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Background: Rabbit hemorrhagic disease (RHD) is an acute infectious disease that damages the rabbit industry by producing significant mortality rates in young and adult rabbits. RHD is better controlled by vaccination., Objective: The current study's goal was to prepare and evaluate the immuno-enhancing effect of montanide ISA70 and aluminum hydroxide (Al(OH) 3 ) gel incorporated within the inactivated RHDV2 vaccine and assess the vaccine's protective efficacy against the homologous and heterologous local RHDV2 strains in rabbits., Methods: Inactivated RHDV vaccines were prepared using Montanide ISA70 oil or Al(OH) 3 gel adjuvants and submitted to sterility, safety, and potency tests. 200 rabbits were equally divided into 4 groups: G1 (control), G2 (vaccinated with gel-incorporated vaccine), G3 (vaccinated with montanide-incorporated vaccine), and G4 (vaccinated with gel- and montanide-incorporated vaccines). Individual blood samples were collected from one week to six months from all groups. The vaccine's potency was measured by the HI test and protection percentage post challenge., Results: Data revealed slightly increasing HI titer means reaching the 1st peak at 4 weeks post-vaccination (7.33, 7.67, and 7.33 log2 in the 2nd, 3rd, and 4th groups, respectively), then slightly decreasing and peaked again, giving 9.33 log2 for the2 nd group at 3 months post-vaccination (MPV), 10.67 log2 for 3rd the group, and 10.33 log2 for the 4th group at 5 months post-vaccination. Titer gradually decreased but remained protective. The protection rate ranged from 80-100% and 80-90% for homologous and heterologous local RHDV2 vaccines, respectively, within 3 weeks and 6 months post-challenge. The montanide oil RHDV2 vaccine induced better protection than the aluminum gel RHDV2 vaccine., Conclusion: The results demonstrated evidence of cross-protection between RHDV2 strains. The oil emulsion vaccine induced higher and longer-lasting antibody titers than those obtained with the RHDV2 aluminum gel vaccine., (© 2024. The Author(s).)

A library of 16 3-benzyl- N 1 -substituted quinoxalin-2-ones was synthesized as N 1 -substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6 , 9 , 14 , and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC 50 0.05-0.07 μM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Silybum marianum commonly known as milk thistle is one of the most imperative medicinal plants due to its remarkable pharmacological activities. Lately, the antiviral activities of S. marianum extract have been studied and it showed effectiveness against many viruses., Objective: Although most previous studies were concerned mainly with silymarin content of the fruit, the present study provides comprehensive comparative evaluation of S. marianum different organs' chemical profiles using UPLC-MS/MS coupled to chemometrics to unravel potentially selective antiviral compounds against human coronavirus (HCoV-229E)., Methodology: UPLC-ESI-TQD-MS/MS analysis was utilized to establish metabolic fingerprints for S. marianum organs namely fruits, roots, stems and seeds. Multivariate analysis, using OPLS-DA and HCA-heat map was applied to explore the main discriminatory phytoconstituents between organs. Selective virucidal activity of organs extracts against coronavirus (HCoV-229E) was evaluated for the first time using cytopathic effect (CPE) inhibition assay. Correlation coefficient analysis was implemented for detection of potential constituents having virucidal activity., Results: UPLC-MS/MS analysis resulted in 87 identified metabolites belonging to different classes. OPLS-DA revealed in-between class discrimination between milk thistle organs proving their significantly different metabolic profiles. The results of CPE assay showed that all tested organ samples exhibited dose dependent inhibitory activity in nanomolar range. Correlation analysis disclosed that caffeic acid-O-hexoside, gadoleic and linolenic acids were the most potentially selective antiviral phytoconstituents., Conclusion: This study valorizes the importance of different S. marianum organs as wealthy sources of selective and effective antiviral candidates. This approach can be extended to unravel potentially active constituents from complex plant matrices., (© 2024. The Author(s).)

Background: Type 2 Diabetes mellitus (DM) is an affliction impacting the quality of life of millions of people worldwide. An approach used in the management of Type 2 DM involves the use of the carbohydrate-hydrolyzing enzyme inhibitor, acarbose. Although acarbose has long been the go-to drug in this key approach, it has become apparent that its side effects negatively impact patient adherence and subsequently, therapeutic outcomes. Similar to acarbose in its mechanism of action, bee propolis, a unique natural adhesive biomass consisting of biologically active metabolites, has been found to have antidiabetic potential through its inhibition of α-amylase. To minimize the need for ultimately novel agents while simultaneously aiming to decrease the side effects of acarbose and enhance its efficacy, combination drug therapy has become a promising pharmacotherapeutic strategy and a focal point of this study., Methods: Computer-aided molecular docking and molecular dynamics (MD) simulations accompanied by in vitro testing were used to mine novel, pharmacologically active chemical entities from Egyptian propolis to combat Type 2 DM. Glide docking was utilized for a structure-based virtual screening of the largest in-house library of Egyptian propolis metabolites gathered from literature, in addition to GC-MS analysis of the propolis sample under investigation. Thereafter, combination analysis by means of fixed-ratio combinations of acarbose with propolis and the top chosen propolis-derived phytoligand was implemented., Results: Aucubin, identified for the first time in propolis worldwide and kaempferol were the most promising virtual hits. Subsequent in vitro α-amylase inhibitory assay demonstrated the ability of these hits to significantly inhibit the enzyme in a dose-dependent manner with an IC 50 of 2.37 ± 0.02 mM and 4.84 ± 0.14 mM, respectively. The binary combination of acarbose with each of propolis and kaempferol displayed maximal synergy at lower effect levels. Molecular docking and MD simulations revealed a cooperative binding mode between kaempferol and acarbose within the active site., Conclusion: The suggested strategy seems imperative to ensure a steady supply of new therapeutic entities sourced from Egyptian propolis to regress the development of DM. Further pharmacological in vivo investigations are required to confirm the potent antidiabetic potential of the studied combination., (© 2024. The Author(s).)

Vascular endothelial growth factor receptor-2 is a vital target for therapeutic mediation in various types of cancer. This study was aimed at exploring the cytotoxic activity of seventeen novel quinoxaline-3-propanamides against colon cancer (HCT-116) and breast cancer (MCF-7) using MTT assay. Results revealed that compounds 8, 9, and 14 elicited higher cytotoxicity than the reference drugs, doxorubicin (DOX) and sorafenib. Interestingly, they are more selective for HCT-116 (SI 11.98-19.97) and MCF-7 (SI 12.44-23.87) compared to DOX (SI HCT-116 0.72 and MCF-7 0.9). These compounds effectively reduced vascular endothelial growth factor receptor-2; among them, compound 14 displayed similar VEGFR-2 inhibitory activity to sorafenib (IC 50 0.076 M). The ability of 14 to inhibit angiogenesis was demonstrated by a reduction in VEGF-A level compared to control. Furthermore, it induced a significant increase in the percentage of cells at pre-G1 phase by almost 1.38 folds (which could be indicative of apoptosis) and an increase in G2/M by 3.59 folds compared to the control experiment. A flow cytometry assay revealed that compound 14 triggered apoptosis via the programmed cell death and necrotic pathways. Besides, it caused a remarkable increase in apoptotic markers, i.e. , caspase-3 p53 and BAX. When compared to the control, significant increase in the expression levels of caspase-3 from 47.88 to 423.10 and p53 from 22.19 to 345.83 pg per ml in MCF-7 cells. As well, it increased the proapoptotic protein BAX by 4.3 times while lowering the antiapoptotic marker BCL2 by 0.45 fold. Docking studies further supported the mechanism, where compound 14 showed good binding to the essential amino acids in the active site of VEGFR-2. Pharmacokinetic properties showed the privilege of these hits over sunitinib: they are not substrates of P-gp protein; this suggests that they have less chance to efflux out of the cell, committing maximum effect; and in addition, they do not allow permeation to the BBB., Competing Interests: The authors declare that they have no conflicts of interest. The authors alone are responsible for the content and writing of this manuscript., (This journal is © The Royal Society of Chemistry.)

Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC 50 's 4.28-9.31 µM) and MCF-7 (IC 50 's 3.57-7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69-23.19) and MCF-7 (SI 9.48-27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Activity-guided fractionation of the ethanolic extracts of Thymelaea hirsuta and Ziziphus spina-christi furnished eight compounds with pancreatic lipase inhibitory activity. Six compounds were isolated from the chloroform fraction of T. hirsuta . It is worth mentioning that this is the first report for the isolation of 5,7,4'-trihydroxy-8-methoxycarbonyl flavanol (2), daphnodorin G-3''-methyl ether (4) and daphnodorin G (5) from genus Thymelaea . Moreover, daphnoretin (1), neochamaejasmin A (3) and daphnodorin B (6) were also isolated from the chloroform fraction of the same plant. On the other hand, quercetin 3- O -α-l-rhamnopyranosyl-(1 → 2)-[α-l-rhamnopyranosyl-(1 → 6)]-β-d-galactopyranoside (7) and 3- O -[α-l-fucopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 3)-α-l-arabinopyranosyl] jujubogenin (christinin A) (8) were isolated from the n -butanol fraction of Z. spina-christi . Structure elucidation of the isolated compounds was carried out by detailed analysis of 1D and 2D spectral data. These compounds showed percentage inhibitions of 72% (1), 52% (2), 61.8% (3), 39% (4), 69.5% (5), 3.5% (6), 68% (7) and 75% (8) at the concentration of 250 μM and XP-G scores of lipase inhibition were 11.40 (1), 8.71 (2), 6.13 (3), 8.23 (4), 6.22 (5), 9.76 (6), 14.66 (7) and 12.00 (8). This is the first report of the isolation of lipase inhibitors from both plants T. hirsuta and Z. spina-christi . In addition to that, this might result in presenting the biscoumarin, daphnoretin, and the dammarane saponin, christinin A, as potent lipase inhibitors., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Cancer is one of the leading causes of death worldwide. Recently, it was shown that many natural extracts have positive effects against cancer, compared with chemotherapy or recent hormonal treatments. A. annua is an annual medicinal herb used in the traditional Chinese medicine. It has also been shown to inhibit the proliferation of various cancer cell lines., Methods: Multi-level modes of action of A. annua constituents in cancer therapy were investigated using an integrated approach of network pharmacology, molecular docking, dynamic simulations and in-vitro cytotoxicity testing on both healthy and cancer cells., Results: Network pharmacology-based analysis showed that the hit Artemisia annua constituents related to cancer targets were 3-(2-methylpropanoyl)-4-cadinene-3,11-diol, artemisinin G, O-(2-propenal) coniferaldehyde, (2-glyceryl)-O-coniferaldehyde and arteamisinin III, whereas the main cancer allied targets were NFKB1, MAP2K1 and AR. Sixty-eight significant signaling KEGG pathways with p < 0.01 were recognized, the most enriched of which were prostate cancer, breast cancer, melanoma and pancreatic cancer. Thirty-five biological processes were mainly regulated by cancer, involving cellular response to mechanical stimulus, positive regulation of gene expression and transcription. Molecular docking analysis of the top hit compounds against the most enriched target proteins showed that 3-(2-methylpropanoyl)-4-cadinene-3,11-diol and O-(2-propenal) coniferaldehyde exhibited the most stabilized interactions. Molecular dynamics simulations were performed to explain the stability of these two compounds in their protein-ligand complexes. Finally, confirmation of the potential anticancer activity was attained by in-vitro cytotoxicity testing of the extract on human prostate (PC-3), breast (MDA-MB-231), pancreatic (PANC-1) and melanoma (A375) cancerous cell lines., Conclusion: This study presents deeper insights into A. annua molecular mechanisms of action in cancer for the first time using an integrated approaches verifying the herb's value., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Human adenovirus type-7 (HAdV-7) is a common pathogen that may cause significant morbidity as well as severe complications. Currently, there is no approved drug for the treatment of HAdV-7 infections and the contemporary strategy mainly rely on nonspecific antivirals. Glycyrrhiza glabra; (licorice), is a well-recognized edible plant used in food and beverages. The plant is renowned for its pharmacological and biological activities including antiviral activities against wide range of viruses. The following study reported for the first time the anti-adenoviral activity of licorice extract using in-vitro cytopathic inhibitory assay. Different solvent fractions showed promising activity with IC 50 reaching 1.431 μg/ml. Certain fractions had selectivity index (SI) greater than 10 indicating their efficacy together with relatively low cytotoxic effect. Metabolic profiling using LC-HRMS/MS resulted in identification of 41 compounds from licorice fractions. Chemometric modeling using Orthogonal Projections to Latent Structures (OPLS) suggested the compounds; kaempferol-3-O-rutinoside, violanthin, rhamnoliquiritin, isoliquiritigenin isomer, licoagroside B and liquiritin apioside as potential markers against (HAdV-7). Finally, kaempferol-3-O-rutinoside was further confirmed via in-vitro adenovirus inhibitory assay to possess strong antiviral activity with IC 50 and CC 50 of 54.7 ± 1.93 μM and 655.7 ± 2.22 μM, respectively., (© 2023. The Author(s).)

Sarcoidosis is a multisystem granulomatous disease of unknown origin. Ninety percent of patients with sarcoidosis have lung involvement. The onset can be acute or non-acute and the severity of sarcoidosis ranges widely from asymptomatic patients with accidental radiographic findings to patients with severe organ involvement. This case control analytic prospective study was conducted at the Chest Clinic, Al Zahraa hospital, to assess the diagnostic value of serum soluble interleukin 2 receptor (sIL-2R), cluster of differentiation 4 (CD4)/CD8 ratio and CD103 in sarcoidosis. We investigated the value of serum sIL-2R using ELISA and blood CD103, blood CD4/CD8 ratio using flow cytometry for 30 cases of sarcoidosis in different stages and 30 control persons to detect their use as a marker for diagnosis. We found a significant increase in sIL-2R in the sarcoidosis group as compared to the control group (p˂0.0001), while there was a significant decrease in CD103/CD4 in sarcoidosis group as compared to the control group (p < 0.001). In conclusion, sIL-2R and CD103 can be used as diagnostic markers for sarcoidosis., (Copyright© by the Egyptian Association of Immunologists.)

Glioblastoma, a malignant brain tumor, is a common primary brain tumor in adults, with diabetes mellitus being a crucial risk factor. This review examines how the antidiabetic drug metformin and dietary supplement resveratrol can benefit the treatment of glioblastoma. Metformin and resveratrol have demonstrated action against relevant pathways in cancer cells. Metformin and resveratrol inhibit cell proliferation by downregulating the PI3K/Akt pathway, activating mTOR, and increasing AMPK phosphorylation, resulting in lower proliferation and higher apoptosis levels. Metformin and resveratrol both upregulate and inhibit different cascades in the MAPK pathway. In vivo, the drugs reduced tumor growth and volume. These actions show how metformin and resveratrol can combat cancer with both glucose-dependent and glucose-independent effects. The pre-clinical results, alongside the lack of clinical studies and the rise in novel delivery mechanisms, warrant further clinical investigations into the applications of metformin and resveratrol as both separate and as a combination complement to current glioblastoma therapies.

The total alcohol extract obtained from the aerial parts of R. stricta and fractions of the liquid-liquid fractionation process were tested against picornavirus-causing foot-and-mouth disease (FMD) based on the traditional use of the plant in Saudi Arabia. The most active petroleum ether soluble fraction was subjected to chromatographic purification, and nine compounds were isolated, identified using various chemical and spectroscopic methods, and tested for their anti-viral potential. The new ester identified as α -Amyrin 3-(3'R-hydroxy)-hexadecanoate ( 1 ) was the most active compound with 51% inhibition of the viral growth and was given the name Rhazyin A. Compounds with ursane skeleton were more active than those with lupane skeleton except in the case of the acid derivatives where betulenic acid showed 26.1% inhibition against the viral growth, while ursolic acid showed only 16.6% inhibition. Moreover, molecular docking analysis using a glide extra-precision module was utilized for investigating the possible molecular interactions accounting for anti-viral activity against picornavirus of the nine isolated compounds. Molecular docking studies revealed a strong binding of the discovered hits within the active site of FMDV 3C pro . Compound 1 showed the lowest docking score within the nine isolated compounds comparable to the two known anti-viral drugs; glycyrrhizic acid and ribavirin. The results of this research will provide lead candidates from natural origin with potential safety and efficacy compared to the synthetic ones with lower production costs for managing FMVD.

Most synthetic immunomodulatory medications are extremely expensive, have many disadvantages and suffer from a lot of side effects. So that, introducing immunomodulatory reagents from natural sources will have great impact on drug discovery. Therefore, this study aimed to comprehend the mechanism of the immunomodulatory activity of some natural plants via network pharmacology together with molecular docking and in vitro testing. Apigenin, luteolin, diallyl trisulfide, silibinin and allicin had the highest percentage of C-T interactions while, AKT1, CASP3, PTGS2, NOS3, TP53 and MMP9 were found to be the most enriched genes. Moreover, the most enriched pathways were pathways in cancer, fluid shear stress and atherosclerosis, relaxin signaling pathway, IL-17 signaling pathway and FoxO signaling pathway. Additionally, Curcuma longa, Allium sativum, Oleu europea, Salvia officinalis, Glycyrrhiza glabra and Silybum marianum had the highest number of P-C-T-P interactions. Furthermore, molecular docking analysis of the top hit compounds against the most enriched genes revealed that silibinin had the most stabilized interactions with AKT1, CASP3 and TP53, whereas luteolin and apigenin exhibited the most stabilized interactions with AKT1, PTGS2 and TP53. In vitro anti-inflammatory and cytotoxicity testing of the highest scoring plants exhibited equivalent outcomes to those of piroxicam., (© 2023. The Author(s).)

Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms "neuroblastoma", "flavonoid", and "apoptosis". The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research.

The critical function of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis attracted a great interest throughout beyond decades. Inhibitors of human DHODH (hDHODH) have validated efficacy for remedy of many immunological diseases. Brequinar and leflunomide are examples of such compounds. However, most of such immunosuppressive medications suffer from a lot of side effects and accompanied by adverse metabolic disturbances and toxicities. So that, immunomodulation utilizing natural products received the attention of many researchers. In this study, computer-aided molecular docking, molecular dynamic (MD) simulations and biochemical testing were utilized to find new pharmacologically active chemical entities from natural sources to combat immunosuppressive diseases. More specifically, Glide docking was used for a structure-based virtual screening of in-house 3D database of compounds retrieved from some traditionally known immunomodulatory plants surveyed from literature. The top five scored plants were found to be Zingiber officinale, Curcuma longa, Glycyrrhiza glabra, Allium sativum and Olea europaea. In vitro hDHODH inhibitory assays illustrated the ability of Allium sativum and silymarin standard hits; specifically, silibinin, to significantly inhibit the hDHODH enzyme. Molecular docking and MD simulations revealed a strong binding of the discovered hits within the active site. Following that, the most promising hits were tested separately with brequinar in a fixed-ratio combination setting to assess their combined effects on hDHODH catalytic inhibition. The binary combination of silibinin and brequinar revealed that in this combination, brequinar could be utilized at a dose 9.33-fold less when compared to its single-use to produce 99% inhibition for hDHODH enzyme. These findings confirmed that this binary mixture is an excellent combination providing better therapeutic effects and lower side effects., (© 2022. The Author(s).)

Liver cirrhosis is a late-stage liver disease characterized by excessive fibrous deposition triggering portal-hypertension (PH); the prime restrainer for cirrhosis-related complications. Remedies that can dually oppose hepatic fibrosis and lower PH, may prevent progression into decompensated-cirrhosis. Different Astragalus-species members have shown antifibrotic and diuretic actions with possible subsequent PH reduction. However, A.spinosus and A.trigonus were poorly tested for eliciting these actions. Herein, A.spinosus and A.trigonus roots and aerial parts extracts were subjected to comprehensive metabolic-fingerprinting using UHPLC-MS/MS resulting in 56 identified phytoconstituents, followed by chemometric untargeted analysis that revealed variable metabolic profiles exemplified by different species and organ types. Consequently, tested extracts were in-vivo evaluated for potential antifibrotic/anticirrhotic activity by assessing specific markers. The mechanistic prospective to induce diuresis was investigated by analyzing plasma aldosterone and renal-transporters gene-expression. Serum apelin and dimethylarginine-dimethylaminohydrolase-1 were measured to indicate the overall effect on PH. All extracts amended cirrhosis and PH to varying extents and induced diuresis via different mechanisms. Further, An OPLS model was built to generate a comprehensive metabolic-profiling of A.spinosus and A.trigonus secondary-metabolites providing a chemical-based evidence for their efficacious consistency. In conclusion, A.spinosus and A.trigonus organs comprised myriad pharmacologically-active constituents that act synergistically to ameliorate cirrhosis and associated PH., (© 2022. The Author(s).)

Marine algae have served as a treasure trove of structurally variable and biologically active metabolites. The present study emphasizes on UPLC-MS metabolites fingerprinting for the first systematic broad scale metabolites characterization of three different phyla of marine seaweeds; Ulva fasciata, Pterocladia capillacea and Sargassum hornschuchii along with Spirulina platensis harvested from the Mediterranean Sea. A total of 85 metabolites belonging to various classes including mostly fatty acids and their derivatives, terpenoids, amino acids and dipeptides with considerable amounts of polyphenolic compounds. OPLS-DA model offered a better overview of phylum-based discrimination rapidly uncovering the compositional heterogeneity in metabolite profiles of algae extracts. An OPLS model was constructed using the cytotoxic activities against PC3 and MDA-MB-231 tumor cells to succinctly screen cytotoxic discriminatory metabolites among the tested algae species. The coefficient plot revealed that unsaturated fatty acids as stearidonic acid and linolenic acid, terpenoids namely as rosmanol, campestanol, dipeptides primarily glutamylglycine, glycyltyrosine along with polyphenolic compounds being abundantly present in S. platensis and U. fasciata samples with relatively marked cytotoxic potential might be the significant contributors synergistically meditating their anti-proliferative activity against PC3 and MDA-MB-231 tumor cells. Such results serve as baseline for understanding the chemistry of these species and performing strict correlation between metabolite and activity where a lack of information in this regard is observed., (© 2022. The Author(s).)

Xanthine oxidase (XO) has been well-recognized as a validated target for the treatment of hyperuricemia and gout. Currently, there are two drugs in clinical use that shut down XO overactivity, allopurinol and febuxostat; however, detrimental side effects restrict their applications. Propolis is a unique natural adhesive biomass of structurally variable and biologically active metabolites that exert remarkable health benefits. Moreover, combination drug therapy has become a promising pharmacotherapeutic strategy directed for reformulating existing drugs into new combination entities with potentiating therapeutic impacts. In this study, computer-aided molecular docking and MD simulations accompanied by biochemical testing were used for mining novel pharmacologically active chemical entities from Egyptian propolis to combat hyperuricemia. Further, with a view to decrease the potential toxicity of synthetic drugs and enhance efficacy, propolis hits were subjected to combination analysis with each of allopurinol and febuxostat. More specifically, Glide docking was utilized for a structure-based virtual screening of in-house datasets comprising various Egyptian propolis metabolites. Rosmarinic acid, luteolin, techtochrysin and isoferulic acid were the most promising virtual hits. In vitro XO inhibitory assays demonstrated the ability of these hits to significantly inhibit XO in a dose-dependent manner. Molecular docking and MD simulations revealed a cooperative binding mode between the discovered hits and standard XO inhibitors within the active site. Subsequently, the most promising hits were tested in a fixed-ratio combination setting with allopurinol and febuxostat separately to assess their combined effects on XO catalytic inhibition. The binary combination of each techtochrysin and rosmarinic acid with febuxostat displayed maximal synergy at lower effect levels. In contrast, individually, techtochrysin and rosmarinic acid with allopurinol cooperated synergistically at high dose levels. Taken together, the suggested strategy seems imperative to ensure a steady supply of new therapeutic options sourced from Egyptian propolis to regress the development of hyperuricemia., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (This journal is © The Royal Society of Chemistry.)

A comprehensive approach of untargeted and targeted fatty acid bioprofiling of different royal jelly commercial and pharmaceutical products based on HPTLC-image analysis and melanoma cytotoxic activity together with chemometric analysis was applied in this study for discovering efficient biomarkers. Principal component analysis based on HPTLC-image analysis fingerprints of fatty acid loading plots were used to determine the chemical markers responsible for classification of royal jelly samples into fresh and lyophilized ones. These markers were identified using the HPTLC-MS technique as 8-hydroxyoctanoic acid, 3,10-dihydroxydecanoic acid, 10-hydroxy-2-decenoic acid, decanedioic acid and 10-hydroxydecanoic acid. These discriminating markers were quantified via the HPTLC-imaging technique for targeted profiling using two different methods: parametric and non-parametric regression. The non-parametric regression method exhibited superiority in terms of linearity, accuracy and precision. Biomarkers were determined from the 3D-loading plot of orthogonal projection to latent structures model based on the fatty acid quantitative data together with the melanoma cytotoxic activity data. 10-Hydroxy-2-decenoic acid showed the greatest reduction in melanoma cell viability followed by decanedioic acid then 8-hydroxyoctanoic acid. The present study is considered the first attempt to discriminate fresh and lyophilized royal jelly samples based on their holistic lipidomic profile to discover efficient fatty acid reducing melanoma cell viability., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cancer is one of the predominant causes of death worldwide. The new trend nowadays is to exploit natural products with the hope of developing new anticancer agents with fewer side effects. Propolis is one of these natural products which showed effectiveness in cancer treatment. The aim of this study is to understand the multi-level mechanism of action of propolis constituents in cancer treatment using an integrated approach of network pharmacology-based analysis, molecular docking and in vitro cytotoxicity testing. An inhouse database of chemical constituents from Egyptian propolis was compiled and assessed for its ADME properties using the QikProp module in the Schrodinger software. STITCH, UniProt, STRING, KEGG and DAVID databases were used for construction of constituent-target gene, gene-pathway, and constituent-target gene-pathway networks with the aid of Cytoscape 3.8.2. The network pharmacology-based analysis showed that the hit propolis constituents related to cancer targets were genistein, luteolin, benzoic acid, quercetin and vanillic acid, whereas the main cancer-associated targets were CYP1A1, CYP19A1, ESR1, NOS3, CASP3 and AKT1. Twenty-four cancer-related pathways were recognized where the most enriched ones were pathways in cancer and estrogen signaling pathway. The most enriched biological processes involved in the mechanism of action of propolis constituents in cancer treatment were negative regulation of the apoptotic process and the metabolic process and negative regulation of cellular glucuronidation. Molecular docking analysis of the top hit compounds against the most enriched target proteins in the constructed networks was carried out using the Maestro interface of the Schrodinger software. Among hit compounds, quercetin and genistein exhibited the most stabilized interaction. Finally, confirmation of the potential anticancer activity of propolis was assured by in vitro cytotoxicity testing of propolis extract on human prostate cancer (DU-145), breast adenocarcinoma (MCF-7) and colorectal adenocarcinoma (Caco-2) cell lines. This study presents deeper insights about propolis molecular mechanisms of action in cancer for the first time using an integrated approach of network pharmacology, molecular docking and in vitro testing., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Selective factor Xa inhibitors effectively block coagulation cascade with a broader therapeutic window than multitargeted anticoagulants. They have evolved as a crucial part of prevention and treatment of thromboembolic diseases and in therapeutic protocols involved in many clinical trials in coronavirus disease 2019 (COVID-19) patients. Biologically-guided isolation of specific FXa inhibitors from licorice ( Glycyrrhiza glabra ) root extract furnished ten flavonoids. By detailed analysis of their 1 H, 13 C NMR and MS data, the structures of these flavonoids were established as 7,4'-dihydroxyflavone (1), formononetin (2), 3- R -glabridin (3), isoliquiritigenin (4), liquiritin (5), naringenin 5- O -glucoside (6), 3,3',4,4'-tetrahydroxy-2-methoxychalcone (7), liquiritinapioside (8) and the two isomers isoliquiritigenin-4'- O -β-d-apiosylglucoside (9) and isoliquiritigenin-4- O -β-d-apiosylglucoside (10). All the isolated compounds were assessed for their FXa inhibitory activity using in vitro chromogenic assay for the first time. Liquirtin (5) showed the most potent inhibitory effects with an IC 50 of 5.15 μM. The QikProp module was implemented to perform ADMET predictions for the screened compounds., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFβR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC 50 's 1.1-6.29 µM), than that of the reference standard, 5-FU (IC 50 7.53 µM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFβR1 inhibitors; remarkable inhibition of TGFβR1 by these hits was observed at the range of IC 50 0.087-3.276 μM. The cell cycle analysis of the most potent TGFβR1 inhibitor, 4b revealed cell cycle arrest at G 2 /M phase on prostate cancer cells. Additionally, it is clearly indicated apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of apoptosis mediator, caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFβR1 to predict their affinities toward the receptor., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hyperthyroidism is a common endocrine disorder associated with increased risk of cardiovascular complications and mortality. Although antithyroid drugs (ATDs) are approved as first line option for many hyperthyroidism cases, including pregnancy and childhood, they exert significant toxic profile. Medicago sativa L. (alfalfa) also called "The father of all food" was among the diet consumed by mares that gave birth to foals with congenital hypothyroidism. Since, greenfeed was accused for the development of such condition, alfalfa may possess constituents with promising antithyroid potential that could be a valuable substitute for the conventional ATDs. The current work was designed to identify the most biologically active antithyroid phytoconstituent separated from alfalfa sprouts and comparing its antithyroid mechanism, efficacy and toxic profile to the standard ATD; propylthiouracil (PTU). The most biologically active solvent fractions from alfalfa sprouts extract were identified by in vitro screening for anti-thyroid peroxidase (TPO) activity, from which different phytoconstituents were separated and identified by interpretation of spectroscopic data. These compounds were then in vitro screened for anti-TPO and virtually screened via GLIDE XP docking into the crystal structures of the enzymes; bovine lactoperoxidase, as an alternative to TPO, and mammalian selenocysteine-dependent iodothyronine deiodinase (IDI), that are both uniquely dually prohibited by PTU. The compound that showed the least TPO IC 50 and highest combined docking XP score was elected for comparing its antithyroid mechanism, efficacy, tendency to reverse hyperthyroidism-triggered complications and toxicity to PTU using L-thyroxine-induced hyperthyroidism model in rats. Seven compounds (1-7) were isolated from the most biologically active fraction, whilst, compounds (4-7) were reported for the first time from alfalfa sprouts. Compound 5 (apigenin) showed the least TPO IC 50 and highest in-silico combined score, thus, apigenin was selected for further in-vivo investigations. Apigenin was found to more effectively interfere with type 1-IDI than with TPO in vivo. Apigenin therapy resulted in nearly euthyroid state, without incidence of hypothyroidism, thyroid hypertrophy, hepatotoxity or WBCs count reduction. In addition, apigenin, but not PTU, corrected hyperthyroidism-induced left ventricular hypertyrophy. Therefore, apigenin is a natural lead antithyroid drug that represents a possible safer alternative to conventional ATDs.

Since the outbreak of Coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy. In this work, the potential use of medicinal plants and more than 16 500 of their constituents was investigated within two suggested therapeutic strategies in the fight against SARS-CoV-2 including prevention of SARS-CoV-2 RNA synthesis and replication, through targeting vital proteins and enzymes as well as modulation of the host's immunity through production of virulence factors. Molecular docking studies on the viral enzymes 3Clpro, PLpro and RdRp suggested rocymosin B, verbascoside, rutin, caftaric acid, luteolin 7-rutinoside, fenugreekine and cyanidin 3-(6''-malonylglucoside) as promising molecules for further drug development. Meanwhile, the medicinal plants Glycyrrhiza glabra , Hibiscus sabdariffa , Cichorium intybus , Chrysanthemum coronarium , Nigella sativa , Anastatica hierochuntica , Euphorbia species , Psidium guajava and Epilobium hirsutum were enriched in compounds with the multi-targets PTGS2, IL2, IL1b, VCAM1 and TNF such as quercetin, ursolic acid, kaempferol, isorhamnetin, luteolin, glycerrhizin and apigenin. Enriched pathways of the molecular targets included cytokine-cytokine receptor interaction, TNF signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT3 signaling pathway which are all closely related to inflammatory, innate and adaptive immune responses. The present study identified natural compounds targeting SARS-CoV-2 for further in vitro and in vivo studies and emphasizes the potential role of medicinal plants in the mitigation of SARS-CoV-2., Competing Interests: None., (This journal is © The Royal Society of Chemistry.)