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Olea europaea is an evergreen tree used for centuries to produce oil, diet, and medicines. The olive leaves extract (OLE) was investigated thoroughly to identify its phytochemical components and its bioactivities, since it showed remarkable pharmacological effect for prevention and treatment experimentally induced metabolic diseases such as cataract, we decided to reveal how active constituents found in OLE exert their actions using in silico tools and literature survey. The in silico studies showed the ability of several compounds in OLE to inhibit multiple pathways that contribute in cataract formations such as proliferator peroxisome–activated receptor alpha, aldose reductase, and calpain-1, which was supported by several studies that also showed that OLE polyphenolic prevents advanced glycation end products formation. Since the control of metabolic diseases usually requires more than therapeutic agent, it is safe to consider OLE as a perfect candidate; however, more clinical trials are needed to ensure its safety and effectiveness.

Objective: The current study aimed to investigate and compare the efficiency of the total extract and ethyl acetate (EtOAc) extract of Mangifera indica leaves to attenuate iron overload-induced hepatic and splenic dysfunctions, using an in-vivo iron-overload rat model. Methods: Rats received water supplemented with iron for 2 months, followed by treatment with either total extract or EtOAc extract of M. indica leaves for an extra 2 months. Results: Rats treated with EtOAc fraction of M. indica leaves, and the total extract, had significantly diminished iron accumulation within hepatic and splenic tissues. Both extracts normalized the hepatic enzymatic and non-enzymatic biomarkers like alkaline phosphatase (ALP), alanine aminotransferase (AST), and total bilirubin. Moreover, they restored the oxidants/antioxidants balance within the liver and spleen tissues. Additionally, they suppressed HO-1 levels, increased Nrf2 expression, and downregulated MMP-9 expression. Conclusion: Briefly, M. indica extracts showed iron-chelation, antioxidant, and antifibrotic potentials. These findings pointed out the usefulness of the mango leaves as a natural, affordable by-product in managing iron overload complications. However, the results also demonstrated that EtOAc extract is more accountable for such activities.

A new lupane caffeoyl ester, lup-20(29)-ene 3β-caffeate-30-al (7), and a new oleanane-type triterpene, 3β-hydroxyolean-13(18)-en-12-one (17), were isolated from the aerial parts of Dobera glabra (Forssk), along with ten known triterpenes, including seven lupane-type lupeol (1), 30-nor-lup-3β-ol-20-one (2), ∆1-lupenone (3), lup-20(29)-en-3β,30-diol (4), lupeol caffeate (5), 30-hydroxy lup-20(29)-ene 3β-caffeate (6), and betunaldehyde (8); three oleanane-type compounds were also identified, comprising δ-amyrone (15), δ-amyrin (16), and 11-oxo-β-amyrin (18); together with six sterols, comprising β-sitosterol (9), stigmasterol (10), 7α-hydroxy-β-sitosterol (11), 7α-hydroxy-stigmasterol (12), 7-keto-β-sitosterol (13), and 7-keto-stigmasterol (14). Their structures were elucidated using a variety of spectroscopic techniques, including 1D (1H, 13C, and DEPT-135 13C) and 2D (1H–1H COSY, 1H–13C HSQC, and 1H–13C HMBC) nuclear magnetic resonance (NMR) and accurate mass spectroscopy. Subsequently, the different plant extracts and some of the isolated compounds (1–9, 11 and 13) were investigated for their possible cytotoxic activity in comparison to cisplatin against a wide array of aggressive cancer cell lines, such as colorectal cancer (HCT-116), hepatocellular carcinoma (HepG-2), and prostate cancer (PC-3) cell lines. Compound 11 displayed broad cytotoxicity against all of the tested cell lines (IC50 ≅ 8 µg/mL in all cases), and a high safety margin against normal Vero cells (IC50 = 70 µg/mL), suggesting that 11 may be a highly selective and effective anticancer agent candidate. Notably, the evidence indicated that the mode of action of compound 11 could possibly consist of the inhibition of phosphodiesterase I (80.2% enzyme inhibition observed at 2 µM compound concentration).

Background Hepatocellular carcinoma (HCC) is the second most common cancer-related death in the world. No effective curative option exists for the treatment of HCC. The available drugs exhibit severe toxic effects and low therapeutic index. Aim This work aimed to examine different monocationic arylthiophene derivatives for possible use as chemotherapeutic agents against HCC. Methods The IC50 values for the compounds were determined. The mechanism of cytotoxicity was further investigated using different methods. Results Compound 2j proved to retain the highest cytotoxicity in comparison to as a positive control. The selectivity index of compound 2j revealed the safety to normal cells. Moreover, compound 2j was able to inhibit HepG2 cells´ migration and division. The anticancer effect of compound 2j was found to be partially via cell cycle arrest, activation of the tumour suppressor p53 protein, and induction of apoptosis via both intrinsic and extrinsic pathways. Compound 2j has a potential sensitization activity and significantly reduced the IC50 values for the anticancer drugs doxorubicin, cisplatin, and taxol. Conclusion The tested arylthiophenes showed a potent cytotoxicity against HepG2 cells and were safe to normal cells. The most active compound 2j was found to be able to inhibit cell division and migration and also to induce apoptosis. Compound 2j also proved to have a sensitization effect on standard anticancer drugs.

Sodium valproate (SV) is an antiepileptic drug that is widely used in the treatment of different seizure disorders. The topical SV has a hair regenerative potential through activating the Wnt/&beta, catenin pathway and anagen phase induction. The aim of the current investigation was to fabricate nanospanlastics of SV for improving its dermal delivery by providing prolonged drug effect and increasing its permeability for treatment of androgenic alopecia (AGA). SV-loaded nanospanlastics were formulated according to 23 factorial design by ethanol injection method using a non-ionic surfactant (Span 60) and edge activators (EAs), such as Tween 80 and Cremophor RH 40, to explore the influence of different independent variables on entrapment efficiency (EE%) and percentage drug released after 12 h (Q12h) in order to choose the optimized formula using Design-Expert software. The optimized formula (F8) appeared as spherical deformable vesicles with EE% of 90.32 &plusmn, 2.18% and Q12h of 90.27 &plusmn, 1.98%. F8 exhibited significant improvement of ex vivo permeation than free SV. The clinical study exhibited no comparable difference between F8 and marketed minoxidil lotion. However, F8 demonstrates less adverse effects than minoxidil lotion. Nanospanlastics could be a safe and effective method for improving the topical delivery of SV in the management of AGA.

The withdrawal of several blockbuster drugs due to severe adverse effects and the failure of several developed drugs in clinical trials raised questions about the efficacy of current approaches of drug discovery. Moreover, the limitation of resources and the long and costive process of drug discovery made a lot of pharmaceutical companies to employ drug repurposing strategies to get new insights about activities that were not considered during their initial discovery. The development of therapeutics for treatment of dermatological condition is not considered as priority although it affects the lifestyle of thousands of people around the world. Serendipity and observations have contributed significantly in this field but immerse efforts have been exerted to find systematic methods to identify new indications for drugs, especially with the unprecedented progress in molecular biology and omics. So, in this chapter, we will emphasize on different approaches used for drug repositioning and how it was applied to find new therapeutics for different dermatoses.

Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71–89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC50 = 7 ± 0.27 µM, SI: 3.7), and HepG2 (IC50 = 5.5 ± 0.2 µM, SI: 4.7) in comparison to (IC50 = 12.6 ± 0.5, SI: 0.4 and 5.5 ± 0.3 µM, SI: 0.9, respectively). Compound 4k was less active (IC50 = 6 ± 0.3 µM, SI: 4.3) than cisplatin (IC50 = 5 ± 0.56 µM, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.

A one-pot, single-step, and an atom-economical process towards the synthesis of highly functionalized spirooxindoles analogues was efficiently conducted to produce a satisfactory chemical yields (70&ndash, 93%) with excellent relative diastereo-, and regio-selectivity. An in vitro antiproliferative assay was carried out on different cancer cell lines to evaluate the biological activity of the synthesized tetrahydro-1&rsquo, H-spiro[indoline-3,5&rsquo, pyrrolo[1,2-c]thiazol]-2-one 5a&ndash, n. The prepared hybrids were then tested in vitro for their antiproliferative effects against three cancer cell lines, namely, HepG2 (liver cancer), MCF-7 (breast cancer), and HCT-116 (colon cancer). The spirooxindole analogue 5g exhibited a broad activity against HepG2, MCF-7, and HCT-116 cell lines of liver, breast, and colorectal cancers when compared to cisplatin. Modeling studies including shape similarity, lipophilicity scores, and physicochemical parameters were calculated. The results of this study indicated that spirooxindole analogue 5g retained a good physiochemical parameters with acceptable lipophilicity scores.

Liver cirrhosis, the end stage of chronic liver disease, is one of the major risk factors for the development of liver cancer, and may result in premature death. This research proposes a fuzzy fibrosis decision support (F2DS) system. It is a fuzzy knowledge-based expert system for liver fibrosis stage prediction. F2DS is carefully based on a set of knowledge acquisition and machine learning techniques. In addition, the system depends on domain expert knowledge for designing the membership functions and validating the fuzzy knowledge base. It depends on a suitable list of 17 symptoms, and laboratory test features that can accurately and significantly describe fibrosis patients. The experimental results of the expert system were obtained using a real dataset from the Liver Institute, Mansoura University, Egypt, of 119 patients infected by chronic viral hepatitis C. The performance of the system was evaluated with many metrics, achieving a testing accuracy of 95.7%. The evaluation of proposed fuzzy expert system shows its capability of diagnosing the stages of liver fibrosis with a high degree of accuracy, and it can be embedded as a component in a healthcare system to assist physicians in their daily practice. In addition, students training in medicine can benefit from this system.

In this study, we present the synthesis of novel isothiochromenes, thiazolidonone, thiazinone, arylidines, triazoles, and pyrimidinone compounds based on the starting material 3-amino- isothiochromene-4-carbonitrile 3. The chemical structures were confirmed using spectroscopic methods and elemental analyses. These compounds were screened for their in vitro antiviral and antitumor activities. Compounds 10a-c and 22a-b showed activity against herpes simplex virus-1 (HSV-1) and human immunodeficiency virus-1 (HIV-1). Compounds 15 and 21a-b exhibited activity against various types of cancer cell lines.

Ricinine (1), a known major alkaloid in Ricinus communis plant, was used as a starting compound for the synthesis of six ricinine derivatives; two new and four known compounds. The new derivatives; 3-amino-5-methyl-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (2), and 3-amino-5-methyl-1-(phenylsulfonyl)-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (3), as well as the previously prepared derivatives (4-7) were subjected for antimicrobial and antiquorum-sensing evaluation in comparison to different R. communis extracts. Acetyl ricininic acid derivative (5) showed the highest antimicrobial activity among all tested derivatives against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeuroginosa and Candida albicans. However, compound 7 (4-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide) showed the highest antiquorum-sensing activity among all tested compounds and extracts. These findings proved the usefulness of ricinine as a good scaffold for the synthesis of new antimicrobial and antiquorum-sensing derivatives in spite of its poor contribution to the antimicrobial activity of the plant extracts.

Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast. Here, we demonstrate a one-pot three-component reaction via a [3 + 2] cycloaddition/ring contraction sequence of a dipolarophile (activated alkene) with in situ-generated azomethine ylide (1,3-dipoles) without the use of any catalyst. The reaction provides efficient access to synthetically useful and biologically important spirooxindoles in high yield (69–94%) with high diastereoselectivity. The synthesized compounds were subjected to cytotoxicity evaluation using colorectal cancer (HCT-116), hepatocellular carcinoma (HepG2), and prostate cancer (PC-3) cells. Compounds 4i, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 cells when compared to cisplatin. Meanwhile compound 4d retained high cytotoxic activity and selectivity against HepG2 and PC-3 cells in comparison to cisplatin. The mechanism of compound 4d was further studied using phosphodiesterase 1 enzyme and showed 74.2% inhibitory activity. A possible binding mode for compound 4d to PDE-1 was investigated by molecular modeling using OpenEye software. Pose predictions for the active compounds were demonstrated by ROCS alignments. Compound 4d has a special geometry and differs from other active compounds.

Diagnosis of deadly diseases, such as liver fibrosis, is very important. Clinical decision support systems (CDSSs) based on patient’s historical medical data and accurate AI techniques can aid physicians in their decision-making process. The task of arriving at an accurate and timely diagnosis decision is always complex because of the dynamic, vagueness, and uncertainty associated with this disease. Fuzzy logic can perfectly handle these issues. In recent years, two of the most interesting techniques are a fuzzy analytical hierarchy process (FAHP) and an adaptive neuro-fuzzy inference system (ANFIS). The FAHP is popular for dealing with uncertainty in multi-criteria decision-making, and the ANFIS is popular in learning fuzzy inference system from data based on artificial neural networks. To the best of our knowledge, these two methods have not been used to model CDSSs in fibrosis stage detection domain. In this paper, we develop a CDSS based on a case comparison of the effectiveness of the FAHP and the ANFIS in the medical diagnosis of the fibrosis disease. We carefully design and implement two frameworks based on these two techniques. Diagnostic real data of 119 cases infected by chronic viral hepatitis C from the Liver Institute at Mansoura University in Egypt are used to train and test both the FAHP and ANFIS. Criteria and subcriteria weights are based on opinions of two domain experts. The ANFIS model is designed using trial and error based on the analysis of various experiments. Results are later compared with the diagnostic conclusions of medical expert and other three medical and fuzzy techniques. The comparison results show that these two techniques can successfully be employed in designing a diagnostic CDSS system for fibrosis diagnosis. The two techniques achieve a classification accuracy of 93.3%. The results confirm the efficiency and effectiveness of both methods. Therefore, both the FAHP and ANFIS are viable approaches in modeling CDSS for diagnosis of a liver fibrosis stage.

Triple negative breast cancer (TNBC) is the most aggressive subtype of the breast cancer commonly occurring in females. It was estimated that around 17%–25% of people with breast cancer are triple negative. Despite the availability of various therapeutics and approaches for breast cancer treatment, there is still an increasing need to develop safe and efficacious agents for cancer therapy. Azadiradione (AZD), a bioactive agent isolated from Azadiractaindica, is known to possess anti-nociceptive and anti-inflammatory activities. However, AZD use is limited due to its poor bioavailability. In the current study, the bioavailability of AZD-loaded liposomes in mice was investigated. The anticancer efficacy of AZD-loaded liposomes against TNBC cell line (MDA-MB-231) was also assessed. Data have shown that the oral bioavailability of AZD from liposomes was significantly higher in comparison to free AZD. Also, the anticancer activity of AZD-loaded liposomes against TNBC cells in vitro was markedly enhanced and was found to be via down regulation of the proteins required for proliferation, survival and angiogenesis such as cyclin D1, COX-2, survivin, VEGF-A and autophagy. In conclusion, this study suggested that AZD-loaded liposomes might be a potential oral delivery system to improve bioavailability and hence, therapeutic efficacy of AZD. However, further surface modification of AZD liposomes via PEGylation is required to increase drug blood circulation and reduce phagocytosis and uptake by RES.

Alkaloids extracted from mature Vinca minor leaves were fractionated by preparative HPLC. By means of HRMS and NMR data, the main alkaloids were identified as vincamine, strictamine, 10-hydroxycathofoline, and vincadifformine. Upon treatment with methyl jasmonate (MeJA), the pattern and composition of the indole alkaloids changed extensively. While 10-hydroxycathofoline and strictamine concentrations remained unaltered, vincamine and vincadifformine levels showed a dramatic reduction. Upon MeJA treatment, four other indole alkaloids were detected in high quantities. Three of these alkaloids have been identified as minovincinine, minovincine, and 9-methoxyvincamine. Whereas minovincinine and minovincine are known to occur in trace amounts in V. minor, 9-methoxyvincamine represents a novel natural product. Based on the high similarities of vincamine and 9-methoxyvincamine and their inverse changes in concentrations, it is postulated that vincamine is a precursor of 9-methoxyvincamine. Similarly, vincadifformine seems to be converted first to minovincinine and finally to minovincine. Because MeJA treatment greatly altered the alkaloidal composition of V. minor, it could be used as a potential elicitor of alkaloids that are not produced under normal conditions.

A phytochemical study on the stem bark of Commiphora opobalsamum looking for cytotoxic compounds afforded eleven flavonoids, including six previously undescribed prenylated congeners, comophorin A – E, and comophoroside A. The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Isolated compounds were biologically evaluated using in vitro cytotoxicity MTT-based assay against two cancer cell lines; namely human hepato-cellular carcinoma (HepG-2) and human breast adenocarcinoma (MCF-7). Comophoroside A revealed to retain the strongest cytotoxic activity against MCF-7 and HepG-2 cell lines with IC 50 values of 8 and 12 μg/mL, respectively.

Enzyme activity modulation by synthetic compounds provide strategies combining the inhibitory and therapeutic mode of action of the confirmed inhibitors. However, natural modulators could offer a valuable alternative for synthetic ones for the treatment of different chronic diseases (diabetes, hypertension, cancer); due to the numerous side effects of the latter. In vitro screening assays were conducted for Psidium guajava leaf methanolic extract against three metabolism-related enzymes; α-amylase, tyrosinase, and hyaluronidase. The obtained results showed that the examined extract retained weak and moderate multitarget inhibition against α-amylase, tyrosinase, and hyaluronidase, respectively; however, the leaf fractions exhibited stronger inhibitions for the three investigated enzymes. Fractionation of P. guajava leaf extract revealed that anthraquinones and ellagic acid are of the major active compounds with inhibitory activities for α-amylase, tyrosinase, and hyaluronidase. Kinetic studies showed that quinalizarin inhibition is competitive for both α-amylase and hyaluronidase, and ellagic acid inhibition for tyrosinase and hyaluronidase is competitive and un-competitive, respectively. The molecular docking studies of quinalizarin and ellagic acid with α-amylase, tyrosinase, and hyaluronidase showed high binding energies with different bonds stabilizing the ligand-protein complex. Compiling all obtained results led to conclude that both P. guajava leaf fractions, quinalizarin and ellagic acid, have multitarget activities with potential therapeutic applications in many metabolic disorders.

Sixteen new analogues were synthesized from ricinine and tested alongside with seven known analogues for their cytotoxic activity against oral cancer (SAS cells) and normal epithelial cells (L132 cells). In contrast to 5-FU, the synthesized ricinine analogues did not show toxicity to normal cells. However, some of them inhibited the proliferation of oral cancer cells at 25 µM as evident from the MTT assay results. Ricinine analogue (

Fundus camera or fluorescein angiography (FA) provides information about the back structure of the human eye. It has a significant role in documenting the feedback and conditions of most retinal diseases, especially diabetic retinopathy (DR).

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N&prime, di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC50 = 5 &plusmn, 0.25 &micro, M] &gt, 3e [IC50 = 5 &plusmn, 0.5 &micro, 3c [IC50 = 7 &plusmn, 1.12 &micro, 3d [IC50 = 18 &plusmn, 0.87 &micro, 3j [IC50 = 45 &plusmn, 3 &micro, M]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 &plusmn, 0.78 &micro, M) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 &plusmn, 0.3 &micro, M). These values were three times higher than the values reported for cisplatin (IC50 of 8 &plusmn, 0.76 and 14.7 &plusmn, M against HCT-116 and HuH-7 cells, respectively). The highest &alpha, glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.

Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies. Methyl shogoal (D8) showed to be the most potent compound against HCT-116 cells (IC50; 1.54μM). Remarkably, D8 proved to be non-cytotoxic to normal cells; (TIG-1) and (HF-19) with high selective index (SI; 52.3). Furthermore [6]-gingerol derivatives showed potent LTA4H inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, [10]-gingerol (N3) exhibited the highest LTA4H aminopeptidase and epoxide hydrolase inhibitory activities with IC50; 21.59 and 15.24μM, respectively. Meanwhile, methyl shogoal (D8) and 4'-O-prenyl-[6]-gingerol (D10) retained the highest inhibition with IC50; 4.92 and 3.01μM, for aminopeptidase, and 11.27 and 7.25μM for epoxide hydrolase activities, respectively.

Vorinostat is the first histone deacetylase inhibitor approved by US FDA for use in cancer therapy. However, its limited aqueous solubility, low permeability, and suboptimal pharmacokinetics hinder its delivery. Thus, in this study, micelles of vorinostat with each of pluronic F68 (PF68) and pluronic F127 (PF127) were developed and optimized based on drug loading and entrapment. The optimized micelles were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), zeta analyzer, and electron transmission microscopy. Their in vitro release, stability, in vitro cytotoxicity against HepG2, Caco-2, and MCF-7 cell lines, and finally, in vivo antitumor activity in mice bearing Ehrlich Ascites Carcinoma (EAC) were assessed. The highest entrapment efficiency was 99.09±2.16% and 94.19±2.37% for micelles of 1:50 drug to polymer ratio with each of PF127 and PF68, respectively. These micelles were nearly spherical with nanoscopic mean diameters of 72.61±10.66nm for PF68 and 91.88±10.70nm for PF127 with narrow size distribution. The micelles provided prolonged release at phosphate buffer saline pH7.4 up to 24h for PF68 and 72h for PF127. Potentiation of in vitro cytotoxicity of vorinostat was more pronounced with PF127 micelles particularly against MCF-7 cells. Compared with free vorinostat, the micelles with PF127 were more effective in inhibiting tumor growth as well as exhibiting significantly (p

Obesity has a tight relationship with increased risks of different cancer types, such as Colorectal, Ovarian, Female Breast, Gallbladder, Adenocarcinoma, Kidney (Renal-Cell), Liver, and Pancreatic. It can also lead to some other diseases like diabetes and heart diseases. This paperproposes a fuzzy ontology that is based on OWL 2to represent the Obesity Related Cancer (ORC) domain knowledge. The diseases taxonomy isconstructed using the standard Disease Ontology. The presented FuzzyOntology includes more concepts than in crisp one and copes with the domain linguistic variables. It allows the users to query the Fuzzy Dl reasoner for element and get them back the fuzzy ontology for that element. It is expected to be good practice for ontologists and knowledge engineers in medical field aiding them to solve the overlapping concepts, linguistic variables, and reasoning problems by building their fuzzy ontologies. Building FOORC as an open ontology is a first attempt to organize information related to the obesity and cancer diseases in a formalized, structured manner that both physicians and intelligent systems can exploit it in knowledge sharing, reusability, and reasoning.

A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC50 values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.

Background: Liver cancer is a life threating disease as it is the fifth most common cancer and the third most common cause of death worldwide with no safe, efficient, and economic drug available for treatment. Methods: This study intended to investigate glycyrrhizin and its derivatives for possible use as a cytotoxic agent and as a drug for liver cancer treatment. Thus, after treatment of liver cancer cell line HepG-2 with 50 μM of each compound, cell viability was determined. Results: The cytotoxicity assay showed glycyrrhizin derivatives ME-GA (18β-Glycyrrhetinic-30-methyl ester) and AKBA (3-acetyl-11- keto-β-Boswellic acid) to be the most potent drug against liver cancer cell line HepG-2 with IC50 values 25.50 ± 1.06 and 19.73 ± 0.89 μM, respectively. Both the compounds showed higher selectivity towards hepatocellular carcinoma rather than the normal lung fibroblast cell line WI-38. The presence of methyl ester at C-30 greatly increased the cytotoxicity of ME-GA which might be attributed to its higher activity and selectivity. Both ME-GA and AKBA contributed to inhibit cancer cell migration in the wound healing assay and impeded colony formation. The use of flow cytometry to carry out cell cycle analysis and the determination of possible mechanisms of action for apoptosis revealed that ME-GA arrested the cell cycle at G2/M that led to the inhibition of hepatocellular carcinoma and induced apoptosis via the extrinsic pathway and its ability to increase p53 transactivation. Conclusion: This work highlights the cytotoxicity of glycyrrhizin and its derivatives for possible use as a chemotherapeutic agent against hepatocellular carcinoma cells HepG-2. The most cytotoxic compound was ME-GA (18β-Glycyrrhetinic-30-methyl ester) with no cytotoxic effect on the normal cell line. In summary, this new derivative may be used as an alternative or complementary medicine for liver cancer.

Acetylcholinesterase inhibitors (AChE-Is) increase both level and duration of action of acetylcholine (ACh); thus, alleviate symptoms of Alzheimer’s disease (AD). Glycyrrhizin, is the main active compound in liquorice root. Its aglycone, glycyrrhetinic acid, has shown several beneficial pharmacological activities. This study reports the synthesis and screening of a series of glycyrrhetinic acid analogs as AChE-Is. Fourteen derivatives were prepared, of which five derivatives are recorded as new viz., 3-phenyl-carbamoyl-18β-glycyrrhetinic acid (J9), 3-acetyl-18β-glycyrrhetinic-30-anilinamide (J10), 3-acetyl-18β-glycyrrhetinic-30-ethanolamide (J11), 3-acetyl-18β-glycyrrhetinic-30-n-butylamide (J12) and 18β-glycyrrhetinic acid-30-prenyl ester (J14), in addition to nine known derivatives (J1-J8 & J13). Compounds J12, J11, J0 and J3 showed remarkable AChE-I activity with IC50 values of 3.43, 5.39, 6.27 and 8.68 μM, respectively. These results are in full agreement with the docking study. The active compounds were non-cytotoxic to normal cells (WI-38).

Considerable attention has been focused on the [1,3] dipolar cycloaddition reaction approach of olefin with amino acid (sarcosine), and isatin which underwent smoothly, and afforded a highly functionalized complex molecule. The target spiroindolone analogue 4 was synthesized in excellent yield. The desired compound was elucidated based on X-ray single crystal diffraction technique. Compound 4 was examined against three different cancer cell lines for liver, breast and colorectal cancer (HepG2, MCF-7 and HCT-116, respectively). It showed high selectivity against colon cancer (HCT-116). Hirshfeld molecular packing analysis of 4 showed that the H⋯H, Cl⋯H and C⋯H contacts are the most abundant while the N⋯H and O⋯H hydrogen bonding interactions are the strongest. Molecular and electronic structures as well as the Uv–Vis and NMR spectra of 4 were discussed based on DFT calculations. The longest wavelength band observed at 298 nm was assigned for the HOMO-2/HOMO-1→LUMO excitations. The 1H and 13C NMR chemical shifts of 4 were calculated and compared with the experimental data (0.934–0.954).

Iron overload is implicated in many disorders in the body such as heart failure, liver cirrhosis and fibrosis, gallbladder disorders, diabetes, arthritis, depression, infertility, and cancer. Even though synthetic chelating agents are available, they have several limitations such as poor oral bioavailability, short plasma half-life, high cost and numerous side effects. Therefore, the aim of this study is using agricultural residues as sources for alternative efficient, benign, and economic iron chelators of natural origin. Eighteen agricultural residues were screened for iron chelating activity using 2, 2'-bipyridyl assay. The results showed that the extract of Mangifera indica leaves had the highest iron chelation activity (69.7%), in comparison to ethylenediaminetetraacetic acid (EDTA) (70.3%) (standard iron chelator). The M. indica leaves extract was further investigated for its flavonoidcontent, phenolic content and antioxidant activity. The high concentration of phenolic (405.5µg/g expressed as gallic acid equivalent) and flavonoid (336.9 µg/g expressed as quercetin equivalent) phytochemicals in the extract, as well as its significant antioxidant capacity (96.95%) compared to ascorbic acid (91.90%) (standard antioxidant agent), suggested that the M. indica leaves could represent a good source for new iron chelating agents in iron overload disorders.

The designed compounds, 4a-p, were synthesized using a simple and smooth method with an asymmetric 1,3-dipolar reaction as the key step. The chemical structures for all synthesized compounds were elucidated and confirmed by spectral analysis. The molecular complexity and the absolute stereochemistry of 4b and 4e designed analogs were determined by X-ray crystallographic analysis. The anticancer activities of the synthesized compounds were tested against colon (HCT-116), prostate (PC-3), and hepatocellular (HepG-2) cancer cell lines. Molecular modeling revealed that the compound 4d binds through hydrophobic-hydrophobic interactions with the essential amino acids (LEU: 57, GLY: 58, ILE: 61, and HIS: 96) in the p53-binding cleft, as a standard p53-MDM2 inhibitor (6SJ). The mechanism underlying the anticancer activity of compound 4d was further evaluated, and the study showed that compound 4d inhibited colony formation, cell migration, arrested cancer cell growth at G2/M, and induced apoptosis through intrinsic and extrinsic pathways. Transactivation of p53 was confirmed by flow cytometry, where compound 4d increased the level of activated p53 and induced mRNA levels of cell cycle inhibitor, p21.

Antisense oligonucleotides (ASO) represent an attractive trend as specific targeting molecules but sustain poor cellular uptake meanwhile superparamagnetic iron oxide nanoparticles (SPIONs) offer stability of ASO and improved cellular uptake. In the present work we aimed to functionalize SPIONs with ASO targeting the mRNA of Cyclin B1 which represents a potential cancer target and to explore its anticancer activity. For that purpose, four different SPIONs-ASO conjugates, S-M (1–4), were designated depending on the sequence of ASO and constructed by crosslinking carboxylated SPIONs to amino labeled ASO. The impact of S-M (1–4) on the level of Cyclin B1, cell cycle, ROS and viability of the cells were assessed by flowcytometry. The results showed that S-M3 and S-M4 reduced the level of Cyclin B1 by 35 and 36%, respectively. As a consequence to downregulation of Cyclin B1, MCF7 cells were shown to be arrested at G2/M phase (60.7%). S-M (1–4) led to the induction of ROS formation in comparison to the untreated control cells. Furthermore, S-M (1–4) resulted in an increase in dead cells compared to the untreated cells and SPIONs-treated cells. In conclusion, targeting Cyclin B1 with ASO-coated SPIONs may represent a specific biocompatible anticancer strategy.

Acetylcholinesterase inhibitors (AChE-Is) increase both level and duration of action of acetylcholine (ACh); thus, alleviate symptoms of Alzheimer's disease (AD). Glycyrrhizin, is the main active compound in liquorice root. Its aglycone, glycyrrhetinic acid, has shown several beneficial pharmacological activities. This study reports the synthesis and screening of a series of glycyrrhetinic acid analogs as AChE-Is. Fourteen derivatives were prepared, of which five derivatives are recorded as new viz., 3-phenyl-carbamoyl-18β-glycyrrhetinic acid (

From diethyl ether fraction of the Red Sea soft coral, Litophyton arboreum, two new terpenoidal derivatives, himachalene-type sesquiterpene (3α,6α-epidioxyhimachal-1-ene, 1) and secosteroidal derivative (22-norerogostane derivative, 13,14-seco-22-norergosta-4,24(28)-dien-19-hydroperoxide-3-one, 2), were identified. In addition to di-acetyl cembranoid derivative, (3) was isolated for the first time from the nature. Along with three known metabolites, sarcophytol M (4), 7β-acetoxy-24-methylcholesta-5-24(28)-diene-3,19-diol (5) and erythro-N-dodecanoyl-docosasphinga-(4E,8E)-dienine (6) were obtained. Spectroscopic measurements including 1D and 2D NMR were used for identification of chemical structures. All compounds were evaluated to assess their antiproliferative effect toward three different cancer cell lines MCF-7 (human breast carcinoma), HCT116 (human colon cancer) and HepG-2 (human hepatic carcinoma) in comparison with standard anticancer drug (Doxorubicin) by employing SRD assay. Compound 3 showed significant antiproliferative activities to MCF-7 (IC50 19.1 ± 0.032 µM), to HepG2 (IC50 24.0 ± 0.032 µM) and to HCT116 (IC50 22.0 ± 0.092 µM). The antiproliferative activities of 3 can be attributed, at least partly, to their ability to do cell cycle arrest, particularly, in G0/G1 and S phases.

A new eudesmane sesquiterpenoid, eudesma-4(15),7-diene-5,11-diol (1) along with the known trinor-sesquiterene, teuhetenone (2), and a seco-eudesmane sesquiterpene, chabrolidione B (3), have been isolated from the Red Sea red alga Laurencia obtusa. The chemical structures were elucidated on the basis of extensive spectroscopic analysis. The antifungal and cytotoxic activities of the isolated metabolites were tested against several fungi, yeast and human mammary carcinoma cell line (MCF-7). Compounds 1 and 3 showed a much better activity [minimum inhibitory concentration (MIC): 2.9 μM] than that of amphotericin B (MIC: 4.6 μM). Interestingly, compound 2, the least active antifungal compound, retained the high anticancer activity against MCF-7 (22 μM) in comparison with cisplatin (59 μM), which was determined by employing lactate dehydrogenase assay. Compounds 1–3 are recorded here for the first time from algal flora. The chemotaxonomic importance of the isolated metabolites was discussed.

Chromatographic fractionation of the organic extract obtained from the brown alga Cystoseira trinodis led to the isolation of a known carotene pigment (7), five C-29 steroids (2–6), including two new ones (2 and 5), and an unexpected metabolite, halogenated cyclic ene-yne ether (1). Compound 1 was isolated from the genus Cystoseira for the first time. This finding plays an important role in the chemo-taxonomical differentiation of C. trinodis from other Cystoseira species. All compounds (1–7) were evaluated for their in vitro cytotoxic activities against four human tumor cell lines MCF-7, HepG2, WI 38, and Vero. They showed moderate cytotoxicity with IC50 in the range 7–33 μM, where 7 exhibited the highest antioxidant activity with 72.1% inhibition.

This study revealed a differential cytotoxic activity of the petroleum ether extract (IC50=5 μg/mL) of the resinous exudates of Commiphora molmol against two mouse cell lines KA31T and NIH3T3 (untransformed and transformed mouse fibroblasts, respectively). Four new compounds (1–4) and five known compounds (5–9) were isolated from the petroleum ether extract. The identity of these new compounds was determined as γ-elemane lactone (1), 5-αH,8-βH-eudesma-1,3,7(11)-trien-8,12-olide (2), 2-hydroxy-11,12-dihydrofuranodiene (3), and 2-hydroxyfuranodiene (4). 1 and 2 displayed the highest cytotoxic activity against NIH3T3 cells. 7 and 9 exhibited moderate cytotoxic activity against KA31T cells. Compounds 3–6 showed weak cytotoxic activities against both cell lines. These results may explain the high efficacy of the petroleum ether fraction in several myrrh-derived pharmaceutical preparations.

Elham Abdelmonem Mohamed,1 Irhan Ibrahim Abu Hashim,1 Rehab Mohammad Yusif,1,2 Ahmed Abdel Aziz Shaaban,3 Ahmed Ramadan El-Sheakh,3 Mohammed Fawzy Hamed,4 Farid Abd Elreheem Badria5 1Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 2Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 4Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; 5Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Abstract: Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol-induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80±6.56nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14±2.29). The micelles exhibited prolonged release up to 48 vs 10h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99±3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor-alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin–PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities. Keywords: naringin, pluronic F68, polymeric micelles, in vitro cytotoxicity, antiulcer, antitumor activity

Ricinine (

Three new sesquiterpene alcohols, laur-2-ene-3,12-diol (1), cuparene-3,12-diol (2), and 8,11- dihydro-1-methoxylaurokamuren-12-ol (3), along with one known diterpene, kahukuen-10-ol (4) have been isolated from the organic extract of the red alga Laurencia obtusa. The chemical structures were elucidated on the basis of spectroscopic analysis. The cytotoxicity of the isolated compounds were evaluated against three cancer cell lines, i.e., KB, HepG2, and MCF-7. Compound 4 exhibited a wide range of cytotoxic activity against KB, HepG2, and MCF-7 cell lines with IC50 of 0.100, 0.057, and 0.054 mm, respectively. In addition, 1 showed moderate activities towards KB and MCF-7 cell lines with IC50 values of 0.171 and 0.184 mm, respectively and 2 exhibited a moderate activity against KB cell line at a concentration of 0.213 mg/ml. On the other hand, compound 3 exhibited no cytotoxic activity against any of the three cell lines.

Acanthamoeba spp. commonly cause Acanthamoeba keratitis which is typically associated with the wear of contact lenses. Therefore, finding an economic, efficient, and safe therapy of natural origin is of outmost importance. This study examined the in vitro lethal potential of ethyl acetate and methanol extracts of Helianthemum lippii (L.) (sun roses) against Acanthamoeba castellanii cysts isolated from patients with amoebic keratitis. Both extracts proved to be potent as regard to their lethal effects on A. castellanii cysts with comparable results to chlorhexidine. The ethyl acetate was more promising with cumulative lethality. It showed a highly significant lethal percentage along the duration of treatment. The analysis of the more potent ethyl acetate extract revealed the presence of 2.96 mg/100 g of total phenolics, 0.289 mg/100 ml of total flavonoids and 37 mg/100 mg of total tannins which highlighted their phytomedicinal role.

Cassia nodosa Buch.-Ham. ex Roxb. is an ornamental plant which belongs to the family Fabaceae. It does not have the appropriate phytochemical and biological investigation. This was the first time to investigate anti-oxidant and cytotoxic activity of Cassia nodosa flowers, leaves, stem bark methanolic extracts and their fractions (petroleum ether, methylene chloride, ethyl acetate and n-butanol). Besides, some pure constituents isolated from C. nodosa were assessed as anti-oxidant and cytotoxic agents. Remarkable results were obtained specially for stem bark methanolic extract as a strong cytotoxic agent against MCF-7 and VERO cell lines. Chrysophanol (IV) displayed the highest activity as anti-oxidant (anti-hemolytic and DNA protective agent). Anti-oxidant activity of it was higher than ascorbic acid which was the positive control. This was the first time to isolate Kaempferol-3-O-α-L-rhamnopyranosyl (1→2)-β-D-glucoside (I) from ethyl acetate fraction of leaves. Isolation of 4,5-dihydroxyanthraquinone-2-carboxylic acid (rhein) (III) and 1,8-dihydroxy-3-methyl anthraquinone (chrysophanol) (IV) was achieved from methylene chloride fraction of flowers and stem bark, respectively. Kaempferol 3-O-α-L- rhamnoside (II) was isolated from ethyl acetate fraction of leaves besides compound (I). Key words: Cassia nodosa, erythrocyte hemolysis, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, bleomycin, cytotoxic, kaempferol rhamnosyl glucoside, kaempferol rhamnoside, rhein, chrysophanol.