Targeting the PI3K/pAKT/mTOR/NF-κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk.

Liver malignancy is well recognized as a prominent health concern, with numerous treatment options available. Natural products are considered a renewable source, providing inspiring chemical moieties that could be used for cancer treatment. Suaeda vermiculata Forssk has traditionally been employed for management of hepatic conditions, including liver inflammation, and liver cirrhosis, as well as to improve general liver function. The findings of our earlier study demonstrated encouraging in vivo hepatoprotective benefits against liver injury generated by paracetamol and carbon tetrachloride. Additionally, Suaeda vermiculata Forssk exhibited cytotoxic activities in vitro against Hep-G2 cell lines and cell lines resistant to doxorubicin. The present investigation aimed to examine the potential in vivo hepatoprotective efficacy of Suaeda vermiculata Forssk extract (SVE) against hepatocellular carcinoma induced by diethylnitrosamine (DENA) in rats. The potential involvement of the PI3K/AKT/mTOR/NF-κB pathway was addressed. Sixty adult male albino rats were allocated into five groups randomly (n = 10). First group received a buffer, whereas second group received SVE only, third group received DENA only, and fourth and fifth groups received high and low doses of SVE, respectively, in the presence of DENA. Liver toxicity and tumor markers (HGFR, p-AKT, PI3K, mTOR, NF-κB, FOXO3a), apoptosis markers, and histopathological changes were analyzed. The current results demonstrated that SVE inhibited PI3K/AKT/mTOR/NF-κB pathway as well as increased expression of apoptotic parameters and FOXO3a levels, which were deteriorated by DENA treatment. Furthermore, SVE improved liver toxicity markers and histopathological changes induced by DENA administration. This study provided evidence for the conventional hepatoprotective properties attributed to SV and investigated the underlying mechanism by which its extract, SVE, could potentially serve as a novel option for hepatocellular carcinoma (HCC) treatment derived from a natural source.

Involvement of PI3K/HIF-1α/c-MYC/iNOS Pathway in the Anticancer Effect of Suaeda vermiculata in Rats.

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study evaluated the protective effect of SV, administered against N-diethylnitrosamine (NDEA)-induced HCC in rats. The possible modulatory effect of SV on the PI3K/HIF-1α/c-MYC/iNOS pathway was investigated. Sixty male adult albino rats (200 ± 10 g) were equally classified into five groups. Group I served as a control; Group 2 (SV control group) received SV (p.o., 200 mg/kg body weight); Group 3 (NDEA-administered rats) received freshly prepared NDEA solution (100 mg/L); and Groups 4 and 5 received simultaneously, for 16 weeks, NDEA + SV extract (100 and 200 mg/kg, orally). NDEA-treated rats displayed significant increases in serum levels of AFP, CEA, PI3K, malondialdehyde (MDA), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGFR), with increased liver tissue protein expression of fibrinogen concomitant and significantly decreased concentrations of antioxidant parameters (catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH)) in comparison to normal rats. On the flip side, AFP, CEA, PI3K, MDA, EGFR, and VEGFR serum levels were significantly reduced in rats that received NDEA with SV, both at low (SV LD) and high (SV HD) doses, accompanied by significant improvements in antioxidant parameters compared to the NDEA-treated group. Conclusions: SV possesses a significant hepatoprotective effect against NDEA-induced HCC via inhibiting the PI3K/HIF-1α/c-MYC/iNOS pathway, suggesting that SV could be a promising hepatocellular carcinoma treatment.

Characterization of Promising Cytotoxic Metabolites from Tabebuia guayacan Hemsl.: Computational Prediction and In Vitro Testing.

Genus Tabebuia is famous for its traditional uses and valuable phytoconstituents. Our previous investigation of Tabebuia species noted the promising anticancer activity of T. guayacan Hemsl. leaves extract, however, the mechanism underlying the observed anticancer activity is still unexplored. The current research was designed to explore the phytochemical content as well as to address the phytoconstituent(s) responsible for the recorded anticancer activity. Accordingly, sixteen compounds were isolated, and their structures were elucidated using different spectroscopic techniques. The drug-likeness of the isolated compounds, as well as their binding affinity with four anticancer drug target receptors: CDK-2/6, topoisomerase-1, and VEGFR-2, were evaluated. Additionally, the most promising compounds were in vitro evaluated for inhibitory activities against CDK-2/6 and VEGFR-2 enzymes using kinase assays method. Corosolic acid (3) and luteolin-7-O-ß-glucoside (16) were the most active inhibitors against CDK-2 (-13.44 kcal/mol) and topoisomerase 1 (-13.83 kcal/mol), respectively. Meanwhile, quercetin 3-O-ß-xyloside (10) scored the highest binding free energies against both CDK-6 (-16.23 kcal/mol) as well as against VEGFR-2 protein targets (-10.39 kcal/mol). Molecular dynamic simulation indicated that quercetin 3-O-ß-xyloside (10) exhibited the least fluctuations and deviations from the starting binding pose with RMSD (2.6 Å). Interestingly, in vitro testing results confirmed the potent activity of 10 (IC50 = 0.154 µg/mL) compared to IC50 = 0.159 µg/mL of the reference drug ribociclib. These findings suggest the three noted compounds (3, 10, and 16) for further in vivo anticancer studies.

Simvastatin mitigates streptozotocin-induced type 1 diabetes in mice through downregulation of ADAM10 and ADAM17.

BACKGROUND: T cell mediates immune response in type 1 diabetes mellitus (T1DM) through its trafficking into pancreatic islets. The role of A Disintigrin And Metalloproteinase 10 (ADAM10) and 17 (ADAM17) in pancreatic T-cells recruitment into the pancreatic islets during T1DM is not known. AIM: Explore the role of ADAM10 and ADAM17 in the processing of CXCL16 in T1DM and possible protective effect of simvastatin (SIM) in streptozotocin (STZ)-induced T1DM. MAIN METHODS: Balb/c mice were classified into 4 groups, 10 each. Control group received buffer while SIM group received 50 mg/kg, i.p daily for 12 days starting from day 4 of the experiment. Diabetic group; received STZ (55 mg/kg, i.p.) for 5 consecutive days starting from day 1 of the experiment. SIM + STZ group; received SIM (50 mg/kg, i.p.) daily for 12 days and STZ (55 mg/kg, i.p.) for 5 consecutive days. Biochemical, inflammatory and apoptotic markers as well as expression of CXCL16, ADAM10, NF-κB and pancreatic T-cells expression were analyzed. KEY FINDINGS: Significant increase in biochemical, inflammatory, apoptotic parameters, expression of ADAM10, ADAM17, CXCL16, NF-κB, and infiltrated T-cells to the pancreatic islets were found in STZ group. SIM treatment in the presence of STZ improved biochemical and inflammatory parameters as well as it reduced the expression of CXCL16, ADAM10, ADAM17, NF-κΒ, T-cells migration and apoptosis in the pancreatic islets. SIGNIFICANCE: SIM mitigated pancreatic ß-cell death induced by STZ through down regulation of ADAM10, ADAM17and CXCL16. Therefore, ADAM10/ADAM17 and CXCL16 may serve as novel therapeutic targets for T1DM.

Mental depression: Relation to different disease status, newer treatments and its association with COVID-19 pandemic (Review).

The present study aimed to review major depression, including its types, epidemiology, association with different diseases status and treatments, as well as its correlation with the current COVID-19 pandemic. Mental depression is a common disorder that affects most individuals at one time or another. During depression, there are changes in mood and behavior, accompanied by feelings of defeat, hopelessness, or even suicidal thoughts. Depression has a direct or indirect relation with a number of other diseases including Alzheimer's disease, stroke, epilepsy, diabetes, cardiovascular disease and cancer. In addition, antidepressant drugs have several side effects including sedation, increased weight, indigestion, sexual dysfunction, or a decrease in blood pressure. Stopping medication may cause a relapse of the symptoms of depression and pose a risk of attempted suicide. The pandemic of COVID-19 has affected the mental health of individuals, including patients, individuals contacting patients and medical staff with a number of mental disorders that may adversely affect the immune ability of their bodies. Some of the drugs currently included in the protocols for treating COVID-19 may negatively affect the mental health of patients. Evidence accumulated over the years indicates that serotonin (5HT) deficiencies and norepinephrine (NE) in the brain can lead to mental depression. Drugs that increase levels of NE and 5HT are commonly used in the treatment of depression. The common reason for mood disorders, including mania and bipolar disease are not clearly understood. It is assumed that hyperactivity in specific parts of the brain and excessive activity of neurotransmitters may be involved. Early diagnosis and developing new treatment strategies are essential for the prevention of the severe consequences of depression. In addition, extensive research should be directed towards the investigation of the mental health disturbances occurring during and/or after COVID-19 infection. This may lead to the incorporation of a suitable antidepressant into the current treatment protocols.

Metabolic profiling of cytotoxic metabolites from five Tabebuia species supported by molecular correlation analysis.

Tabebuia is the largest genus among the family Bignoniaceae. Tabebuia species are known for their high ornamental and curative value. Here, the cytotoxic potential of extracts from the leaves and stems of five Tabebuia species was analyzed. The highest activity was observed for T. rosea (Bertol.) DC. stem extract against HepG2 cell line (IC50 4.7 µg/mL), T. pallida L. stem extract against MCF-7 cell line (IC50 6.3 µg/mL), and T. pulcherrima stem extract against CACO2 cell line (IC50 2.6 µg/mL). Metabolic profiling of the ten extracts using liquid chromatography-high-resolution mass spectrometry for dereplication purposes led to annotation of forty compounds belonging to different chemical classes. Among the annotated compounds, irridoids represent the major class. Principle component analysis (PCA) was applied to test the similarity and variability among the tested species and the score plot showed similar chemical profiling between the leaves and stems of both T. pulcherrima and T. pallida L. and unique chemical profiling among T. rosea (Bertol.) DC., T. argentea Britton, and T. guayacan (Seem.) Hemsl. leaf extracts and the stem extract of T. rosea (Bertol.) DC. Additionally, a molecular correlation analysis was used to annotate the bioactive cytotoxic metabolites in the extracts and correlate between their chemical and biological profiles.

Anti-Inflammatory and Antioxidant Activities of Terpene- and Polyphenol-Rich Premna odorata Leaves on Alcohol-Inflamed Female Wistar Albino Rat Liver.

Premna odorata Blanco (Lamiaceae) is an ethnomedicinal plant native to different tropical regions. Although some reports addressed their anti-inflammatory, cytotoxic, and antituberculotic effects, their hepatoprotective potential is yet to be discovered. Accordingly, this study investigated the crude extract and different fractions of the plant leaves; metabolic profiling using liquid chromatography/high-resolution electrospray ionization mass spectroscopy (LC-HRESIMS) analysis, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties for the dereplicated metabolite via online PreADMET program, ROS scavenger activity on the Hep G2 human liver cancer cell line, and the possible hepatic cellular treatment effects in alcohol-inflamed liver female Wistar albino rats. Metabolic profiling dereplicated a total of 28 metabolites from the crude extract and its various fractions. In silico ADMET and ROS scavenger activity screening suggested plant metabolites are of potential bioactivity. In vivo hepatic treatment with crude, defatted crude, and n-hexane leave extracts suggested all extracts significantly improved liver damage, which was indicated by the reduction of elevated serum levels of bilirubin, AST, ALT, ALP, CRP, TNF-α, ICAM-1, VCAM-1, and MDA. The reduced levels of GSH and TAC were normalized during the study. Histological examinations of liver tissue showed collagen fiber distribution nearly back to its normal pattern. The anti-inflammatory and antioxidant potentials of Premna odorata extracts could be partly related to the combined effects of these phytochemicals or their synergistic interactions.

Cytotoxic Activity and Metabolic Profiling of Fifteen Euphorbia Species.

Euphorbia is a large genus of flowering plants with a great diversity in metabolic pattern. Testing the cytotoxic potential of fifteen Euphorbia species revealed highest activity of E. officinarum L. against CACO2 cell line (IC50 7.2 µM) and of E. lactea Haw. against HepG2 and MCF-7 cell lines (IC50 5.2 and 5.1 µM, respectively). Additionally, metabolic profiling of the fifteen tested species, using LC-HRMS, for dereplication purposes, led to the annotation of 44 natural compounds. Among the annotated compounds, diterpenoids represent the major class. Dereplication approach and multivariate data analysis are adopted in order to annotate the compounds responsible for the detected cytotoxic activity. Results of PCA come in a great accordance with results of biological testing, which emphasized the cytotoxic properties of E. lactea Haw. A similarity correlation network showed that the two compounds with the molecular formula C16H18O8 and C20H30O10, are responsible for cytotoxic activity against MCF-7 and HepG2 cell lines. Similarly, the compound with molecular formula C18H35NO correlates with cytotoxic activity against CACO2.

Bioactive Brominated Oxindole Alkaloids from the Red Sea Sponge Callyspongia siphonella.

In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.

New Antiproliferative Cembrane Diterpenes from the Red Sea Sarcophyton Species.

The combination of liquid chromatography coupled to high resolution mass spectrometry (LC-HRESMS)-based dereplication and antiproliferative activity-guided fractionation was applied on the Red Sea-derived soft coral Sarcophyton sp. This approach facilitated the isolation of five new cembrane-type diterpenoids (1-5), along with two known analogs (6 and 7), as well as the identification of 19 further, known compounds. The chemical structures of the new compounds were elucidated while using comprehensive spectroscopic analyses, including one-dimensional (1D) and two-dimensional (2D) NMR and HRMS. All of the isolated cembranoids (1-7) showed moderate in vitro antiproliferative activity against a human breast cancer cell line (MCF-7), with IC50 ranging from 22.39-27.12 µg/mL. This class of compounds could thus serve as scaffold for the future design of anticancer leads.

Epigenetic Modifiers Induce Bioactive Phenolic Metabolites in the Marine-Derived Fungus Penicillium brevicompactum.

Fungi usually contain gene clusters that are silent or cryptic under normal laboratory culture conditions. These cryptic genes could be expressed for a wide variety of bioactive compounds. One of the recent approaches to induce production of such cryptic fungal metabolites is to use histone deacetylases (HDACs) inhibitors. In the present study, the cultures of the marine-derived fungus Penicillium brevicompactum treated with nicotinamide and sodium butyrate were found to produce a lot of phenolic compounds. Nicotinamide treatment resulted in the isolation and identification of nine compounds 1⁻9. Sodium butyrate also enhanced the productivity of anthranilic acid (10) and ergosterol peroxide (11). The antioxidant as well as the antiproliferative activities of each metabolite were determined. Syringic acid (4), sinapic acid (5), and acetosyringone (6) exhibited potent in vitro free radical scavenging, (IC50 20 to 30 µg/mL) and antiproliferative activities (IC50 1.14 to 1.71 µM) against HepG2 cancer cell line. Furthermore, a pharmacophore model of the active compounds was generated to build up a structure-activity relationship.

Development and Validation of a Practical Two-Step Prediction Model and Clinical Risk Score for Post-Thrombotic Syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a common chronic consequence of deep vein thrombosis that affects the quality of life and is associated with substantial costs. In clinical practice, it is not possible to predict the individual patient risk. We develop and validate a practical two-step prediction tool for PTS in the acute and sub-acute phase of deep vein thrombosis. METHODS: Multivariable regression modelling with data from two prospective cohorts in which 479 (derivation) and 1,107 (validation) consecutive patients with objectively confirmed deep vein thrombosis of the leg, from thrombosis outpatient clinic of Maastricht University Medical Centre, the Netherlands (derivation) and Padua University hospital in Italy (validation), were included. PTS was defined as a Villalta score of ≥ 5 at least 6 months after acute thrombosis. RESULTS: Variables in the baseline model in the acute phase were: age, body mass index, sex, varicose veins, history of venous thrombosis, smoking status, provoked thrombosis and thrombus location. For the secondary model, the additional variable was residual vein obstruction. Optimism-corrected area under the receiver operating characteristic curves (AUCs) were 0.71 for the baseline model and 0.60 for the secondary model. Calibration plots showed well-calibrated predictions. External validation of the derived clinical risk scores was successful: AUC, 0.66 (95% confidence interval [CI], 0.63-0.70) and 0.64 (95% CI, 0.60-0.69). CONCLUSION: Individual risk for PTS in the acute phase of deep vein thrombosis can be predicted based on readily accessible baseline clinical and demographic characteristics. The individual risk in the sub-acute phase can be predicted with limited additional clinical characteristics.

Acylated Iridoids and Rhamnopyranoses from Premna odorata (Lamiaceae) as Novel Mesenchymal-Epithelial Transition Factor Receptor Inhibitors for the Control of Breast Cancer.

Phytochemical investigation of Premna odorata Blanco, Lamiaceae, leaves afforded three new acylated iridoid glycosides 1-3 and two new acylated rhamnopyranoses 9 and 10, in addition to ten known compounds. The structures of the new compounds were confirmed using extensive 1D and 2D NMR analysis. Molecular modeling study suggested the potential of the acylated rhamnopyranoses to bind at the c-Met kinase domain. Cell-free Z'-LYTE™ assay testing revealed the good c-Met phosphorylation inhibitory activity of 9, followed by 8, and 10, with IC50 values of 2.5, 6.9, and 12.7 µM, respectively. The (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay testing against the human c-Met expressing highly invasive MDA-MB-231 suggested compound 9 as the most active with IC50 value of 13.3 µM. Testing of compound 9 against multiple phenotypic breast cancer cell lines including MCF-7, BT-474 cells, and MDA-MB-468 proved enhanced activity against the highly c-Met expressing triple-negative breast cancer cell lines. Acylated rhamnopyranoses are potential novel c-Met inhibitors appropriate for future optimizations to control c-Met-dependent breast malignancies. Copyright © 2017 John Wiley & Sons, Ltd.

Chemical Composition and Biting Deterrent Activity of Essential Oil of Tagetes patula (Marigold) against Aedes aegypti.

The hydrodistilled leaf essential oil (EO) of Tagetes patula L. was analyzed by GC-FID and GC-MS. The main components of the oil were characterized as caryophyllene oxide (18.4%), p-caryophyllene (18.0%) and spathulenol (9.1%). The EO was screened for its biting deterrent activity against Aedes aegypti L. using the in vitro K&D module system. T. patula EO exhibited good biting deterrent activity. The results suggest that these sesquiterpenes may contribute to biting deterrent activity, but the role of minor components cannot be excluded. T. patula EO also showed 100, 90 and 10% mortality at dosages of 125, 62.5 and 31.25 ppm, respectively, in I-day-old larvae of Ae. aegypt.