become effective targets for liver and kidney toxicity management. In conclusion, the current study presents new insights into the hepato- and renoprotective mechanisms of naringenin against CCl4-induced toxicity.

Gastro-protective effect of Artemisia Sieberi essential oil against ethanol-induced ulcer in rats as revealed via biochemical, histopathological and metabolomics analysis.

CONTEXT: Gastric ulcer is regarded as one of the main clinical ailments with high morbidity and mortality rates. MATERIALS AND METHODS: Gastro-protective effect of Artemisia sieberi essential oil (AS-EO) in ethanol-induced rats was evaluated via biochemical, histopathological and large-scale metabolomics analyses. Glutathione (GSH), total antioxidant capacity (TAC), prostaglandin (PGE2) and tumour necrosis factor α (TNF-α) alongside with histopathological examination of gastric mucosa were analysed. Metabolites profiling coupled to Global Natural Products Social molecular networking platform (GNPS) and multivariate data analyses to reveal for changes in rats metabolome with treatments and involved action mechanisms. RESULTS: Pre-treatment with 100 and 200 mg/kg of AS-EO in EtOH-treated rats restored all parameters towards normal status compared to disease model. AS-EO alleviated the histological and pathological damage of gastric tissue caused by ethanol. Metabolites profiling revealed an increase in uracil, cholesterol and fatty acids/fatty acyl amides levels in ulcer rats and restored to normal levels post AS-EO intervention. These results indicated the efficacy of AS-EO in a dose-dependent manner, and to exert protective effects in ulcer rat model by targeting several metabolic pathways viz. lipid, energy, and nucleotide metabolisms. CONCLUSION: AS-EO adds to the known uses of genus Artemisia as anti-ulcerogenic agent by attenuating oxidative stress and inflammatory responses associated with an ulcer. Several novel biomarkers for ulcer progression in rats were identified and have yet to be confirmed in human models.

Design, synthesis, in vitro antiproliferative evaluation and in silico studies of new VEGFR-2 inhibitors based on 4-piperazinylquinolin-2(1H)-one scaffold.

Angiogenesis is essential in the growth of solid tumors which need oxygen and nutrients supply to grow in size. The VEGF/VEGFR-2 signaling pathway plays an important role in tumor angiogenesis. Sorafenib is an FDA approved cancer therapeutic with activity against many protein kinases, including VEGFR. We designed 4-piperazinylquinolin-2(1H)-ones with variable aromatic moieties and Mannich bases as Sorafenib analogues as potential inhibitors of angiogenesis. In this study, we investigated the impact of replacing the linker aromatic ring with cyclic tertiary amines and the effect of incorporation of variably substituted distal rings. We hypothesized that cyclic tertiary amines would improve pharmacokinetic properties and contribute to enzyme interactions. Two series of piperazinylquinolinone-based compounds were synthesized, characterized, and evaluated for bioactivity against adenocarcinoma EKVX NSCLC and T-47D breast cancer cells. Ability to inhibit VEGFR-2 and apoptosis were investigated and molecular docking into the enzyme active site and theoretical ADME properties were determined. Notably, amongst series I three compounds exhibited higher anticancer activity than Staurosporine against EKVX NSCLC adenocarcinoma cell line. In series II, nine compounds exhibited higher antiproliferative activity than Staurosporine against T-47D breast cancer cell line. Two compounds; 5d and 7z exhibited lower toxicity against normal cell line (MCF 10A) than Staurosporine. Compound 7z was the most potent agent with IC50 38.76 nM. Moreover, 7z showed VEGFR-2 inhibitory activity higher than sorafenib and induced remarkable levels of both early and late apoptosis (2.82% and 21.30%, respectively). Hence, 5d and 7z are considered promising VEGFR-2 inhibitors with high efficacy against adenocarcinoma EKVX and T-47D breast cancer cells. The target compounds also possessed favorable physicochemical properties and pharmacokinetic parameters These studies further suggested that the 4-piperazinylquinolin-2(1H)-one derivatives developed in this study play a critical role in modulating VEGFR, and guide the design of innovative anticancer therapies.

First Report of Two Egyptian Patients with Desbuquois Dysplasia due to Homozygous CANT1 Mutations.

Desbuquois dysplasia type 1 (DBQD1) is a very rare skeletal dysplasia characterized by growth retardation, short stature, distinct hand features, and a characteristic radiological monkey wrench appearance at the proximal femur. We report on 2unrelated Egyptian patients having the characteristic features of DBQD1 with different expressivity. Patient 1 presented at the age of 45 days with respiratory distress, short limbs, faltering growth, and distinctive facies while patient 2 presented at 5 years of age with short stature and hypospadias. The 2 patients shared radiological features suggestive of DBQD1. Whole-exome sequencing revealed a homozygous frameshift mutation in the CANT1 gene (NM_001159772.1:c.277_278delCT; p.Leu93ValfsTer89) in patient 1 and a homozygous missense mutation (NM_138793.4:c.898C>T; p.Arg300Cys) in patient 2. Phenotypic variability and variable expressivity of DBQD was evident in our patients. Hypoplastic scrotum and hypospadias were additional unreported associated findings, thus expanding the phenotypic spectrum of the disorder. We reviewed the main features of skeletal dysplasias exhibiting similar radiological manifestations for differential diagnosis. We suggest that the variable severity in both patients could be due to the nature of the CANT1 gene mutations which necessitates the molecular study of more cases for phenotype-genotype correlations.

Quaternary diagnostics scheme for mucolipidosis II and detection of novel mutation in GNPTAB gene.

BACKGROUND: Mucolipidosis II (ML II α/ß) is an inherited lysosomal storage disorder caused by deficiency of GlcNAc-phosphotransferase enzyme and results in mis-targeting of multiple lysosomal enzymes. Affected patients are characterized by skeletal deformities and developmental delay. Homozygous or compound heterozygous mutations in GNPTAB gene are associated with the clinical presentation. This is the first study to characterize the underlying genetics of ML among a cohort of Egyptian patients. ML II diagnosis established by clinical assessment, biochemical evaluation of enzymes, electron microscopy examination of gingival inclusion bodies, and molecular study of GNPTAB gene using targeted next-generation sequencing panel in 8 patients form 8 unrelated Egyptian families. RESULTS: Sequencing revealed 3 mutations in GNPTAB gene; 1 novel frame-shift mutation in exon 19 (c.3488_3488delC) and 2 previously reported mutations (c.1759C>T in exon 13 and c.3503_3504delTC in exon 19). All patients were homozygous for their corresponding mutations and the parents were consanguineous. CONCLUSIONS: According to the established quaternary diagnostic scheme, ML II was the final diagnosis in eight patients. The most common mutation was the frame shift c.3503_3504delTC mutation, found in 5 patients and associated with a severe phenotype.